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INTERDISCIPLINARY
MEDICINE AND
HEALTH SCIENCES
Concepts, Researches and Practice
Prof. Dr. A. Erdinç Yalın
Lyon 2022
INTERDISCIPLINARY
MEDICINE AND
HEALTH SCIENCES
Concepts, Researches and Practice
Prof. Dr. A. Erdinç Yalın
Lyon 2022
• Prof. Dr. A. Erdinç Yalın • Orcid: 0000-0002-3351-6885
Assoc. Prof. Dr. Meriç Eraslan • Orcid: 0000-0001-7541-7554
Motion Graphics
Mirajul Kayal
• December 2022, Lyon
978-2-38236-487-1
All rights reserved. No part of this publication may be reproduced, stored
in a retrieval system, or transmitted in any form or by any means,
electronic, mechanical, photocopying, recording, or otherwise, without prior
written permission from the Publisher.
• Livre de Lyon
• 37 rue marietton, 69009, Lyon France
• http://www.livredelyon.com
• livredelyon@gmail.com
I
The field of health and life sciences is constantly evolving and expanding,
as we continue to learn more about the processing information and discoveries
and breakthroughs being made on the related technologies. İn this book, we aim
to provide a comprehensive overview of the latest research and developments
in this interdisciplinary field, with a focus on the biological and physiological
mechanisms underlying health and disease and latest developments in medical
treatments and therapies.
The book is designed for students, professionals, and anyone with an
interest in the medical and life sciences. It is written in a clear and concise
manner, with an emphasis on providing practical information and real-world
examples. We hope that this book will serve as a valuable resource for those
looking to learn more about this exciting and constantly evolving field.
We would like to thank all of the contributors to this book, who have
generously shared their expertise and insights. We would also like to thank the
editorial and production teams who have worked tirelessly to bring this book to
fruition.
Assoc. Prof. Dr. Meriç ERASLAN
III
PREFACE I
CHAPTER I. RECOGNIZING THE IMPORTANCE OF BIOCHEMISTRY
IN FACILITATING TRANSDISCIPLINARY
INTERACTIONS IN MEDICAL SCIENCES 1
Muhammed Emin DÜZ
CHAPTER II. FREE RADICALS AND THEIR BIOLOGICAL
RESOURCES 11
Naci Ömer ALAYUNT
CHAPTER III. EFFECTS OF ANTIOXIDANTS AND NUTRITION ON
THE DEFENSE SYSTEM 19
Naci Ömer ALAYUNT
CHAPTER IV. HERBAL ANTIOXIDANTS: NARINGENIN, CURCUMIN
AND ARONIA 29
Ali Erdinç YALIN & Serap YALIN
CHAPTER V. MECHANISM OF ANTIOXIDANT DEPLETION IN
AMYOTROPHIC LATERAL SCLEROSIS 43
Mehmet BERKÖZ
CHAPTER VI. PEDIATRIC CONGENITAL DEFORMITIES 59
Pelin KUZUCU
CHAPTER VII. GASTROINTESTINAL ATRESIAS IN NEWBORN 69
Serkan ARSLAN
CHAPTER VIII. IODINE AND COGNITIVE DEVELOPMENT 81
Betül ULU & Nurcan YABANCI AYHAN
CHAPTER IX. DIABETES AND COMPLICATIONS 93
NazlıAyşeşek
CHAPTER X. DIABETIC KETOACIDOSIS 99
Sedat YILDIZ
CHAPTER XI. GUILLAIN-BARRÉ SYNDROME 113
HasanHüseyinKIR&AyşenurİNCE
CHAPTER XII. SYNCOPE in THE EMERGENCY DEPARTMENT 127
MürselŞAHİN
IV INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
CHAPTER XIII. THE STATE OF ANXIETY-LIKE BEHAVIORS IN
ANIMALS WITH METABOLIC SYNDROME 141
HasanÇALIŞKAN&SedaKOÇAK
CHAPTER XIV. EYE ANATOMY AND PECTEN OCULI 147
MuhammetLütSELÇUK
CHAPTER XV. RECENT DRUG DEVELOPMENT STUDIES ON
NOVEL AND SELECTIVE COX-2 INHIBITORS 157
OnurBALTACIOGLU&SeydaDONMEZ&CemYAMALI
CHAPTER XVI. DRUG REPURPOSING STUDY FOR TRIAZOLE
RING BEARING AZOLE ANTIFUNGALS AS CHEI
CANDIDATES 179
İremBOZBEYMERDE&BurçinTÜRKMENOĞLU
CHAPTER XVII. VACCINE HESITANCY: A GLOBAL THREAT 189
BanuTufanKOÇAK&SerhatSİREKBASAN
CHAPTER XVIII. SOME EXAMPLES OF PSYCHOACTIVE
193
PLANT SPECIES
HulyaOZPINAR&DeryaCAMLIOGLU
CHAPTER XIX. CHEESE, HISTORY AND DIVERSITY IN TURKISH
CULTURE 209
PelinDEMİR&BahriPATIR
1
MD, Ph.D., Medical Biochemistry, Sabuncuoğlu Şerefeddin
Training and Research Hospital, Amasya University
E-mail: cerrahemin@gmail.com
ORCID: 0000-0002-1837-6415
Biochemistry is the molecular arrangement of the atoms in a biomolecule.
“Bios” means “life” in Greek. Thus, biochemistry is the study of the
molecular foundation of life. Simple organic molecules, which are the
elements of organisms, are unique to the living world and result from biological
activity. These substances are biomolecules and act as building blocks in
developing biological structures (1). They were chosen by evolution for their
capacity to execute activities that are precisely specified in live cells. These
molecules are comparable and interconnected in all living creatures, interacting
and participating in energy transmission and material change processes. These
biomolecules, for example, can be characterized in two ways: chemically and
biologically, implying that biochemistry is a matter of super-chemistry organized
perfectly, offering great possibilities in studying the secrets of living organisms,
a chemical of the most perfectly organized matter (2). Biochemistry studies
the chemical makeup of living creatures, the structure, and characteristics of
component substances, and the transformations these substances undergo inside
living organisms. These biomolecules are investigated in structural or descriptive
biochemistry, a branch of organic chemistry. The conversion of biomolecules
into plant and animal life is a topic in dynamic biochemistry or metabolism
2 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
(3). Biochemistry is closely related to life sciences such as agriculture, animal
husbandry, and veterinary medicine. Understanding biochemical processes
occurring at the level of plant and animal organisms is essential for influencing
plant productivity and rational animal husbandry. Analytical biochemistry is the
science of techniques for determining the qualitative and quantitative composition
of substances or mixtures of substances or the science of methods for analyzing
substances (2). The analysis is a technique of scientific investigation that is
focused on the examination of each component. Analysis methods are generally
categorized into biochemical, instrumental, and biological. Biochemical
analysis studies the content, structure, characteristics, and methods of acquiring
substances in biochemistry as a science. Biochemical analysis techniques rely
on biochemical processes to produce a visual representation of the result of the
study. Biochemical analysis approaches are qualitative, quantitative, structural,
and systemic (4).
The qualitative biochemical analysis aims to determine what elements,
groups of atoms, ions, or molecules make up the analyte or combination
of substances. Next, the biochemical quantitative analysis-the quantitative
composition of the biochemical studied is determined. Finally, the structural
analysis seeks to determine the structure of substances, i.e., how the components
in the substances are bound together (4).
Biochemistry, often known as biological chemistry or physiological
chemistry, is the science that uses chemical techniques of analysis to investigate
the chemical composition of living organisms and the chemical processes that
occur in them. Biochemistry is a science that deals with life-long molecular
research. It is a blend of chemistry, which investigates atomic interactions, and
molecular biology, which analyzes the structure and relationships of the body.
The initial ingredients of living matter are the atoms of H and O and the atom of
C (5-7). The atom of N is an element since, together with C, H, and O, it is found
in the composition of proteins, that is, compounds that reflect the molecular
structures of critical concerns in living matter. Atoms of C, H, O, and N share
ownership, and certain may form covalent connections by distributing electrons.
Slightly abundant elements (P, S, Ca, Mg) form an element construction in the
molecules’ composition in forming live things. Cl, Na, and K are also vital to
life and are termed biomolecules. They influence both the biochemical structure
and function (8-10).
The organism’s macromolecules are composed of very simple, low
molecular weight environmental antecedents (CO2, H2O, NH3). These
RECOGNIZING THE IMPORTANCE OF BIOCHEMISTRY IN FACILITATING . . . 3
environmental precursors are transformed by living organisms through metabolic
mechanisms (with intermediates: pyruvate, citrate, malate, glyceraldehyde-3-
phosphate) into organic compounds with a slightly higher molecular weight,
also known as basic biomolecule constituent units: nucleotides, amino acids,
monosaccharides, fatty acids, glycerol. Biomolecules from the base form
covalent connections with one another, resulting in macromolecules unique to
the living cell: nucleic acids, proteins, polysaccharides, and lipids; inorganic
biomolecules: Inorganic molecules include water and mineral salts; organic
biomolecules include proteins, lipids, carbohydrates, enzymes, hormones, and
so on (11-15).
Buffers are solutions that maintain a nearly constant concentration of
hydrogen ions after dilution and even when a strong acid or basic is added. When
modest quantities of strong acid or strong base are added to these solutions,
they include two compounds that oppose ambient pH changes. Precipitation
bioreactions are used in the analysis to separate the ions into groups and
subgroups (16-18).
The majority of bioreactions occur in the aqueous phase, which is a
fundamental scientific consensus. At the same time, there are numerous
identification indicators and methods, such as those based on the size, charge,
color, and heat change of molecules or reactions, not to mention numerous
spectroscopic methods based on the electromagnetic properties of molecules.
Precipitation bioreactions are used in several identification bioreactions (19). A
precipitation phenomenon is also used in several dosing methods (quantitative
determination) (20). Precipitation is forming a new solid phase in a liquid
system. Both biochemical and physical processes can cause it. For example, if
alcohol is added to a salt solution, the liquid outflow may drop below the solid
form.
Biochemistry is a fundamental discipline in the practice of clinical medicine.
Many diseases have long been known to have a biochemical foundation, and
biochemistry research increasingly gives molecular descriptions of pathological
processes. Because of applying biochemical concepts and techniques to
studying human fluids and tissues, clinicians now have access to a diverse and
expanding spectrum of biochemical studies to help clinical decision-making.
Such examinations can give critical information for diagnosing and managing
4 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
a wide range of illnesses, including those with a clear metabolic foundation
(e.g., diabetes mellitus) and others in which metabolic changes emerge from the
disease (e.g., renal failure). On the other hand, many disorders are effectively
identified and treated without biochemical investigations. At the same time,
there are other situations for which biochemical investigations would be helpful
but for which relevant tests are not yet accessible (21,22).
The potential variety of studies available to assist clinicians is extensive,
ranging from simple, low-cost urine dip-stick tests to magnetic resonance
imaging employing costly equipment. Clinical biochemists naturally believe
biochemical investigations are the most important of all studies. In some
cases, they are; in others, they play no part, and in many others, their worth is
substantially boosted when combined with the results of other studies, such as
imaging. Therefore, the physician should know all possible investigations and
recognize their distinct advantages and limits. The clinical biochemist must also
be aware of the function of other investigations to evaluate biochemical tests
in context and advise on their usefulness and interpretation in specific clinical
situations.
Although not always necessary for individual patient care, it may be able to
expand the clinical diagnosis by further inquiry to discover the pathophysiology
of the ailment and, ultimately, its underlying cause. For instance, angiography
might be performed to demonstrate coronary atherosclerosis before surgery
or angioplasty; the discovery of hypercholesterolemia would indicate a causal
component for atherosclerosis, and a family history of early heart disease would
imply that hypercholesterolemia is the cause of atherosclerosis (23,24). Whatever
function biochemical data are utilized for, they must be dependable and available
promptly. Under certain conditions, it may be acceptable to compromise some
quality to achieve a result quickly. However, in general, every effort should be
taken to limit the impact of both analytical and preanalytical variables on data
accuracy and precision.
Most biochemical studies are quantitative, and the more aberrant a result,
the more probable a pathological disturbance is to blame. The degree to which
a result is abnormal is frequently related to the severity of a problem, but
this is not always the case. The diagnostic test may not reflect the essential
aspect of the condition in terms of severity; for example, two patients with
RECOGNIZING THE IMPORTANCE OF BIOCHEMISTRY IN FACILITATING . . . 5
hepatitis may have identically elevated plasma aminotransferase activities
(reflecting tissue damage), but the condition will be judged more severe if one
patient’s prothrombin time is prolonged (reflecting impaired hepatic functional
capacity) (25).
Biochemical test findings are often reliable predictors of prognosis. For
example, in patients with primary biliary cirrhosis, plasma bilirubin concentration
correlates well with prognosis; a high plasma concentration of a-fetoprotein in a
patient with testicular teratoma is predictive, whereas paraprotein concentration
in a patient with myeloma is not (26).
Serial measurements can be extremely useful in tracking the progression
of an illness or its response to therapy. The greater the relationship between the
variable being assessed and the underlying pathological process or functional
impairment, the better it will be for this purpose. Biochemical data must always
be interpreted in the light of clinical assessment and the results of other relevant
investigations, not in isolation. Nevertheless, intervention may sometimes
be appropriate based on a biochemical change alone if this has been shown
reliably to predict a significant clinical change, for example, in hyperkalemia
in a patient with renal failure (27). When repeated biochemical tests are used
to track therapy response, the lack of an expected change to occur may indicate
that the treatment is insufficient or unsuitable or that the diagnosis is erroneous.
Biochemical parameters in therapeutic drug monitoring (TDM) may suggest a
probable reason for non-response to therapy.
Screening for disease aims to identify illness before it becomes clinically
obvious. Screening might entail clinical evaluation and lab tests. Some
disorders (primarily hereditary metabolic diseases) may only require one
biochemical test (28). The phrase is also used to describe the performance
of a range of biochemical tests (sometimes coupled with other forms of
research) in healthy persons to identify several diseases on the premise that
‘normal’ findings – results within the applicable reference limits – exclude
these disorders. A set of ‘normal’ findings may appear comforting and rule
out the existence of some diseases; nevertheless, they may also provide the
wrong impression and potentially cause a delay in identifying a disease in
its early stages. Because of the way that reference ranges are specified, the
greater the number of tests that are carried out, the greater the likelihood
that an ‘abnormal’ result will be generated that is not related to the presence
of disease. This is because results that fall outside the reference limits are
considered abnormal. Economic and logistic constraints limit whole screening
6 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
populations for diseases, but all adults (some say only men, others both)
should be examined for hypercholesterolemia (29). In wealthy nations,
selective biochemical screening for illness is widely used. Among the most
well-known examples are screening programs for phenylketonuria, congenital
hypothyroidism, sickle cell disease, and cystic fibrosis in newborns. Tandem
mass spectrometry has made it feasible to test for a plethora of diseases with a
minimal amount of blood and a manageable budget, including medium-chain
fatty acid oxidation disorders, some organic acidaemias, and the most frequent
form of congenital adrenal hyperplasia (30).
Biochemistry is a modern scientific discipline that studies biological
matter and the specific processes governing its composition, type, molecular
structure, assemblage, and correlation of component biomolecules. Additionally,
biochemistry investigates the biosynthesis and biodegradation processes that
govern how living things produce and consume the energy required for life. The
compounds produced as a result of these iterative transformations fulfill various
functions in plant life, including those of polymers, storage, active substances,
and by-products. Understanding the mysteries of life in all its manifestations
is the ultimate objective of biochemistry as a scientific discipline. In the field
of medicine, biochemical data are put to practical use, both in the treatment of
patients and in the conduct of research. However, before requesting an inquiry,
one must always consider the reasons for testing. Although the cost of using
automated analyzers to carry out several tests is relatively low compared to
the overall cost of providing medical care, this does not mean it is free. The
sufferer may also incur a financial burden. Repeated venepunctures to obtain
blood for so-called “routine” tests are, at best, an annoyance and, at worst, can
cause a significant drop in the hematocrit, which is especially likely to occur in
very young children. The following guidance for junior medical staff used to be
included in the laboratory handbook at one of the hospitals where the authors
have acquaintances. It read, “If you need advice or time to think, ask for it; do
not ask for a complete blood count and measurement of “urea and electrolytes. “
In the same way as with other kinds of investigations, biochemical investigations
ought to be requested to find answers to particular questions; if there are no such
questions, the results cannot give any.
RECOGNIZING THE IMPORTANCE OF BIOCHEMISTRY IN FACILITATING . . . 7
1. Butnariu M, Sarac I. Interdisciplinary Character of Biochemistry
and Analytical Biochemistry. Biochem Anal Biochem. 2018;7(4):367.
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2011;50(5):770-779. doi:10.1021/bi101837u.
9. Glover WJ, Larsen RE, Schwartz BJ. Nature of sodium atoms/(Na(+),
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10. Kania A, Bratek M, Majta J, et al. The importance of atomic partial
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11. Griffiths WJ, Wang Y. Cholesterol metabolism: from lipidomics to
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12. Martin SA, Brash AR, Murphy RC. The discovery and early structural
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13. Chen M, Talarovicova A, Zheng Y, Storey KB, Elphick MR.
Neuropeptide precursors and neuropeptides in the sea cucumber Apostichopus
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15. Gruszka DT. Biochemistry: one molecule at a time. Essays Biochem.
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16. Brodersen R. Buffers in biochemistry. Z Vitam Horm Fermentforsch.
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17. Pielak GJ. Buffers, Especially the Good Kind. Biochemistry.
2021;60(46):3436-3440. doi:10.1021/acs.biochem.1c00200.
18. Sun S, Zhou JY, Yang W, Zhang H. Inhibition of protein carbamylation
in urea solution using ammonium-containing buffers. Anal Biochem.
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20. Ghaderinia P, Shapouri R. Assessment of immunogenicity of alginate
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of Renal Nutrition and Metabolism Commentary on the National Kidney
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11
(Assoc.Prof.Dr.) Siirt University, Faculty of Medicine,
Department of Medical Biochemistry,
e-mail:nacialayunt@hotmail.com
ORCID: 0000-0003-2215-0934
Free radicals are constantly produced by normal metabolic processes, but
their production rate is increased in certain inflammatory or other disease
conditions. Normally, the body is protected by a wide range of defense
mechanisms against reactive oxygen metabolites and their toxic products. An
imbalance between reactive oxygen metabolites and their safe disposal can
initiate oxidative chain reactions and lipid peroxidation. Transport, which is one
of the important activities of farm management, is one of the factors that affect
animal welfare and create stress in animals. These molecules, which have a lot
of destructive effects, can be at the starting point of human diseases. Therefore,
it is important to talk about the molecular effects and structures of free radicals
and to make suggestions primarily for the prevention of cancer and other chronic
diseases.
Electrons in atoms or molecules move around the nucleus in regions
defined as orbitals. Each orbital has at most two electrons moving in opposite
directions. An atom or molecule is called a free radical (SR) if it has one or more
unpaired electrons in its outer orbitals. Such molecules are highly reactive due
to their unpaired electrons (1, 2). The simplest free radical is the hydrogen atom,
which has an electron and a proton.
12 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Normally, the electron arrangement of molecules containing two or more
chemically bonded electrons determines the stability of a molecule. If the
electron in the structure of this molecule does not have a partner, the molecule
behaves extremely reactively and tends to form a pair with an electron in order
to become stable (3). Recent studies show that free radicals play a major role
in the formation of many important diseases such as atherosclerosis, diabetes,
rheumatoid arthritis, some aging-related diseases, autoimmune diseases, and
various cancer types, especially neurodegenerative diseases such as Alzheimer’s,
Parkinson’s, and hungtington’s (4, 5).
The oxygen we need to live is also the source of free radicals. These
molecules have extra energy and they discharge this energy to the cells in the
body and change their normal functions. Free radicals are structures that have
chemically lost an electron in their outermost electron orbit. The most important
reason for its various harmful effects is that it tries to share the electrons of
other atoms in order to close this electron gap. Studies have shown that free
radicals interfere with the functioning of the tissue or molecule they affect.
Depending on the biological significance of the affected tissue or molecule, it
can cause a variety of significant or insignificant ailments. If free radicals of
oxygen, hydrogen and hydroxyl type obtain the electron they want to take from
antioxidants, it is prevented that they are expected to damage another structure.
In the scientific studies carried out on these molecules so far, it has been
stated that free radicals can cause various diseases. The most important of them
are; cancer, aging, heart attack, chronic fatigue. Due to various physical factors
and chemical events, there is a constant formation of radicals in the environment
and cellular conditions. Free radicals occur during the functioning of normal
metabolic pathways in the organism or under the influence of various external
factors such as environmental agents (pesticides, aromatic hydrocarbons,
toxins, solvents, etc.), stress and radiation. Free radicals can be formed during
the normal metabolic activities of our body (for example, after a meal). In
addition, industrial wastes, sun rays, cosmic rays, ozone, gases especially from
automobile exhausts, heavy metals, viruses, cigarettes, alcohol, stress, waste
products formed as a result of fat metabolism in the body, various chemicals,
water and air are environmental factors that create free radicals.
2.1.FormationMechanismsofFreeRadicals
In biological systems, free radicals are mostly formed as a result of
electron transfer. Free radicals can be formed when the two electrons in the
FREE RADICALS AND THEIR BIOLOGICAL RESOURCES 13
bond structure remain on separate atoms during the breakage of the covalent
bond in the molecule with the homolytic splitting of the covalent bonds in the
molecules (1). If an unpaired electron remains in its outer orbital during the loss
of electrons in a molecule without radical properties, a radical form is formed.
For example, cellular antioxidants such as tocopherol and ascorbic acid donate
a single electron to radical species and reduce radicals, while their own radical
form is formed (6). If an unpaired electron is formed in its outer orbital with a
single electron transfer to a non-radical molecule, such a reduction may lead
to radical formation. For example, molecular oxygen is reduced with a single
electron to form the radical form, superoxide (7).
In biological systems, free radicals can be positively charged, negatively
charged, or neutral. Although the most important radicals are free oxygen radicals
(SOR); There are also radicals and inorganic molecules that are derivatives of
C, N, S. According to the definition of free radical, transition metals such as
Cu2+, Fe3+, Mn2+, Mo5+ are not considered free radicals even though they have
unpaired electrons. However, since these ions catalyze reactions, they play an
important role in the formation of free radicals (1, 2, 6).
2.2.SourcesofFreeRadicals
Free radicals are short-lived, reactive molecules that contain unpaired
electrons in their outer orbitals. At the same time, reactive oxygen species are
formed as a natural result of oxygen use in aerobic organisms (8). Free radicals
and other reactive oxygen species are also produced during special metabolic
events in the organism or they can be taken from the outside.
2.2.1.biologicalresources
Mature macrophages, neutrophils, eosinophils, and phagocytic leukocytes
are cells that provide the reaction of various biological targets and initiate
the body’s cellular response to infections. During the phagocytic respiratory
burst, free oxygen radicals such as H2O2, superoxide and hydroxyl radicals are
formed. Phagocytized microorganisms and bacteria in the target environment
are destroyed by the effect of these products. However, when these oxidant
products exceed the antioxidant defense powers of the cells , they also damage
normal host cells and play a role in the pathogenesis of various diseases.
Radiation and environmental agents also trigger the formation of free radicals.
Environmentally, air pollution, pesticides, cigarette smoke, solvents, anesthetics,
aromatic hydrocarbons cause free radical formation. Antineoplastic agents such
14 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
as doxorubicin and adrioxmicine can also generate free radicals. For example,
doxorubicin, an anticarcinogen agent, inhibits the cell’s DNA replication, leading
to the formation of H2O2. Thus, it leads to the initiation of lipid peroxidation
(9, 10). Finally, neural stimuli increase the synthesis of catecholamines (11).
Oxidation of catecholamines is also a cause of free radical formation.
2.2.2.IntracellularResources
According to the acceptance of the scientific community, normally the
largest source of free oxygen radicals in cells is leakage in the mitochondrial
electron transport chain. Cells in living systems reduce most of the oxygen used
(about 95%) to water by taking four electrons with the oxidative phosphorylation
chain located in the inner mitochondrial membrane. Electron leakage in this
system can convert 1-3% of oxygen to superoxide radical. Free radical generation
in the endoplasmic reticulum and nuclear membranes may result from oxidation
of membrane-bound cytochromes.
H2O2 may occur during the catalytic cycle of many enzymes (xanthine
oxidase, aldehyde oxidase, flavoprotein dehydrogenase, amino acid oxidase)
(11). Autooxidation of small molecules and some compounds such as thiols,
catecholamine, tetrahydrofolate can produce superoxide radical. Especially
transition metals such as iron and copper are involved in oxidation-reduction
reactions under physiological conditions. Because of these properties, they act
as catalysts that accelerate free radical reactions.
Iron and copper especially catalyze thiyl synthesis from thiols, H2O2,
superoxide and hydroxyl radical synthesis. Arachidonic acid metabolism is also
an important source of reactive oxygen metabolites. As a result of stimulation
of phagocytic cells, arachidonic acid in the plasma membrane is liberated and
various free radical intermediates may occur by enzymatic oxidation (6). In
addition, toxic substances increase the production of free radicals in the cell with
various effects. The toxin itself is a free radical, the toxin may be metabolized
to a free radical, or a free oxygen radical may be formed as a result of the
metabolism of the toxin.
2.3.FormationFormsintheBody
The main source of free radicals in mammals with aerobic metabolism
in the body is reactive particles formed as a result of single electron transfers
during the reduction of oxygen to water (12).
FREE RADICALS AND THEIR BIOLOGICAL RESOURCES 15
O2 + H+ +e → HO2 (hydroperoxyl radical)
HO2 → ++ O2
. (superoxide radical)
O2 + 2H+ +e → H2O2 (hydrogen peroxide)
H2O2 + e → OH-+ OH (hydroxyl radical)
OH +e +H → H2O (water)
Table 1. Free radical formation in mitochondria
These formation reactions are as follows (Table 1 ).
1. Superoxide radical; It is a strong reducing agent. It rapidly dismutates
to form H2O2 and O2. The protonated form, the hydroperoxyl radical (HO2), is a
stronger oxidant. H2O2 is a weak oxidoreductant. It is quite stable in the absence
of transition metals (Fe, Cu) in the environment . It is broken down by catalase
and glutathione peroxidase (GSHPL). The OH• radical is the main radical that
stimulates lipid peroxidation and is formed from the superoxide radical or H2O2
with the effect of Fe ions (13).
2. Activated neutrophils; Hypochlorous acid is a powerful oxidant produced
from activated neutrophils. Myeloperoxidase (MPO), an enzyme found in
the phagocyte cytoplasm and containing HEM, catalyzes the formation of
hypochlorous acid (HOCl) from H2O2 and Cl ions. HOCl reacts with superoxide
radical or iron salts to form hydroxyl radical (14, 15).
3. Nitric oxide and nitrogen dioxide carry an odd number of electrons, so
they are free radicals. Although nitric oxide itself is a weak reducing agent, it
combines with endogenous free radicals to form the peroxynitrite radical. It is a
strong oxidant and can easily form the hydroxyl radical.
4. Mitochondrial electron transport system; During the reduction of
oxygen to water in the mitochondria, a superoxide radical is formed by the
autoxidation of a part of the electron transport chain localized in the inner
membrane (16).
5. Endoplasmic reticulum; these intracellular membranes contain the
cytochrome P-450 and cytochrome b5 systems. These systems are involved in
the oxidation of unsaturated fatty acids and xenobiotics. During the formation
of these reactions, free radicals occur (17).
6. Peroxisomes; Since peroxisomes contain high levels of oxidase, they
constitute a strong source of cellular H2O2. These peroxisomal enzymes include
D-amino acid oxidase, urate oxidase, and acyl-CoA oxidase (18).
7. Plasma membranes; Plasma membrane enzymes that cause free radical
production are lipoxygenase and cyclooxygenase. As a result of the reactions
16 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
catalyzed by these enzymes, prostaglandins, thromboxanes, leukotrienes and the
slow-acting substance of anaphylaxis are synthesized (19).
2.4.EectsofFreeRadicals
Free radicals, which are known to have strong reactive properties due
to their tendency to react, can easily interact with all cell components. If they
are not eliminated by the defense mechanisms of the cells responsible for the
defense system, they may react with biological molecules and initiate a chain
reaction in which new free radicals are formed (1).
Free radicals are highly reactive molecules. They react with many
biomolecules to form various compounds. These compounds often have toxic
properties. Membrane damage is one of the most harmful effects. The most
damaged structures inactivate the enzymes in the membrane with the damage
of free radicals to the membranes. Thus, they easily react with unsaturated
bonds of fatty acids in membranes and cholesterol to form various peroxidation
products. It has also been reported that they impair the structure, permeability
and function of membranes (6).
Free radicals can come from outside the body, or they can occur as a
natural result of human metabolism. The endogenous production of free radicals
occurs in different ways. In contrast, living organisms have various mechanisms
to protect themselves against the potentially destructive effects of free radicals.
Free radicals are molecules that need attention as they are extremely harmful
compounds that can be seen as the first starting point of all diseases such as
vagrant mines. For this reason, some warnings should be given to human
populations and it should be recommended to stay away from negative effects
that trigger free radicals such as external effects, smoking, polluted and poor
quality air, stress, heavy working conditions, radiation, electromagnetic waves.
1. İşbilir ŞS. (2008). Yaprakları salata-baharat olarak tüketilen bazı bitkilerin
antioksidan aktivitelerinin incelenmesi. Doktora Tezi, Trakya Üniversitesi Fen
Bilimleri Enstitüsü, Edirne.
2. Halliwell B., Gutteridge JMC. (1990). Role of free-radicals and catalytic
metal-ions in human disease - an overview. Methods in Enzymology, 186: 1-85.
FREE RADICALS AND THEIR BIOLOGICAL RESOURCES 17
3. Kaur C., Kapoor HC. (2001). Antioxidants in fruits and vegetables – the
millennium’s health. Inti. J. Food Sci. Tech. 36, 703-725.
4. Süzen S. (2007). Antioxidant Activities of Synthetic Indole Derivatives
and Possible Activity Mechanisms, Khan. Topics in Heterocyclic Chemistry,
Bioactive Heterocycles.
5. Süzen S. (2006). Recent developments of melatonin related antioxidant
compounds, Com. Chem High T Synt. 9(6), 409-419.
6. Akkuş İ. (1995). Serbest radikaller ve fizyopatolojik etkileri. Mimoza
Yayınları, Konya.
7. Onat T., Emerk K., Sözmen EY. (2002). İnsan biyokimyası. Palme
Yayıncılık, Ankara.
8. Frenkel K. (1992). Carcinogen-mediated oxidant formation and oxidatif
DNA damage. Pharmac. Ther. 53, 127-166.
9. Wınternbourn CC., Gutteridge JMC., Halliwell B. (1985). Doxorubicin-
dependent lipid peroxidation at low partial pressures of O2. Journal of Free
Radicals in Biology and Medicine. 1(1), 43-49.
10. Weijl NI., Cleton FJ., Osanto S. (1997). Free radicals and antioxidants
in chemothraphy-induced toxicity. Cancer Treatment Reviews. 23, 209- 240.
11. Murray RK., Granner DK., Mayes PA., Rodwell VW., (Çev: Dikmen
N., Özgünen T.). (1996). Harper‟ın Biyokimyası 24. baskı, Barış Kitabevi,
İstanbul.
12. Reilly PM., Schiller HJ., Bulkley GB. (1991). Pharmacologic approach
to tissue injury mediated by free radicals and other reactive oxygen metabolites.
Am J. Surgery. 161, 488-501.
13. Halliwell B., Gutteridge JMC. (1984). Oxygen toxicity, oxygen
radicals, transition metals and disease. Biochem J. 219, 744-52.
14. Klebanoff SJ. (1980). Oxygen metabolism and the toLic properties of
phagocytes. Ann Intern Med. 100, 480-9.
15. Simpson R., Alon R., Kobzik L., Valeri R., Shepro D. (1993). Hechtman
HB. Neutrophil and nonneutrophil-mediated injury in intestinal ischemia
reperfusion. Annals of Surgery. 218(4), 444-54.
16. Halliwel B., Chirico S. (1993). Lipid peroxidation: its mechanism,
measurement, and significance. Am J Clin Nutr. 57, 7155-65.
17. Jabs CM., Heglen P., Eklof B. (1995) Breakdown of adenine nucleotides
formation of oxygen free radicals, and early markers of cellular injury in
endotoxic shock. Eur J Surg. 161, 147-55.
18 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
18. Lefer AM., (1977). Eicosanoids of ischemia and shock. Fed Proc. 19
(44), 275- 80.
19. Kellogg EW., Fridovich I. (1977). Liposome oxidation and erythrocyte
lysis by enzymically generated superoxide and hydrogen peroxide. J Biol Chem.
252(19), 6721-672.
19
(Assoc.Prof.Dr.) Siirt University, Faculty of Medicine,
Department of Medical Biochemistry,
e-mail:nacialayunt@hotmail.com
ORCID: 0000-0003-2215-0934
Inflammations and chronic diseases, especially cancer. There are various
defense mechanisms in our body to prevent diseases and cancer caused by
these adverse conditions. These mechanisms are known as “antioxidant
defense systems” or “antioxidants” for short. Antioxidants are of vital importance
in the prevention and treatment of many diseases, as they are agents that remove
free radicals, in other words, reactive oxygen species (ROS), and prevent the
damage that can be caused by them. In every cell that makes up our body against
radicals, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase
(GSH- Px), glutathione There is a defense mechanism called the radical
scavenging enzyme system consisting of enzymes such as reductase (GSSGR)
and an auxiliary defense mechanism consisting of antioxidant vitamins such
as A, E, C, and lipoic acid (1). Antioxidants effectively reduce these reactive
oxygen and nitrogen species, which damage cells, into low- toxic or non- toxic
products. The presence of these harmful compounds makes antioxidants an
indispensable part of life for a healthy life (2).
Antioxidants; As they are produced by cells, they can also be taken through
food. The main natural antioxidants present in foods and destroy the human
body from harmful free radicals; vitamins (vitamins A, E and C), flavonoids,
carotenoids, and polyphenols. Many studies have shown an inverse relationship
20 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
between fruit and vegetable consumption and the occurrence of certain cancers
and heart diseases (3). Medicinal plants, which started to be used in 3000 years,
began to lose their popularity with the development of modern medicine in
the 1900s. It largely left its place to chemical drugs and began to be called an
alternative medicine branch.
2.1.EndogenousAntioxidants
The body’s endogenous defense system should be supported by antioxidant
compounds to be taken with a regular and balanced diet. Therefore, increasing
dietary intake of antioxidants or foods enriched with antioxidants are becoming
increasingly important. In the food industry, usually butylated for the preservation
and shelf life of oils and other oil-containing products. hydroxytoluene (BHT)
and butylated hydroxyanisole (BHA) is used. However, the studies carried
out mention the toxicity of these compounds, revealing the risk of their being
carcinogenic (4). Endogenous antioxidants are divided into two classes, enzyme
and non-enzyme (5).
2.2.ExogenousAntioxidants
Exogenous antioxidants as vitamins, drugs and food oxidants . α- tocopherol,
β-carotene, ascorbic acid and folic acid (Vitamin B9) are exogenous antioxidants
that are vitamins. Exogenous antioxidants; includes vitamins, foods, and drug
forms (6). Exogenous antioxidants used as drugs; xanthine oxidase inhibitors
(allopurinol, oxypurinol, folic acid), NADPH oxidase inhibitors (adenosine,
local anesthetics, calcium channel blockers, non-steroids anti-inflammatory
drugs), recombinant SOD, those that increase endogenous antioxidant activity
(ebselen, acetyl cysteine), nonenzymatic radical scavengers (mannitol,
albumin), cytokines, iron chelators, iron redox cycle inhibitors (desferrocamine ,
ceruloplasmin)(7). Iron chelators: They enter the cell and bind free iron, thereby
inactivating it, thus inhibiting the Fenton reaction and ultimately the formation
of hydroxyl radicals. Cytokines: They activate antioxidant enzymes, especially
catalase. However, they can be harmful because they also activate proteolytic
enzymes.
2.3.NaturalSourcesofAntioxidants
Some plants are a good source of natural antioxidants. Studies with
antioxidant compounds found in fruits have reported significant amounts of
EFFECTS OF ANTIOXIDANTS AND NUTRITION ON THE DEFENSE SYSTEM 21
antioxidants in strawberries, cherries, citrus fruits, kiwi, prunes, and olives
(5). Lemons and oranges have high concentrations of vitamin C and, due to
these properties, have a good antioxidant capacity (8). Most of the vegetables,
especially cocoa beans , potatoes, tomatoes, spinach, phaseolus The antioxidant
potential was analyzed in vegetables such as lupine seeds such as vulgaris ,
buckwheat, sunflower or red pepper, and corn on the cob (5). Broccoli, which
is among the most consumed vegetables especially in America and Europe,
has vitamins (A, E, C) and flavonoids, and because it contains quercetin and
kaempferol, which provide antioxidant properties, it has both immune-enhancing
and antioxidant properties. Broccoli, which has a fibrous structure, ensures the
removal of heavy metals from the intestines. In addition to this feature, broccoli
has many benefits, especially prostate and breast cancer preventive power.
Carotenes are an extremely colorful (red, orange, yellow) group of oil-soluble
vegetable pigments. Carotenes, which play an important role in the human body,
are converted to vitamin A in the body and have an antioxidant effect. These are
called “ provitamin A”. Examples of this carotene group are lutein, lycopene
, and zeaxanthin (9). Tomato, an annual plant native to Mexico and Peru, is
considered a natural antioxidant due to its lycopene content. Lycopene is a
pigment belonging to the carotene family found naturally in some vegetables and
fruits. The human body cannot produce lycopene and must take this substance
from outside.
In a study conducted to examine the relationship between carotenes
and prostate cancer risk, it was explained that a carotene called lycopene has
a protective feature against this cancer risk. It has been shown that men who
receive high amounts of lycopene in their daily diet (6.5 mg/day or higher)
have a 21% reduced risk of prostate cancer compared to those who receive
less lycopene (10). In a study on whether pomegranate juice has an effect on
antioxidant activity in liver and testis tissue of rats , it was determined that lipids
in liver and testis tissues of rats given pomegranate juice. glutathione while
peroxidation is reduced perosidase (GSH-Px ) and catalase (CAT) were observed
to increase (11). Green tea, polyphenol components camellia It is obtained from
dehydration of sinensis leaves without oxidation (12). It has been shown that
the flavonoids in the structure of tea have a very strong antioxidant effect and
that these flavonoids protect cells from damage caused by free radicals (13).
In addition to the enzymatic defense systems in the organism, there are also
molecules with antioxidant properties that are formed endogenously or taken
with food. These antioxidants can neutralize ROS directly .
22 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
2.4.VitaminC(AscorbicAcid)
Vitamin C is a water-soluble vitamin. It acts as a reducing agent for
many compounds in the organism. It is also a powerful antioxidant due to its
strong reducing activity. Ascorbate effectively scavenges H2O2, hypochlorite,
superoxide, hydroxyl and peroxyl radicals and singlet oxygen. Converts all
peroxyl radicals in the liquid phase to plasma lipids. keeps it without diffusing
and in this way the lipid Inhibits the onset of peroxidation. It reacts with the
α- tocopherol radical formed in the membranes to form α- tocopherol. Provides
regeneration (6). Vitamin C has also been shown to be important for phagocytosis;
It protects plasma lipids against peroxidation caused by activated neutrophils and
is a potent hypochlorate scavenger (13). It provides protection against reactive
oxygen species in cigarette smoke, and plasma vitamin C levels were found to
be lower in smokers and passive smokers compared to non-smokers.
Nitrosamines found in some foods and cigarette smoke in various studies
it has been shown to have an antitumorgenic role by inactivating it (14). It has
been reported that ascorbic acid has antioxidant activity at high concentrations,
as well as prooxidant activity at low concentrations. By reducing iron in the
presence of transition metals, it contributes to the formation of •OH radical with
the Fenton reaction. Since transition metal ions are bound to proteins in healthy
organisms, this situation is very limited in vivo and the antioxidant property of
ascorbic acid is more dominant than the prooxidant property (15).
2.5.α-tocopherol
It is the main component of the vitamin E family, which is widely
found in nature. Its antioxidant activity is due to the aromatic ring with the
phenolic hydroxyl group in its structure (6). Lipid due to its lipophilic property.
It is the most important chain breaking antioxidant of cell membranes and
plasma lipoproteins against peroxidation. Lipid by removing peroxyl radicals
peroxidation inhibits.
The α-tocopherol radical (αT•) is a relatively stable radical with little
reactivity. It can be conjugated with glucuronic acid and excreted in the bile.
It can be re-reduced by ascorbic acid and glutathione after oxidation or before
disposal. Thus, it is regenerated . Of in vivo and in vitro studies α- tocopherol
and glutathione showed that peroxidase has complementary effects against free
radicals. GSH- Px removes formed peroxides, while α- tocopherol inhibits the
formation of peroxides (6).
EFFECTS OF ANTIOXIDANTS AND NUTRITION ON THE DEFENSE SYSTEM 23
In the development of atherosclerosis in recent years, lipid it is reported
that peroxidation, especially LDL peroxidation, plays an effective and critical
role. Lipid by α-tocopherol peroxidation is inhibited in the propagation step.
It has been experimentally shown that the risk of coronary heart disease is
reduced with the intake of α- tocopherol (16). α- tocopherol nitrites it acts as
an anticarcinogen by inhibiting the conversion to nitrosamines, it is effective in
preventing peroxidative damage associated with ischemia / reperfusion, increases
immunity, essential for its stability. α-tocopherol also plays an important role in
selenium metabolism by preventing the loss of selenium from the organism and
keeping it active (16).
2.6.carotenoids
They are natural color pigments commonly found in plants. photooxidative
Protects plants against processes. The most well-known is β-carotene, a precursor
to vitamin A. Carotenoids are especially effective antioxidants that remove
singlet oxygen (1O2) and peroxyl radicals. The most effective 1O2 scavenger
among carotenoids; It is lycopene , the open-chain analogue of β-carotene (17).
LDL It also prevents the development of atherosclerosis and other coronary
diseases by protecting against oxidative damage (17).
Lycopene photooxidative the process is an event that causes some diseases
in tissues exposed to light such as eyes and skin and leads to the formation
of ROS. In age-related macular damage that causes blindness, singlet oxygen-
protecting pigments are particularly lutein and zeaxanthin. The pigment that
protects against erythema and prevents photooxidative damage in sunburns
is β- carotene. Due to their lipophilic properties, they play an important role
in protecting cellular membranes and lipoproteins against oxidative damage.
β-carotene exerts a synergistic effect with vitamins C and E in removing reactive
nitrogen species (17, 18).
2.7.Flavonoids
They are yellow-white pigments found in high proportions in many fruits
and vegetables. Secondary of plants metabolites are polyphenolic compounds.
According to their ring structure, they are classified as flavonols, flavones,
flavanones, anthocyanins, catechins and isoflavonoids. O2•-, lipid content of
flavonoids and other plant phenolics alkoxyl (RO•), lipid scavenging peroxyl
(ROO•) and NO• radicals, chelating Fe and Cu, α- tocopherol It has also been
24 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
reported to participate in functions such as regeneration (19-21). This antioxidant,
which is found in most of the plants, can be taken into the body in large amounts,
especially with a fruit and vegetable-based diet, since it is found in much higher
amounts than the antioxidant vitamins C and E.
2.8.Glutathione
Tripeptide it is a peptide containing three amino acids linked together by
a peptide bond. It has three double bonds. Glutathione (γ-glutamyl-cysteine-
glycine) is an antioxidant that protects cells from toxins such as free radicals. It
plays a role in preventing the conversion of hemoglobin to methemoglobin by
oxidation. It also keeps the sulfhydryl groups in proteins in a reduced state and
protects these groups against oxidation . It is a powerful antioxidant and three
effective anti- aging amino acids synthesized from L-cysteine, L-glutamic acid
and glycine.
2.9.Melatonin
Melatonin is secreted from cells of the pineal gland called pineolacid.
Biorhythm (circadian rhythm) determines or influences biorhythm. Pineolacite
cells are light sensitive. As the electromagnetic wave intensity increases,
melatonin secretion decreases. Melatonin is a type of ethanoamide . Melatonin
is a hormone secreted between 23:00 and 05:00, although it varies from person
to person. The main task of the hormone is to maintain the body’s biological
clock and regulate its rhythm. In addition, the strong secretion of melatonin
has a protective effect against cancer. For this reason, it is requested that
those who have leukemia and other cancers should be hospitalized in dark
environments. According to recent studies, the hormone also has an anti-aging
effect. Melatonin is a hormone that plays a role in many biological functions
such as summer-winter, long-short day, regulation of the light-dark cycle (22). It
is a very powerful antioxidant that eliminates the hydroxyl free radical, the most
harmful free radical. It is considered to be the most powerful of the antioxidants
known to date (23).
The body’s antioxidant balance is greatly affected by diet. Pathological
conditions can occur when the body’s defense mechanisms are destroyed due to
nutritional deficiencies. The increase in reactive oxygen species and a deficiency
EFFECTS OF ANTIOXIDANTS AND NUTRITION ON THE DEFENSE SYSTEM 25
in the defense systems lead to the deterioration of the antioxidant balance in the
body and the formation of “oxidative stress” conditions. The effectiveness of the
antioxidant defense system; It depends on adequate intake of foods containing
antioxidant vitamins such as vitamin E, vitamin C and carotenoids and essential
trace minerals (24). These vitamins work together effectively to neutralize the
effects of harmful reactive oxygen species that cause disease and damage. For
example, there are studies investigating the effects of antioxidant vitamins on
patients, such as studies evaluating vitamin B12 and folate levels (25). In some
studies, in vitro antioxidant properties of polymer products synthesized by
organic reactions were compared with synthetic antioxidants such as BHT and
BHA, and new synthetic antioxidants could be used in drug production (26). It
is possible to increase the number of these and similar examples.
Vitamin E (tocopherols), one of the fat-soluble antioxidants, are found in
the membranes of all tissues and cells. Vitamin E inhibits degradation by its
ability to combat the oxidation of polyunsaturated fatty acids, also known as
fat degradation (27). It is reported that high vitamin E supplements strengthen
the defense system by combating oxidative stress in the diet (28). Ascorbic
acid is an important water-soluble antioxidant found in the body’s extracellular
fluids. Since it cannot be synthesized in the body, it must be taken from the
outside with food. In addition to being a reducing agent of ascorbic acid, it also
has the ability to regenerate vitamin E (27). Carotenoids are; They show their
antioxidant activities by participating in free radical reactions and reducing the
rate of formation of harmful hydrogen peroxides (29). β-carotene from important
dietary carotenoids; in yellow, orange vegetables and fruits, green vegetables,
lycopene; and lutein in tomatoes ; found in broccoli and fibrous green vegetables
(27). Phenolic compounds, especially in plant foods, are considered among
important antioxidants because they are reducing agents, hydrogen donors,
singlet oxygen scavengers and metal chelators (30). Minerals such as selenium,
copper, manganese and zinc are also required for the structures and catalytic
activities of protective enzymes (27).
The effect of nutrition on the antioxidant defense system shows its effects
on the mechanisms of action of antioxidants as follows.
They act by trapping free oxygen radicals or converting them to weaker
molecules. They act by adding a hydrogen to free oxygen radicals, reducing
26 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
their activity or making them inactive. They have the effect of breaking the
chains of free oxygen radicals. Hemoglobin, ceruloplasmin and minerals show
chain breaking effects. They have a repairing effect on the damage caused by
free radicals. According to their ability to prevent cellular kinase losses, they
stop oxidation reactions. They show their effects by increasing the synthesis of
antioxidant enzymes such as SOD and non-enzymatic antioxidants.
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Especially Tea Flavonoids are Powerfull Antioxidants Using an in vitro
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phenols in the diet: Their significance as antioxidants. Journal of Nutritional and
Environmental Medicine, 12, 39-51.
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Medical Society Duodecim, 30(1), 103-108.
23. Yazıcı C., Köse K. (2004). Melatonin: Karanlığın antioksidan gücü.
Erciyes Üniv. Sağlık Bilimleri Dergisi. 13(2), 56-65.
24. Duthie GG., Wahle KWJ. and James WPT. (1989). Oxidants,
antioxidants and cardiovascular disease. Nutr. Res. Rev. 2, 51-62.
25. Tahiroğlu V., Alayunt NO., Coskun E., Apa F. (2022). Assessment of
Vitamin B12 and Folate Levels in Psychiatric Patients in the Şırnak Region.
Mas Japs. 7(4), 847–854.
26. Alayunt NO, Soykan S. (2020). Synthesis, spectroscopic
characterization, and in vitro antioxidant activity of polyglycidylmethacrylate/
polyindole conducting polymer composites. Microsc Res Tech. 2020;1–11.
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27. Diplock A. (1998). Healty lifestyles nutrition and physical activity:
Antioxidant nutrients.ILSI Europe concise monograph series. 59 p., Belgium.
28. Reaven PD., Khouw A., Beltz WF., Parthasarathy S. and Witztum JL.
(1993). Effect of dietary antioxidant combinations in humans. Protection of
LDL by vitamin E but not by β-carotene. Arterioscler Thromb. 13(4), 590-600.
29. Mascio P. Murph, ME., Sies H. (1991). AntioLidan defense system:
the role of carotenoids, tocopherols, and thiols. Am. J. Clin. Nutr. 53,194-200.
30. Rice-Evans CA., Miller NJ., Bolwell PG., Bramley PM. and Pridham
JB. (1995). The relative antioLidant activities of plant-derived polyphenolic
flavonoids. Free Rad. Res. 22, 375-383.
29
1
1(Prof. Dr.) Mersin University, e-mail: aeyalin@gmail.com,
ORCID: 0000-0002-3351-6885
2(Prof. Dr.) Mersin University, e-mail: syalin@mersin.edu.tr,
ORCID: 0000-0002-1286-2172
Free radicals are defined as energy rich atoms or molecules that carry one
or more unpaired electrons in their valance shell (1). Free radicals can
easily react with other substances because they have unpaired electrons.
Since atoms or molecules that have their electrons paired (conjugated) have a
stable structure, their tendency to react with other molecules is not as great as
that of free radicals. Therefore, molecules that are stable, do not have unpaired
electrons, and react more weakly with other substances than radicals are defined
as nonradicals (2). Free radicals can originate from oxygen and nitrogen.
Radicals originating from molecular oxygen are called reactive oxygen species
(ROS) and radicals originating from molecular nitrogen are called reactive
nitrogen species (RNS) (3).
There are several defense mechanisms to keep the levels of reactive oxygen
species in the body under control and prevent the damage they can cause (4,5).
These substances that metabolize free radicals, prevent the formation of free
radicals, or increase the scavenging ability of free radicals are called antioxidants.
Antioxidants prevent lipid peroxidation by preventing the peroxidation chain
reaction or scavenging reactive oxygen species. Antioxidant molecules donate
electrons to free radicals to reduce their reactivity and maintain the cellular
balance between pro-oxidants and antioxidants. There are many antioxidant
systems in aerobic cells. These antioxidants are divided into two groups,
endogenous and exogenous (5-8).
30 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Based on their mechanism of action, endogenous antioxidants are most
commonly classified as enzymatic and nonenzymatic antioxidants. Glutathione
transferase (GST), glutathione reductase (GR), mitochondrial oxidase,
glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase
(SOD) are considered as enzymatic antioxidants. Examples of non-enzymatic
antioxidants are substances such as ceruloplasmin, glutathione, α-tocopherol,
ferritin, albumin, bilirubin, ascorbic acid, transferrin, and uric acid. They form
the earliest line of defense against oxygen radicals (5,9,10).
Allopurinol, folic acid, vitamin C, vitamin E, acetylcysteine, mannitol,
adenosine, calcium channel blockers, nonsteroidal anti-inflammatory drugs, and
iron chelators can be counted among exogenous antioxidants (5,6).
Antioxidants occur naturally in our body and in various foods. Antioxidants
have a high affinity for free radicals and thus scavenge harmful molecules in our
body to protect our health.
Polyphenols are phytochemicals found primarily in tea, chocolate, coffee,
fruits, legumes, vegetables, beverages, and grains. There are more than 8000
species of polyphenols found in nature. Since the main effect of polyphenols is
antioxidant, they can assist in coping with free radical damage and ward off UV
radiation or pathogen attack.
In recent years, the potential health benefits of dietary polyphenols as
antioxidants have attracted more attention. Consumption of products such as
grains, vegetables, legumes, and chocolate contributes to the absorption of
polyphenols, thus protecting our bodies from chronic diseases like cancer,
aging, cardiovascular, cerebrovascular, neurodegenerative diseases, and
diabetes mellitus (11). Flavonoids, Stilbenes, Lignans, and Phenolic acids are
four different classes polyphenols classified according to the number of phenolic
groups and other structural components (12). There are two subgroups, hydroxy
benzoic acids and hydroxy cinnamic acids.
Studies have shown that diets rich in fruits and vegetables reduce the risk of
several diseases, especially cardiovascular disease and some cancers (13). These
positive health effects are largely due to vitamins and flavonoid components.
The advantageous outcomes of flavonoids found in the plant kingdom in vivo
HERBAL ANTIOXIDANTS: NARINGENIN, CURCUMIN AND ARONIA 31
are suggested by their ability to scavenge oxygen-free radicals, reduce the
activity of transition metals, and/or strengthen the endogenous antioxidant
defense system (14). Flavonoids are classified into flavanones, anthocyanidins,
catechins, flavonols, isoflavones, flavones, and chalcones (15).
Naringenin is one of the major naturally occurring flavonoids found in
some edible fruits such as citrus fruits, tomatoes and also in figs of the genus
Ficus carica (16,17). Naringenin has broad biological effects on human health. It
reduces lipid peroxidation and protein carbonylation and supports carbohydrate
metabolism, strengthens the antioxidant defense system, eliminates reactive
oxygen species in the biological environment, regulates immune system activity,
and also has antiatherogenic and anti-inflammatory effects (17).
Studies have shown that consumption of citrus plants, which are high in
flavonoid antioxidants, has many beneficial properties such as anticarcinogenic,
antiviral and anti-inflammatory effects (18). The flavanone naringenin and its
glucosides are widely distributed in nature. Citrus juice [such as grapefruit]
contains high amounts of naringenin (19).
In vitro studies on various cell models have shown that naringenin, the
major flavanone of grapefruit (Citrus paradisi), is a potent antioxidant (20). In
vivo studies, naringenin partially protected against oxidative stress induced by
oxytetracycline in rat liver (21).
Flavonoids are structurally composed of 15 carbon atoms, 3 carbon chains,
2 benzene rings, and 3 chains. Naringenin is commonly found in the skin of grapes
and tomatoes and in citrus fruits such as oranges and grapefruits. Naringenin is
particularly responsible for the bitter taste of the fruit and is therefore abundant
in grape fruit (21,22).
Figure 2.1. Structure of naringenin (21)
32 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
In studies on mice, naringenin has been shown to have an effect on obesity
and hepatitis C in the liver and to reduce sugar-induced neuropathy in diabetes
mellitus (23).
In a study conducted to examine the role of naringenin in glucose and
lipid metabolism, one group was given a normal diet, while the other group
was given a diet containing naringenin. It was determined that the postprandial
glucose level and insulin level were lower in the naringenin group compared
to the control group. At the same time, it was determined that intra-abdominal
and subcutaneous adiposity and monocyte chemotactic protein-1 and IL-6 levels
decreased and hepatic steatosis improved (24).
In an experimental research, naringenin administration was found to
lower levels of conjugated dienes, lipid hydroperoxides, and thiobarbituric acid
reactive substances (Chtourou et al., 2015). Additionally, it might increase the
activity of antioxidant enzymes such glutathione reductase, catalase, superoxide
dismutase, and glutathione peroxidase (25).
Yao et al. evaluated the safety and therapeutic efficacy of naringen in the
treatment of pediatric bronchial pneumonia. According to the results of the
study, they concluded that naringenin can shorten the time to disappearance of
clinical symptoms, inhibit inflammation, decrease the incidence of bronchial
pneumonia complications and connected adverse reactions, and enhance the
patients’ health (26).
Researchers studied the effects of naringenin treatment on cancer and
discovered that it inhibits inflammatory and survival signaling pathways. In
addition to suppressing tumor growth, naringenin was shown to reduce cancer
metastasis. Naringenin may be used as a chemotherapeutic drug to treat prostate
cancer, according to research by Lim et al. (27).
Some drugs may interact with naringenin during intestinal absorption to
alter circulating drug levels, resulting in increased or decreased drug effects.
Therefore, consumption of citrus fruits (especially grapefruit) and other fruit
juices with drugs is not recommended to avoid interactions with drug absorption
and drug metabolism (21-23).
Turmeric (Curcuma longa) is a spice of great interest to researchers in the
medical world. Turmeric is a rhizomatous herb of the ginger family (28). The
medicinal properties and benefits of turmeric containing curcumin have been
HERBAL ANTIOXIDANTS: NARINGENIN, CURCUMIN AND ARONIA 33
described previously (29). Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione], also called diferuloylmethane, is a natural
polyphenolic constituent found in the rhizome of Curcuma longa. It is a tropical
plant used as a spice and dye. The yellow pigments are obtained by grinding the
roots of the plant.
Figure 2.2. Structure of curcumin (30)
Curcuma longa is traditionally used as a medicinal plant in Asian
countries for its anti-inflammatory, anticancer, antioxidant, antimicrobial, and
antimutagenic properties (29). Polyphenol curcumin has been shown to have
many health benefits as it targets multiple signaling molecules and is also active
at the cellular level (31). It has been shown to help treat inflammatory diseases,
metabolic syndrome, pain, and inflammatory and degenerative eye diseases (32).
It has also been shown to have a beneficial effect on the kidneys (33). Many of
the many benefits of curcumin are due to its antioxidant and anti-inflammatory
effects (32).
Since curcumin has antioxidant and anti-inflammatory properties, it has
several effects on the body (34). Curcumin is effective in reducing oxidative
stress (35). Antioxidants such as superoxide dismutase (SOD) have been found
to increase serum activities. Consumption of turmeric helps to reduce the risk of
developing cancers and has a protective effect in humans (36).
Systematic research and meta-analysis studies on curcuminoids have
shown a significant effect on serum lipid peroxides and glutathione peroxidase
concentrations, including all oxidative stress parameters studied, including
plasma activities of SOD and CAT (35). Since curcuminoids are poorly absorbed,
a form of formulation was prepared to overcome the problems of bioavailability
in meta-analysis studies. The effect of curcumin on free radicals is achieved by
several mechanisms. It can scavenge various forms of free radicals such as ROS
and RNS (37). It can modulate the activity of CAT, SOD, and GSH enzymes
that are active in neutralizing free radicals. It can also inhibit ROS -producing
34 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
enzymes such as lipoxygenase/cyclooxygenase and xanthine hydrogenase/
oxidase (34). In addition, curcumin is a lipophilic compound that effectively
scavenges peroxyl radicals, so curcumin is considered a chain-breaking
antioxidant like vitamin E (38).
Curcumin is able to suppress the expression of various cell survival and
proliferative genes involved in apoptosis, cellular proliferation and transformation
by nuclear factor kappa B activity inhibition. Tumor cell proliferation has been
suppressed in many species by inducing tumor suppressor genes such as p53,
activating caspase, and reducing the expression of reactive oxygen compounds.
It has limited the effect of human EGFR-2 (HER2) and TNF, a growth factor
for tumor cells, which is closely associated with breast, lung, kidney and
prostate cancers. Some experimental studies have demonstrated that curcumin
may exert its efficacy in anti-inflammatory effect via peroxisome proliferator-
activated receptor-c activation, a group of transcription factors that regulate
gene expression (39).
In clinical studies conducted in recent years, the effectiveness of
turmeric and its curcumin content against many diseases have been evaluated.
Some promising effects have been observed in obesity, diabetes, depression,
arthritis, skin diseases, inflammatory bowel disease, muscle lesions,
premenstrual syndrome symptoms, gynecological diseases and inflammatory
diseases (40).
In particular, several clinical studies have evaluated the efficacy of curcumin
consumption in patients with obesity, metabolic syndrome, or diabetes. Based
on the results of these studies, it was found that curcumin consumption has a
positive effect on weight management, lowering blood lipids and improving
glycemic control in obese individuals. These results are supported by a meta-
analysis showing that curcumin supplementation can reduce plasma leptin levels,
and a systematic review demonstrating that it reduces glycosylated hemoglobin
levels A1c and fasting glucose levels (41,42). Curcumins have been reported to
reduce serum total cholesterol, serum triglyceride and liver cholesterol levels.
There is also evidence that it lowers LDL and raises HDL.
Aronia is a shrub plant also known as chokeberry. It is also popularly known
by various names like bird cherry or hunter’s grape. Aronia; the Rosaceae family
belongs to the genus Aronia. There are three known species in this genus. The
most common Aronia cultivars in Europe include ‘Aron’ (Denmark), ‘Viking’
HERBAL ANTIOXIDANTS: NARINGENIN, CURCUMIN AND ARONIA 35
(Finland), ‘Nero’ (Czech Republic), ‘Kurkumachki’ (Finland), ‘Rubin’ (Russia),
‘Hugin’ (Sweden) , ‘Fertoedi’ (Hungary) ‘Albigowa’, ‘Dabrowice’, ‘Egerta’,
‘Kutno’, ‘Nova’, ‘Wies’, ‘Hakkija’, ‘Ahonnen’, ‘Serina’ (Poland) (43-47).
The chokeberry has been used by Native Americans for centuries. Native
Americans, whose homeland is North America, often use the aronia berry in
their meals because of its powerful effects. They have benefited from this fruit to
stay resistant to diseases and protect their immunity in harsh winter conditions.
After 1900, aronia berries began to be cultivated in Europe and Russia from
North America. In Eastern Europe, especially in Germany, it has been grown
commercially since 1950. Most notably, since 2009, the Midwest Aronia Union
has been established in the United States, organizing meetings and events every
year to promote its cultivation. Thanks to scientific research in the last 15-20
years, the amazing ingredients of the chokeberry have been discovered and its
popularity has increased thanks to its health benefits (43-53).
Aronia berry contains various complex chemicals, is rich in phenols,
minerals and vitamins. The phenolic substances in chokeberry are very valuable
for medicine. It contains a very high amount of anthocyanins, proanthocyanidins
and phenolic acid. Anthocyanins make up 25% of the total content of phenolic
substances. The most important anthocyanin is cyanidin-3-glycoside.
Anthocyanins include 3-xyloside, cyanidin-3-glucoside, 3-arabinoside, and
3-galactoside. Aronia melanocarpa (Michx.) Elliott’s (Aronia) contains
significant amounts of hydroxycinnamic acids in addition to anthocyanins:
chlorogenic acid and its isomer neochlorogenic acid (43-53). Aronia berries
are also called chokeberry because they are rich in polyphenolic compounds
such as anthocyanins, because the fruits gain astringent properties and create a
puckering sensation in the mouth.
Fresh fruits have a dominant bitter almond odor because they contain a
large amount of amygdalin. Amygdalin has a great effect on the healing of cancer
cells and the prevention of some cancers, especially stomach, colon, liver and
prostate. About 1 kg of chokeberry contains 20 g of polyphenols and 4-8.5 g of
anthocyanins, quite high amounts of K, Zn, Na, Ca, Mg, Fe and vitamins A, C,
E, K, B1, B2, B6, B12. has. The content of vitamins and minerals in processed
fruit juice ranges from 300-600 mg per 100 ml. In addition, the juice is rich in
potassium and zinc. Fresh fruit contains abundant B1, B2, B6, vitamin C and
niacin. Aronia fruit contains large amounts of carotene, as well as vitamins and
minerals (43-53). It contains all vitamins except vitamin D. That’s why aronia
is called Super Fruit.
36 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Studies on the effects of chokeberry (Aronia melanocarpa (Michx) Elliot),
which belongs to the berry fruits, on human health have shown that its fruits
have a higher value than other berry fruits in terms of antioxidant capacity and
anthocyanin content. Studies conducted in recent years have shown that the
Oxygen Radicals Absorbance Capacity (ORAC) value of chokeberry is quite
high compared to other products. Since aronia has a very high antioxidant
capacity among berry-like fruits, it can be consumed as a fresh fruit in the world,
as well as used in the pharmacy and food industry. It has been used as a medicine
by the natives for centuries. They dried their fruits and used them as an addition
to meals, and dried their leaves to make tea (43-53).
There are many studies in the literature regarding the health benefits of
aronia. Aronia fruits have been found to be beneficial for many diseases and
human health, especially for their anticancer properties. Indeed, many of the
suggested health benefits of aronia are due to its polyphenol content. In the study
of Tolic et al., it was determined that aronia has the highest polyphenol content
among 143 plants (50). In the study on the effects of aronia fruit on chronic
diseases, it was stated that the antioxidant activity of aronia fruit is high, its
phenolic compounds are very valuable, and the importance of anthocyanins and
procyanidins (54). In the study examining the chemical composition of aronia
fruit, fruit juice and concentrate, aronia tea and dried fruit, it was reported that
the total phenolic content of dried fruit was higher when compared to fresh
fruit and fruit juice concentrate (55). It has been determined that the phenolic
component content of aronia fruit varies depending on the maturity period of the
fruit, variety and ecology.
Wang et al. examined the effects of Aronia melanocarpa (AM) on alcohol-
induced liver injury in mice, and concluded that AM prevents alcohol-induced
liver injury by suppressing oxidative stress through the Nrf2 signaling pathway.
In a study evaluating the effects of aronia juice in rats with liver damage, it was
found that the juice reduced the severity and symptoms of liver damage (43).
Omairi et al. determined that aronia application in A549 human lung cancer
cell line showed apoptotic activity by down-regulating PARP-1, caspase-3 and
Bcl-2 proteins, and they predicted that aronia can be used in the treatment
of lung cancer due to its minimal side effects (56). Another study found that
aronia extract helped reduce cell damage due to breast cancer. Researchers
concluded that aronia extract has protective properties in people suffering from
breast cancer. In a study investigating the effects of grape, aronia and blueberry
HERBAL ANTIOXIDANTS: NARINGENIN, CURCUMIN AND ARONIA 37
extracts on colon cancer, it was found that all extracts inhibited the growth of
cancer cells, while aronia had the strongest effect (57).
It has been supported by some studies that aronia is also effective in
preventing the development of diabetes and obesity, strengthening the immune
system and reducing insulin resistance (46,58). In one study, it was thought
that aronia might protect against coronary artery disease, protecting against
plaque that develops inside the arteries. They discovered that aronia is effective
in lowering blood pressure and can help fight high blood pressure in the arteries
(59).
Regular consumption of this fruit has been found to protect against
cardiovascular disease, digestive system diseases and some types of cancer.
Aronia extracts can help lower serum total cholesterol, triglycerides, and low-
density lipoprotein cholesterol in patients with metabolic syndrome, as well
as glucose levels in the blood. Aronia fruit extract has been found to reduce
risk factors for insulin resistance by modulating several signaling pathways
associated with insulin signaling, adipogenesis, and inflammation. Many in
vitro studies and animal studies show the antiproliferative or protective effects
of chokeberry fruits and extracts, especially in colon cancer. Numerous studies
confirm the effects of consumption of Aronia melanocarpa L. varieties on
hypertension, glucose metabolism disorders, dyslipidemia, proinflammatory
conditions and reduction of metabolic syndrome risk factors (43-53).
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43
(PhD., Assistant Professor Doctor),
Van Yuzuncu Yil University, Faculty of Pharmacy,
Department of Biochemistry, Van, TURKEY,
e-mail: mehmet_berkoz@yahoo.com
ORCID: 0000-0003-4219-8054
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s
disease, is a devasting progressive neurodegenerative disease that
results in the death of motor neurons and skeletal muscle atrophy.
Pathology of ALS includes oxidative stress, neuroinflammation, mitochondrial
dysfunction, excitotoxicity, protein aggregation, and changes to axonal transport
and structure. Neuronal cell death is a result of, and contributor to, this process in
ALS. Mutations affecting endogenous antioxidant function, such as in ALS, an
increase in reactive oxygen or nitrogen species (ROS/RNS) occurs. The presence
of ROS/RNS can cause neuroinflammation which is characterized by activation
of glial cells, including astrocytes, microglia, and resident macrophages, along
with infiltrating immune cells, in the central nervous system (CNS). These
cells, particularly astrocytes and microglia, release pro-inflammatory cytokines,
chemokines, and oxidative species which further damage neurons and add to the
oxidative burden. As a result, mitochondria experience damage to the electron
transport chain (ETC) and energy metabolism which result in apoptosis.
Physical and chemical damage from increased ROS/RNS generation by these
dysfunctional mitochondria and neuroinflammatory glial cells can further
contribute to excitotoxicity in ALS (1).
44 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
ALS is a relatively rare but incurable and relentlessly progressive
neurodegenerative disease, characterized by motor neuron loss in the brain
and spinal cord (2). ALS begins insidiously with local symptoms, but rapidly
spreads to majority of muscles, which eventually leads to death commonly due
to respiratory failure. Although around 10% of ALS patients survive 10 years or
longer, vast majority of patients die within 3-5 years after symptom onset (3).
Motor neurons are grouped into corticospinal motor neurons in the motor
cortex (upper motor neurons) and bulbar or spinal motor neurons (lower motor
neurons). In a healthy person, the upper motor neurons make direct or indirect
connections with the lower motor neurons, which subsequently innervate skeletal
muscles and control movement. In ALS patients, however, the communication
between brain and muscles is interrupted by the deficit of either the upper
motor neurons (presenting as stiffness and spasticity) or lower motor neurons
(presenting as fasciculation and amyotrophy), or both (3,4).
2.1.OxidativeStressandMitochondrialDysfunctioninALS
Oxidative stress is the excessive production of ROS/RNS in the form of
free radicals. Oxidative stress markers are elevated in ALS patients (5). In the
case of sporadic ALS, excessive oxidative stress may be due to environmental
factors such as toxins, pesticides, and heavy metals, along with lifestyle
habits (5,6). Epidemiological and case control studies have linked pesticides,
agricultural chemicals, and heavy metal exposure to the development of ALS
(7-9). Lifestyle factors such as smoking, strenuous physical activity, and stress
also may increase oxidative stress and contribute to the development of ALS
(10-12). Lastly, the pathology from single or repeated head trauma, even of mild
severity, results in overt oxidative stress and has been researched as a potential
contributor to ALS in athletes and military personnel (12,13).
These factors, along with dysfunction in the mitochondrial ETC that comes
with aging, likely contributes to oxidative stress in sporadic ALS cases (14). In
fact, mitochondrial function deficits are present prior to symptom onset (15). In
the aging individual, mitochondrial function is reduced, and ROS generation
is increased as a byproduct of dysregulated ATP production. Furthermore, the
number of damaged mitochondria with mutated DNA also increases with age and
further contributes to ROS generation (16). Dysfunctional calcium regulation
and ETC activity, along with morphological changes to mitochondria, have been
observed in cell and animal models of ALS (17).
MECHANISM OF ANTIOXIDANT DEPLETION IN AMYOTROPHIC LATERAL SCLEROSIS 45
Familial ALS cases have been linked to mutations in chromosome 9 open
reading frame 72 (C9orf72), TDP-43, fused in sarcoma (FUS), and SOD-1.
Mutations in C9orf72 and SOD-1 account for the majority of familial ALS
cases. Mutations to SOD-1 account for 20-25% of all familial cases, making
it the second most common ALS mutation behind mutations to C9orf72 (18).
Furthermore, recent data from an analysis of 22 countries has reported that,
out of 2,876 prevalent mutant SOD-1 cases, 47% were familial and 53% were
sporadic cases (19). Also, over 100 mutations in SOD-1 have been identified in
patients with ALS (20).
Superoxide dismutase-1 is an endogenous antioxidant enzyme with a
copper binding site that can be reduced by superoxide to form dioxygen. An
additional molecule of superoxide oxidizes the reduced copper ion to form
hydrogen peroxide (20). In ALS, further research is needed to understand how
mutations in SOD-1 result in increased oxidative stress. Some studies have
reported that SOD-1 loses its function and is unable to reduce superoxide
resulting in increased levels of superoxide and peroxynitrite. Other studies
have reported increased activity of SOD-1 resulting in increased production
of hydrogen peroxide, hydroxyl radicals, and SOD-1 protein aggregation (21).
Mutated SOD-1 may also render normal SOD-1 nonfunctional (14). Mutations
in SOD-1 also contribute to mitochondrial dysfunction as mutant SOD-1
aggregates in the mitochondrial outer membrane (22).
Oxidative stress can result in DNA, lipid, and protein damage. Patients
with ALS have increased levels of MDA, 4-HNE, 8-oxo-2’-deoxyguanosine,
3-NT, and protein carbonyls in blood, cerebrospinal fluid, spinal cord, and/or
motor cortex (5,14). This damage contributes to the motor neuron death that is
characteristic of ALS. Furthermore, there is crosstalk between oxidative stress
and other pathological mechanisms present in ALS, such as those described
below, which further contribute to motor neuron death.
2.2.NeuroinammationinALS
Inflammatory markers and cytokines released from glial and immune cells,
such as IL-6, -8, and -1β, TNF-α, c-reactive protein, and interferon-γ (IFN- γ)
have been found to be upregulated in ALS (23). This dissertation will focus on
the role of activated astrocytes and microglia in ALS, termed neuroinflammation,
as a potential therapeutic target.
In ALS, astrocytes become toxic, release pro-inflammatory cytokines, and
are typically located near dying neurons (24). Astrocytes express mutated genes
46 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
that have implications in ALS, including mutant SOD- 1, and have been shown
to cause neurotoxicity and increased levels of pro-inflammatory cytokines in
culture which likely contributes to motor neuron death (25). Microglia are
resident immune cells of the brain that sense the environment, exhibit macrophage
activity, and respond to toxins. Like astrocytes, microglia also express ALS
mutant genes, such as mutant SOD-1, and contribute to motor neuron death.
Both microglia and astrocytes can adopt anti- and pro-inflammatory phenotypes.
Classically, an M2 phenotype is anti-inflammatory and promotes cell and tissue
regeneration while an M1 phenotype is pro-inflammatory and is characterized by
the generation of ROS/RNS and pro-inflammatory cytokines (26). In a healthy
individual, these phenotypes aren’t polarized but astrocytes and microglia
express these phenotypes on a spectrum. In ALS, it seems that initially, many
microglia adopt an anti-inflammatory, M2 phenotype. However, as the disease
progresses, microglia take on a pro-inflammatory M1 phenotype (27). Activated
M1 microglia have been found in the motor cortex and spinal cord of ALS
patients (28). Lastly, there is crosstalk between astrocytes and microglia. For
example, a reduction in microgliosis has been shown to decrease the activation
of astrocytes (29). Similarly, removal of astrocytes expressing mutant SOD-1
and replacement with wild-type astrocytes resulted in decreased microglial
activation (25). Regardless of the precise hierarchy of glial involvement in ALS
pathogenesis, it is clear that these non-cell autonomous mechanisms play an
important role in disease progression.
Motor neurons also express mutant genes, such as SOD-1, however, this
alone does not seem to cause motor neuron death (25). Furthermore, wild-type
glial cells not expressing mutant ALS genes extend survival of motor neurons
in animal models (30). These data indicate that glial cells such as astrocytes and
microglia contribute to the death of motor neurons through the loss of necessary
functions such as motor neuron support, homeostasis, and synapse support
resulting in excitotoxicity and pro-inflammatory processes. Astrocytes and
microglia also gain a toxic function through expression of mutant genes, pro-
inflammatory activities, and generation of ROS/RNS, which further contribute
to oxidative stress and motor neuron death.
2.3.ExcitotoxicityinALS
As mentioned above, healthy astrocytes have roles in synapse maintenance
and neurotransmitter homeostasis. These processes include a dominant role
in glutamate clearance from the synapse. In ALS, astrocytes have reduced
MECHANISM OF ANTIOXIDANT DEPLETION IN AMYOTROPHIC LATERAL SCLEROSIS 47
functionality in this role which leaves excessive glutamate in the synapse and
causes ionotropic glutamate receptor activation on the post-synaptic neuron
(31). Astrocytes have the EAAT2 transporter which is responsible for uptake of
glutamate from the synapse, and this transporter displays decreased expression in
ALS (32). Also mentioned prior, oxidative stress and mitochondrial dysfunction
are both consequences and causes of excitotoxicity in ALS, as mitochondria
have calcium buffering functions which become unregulated in ALS.
In general, motor neurons express a high number of AMPA receptors and
exhibit an increased response to calcium influx (33). Motor neurons respond
to glutamate as their primary excitatory neurotransmitter and are sensitive to
excitotoxicity, particularly by AMPA ionotropic glutamate receptors. In the
case of mutant SOD-1 ALS, aggregation of mutant SOD-1 causes death of
motor neurons specifically. Calcium influx through AMPA receptors can further
contribute to mutant SOD-1 aggregation and the death of motor neurons (34).
Furthermore, altered glutamate metabolism has been observed in ALS
patients (35). There is sound evidence of excitotoxicity caused by serum,
plasma, and cerebral spinal fluid (CSF) isolated from ALS patients. Plasma,
serum, and CSF from ALS patients induces cytotoxicity in cultured neurons
(36). The neurotoxicity of CSF from ALS patients was blocked by an AMPA
receptor antagonist, and an NMDA receptor antagonist showed a milder
protection which suggests excitotoxicity plays a role (37). Overall, it seems that
glutamate excitotoxicity is an important underlying pathology observed in ALS
(38). However, it remains unclear whether this is due to increased extracellular
glutamate or to changes in glutamate transporters, and what effect it has on
disease phenotype. Andreadou et al. (39) found increased plasma glutamate
levels were correlated with longer disease duration in lower limb onset ALS
but were not observed in bulbar onset ALS. Vesicular glutamate transporters,
which package glutamate into vesicles for synaptic release, when reduced in
expression in a mouse model of ALS, did protect motor neurons from death but
ultimately had no effect on overall survival or disease duration (40).
2.4.ObservedProteinAggregationContributestoALSPathology
Protein aggregation has been observed in both sporadic and familial
cases of ALS. Proteins encoded by genes such as SOD-1, TDP-43, FUS, and
C9orf72 (e.g., dipeptide repeat proteins) have been observed to aggregate in
ALS patients. Cytoplasmic inclusions of these proteins, classified as lewy-
body like or neurofilamentous, have been observed in motor neurons and glial
48 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
cells located in brain and spinal cord isolated from ALS patients (41). RNA
binding proteins specifically, such as TDP-43, FUS, and heterogeneous nuclear
ribonucleoproteins A1/A2 (hnRNP A1/2), can become mutated and/or drawn
into RNA foci and/or stress granules, and cause mislocalization of the protein and
impaired nuclear-cytoplasmic transport. Inclusions of these proteins have been
observed in patients with ALS (42). Their functions and regulation of mRNA
stability vary depending on the location, whether nucleus or cytoplasm, which
further supports the idea that improper localization of RNA binding proteins
may disrupt the regulation of mRNA and resulting in disease pathology (43).
Aggregation of mutant SOD-1 has been observed in sporadic and familial
ALS cases. Although more research is needed, SOD-1 may have similar roles
to RNA binding proteins and its aggregation could have implications in the
processes described above (44). Mutant SOD-1 does localize to RNA rich
structures, support RNA metabolism, and SOD-1 inclusions do contain RNA
(45). Aggregation of SOD-1 has been directly linked to motor neuron and glial
cell death (46).
There are a few hypotheses which help explain why protein aggregation
contributes to ALS disease pathology. Many observed protein aggregates in
ALS have functions as RNA binding proteins or support RNA metabolism and,
when these proteins are mutated and not performing their functions, there is a
loss of regulation of RNA metabolism and disrupted transport of RNA from
nucleus/cytoplasm. The improper formation or disintegration of stress granules
also seems to play a role in ALS. Stress granules control mRNA localization,
stability, and translation (47). In response to stress signals, granules will sequester
mRNA molecules, translation initiation factors, and RNA binding proteins such
as those mentioned above. During stress, bulk translation is inhibited but when
the stress signal dissipates, translation can be reinitiated, and the stress granules
disassemble due to their dynamic nature (43). Mutated RNA binding proteins
that localize to stress granules can prevent their disassembly or can lead to
aberrant formation causing a disruption in these regulatory processes (48). The
accumulation of mutant proteins may also act in a prion-like manner, causing
the aggregation of other normal and mutated proteins such as SOD-1 and TDP-
43 and encouraging misfolding of these proteins (49). Lastly, protein aggregates
may also disrupt axonal transport of proteins, lipids, and mRNA which will be
further described below, although the connection is not fully understood and
conflicting evidence exists (50).
MECHANISM OF ANTIOXIDANT DEPLETION IN AMYOTROPHIC LATERAL SCLEROSIS 49
2.5.DysfunctionalAxonalTransport,SynapticFailure,MotorNeuron
Death,NMJDeterioration,andMuscleAtrophyinALS
Increased oxidative stress, mitochondrial dysfunction, neuroinflammation,
excitotoxicity, and protein aggregation can all contribute to axonal transport
deficits. Mutations to axonal transport machinery such as to dynein or kinesin, or
that affect microtubule stability, have been observed in ALS (51). Excitotoxicity,
oxidative stress, and mitochondrial damage are the cause and result of abnormal
mitochondrial transport along axons (52).
Protein aggregates of TDP-43 and SOD-1 can cause aberrant activation
of signaling pathways, such as activation of p38 mitogen-activated protein
kinases or c-Jun kinases, which play roles in microtubule and kinesin transport
(53). Deficits in anterograde and retrograde axonal transport which transport
mRNA, proteins, lipids, vesicles, and mitochondria have been observed in in
vivo models of ALS. Hyperphosphorylated neurofilament heavy polypeptide
chain, a marker of axonal loss, abnormal accumulation of mitochondria and
lysosomes, and axonal spheroids containing vesicles, lysosomes, mitochondria,
and microtubules, have all been observed in patients with familial and sporadic
forms of ALS (52).
Upper motor neurons have cell bodies in the cerebral (motor) cortex and
lower/spinal motor neurons have cell bodies in the ventral horn of the spinal
cord. Their axons allow for movement and reflex responses, with spinal motor
neuron axons extending for several meters (54). The synthesis of proteins
and lipids occurs in the cell body; therefore, the axon is also crucial for the
transport of neurotrophic factors, proteins, and mitochondria (55). Furthermore,
neurotransmitters in vesicles are transported along the axon for release at axon
terminals. In the case of lower/spinal motor neurons, the neurotransmitter release
of acetylcholine occurs at the NMJ, or the synapse between the motor neuron
axon and the muscle it innervates. An early event in ALS pathogenesis appears
to be the retraction of motor axons away from NMJs: this in turn, leads to loss
of skeletal muscle innervation, muscle atrophy, a dying back process of motor
neuron cell bodies, and resulting loss of movement. However, the precise order
in which these events occur is subject to debate (56).
2.6.EndogenousAntioxidantDepletionUnderliesALSPathology
All of the pathological mechanisms described above contribute to the
overall antioxidant depletion observed in ALS patients (Figure 1). Much of
50 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
the pathology occurs prior to symptom onset and therefore goes undetected for
prolonged periods. Long term oxidative stress, excitotoxicity, mitochondrial
dysfunction, neuroinflammation, and accumulation of toxic protein aggregates
deplete the endogenous antioxidant system (57,58).
Antioxidant Depletion and ALS (57,58)
Depletions in antioxidant defense markers have been observed in ALS
patients, although this is largely dependent on disease stage, progression, and
duration of disease since diagnosis. As described in depth above, GSH is an
endogenous antioxidant which has roles in reducing free radical oxygen.
Glutathione levels, along with enzymes involved in GSH antioxidant activity
such as catalase, GR, and glucose-6-phosphate dehydrogenase, have been
shown to decrease with ALS disease progression and these deficiencies have
been observed in both sporadic and familial forms of ALS (57-59).
MECHANISM OF ANTIOXIDANT DEPLETION IN AMYOTROPHIC LATERAL SCLEROSIS 51
SOD-1 is also a powerful cellular antioxidant. Copper and zinc binding
to SOD-1 helps maintain copper homeostasis and facilitates the conversion
between copper and cuperate, respectively. Many mutations to SOD-1 affect
copper or zinc binding to SOD-1 rendering these processes dysfunctional in
ALS (60). As described above, mutations to SOD-1 can result in loss of function,
cause increased activity and overproduction of ROS, or may inhibit functional
SOD-1 and/or induce its aggregation.
On a transcriptional level, both SOD-1 and GSH play roles in, and are
affected by, activation of the Nrf2 (nuclear factor erythroid 2 [NF-E2]-related
factor 2 [Nrf2])–Keap1 (Kelch-like erythroid cell-derived protein with CNC
homology [ECH]-associated protein 1) signaling pathway. This pathway
becomes activated in response to oxidative stress.
When this occurs, cysteine residues on Keap1 are modified which results
in its degradation and disassociation from Nrf2, targeting Keap1 for degradation
and eliminating the interaction with Nrf2. Once freed from Keap1, Nrf2 forms
a complex on antioxidant response elements in gene promoters and regulates
gene expression of NAD(P)H quinone oxidoreductase 1, GSH S-transferase,
and glutamate-cysteine ligase (61). Nrf2 levels in SOD-1 mutant ALS have been
found to be reduced in animal models and ALS patients (62).
Reduced response of this signaling pathway to oxidative stress helps
explain why GSH and supporting enzymes are reduced in ALS patients (63).
This indicates a loss of the endogenous antioxidant response to oxidative stress
in ALS, although this is likely not the only pathway involved.
ALS is the most common adult motor neuron disease, and the incidence of
ALS is increasing in both females and males worldwide. The median survival
time of ALS patients is approximately three years after the first symptoms have
started, and there is no fully effective treatment for ALS, only two approved
drugs, riluzole, and edaravone, are used for the patients with ALS. These drugs
are only effective at the early stages of ALS, however, the diagnosis of ALS
is usually difficult and takes time, since there are no definitive prognostic
biomarkers or pathognomonic tests are existing, also patients show significant
variability in terms of progression and presentation of the disease symptoms.
Studies have confirmed that there is a link between oxidative stress and the
pathogenesis of ALS disease, that oxidative stress plays a role in the progression
52 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
of ALS disease, and therefore there is a need to develop specific peripheral
biomarkers during the follow-up of the disease.
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fneur.2020.552295
24. Wang R, Yang B, Zhang D. Activation of interferon signaling pathways
in spinal cord astrocytes from an ALS mouse model. Glia. 2011;59(6):946-958.
doi:10.1002/glia.21167
25. Yamanaka K, Komine O. The multi-dimensional roles of astrocytes in
ALS. Neurosci Res. 2018;126:31-38. doi:10.1016/j.neures.2017.09.011
26. Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders:
the roles of microglia and astrocytes. Transl Neurodegener. 2020;9(1):42.
doi:10.1186/s40035-020-00221-2
27. Clarke BE, Patani R. The microglial component of amyotrophic lateral
sclerosis. Brain. 2020;143(12):3526-3539. doi:10.1093/brain/awaa309
28. Dols-Icardo O, Montal V, Sirisi S, et al. Motor cortex transcriptome reveals
microglial key events in amyotrophic lateral sclerosis. Neurol Neuroimmunol
Neuroinamm. 2020;7(5):e829. doi:10.1212/NXI.0000000000000829
29. Gowing G, Philips T, Van Wijmeersch B, et al. Ablation of proliferating
microglia does not affect motor neuron degeneration in amyotrophic lateral
sclerosis caused by mutant superoxide dismutase. J Neurosci. 2008;28(41):10234-
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30. Beers DR, Henkel JS, Xiao Q, et al. Wild-type microglia extend survival
in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl
Acad Sci U S A. 2006;103(43):16021-16026. doi:10.1073/pnas.0607423103
31. Benkler C, Ben-Zur T, Barhum Y, Offen D. Altered astrocytic response
to activation in SOD1(G93A) mice and its implications on amyotrophic lateral
sclerosis pathogenesis. Glia. 2013;61(3):312-326. doi:10.1002/glia.22428
32. Foran E, Trotti D. Glutamate transporters and the excitotoxic path to
motor neuron degeneration in amyotrophic lateral sclerosis. Antioxid Redox
Signal. 2009;11(7):1587-1602. doi:10.1089/ars.2009.2444
33. Kawahara Y, Kwak S. Excitotoxicity and ALS: what is
unique about the AMPA receptors expressed on spinal motor neurons?.
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doi:10.1080/14660820510037872
34. Gregory JM, Livesey MR, McDade K, et al. Dysregulation of AMPA
receptor subunit expression in sporadic ALS post-mortem brain. J Pathol.
2020;250(1):67-78. doi:10.1002/path.5351
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35. Tefera TW, Steyn FJ, Ngo ST, Borges K. CNS glucose metabolism in
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36. Sen I, Nalini A, Joshi NB, Joshi PG. Cerebrospinal fluid from
amyotrophic lateral sclerosis patients preferentially elevates intracellular
calcium and toxicity in motor neurons via AMPA/kainate receptor. J Neurol Sci.
2005;235(1-2):45-54. doi:10.1016/j.jns.2005.03.049
37. Couratier P, Hugon J, Sindou P, Vallat JM, Dumas M. Cell culture
evidence for neuronal degeneration in amyotrophic lateral sclerosis being
linked to glutamate AMPA/kainate receptors. Lancet. 1993;341(8840):265-268.
doi:10.1016/0140-6736(93)92615-z
38. King AE, Woodhouse A, Kirkcaldie MT, Vickers JC. Excitotoxicity in
ALS: Overstimulation, or overreaction?. Exp Neurol. 2016;275 Pt 1:162-171.
doi:10.1016/j.expneurol.2015.09.019
39. Andreadou E, Kapaki E, Kokotis P, et al. Plasma glutamate and glycine
levels in patients with amyotrophic lateral sclerosis. In Vivo. 2008;22(1):137-
141.
40. Wootz H, Enjin A, Wallén-Mackenzie A, Lindholm D, Kullander K.
Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A)
mice. Neurobiol Dis. 2010;37(1):58-66. doi:10.1016/j.nbd.2009.09.006
41. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp
RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol.
2013;125(6):777-794. doi:10.1007/s00401-013-1125-6
42. Shang Y, Huang EJ. Mechanisms of FUS mutations in familial
amyotrophic lateral sclerosis. Brain Res. 2016;1647:65-78. doi:10.1016/j.
brainres.2016.03.036
43. Wolozin B, Apicco D. RNA binding proteins and the genesis
of neurodegenerative diseases. Adv Exp Med Biol. 2015;822:11-15.
doi:10.1007/978-3-319-08927-0_3
44. Da Ros M, Deol HK, Savard A, Guo H, Meiering EM, Gibbings D.
Wild-type and mutant SOD1 localizes to RNA-rich structures in cells and mice
but does not bind RNA. J Neurochem. 2021;156(4):524-538. doi:10.1111/
jnc.15126
45. Butti Z, Patten SA. RNA Dysregulation in Amyotrophic Lateral
Sclerosis. Front Genet. 2019;9:712. doi:10.3389/fgene.2018.00712
46. Thomas EV, Fenton WA, McGrath J, Horwich AL. Transfer of pathogenic
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48. Protter DSW, Parker R. Principles and Properties of Stress Granules.
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50. Guo W, Stoklund Dittlau K, Van Den Bosch L. Axonal transport defects
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60. Boyd SD, Ullrich MS, Calvo JS, Behnia F, Meloni G, Winkler DD.
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freeradbiomed.2008.10.040
59
(MD Dr.) Birecik State Hospital Neurosurgery Clinic, Şanlıurfa, Turkey
E mail: drpelinkuzucu@gmail.com
ORCID: 0000-0003-0049-1316
The nervous system develops from neural plaque in the 3rd week(1). At
the end of the 3rd week, the lateral edges of the neural plate rise, forming
neural folds (2). This region between the folds is called the neural groove.
Neural folds close along the line, approaching each other along the middle line.
As a result of these events, the neural tube is formed (1). The cranial neuropore
closes on the 24th day and the caudal neuropore closes on the 28th day. With the
closure of the neuropores, neurulation is completed. The central nervous system
has become a closed tubular structure consisting of a wide cephalic section with
brain vesicles, a narrow caudal section with a spinal cord (1).
Neural tube defects are formed by factors affecting the embryo in the
first four weeks of life (3). Closure defects of the anterior neuropore are
formed into anencephaly and encephalocele. The closure defects of the
posterior neuropore, on the other hand, cause spina bifida, meningocele and
meningomyelocele (3).
If we look at the etiology, we can collect it into two main groups (4).
The first group; is neural tube defects (NTDs) due to a specific etiology and
usually accompanied by other malformations (10%) (4). These are divided into
two groups themselves; Single gene mutations; Chromosomal abnormalities
(Meckel-Gruber syndrome, Chemke syndrome, etc.); (Trisomy 18 and Trisomy
13, etc.), and pregnancy. Other special conditions such as amniotic rupture,
amniotic band, which occurs before the week. The second group is isolated
developmental NTDs due to multifactorial inheritance (90%)(4).
In the prenatal period in NTDs patients, alpha-fetoprotein is found in the
maternal serum and fetal specific gamma-globulin is found high in the amniotic
fluid.
60 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
It is the mildest form of NTDs. They usually do not give symptoms. The
congenital spinous process and arcus vertebrae are not formed in one or rarely
more than one vertebra. However, the spinal cord and spinal nerves are normal.
In the meninges, there is no herniation. Chiari type II or hydrocephalus is not
observed. There may be signs on the skin such as hairy structure, dermal sinus,
dimple, hemangioma, lipoma (5)( Figure 1).
The images are taken from own clinical archive.
A: Sacral Dimple B: Hairy structure
It is a neural tube defect in which the skin, vertebrae, nerve roots, spinal
cord, and meninges are affected.(Figure 2)(6) The incidence is shown as 2-3/1000
live births. They are usually seen with lumbosacral or lumbar placement. The
proportion of cervical and thoracic lesions is approximately 11%.(7)
PEDIATRIC CONGENITAL DEFORMITIES 61
The image is taken from own clinical archive.
MRI image of a meningomyelocele patient is shown.
It occurs when polygenic or environmental factors are affected together.
Autosomal recessive inheritance can be a factor. Although it is most common in
people of Scottish and Irish descent, the use of medications such as carbamazepine
and valproic acid by the mother is highly effective in the formation of folic acid
deficiency. It is more common in females (60-70%). In addition, the risk is 4-8%
higher in those who have previously given birth to a baby with NTDs.
After childbirth, the thin membrane of the meningomyelocele often
ruptures, and the cerebrospinal fluid flows out. In such a situation, urgent surgery
is required. However, otherwise, surgery can be performed within the first 48
hours (Figure 3). The baby is laid flat/laterally. The lesion is covered with a
wet dressing and soaked intermittently. To prevent meningitis, the combination
of ampicillin + gentamicin is often started. 50% of these patients have a latex
allergy. Therefore, the gloves used should be taken care of in this regard. If they
are not treated, meningeal epithelization develops in the membrane and neural
layer, the fibrous band can curl in the cord, create compression, and death can
occur. In some cases, an epidermoid or dermoid cyst may develop because the
skin cells pass into the scar over time.
62 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
The images are taken from own clinical archive.
Steps of the surgical operation are shown.
It is accompanied by many deformities involving the brain(Chiari II
malformation>90%, Hydrocephalus>90%, Syringomyelia 88%, Brain stem
anomalies 75%, Cerebral ventricle anomalies >90%, Corpus callosum agenesis
12%, Polymicrogria 15-30%), intestinal, cardiac, esophageal, renal, urogenital,
orthopedic systems. It is essential that these patients are managed with a
multidisciplinary system.
It is the least common type of NTDs (8). The closure of the vertebral arch
is incomplete. The nerve tissue is not bagged in the defect consisting of the
meninges sac and the normal structure of the nerves is not disturbed. It often
occurs in the lumbosacral region (9). There is usually no neurological deficit. If
it is covered with skin, there is no problem, but if there is a thin membrane, there
may be anomalies.
Congenital dermal sinus is a type of closed spinal dysraphism and is the
remains of an incomplete closed neural tube. Embryologically, they are formed
as a result of an error in the separation of superficial ectoderm and dermal
structures from the neuroectoderm (10). They are tracts whose inner surface is
paved with flat epithelial cells, one end of which can reach the skin and the other
end to the neural tissue (Figure 4). Approximately 60% of cases contain dermoid
PEDIATRIC CONGENITAL DEFORMITIES 63
or epidermoid cysts. Although dermal sinus tracts can form in any region along
the neural axis, they are most often located in the lumbar and lumbosacral
regions.
The image is taken from own clinical archive.
MRI image of a meningocel patient is shown.
The spinal cord ends at the level of the S1 vertebra in the 6-month-
old fetus, at the level of the L2-3 vertebra in the newborn and at the inferior
border of the L1 vertebra in the adult. The most common causes of tethered
cord are Diastemetamia, Short and thick phylum terminale, Intradural lipoma,
Adhesions that develop after Lipomyelomeningocele and Meningomyelocele
surgery, and conus medullaris is located below the level of the L2 vertebra
(11). Skin symptoms (such as dimpling, hypertrichosis etc) , Motor deficits,
Foot deformities, atrophy of the legs, Urological symptoms (incontinence etc),
Progressive spinal deformities such as kyphosis, Scoliosis are common. In
adults, perineal and perianal pain, urological symptoms and motor losses are in
the foreground.
Radiologically, the presence of the subject medullaries in the L2 horse on
MRI, the fact that the terminals of the anterior phylum are thicker than 2 mm
makes the diagnosis (Figure 5). Cutting the short, thick phylum terminale with
lower lumbar restricted laminectomy, if the tension is due to a lipoma, dissecting
the lipoma from the neural elements and removing it constitutes the plan of
surgical treatment (12).
64 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
The images are taken from own clinical archive.
MRI images of a tethered cord are shown.
Signs and symptoms of tethered cord syndrome are present. There are
two types. Type I Diastematomyelia: There are two half-cords wrapped with
a separate dural sheath along one or two segments of the medulla spinalis (13).
There is a septum (spicule) between the two cords(Figure 6).
Type II split cord malformation (Diplomyelia): The presence of two half-
cords in a single dural sheath along one or two segments of the medulla spinalis.
Between the cords, there is a fibrous septum, which is not rigid (13).
Both types can be combined with thick phylum terminal.
This bone or fibrous septum, which causes tension in the cord, and the
thick phylum, if present, are surgically eliminated to the terminale.
The images are taken from own clinical archive.
PEDIATRIC CONGENITAL DEFORMITIES 65
It is a typical feature of children with spina bifida (14). Most of the
children are happy, extroverted, smart, sweet child types. They answer the
questions asked very well. Such children relate very well to their families and
their environment (14). They become lively, intelligent, bright-witted, talkative,
affectionate children.
Most often it develops after a defect at the embryological stage (15). This
defect can be a segmentation or formation defect, but it is often a combination of
the two. It is quite rare compared to idiopathic scoliosis (16). The ages at which
the fastest spine growth occurs are between the ages of 0-5 years and 10-15
years-old. Increased hair growth at the waist, unsymmetrical skin folds on the
back and waist, different skin color, vertebrae are not arranged properly when
viewed from behind, protrusion (hump) forms on one side of the back when
leaning forward, abnormal bone protrusion is seen in the back (Figure 7)(15).
The images are taken from own clinical archive.
If the curvature of congenital scoliosis is a flexible obliquity that covers
a long part of the spine, corset treatment may be useful. Surgical treatment is
the only option in cases where there is a high probability of progression and
progress is detected during the follow-up process. Surgical treatment is the most
commonly applied treatment method because the obliquity increases in the
majority of cases and corset treatment is not successful (16). The main purpose
of treatment options; correction if the deformity is advanced, prevention of
66 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
development if the deformity is undeveloped, preservation and growth of the
growth potential of the spine, development of the rib cage and protection of
lung-heart functions, short stature, cosmetic and psychological problems can be
listed as prevention (16).
1. Development of the central nervous system [Internet]. Kenhub. [a.yer
30 Kasım 2022]. Erişim adresi: https://www.kenhub.com/en/library/anatomy/
development-of-the-central-nervous-system
2. Development of the Central Nervous System - Spinal Cord -
TeachMeAnatomy [İnternet]. [a.yer 30 Kasım 2022]. Erişim adresi: https://
teachmeanatomy.info/the-basics/embryology/central-nervous-system/
3. Greene NDE, Copp AJ. Neural tube defects. Annu Rev Neurosci.
2014;37:221-42.
4. Copp AJ, Greene NDE. Genetics and development of neural tube
defects. J Pathol. Ocak 2010;220(2):217-30.
5. Graham P. Spina Bifida Occulta. Orthop Nurs. 01 Ağustos
2021;40(4):259-61.
6. Liptak GS, Dosa NP. Myelomeningocele. Pediatr Rev. Kasım
2010;31(11):443-50.
7. Shurtleff DB, Luthy DA, Nyberg DA, Benedetti TJ, Mack LA.
Meningomyelocele: management in utero and post natum. Ciba Found Symp.
1994;181:270-80; discussion 280-286.
8. Bailey IC. Double meningocele. Arch Dis Child. Ağustos
1971;46(248):549-50.
9. Martinez CR, Hemphill JM, Hodges FJ, Gayler BW, Nager GT, Long
DM, vd. Basioccipital meningocele. AJNR Am J Neuroradiol. 1981;2(1):100-2.
10. Foster MT, Moxon CA, Weir E, Sinha A. Dermal sinus tracts. BMJ. 04
Eylül 2019;366:l5202.
11. Yamada S, Colohan ART, Won DJ. Tethered cord syndrome. J
Neurosurg Spine. Ocak 2009;10(1):79-80; author reply 80-81.
12. Bui CJ, Tubbs RS, Oakes WJ. Tethered cord syndrome in children: a
review. Neurosurg Focus. 2007;23(2):E2.
13. Sato N, Sato H. [Diastematomyelia]. Ryoikibetsu Shokogun Shirizu.
2000;(28 Pt 3):387-90.
PEDIATRIC CONGENITAL DEFORMITIES 67
14. Tew B. The “cocktail party syndrome” in children with hydrocephalus
and spina bifida. Br J Disord Commun. Eylül 1979;14(2):89-101.
15. Marks DS, Qaimkhani SA. The natural history of congenital scoliosis
and kyphosis. Spine (Phila Pa 1976). 01 Ağustos 2009;34(17):1751-5.
16. Lonstein JE. Congenital spine deformities: scoliosis, kyphosis, and
lordosis. Orthop Clin North Am. Temmuz 1999;30(3):387-405, viii.
69
(Assoc. Prof. Dr), Dicle University Faculty of Medicine,
Pediatric Surgery Department
Email: drserkanarslan@hotmail.com
ORCID: 0000-0002-3456-9217
It is a common birth defect among newborns. Esophageal Atresia (EA) and
Tracheoesophageal Fistula (TEF)is caused by the incomplete separation of
the tracheobronchial tree from the foregut during the intrauterine period. The
incidence of EA/TEF is 2-4 per 10,000 individuals. It occurs in 2-4 of every 1,000 live
births and is slightly more common in males. With the development of technology
in anesthesia and neonatal intensive care, the survival rate for esophageal atresia
and tracheoesophageal fistula has risen to over 95%. On prenatal ultrasonography,
the presence of polyhydramnios and a small or absent stomach indicate esophageal
atresia. These newborns experience respiratory distress, malnutrition, suffocation,
and aspiration. The cardiovascular, digestive, urogenital, musculoskeletal, and
central nervous systems are frequently affected in infants with esophageal atresia.
60-70 percent of cases exhibit additional anomalies.
Babies born with EA-TEF are more likely to be premature than healthy
infants. These patients are also present in 15% of cases involving vertebral,
anorectal, cardiac, tracheoesophageal, renal, and extremity anomalies, which
are grouped under the name VACTERL. There are also urogenital, skeletal,
anorectal, and gastrointestinal malformations (1-6).
Various classifications have been proposed in the process (1-6).
Gros anatomical typing: 4
a. Isolated esophageal atresia (8%)
b. Proximal TEF + EA (0.6%)
70 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
c. EA+ Distal TEF (most common type (85%)
d. EA, proximal and distal TEF (1.4%)
e. H-type tracheoesophageal fistula - (4%)
Developments in neonatal intensive care, anesthesia
techniques, and devices have now made the Waterston classification obsolete. In
1994 Spitz et al. proposed a new risk grading system based on birth weight and
the presence or absence of congenital heart disease, which is widely practiced
in the modern era.
Newborns with EA have saliva flowing from their
mouths. Cough, choking and cyanosis attacks may occur shortly after birth. In
every feeding attempt, the baby has respiratory distress (1-6).
Clinical findings can be summarized as follows (1-6):
1. Flowing, foaming of saliva from the mouth in a newborn baby
2. After feeding, vomiting, choking, coughing, cyanosis attacks are seen
3. Failure to insert the nasogastric tube into the stomach
4. Abdominal distension (in cases with fistula)
5. Aspiration of saliva and gastric juice
6. The diagnosis is made with the development of pneumonia and failure
to advance the nasogastric tube to the stomach.
When 8 or 10 Fr feeding tubes are advanced orally or nasally into the
stomach, a characteristic resistance is felt about 10 cm from the mouth, the tube
is inserted and cannot enter the stomach.
The tube is inserted and cannot enter the
stomach and lateral pouch radiograph
GASTROINTESTINAL ATRESIAS IN NEWBORN 71
The presence of gas in the abdomen indicates TEF. A gasless abdomen
indicates isolated atresia or absence of distal fistula. The appearance of a
double-bauble on a flat film of the abdomen indicates the presence of associated
duodenal atresia. The features of EA without TEF are the non-flatulent abdomen
on the film without swelling in the abdomen clinically (1-6).
EA surgery is performed in a stable newborn as a planned procedure.
Emergency surgery is not required unless patients with severe respiratory distress
due to gastric distension encounter symptoms of gastric perforation (1-6).
A skin incision is made in the 4th intercostal space
just below the corner of the scapula, followed by a right posterolateral muscle-
splitting thoracotomy. An extrapleural approach is preferred. The azygous vein
may or may not be ligated. TEF ligation and separation are performed. The
surgeon should identify the distal esophagus by following the vagus nerve.
Upper esophageal mobilization helps in reducing the space between the ends
for anastomosis. In most cases of EA with distal TEF, a primary anastomosis is
performed, but sometimes there is a significant amount of tension to complete
the repair. Requires long-term atresia-stage operation (1-6).
If primary anastomosis cannot be
achieved, under these circumstances, cervical esophagostomy and gastrostomy
may be performed. Then esophageal replacement surgery should be performed
at a later date (1-6).
The upper sac should be fully mobilized proximally to the
thoracic inlet. Gastric transposition and colon graft interposition are currently
the most popular operations. Spitz initially recommended evaluating the length
of the gap when performing a gastrostomy. If the gap length is >6 vertebral
bodies (6 cm), replacement should be considered and cervical esophagostomy
should be performed (1-6).
Common complications are anastomotic
leakage, stenosis, recurrent TEF, gastroesophageal reflux (GER) and
tracheomalacia. It is manifested by the development of pneumothorax and
salivary drainage from the chest tube following the repair of EA and TEF. The
esophagus usually heals with adequate drainage, broad-spectrum antibiotics,
and total parenteral nutrition, but a prolonged period may be required with a
chest tube. A large anastomotic leak may require reanastomosis or diversion
procedure more often (1-6).
The incidence of symptomatic strictures requiring
therapeutic dilation following EA repair varies between 37-55%. Patients
should be sought for symptoms of postprandial vomiting, prolonged feeding,
72 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
malnutrition, or related respiratory distress. Balloon dilatation is our preferred
method in the treatment of symptomatic strictures. Some surgeons use steroid
injections or mitomycin (1-6).
Many patients with EA have different rates of
tracheomalacia. It causes a characteristically loud “barking” cough. Infants
with severe tracheomalacia show expiratory stridor that can cause episodes
of desaturation, apnea, cyanosis, and bradycardia (usually feeding-related)
(1-6).
There is a history of coughing and choking attacks
during feeding and recurrent pneumonia. Diagnosis can be made by contrast
esophagography and bronchoscopy + esophagoscopy. The contrast esophagogram
is performed in the prone position, with the tube gradually withdrawn as the
contrast is injected into the distal esophagus through the feeding tube. Surgical
treatment is usually performed with ligation and separation of the fistula, with a
neck incision, or rarely with a thoracotomy (1-6).
All isolated esophageal atresia without
TEF is usually long-gap. When primary esophageal anastomosis is not possible
even after intensive mobilization, it is considered long-range OA (1-6).
Apart from hypertrophic pyloric stenosis, gastric outlet diseases are
rarely seen in children. It is seen at a rate of 1/100000. The most common
prepyloric antral web is seen in this group. Other congenital anomalies are
pyloric atresia, duplications, or ectopic pancreatic tissue. Vascularization
accidents are considered in the etiology of pyloric atresia. In pyloric atresia
that does not allow passage, non-bilious vomiting is observed from the first
day. If there is an opening that allows passage, they pass distally to liquid
foods and give symptoms later. Breastfeeders may not show symptoms until
complementary foods are started. Symptoms vary according to the width of
the opening (7,8).
Nasogastric tube should be started with decompression. The
liquid electrolyte should be regulated. In pyloric atresia, the transition should be
relieved by performing pyloroplasty. If there is a mesenteric defect between
the stomach and duodenum in pyloric atresia, gastrojejunostomy should be
performed (7,8).
GASTROINTESTINAL ATRESIAS IN NEWBORN 73
Pyloric atresia direct radiograph
Congenital duodenal occlusions are the most common cause of intestinal
obstruction in the neonatal period and are seen in one in 5000-10000 live births
in various series. Intestinal atresia is the first anomaly that should be considered
in newborns with complaints of vomiting, abdominal distention, and inability
to remove meconium immediately after birth. The location of atresia can be
estimated based on whether the distension is widespread or localized. Duodenal
atresia is manifested by epigastric distension and collapse of other parts of the
abdomen. The cause of duodenal obstruction may be intrinsic or extrinsic, or
both. The obstruction may be complete or partial. Atresia and stenosis are the
ones that come to mind when an intrinsic obstruction is mentioned (9-13).
Prenatal diagnosis of duodenal atresia is possible and
crucial. Prenatal recognition of atresia allows for an early treatment approach
and prevents increased morbidity and mortality. Detection of polyhydramnios
in prenatal ultrasonography (USG) does not specifically indicate an obstruction
in the gastrointestinal tract, but suggests its possibility and requires detailed
examination. With prenatal USG, the diagnosis can be made with the fluid-filled
“Double Bubble” image of the stomach and duodenum part proximal to the
atresia (9-13).
74 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
“Duoble Bubble” image and the absence of air
further distally in the direct abdominal X-ray taken after birth is characteristic
of the diagnosis of duodenal obstruction. Occasionally, some gas may be seen in
the distal intestines. This is usually seen in association with bile duct anomalies.
If there is a Duoble Bubble image on the direct abdominal X-ray, no further
imaging studies are required for the diagnosis of duodenal atresia (9-13).
Double Bubble Appearance
About half of the patients are premature and
have low birth weight. Vomiting with or without bile is observed according to
the level of atresia on the first day after birth. Vomiting is usually bilious, as
approximately 80% of atresia is distal to the ampulla of Vater. Vomiting is non-
bilious in obstructions proximal to the ampulla of Vater. The newborn baby may
expel some meconium, but then the meconium will not come out. Abdominal
distension is not common and is only in the epigastric region. Duodenal occlusions
can be complete or partial. In partial occlusions, the symptoms appear late, so
the diagnosis may be delayed until childhood or even adolescence. Recurrent
vomiting, aspiration problems, and growth retardation are seen in these patients.
In these patients, serious complications such as dehydration and hypokalemic,
hypochloremic metabolic alkalosis may develop due to delayed diagnosis,
leading to increased morbidity and mortality. Therefore, the diagnosis should
be made early and the metabolic status should be corrected before the operation
(9-13).
Duodenal atresia is the first thing that comes
to mind in newborns with complaints such as biliary vomiting, epigastric
distension, and inability to remove meconium. However, compression of Ladd
GASTROINTESTINAL ATRESIAS IN NEWBORN 75
bands due to malrotation, annular pancreas, and, rarely, the preduodenal portal
vein should also be considered in the differential diagnosis. Contrast radiographs
of the upper gastrointestinal tract are helpful for differential diagnosis. Although
some report that malrotation with duodenal atresia is a common anomaly and
that mid-gut volvulus should be considered in the differential diagnosis, some
claim that duodenal atresia prevents mid-gut volvulus (9-13).
It is to prevent the baby from vomiting by inserting a nasogastric tube in
Duodenal Atresia and starting IV fluid replacement. It is important to maintain
body temperature and protect the baby from hypoglycemia. At this time, the baby
is evaluated in terms of fluid and electrolytes. If there is metabolic alkalosis, it is
corrected. If the physical examination and laboratory findings show that the baby
is not stressed and stable, the operation is performed under elective conditions.
The treatment of duodenal atresia is surgery. Various techniques have been
described for the repair, but mostly the chosen method is the “Diamond-Shaped”
duodenoduodenostomy described by Kimura. Duodenoduodenostomy can be
done end-to-end or end-to-side anastomosis. It has been reported that Diamond
Shaped anastomosis provides early drainage, so enteral feeding is started early
in patients and long-term results are good (9-13).
Babies with duodenal atresia need long-term
follow-up. Because megaduodenum, motility disorder, duodenogastric reflux,
gastritis, peptic ulcer, gastroesophageal reflux, choledochal cyst, cholecystitis
attacks, and cholelithiasis are complications that may occur in these patients
in the late period. As a result, duodenal atresia and stenoses are recognized
antenatally and give symptoms in the early postnatal period. Early diagnosis
and appropriate treatment are required. The early postoperative recovery rate
is 95%, and mortality is usually due to cardiac anomalies. Late complications
are more than expected. To avoid late-term complications, meticulous attention
should be paid to the operation and the patients should be followed closely for
a long time (9-13).
Intestinal atresia is one of the most common causes of intestinal obstruction
in newborns. It constitutes approximately one-third of congenital intestinal
obstructions, the incidence is 1/5,000.
Antenatal detection of jejunoileal atresia has been
reported in approximately half of the cases in some series. Multiple dilated
76 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
loops, cystic masses, ascites, or polyhydramnios may be seen. The combination
of dilated bowel and polyhydramnios can give us an idea (14-17).
Atresia or severe stenosis of the small intestine
presents clinically with bilious vomiting beginning in the first or second day of
life. In general, the more proximal the level of obstruction, the sooner vomiting
begins, whereas vomiting may be delayed in distal intestinal obstruction.
Abdominal distention is often found in distal ileal intestinal atresia, distension
is common, while proximal jejunal atresia is limited to the upper abdomen.
When delayed diagnosis or perforation occurs, severe distention and respiratory
distress may occur. Constipation is usually not absolute, and meconium passage
can range from normal color to more common gray mucus plugs. Sometimes if
ischemic bowel is present, as in type IIIb atresia, blood may pass through the
rectal route. Dilated small bowel loops and air-fluid levels are seen on standing
abdominal X-ray. The lower the obstruction, the larger the intestinal loops, and
the more fluid levels are observed (14-17).
Jejunal atresia İleal atresia
After a few hours of preoperative preparation, the newborn
baby tolerates surgery better, especially if it is diagnosed late. In general, patients
should not be overly delayed during this preparation because they run the risk
of intestinal infarction, fluid and electrolyte disturbance, and infection. Special
attention should be paid to hypothermia, hypoxia, hypovolemia, hypoglycemia,
and hypoprothrombinemia. The surgical field can be covered with a sterile,
transparent adhesive drape to keep it dry during surgery and stop heat loss. For
both diagnosis and treatment, it can be inserted through right transverse incisions
made 2-3 cm above the umbilicus during laparoscopy or open surgery (14-17).
GASTROINTESTINAL ATRESIAS IN NEWBORN 77
To test for distal intestinal patency, warm saline is injected into the
intestinal lumen. Malrotation, if any, is corrected. It is measured how long the
small intestine is overall. The next step is anastomosis of the disproportionate
proximal and distal blunt ends once it is known that the distal small intestine
and colon are fully open. The end-to-end anastomosis can be done with 5-0 or
6-0 polydioxanone sutures if the ends are proportionate. If the intestines are too
small and insufficient, plication or tapering can be used instead of removing the
dilated proximal segment. Primary serial transverse enteroplasty (STEP) can be
used if it is too short (14-17).
Nasogastric decompression is usually required until
proximal intestinal peristalsis has resolved. Proximal jejunal atresia may require
prolonged decompression. If there is no abdominal distension with bile from the
nasogastric tract and feeding is delayed until the baby makes meconium (14-17).
Colon atresia is one of the rare atresia in newborns. 10% of total atresia
are colonic atresia. In its etiopathogenesis, there are causes such as vascular
accidents and embolism showers. There are 3 types of colon atresia. The
proximal dilated distal of atresia is thin and filled with mucus. These patients
may have concomitant small bowel atresia, anorectal malformations, cardiac
and other additional anomalies. In these, clinical symptoms, as in other atresia,
have symptoms such as biliary vomiting, abdominal distension, and inability to
remove meconium.
These patients have images such as air-fluid levels and dilated colon on
standing direct abdominal radiographs. If there is perforation, subdiaphragmatic
free air is seen.
In colon atresia, if the patient is stable, the problem should be corrected
surgically in the early period (18-21).
Esophageal atresia should be suspected in case of foaming
at the mouth and feeding on the first day. Pyloric atresia should be suspected
in case of non-bilious vomiting and collapsed abdomen. Duodenal atresia is
diagnosed in the early period and gives symptoms in the early period. Distal
intestinal atresia should be investigated in case of abdominal distension and
bilious vomiting in newborns.
78 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
1. İlhan H. Özofagus atrezisi ve trakeoözofageal fistül. Yazıcı M, editör.
Yenidoğanın Cerrahi Hastalıkları. 1. Baskı. Ankara: Türkiye Klinikleri; 2019.
p.15-8
2. Ali Erdal Karakaya, Ahmet Gokhan Guler, Ahmet Burak Dogan, Serkan
Arslan. Our Experience with Esophageal Atresia and Tracheoesophageal Fistula.
Osmangazi Journal of Medicine 2021. Osmangazi Journal of Medicine 2021;
43(4):358- 363
3. Baldwin D, Yadav D. Esophageal Atresia. 2022 May 8. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID:
32809683.
4. McGowan NA, Grosel J. An overview of esophageal atresia and
tracheoesophageal fistula. JAAPA. 2022 Jun 1;35(6):34-37.
5. Salik I, Paul M. Tracheoesophageal Fistula. 2022 May 8. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID:
30570997.
6. Keefe G, Culbreath K, Edwards EM, Morrow KA, Soll RF, Modi
BP, Horbar JD, Jaksic T. Current outcomes of infants with esophageal atresia
and tracheoesophageal fistula: A multicenter analysis. J Pediatr Surg. 2022
;57(6):970-974
7. Gharpure V. Pyloric atresia. J Neonatal Surg. 2013 Jan 1;2(1):16. PMID:
26023436; PMCID: PMC4420354.
8. Prasad GR, Rao JVS, Fatima F, Anjum F. Congenital Pyloric Atresia:
Experience with a Series of 11 Cases and Collective Review. J Indian Assoc
Pediatr Surg. 2021;26(6):416-420.
9. Erdem AO, Yazıcı M. Duodenal atreziler. Yazıcı M, editör. Yenidoğanın
Cerrahi Hastalıkları. 1. Baskı. Ankara: Türkiye Klinikleri; 2019. p.78-82
10. Escobar MA, Ladd AP, Grosfeld JL, West KW, Rescorla FJ, Scherer
LR 3rd, Engum SA, Rouse TM, Billmire DF. Duodenal atresia and stenosis:
long-term follow-up over 30 years. J Pediatr Surg. 2004
11. Zhang J, Xu X, Wang X, Zhao L, Lv Y, Chen K. Laparoscopic versus
open repair of congenital duodenal obstruction: a systematic review and meta-
analysis. Pediatr Surg Int. 2022 Nov;38(11):1507-1515.
12. Mentessidou A, Saxena AK. Laparoscopic Repair of Duodenal Atresia:
Systematic Review and Meta-Analysis. World J Surg. 2017;41(8):2178-2184.
GASTROINTESTINAL ATRESIAS IN NEWBORN 79
13. Morris G, Kennedy A Jr, Cochran W. Small Bowel Congenital
Anomalies: a Review and Update. Curr Gastroenterol Rep. 2016;18(4):16.
14. Okur MH, Otçu S. Jejuno-ileal atreziler. Yazıcı M, editör. Yenidoğanın
Cerrahi Hastalıkları. 1. Baskı. Ankara: Türkiye Klinikleri; 2019. p.83-7
15. Choi G, Je BK, Kim YJ. Gastrointestinal Emergency in Neonates and
Infants: A Pictorial Essay. Korean J Radiol. 2022;23(1):124-138.
16. Prasad TR, Bajpai M. Intestinal atresia. Indian J Pediatr.
2000;67(9):671-8.
17. Morris G, Kennedy A Jr, Cochran W. Small Bowel Congenital
Anomalies: a Review and Update. Curr Gastroenterol Rep. 2016
18. Basaklar AC, Türkyılmaz Z. Jejunoileal ve kolonik atreziler. In:
Başaklar AC, editor. Bebek ve çocukların cerrahi ve ürolojik hastalıkları.
Ankara: Palme Yayincilik; 2006. p. 465-487
19. Klyuev SA, Asharur RM, Goremykin IV, Masevkin VG, Shintaev TK,
Azizoğlu M. Two Types of Gastric Volvulus In Children: Case Reports And
Review of The Literature. J Clin Tri Exp Invest. 2022;1(1):10-6.
20. Özalp HG. Trisomy 18 With Multiple Congenital Anomalies: A Rare
Case Report. J Clin Tri Exp Invest. 2022;1(1):28-31.
21. Klyuev SA, Goremykin IV, Masevkin VG, Gorodkov SY, Nikolaev AV,
Shintaev TK, Azizoğlu M. Acute Gastric Dilation With Necrosis: Case Report
And Literature Review: Gastric Necrosis. J Clin Tri Exp Invest. 2022;1(2):32-
40.
81
12
1(Research Assistant), Yüksek İhtisas University, Faculty of Health Sciences,
Department of Nutrition and Dietetics, e-mail: betululu@yiu.edu.tr
ORCID: 0000-0003-2357-5205
2(Prof. Dr.), Ankara University, Faculty of Health Sciences, Department of
Nutrition and Dietetics, e-mail: nyabanci@gmail.com
ORCID: 0000-0003-1233-246
Iodine is a trace element first discovered in 1811. (1) It is an essential nutrient
required in small amounts in the human diet. The amount of iodine in foods
depends on the iodine levels of the environment from which the food is
derived. (2) The amount of iodine in the soil generally decreases due to rain
and glaciation. This causes iodine to be low in the diet and then results in iodine
deficiency in the population. (3) Iodine deficiency is one of the most common
micronutrient deficiencies, but it is easy to prevent. (2)
Iodine deficiency causes problems such as goitre, hypothyroidism,
spontaneous abortion, stillbirth, congenital anomalies, increased perinatal infant
mortality, cretinism, mental dysfunction and delay in physical development. (3).
Iodine status can be monitored by determining the urine iodine
concentration (UIC). UIC is a measure of the amount of iodine excreted in the
urine and is an indirect indicator of dietary iodine intake. The median UIC is
used to diagnose the iodine status of a population. (4) An iodine concentration of
<20 mg/L in the urine indicates severe iodine deficiency, 20-49 mg/L moderate
iodine deficiency, and 50-99 mg/L mild iodine deficiency. While an average
value of UIC between 100-299 mg/L indicates adequate iodine status; a value
over 300 mg/L is classified as excessive iodine intake (Table 1). (2)
82 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Evaluation of Iodine Intake by Mean Iodine Level in Children
Urine Iodine
Level (mcg/L)
The Corresponding
Approximate Iodine
Intake (mcg / day)
Iodine Intake
Status Clinical Effect
< 20 <30 Insufficient Severe Iodine Deficiency
20-49 30-74 Insufficient Moderate Iodine
Deficiency
50-99 75-149 Insufficient Mild Iodine Deficiency
100-199 150-299 Sufficient Optimal Iodine Intake
200-299 300-449 Over Intake
Hyperthyroidism may
develop for 5-10 years
in those with underlying
thyroid disease.
>299 >449 Excessive
Serious side effects
(autoimmune thyroid
disease, hypothyroidism)
According to the World Health Organization (WHO), 2.2 billion people
worldwide are at risk of iodine deficiency, and iodine deficiency is the single
most important preventable cause of brain damage worldwide. (2) Iodine
is converted by the thyroid gland into thyroid hormones: thyroxine (T4) and
triiodothyronine (T3). They are essential for metabolism in almost all body
tissues. (5) But they are especially important for brain development. (6) The
mechanisms by which thyroid hormones affect brain development are not fully
understood. (7) However, research continues that less severe iodine deficiency
(i.e., mild to moderate) may affect cognitive function. (3)
It is known that iodine deficiency can seriously impair brain structure and
function. (8) The low serum iodine level of the mother during pregnancy causes
many negative situations in the mother and baby. For the foetus; there are risks
such as low birth weight, cretinism, microcephaly, stillbirth. For the mother;
there are risks such as insufficient fertilization, preeclampsia, maternal anaemia.
(8) Severe iodine deficiency during pregnancy can cause goitre as well as
IODINE AND COGNITIVE DEVELOPMENT 83
spontaneous abortion, increased infant mortality, and congenital abnormalities,
an irreversible state of mental retardation that presents with dwarfism, deaf-
mutism, and spasticity. (9)
Hormonal changes and metabolic demands during pregnancy cause
significant changes in thyroid function. During pregnancy, iodine requirement
increases due to increased production of thyroid hormones, increased renal
clearance of iodine, and foetal placental acquisition of maternal iodine and
thyroid hormones. (10)
In the first half of pregnancy, T4 and T3 concentrations increase significantly
to maintain maternal euthyroidism. At the beginning of the second trimester,
T4 and T3 concentrations are 30-100% higher than before pregnancy. (11) The
reasons for this increase are; increase in thyroxine-binding globulin (TBG)
concentration, thyrotrophic effect of human chorionic gonadotropin (hCG) and
increased activity of enzyme type 3 iodothyronine deiodinase (D3). (12)
In addition to increased thyroid hormone production, iodine losses during
pregnancy are higher due to the increase in renal iodine clearance resulting
from increased glomerular filtration rate due to hyperestrogenism. (13) Renal
clearance of iodine begins to increase in the first week of pregnancy and
continues until delivery. (14)
The increased iodine requirement during pregnancy can also be explained
by the placental transfer of hormones from the mother to the foetus. (15)
Thyroid development of the foetus begins at 10-12 weeks of gestation and T4 is
secreted by the foetal thyroid gland from 18-20 weeks. (16) During this period,
iodine transfer takes place from the mother to the foetal thyroid gland through
the placenta. Iodine transfer allows the foetal thyroid gland to produce its own
thyroid hormones. (12)
The foetal thyroid grows between 12 and 39 weeks. The most significant
increase in maternal thyroid size occurs during the second trimester, when the
foetal thyroid becomes functionally active. (17) At 10 weeks of gestation, nuclear
T3 receptors can be identified in the foetal brain. T3 hormone is mainly used by
the foetus. A maternal T4 level within the normal range is required to prevent T3
deficiency in the foetus. It has shown better neurological outcomes in the early
treatment of new-borns with congenital hypothyroidism born to mothers with
adequate T4 concentrations. (18) In contrast, normal T3 values associated with
insufficient T4 did not show a protective effect against foetal brain disorder. (18)
Thus, an adequate supply of maternal T4 is required to convert T4 to active T3
for the foetus. (19)
84 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Maternal T4 transfer to the foetus is particularly important in early
pregnancy because before 12-14 weeks of gestation the foetus cannot produce
its own T3 and T4 and these hormones are necessary for normal foetal brain
development. (20, 21) It is involved in various important processes of brain
development through genomic and non-genomic actions in T3 and T4 glial
cells and neurons. (21) Thyroid hormones play a role in neural migration,
neural differentiation, myelination, synaptogenesis and neurotransmission. It is
mainly involved in the development of neural processes in the cerebral cortex,
cochlea and basal ganglia. Deficiency of thyroid hormones in the foetus can
cause a decrease in the number and distribution of dendritic synapse in the
auditory cortex. A similar effect was found in pyramidal cells of the visual
cortex. (12)
Even in iodine-sufficient regions, iodine deficiency can be seen if the thyroid
gland cannot meet the increased demand for thyroid hormone during pregnancy.
(22) Even mild to moderate iodine deficiency during pregnancy can lead to
maternal hypothyroxinaemia. Mild and subclinical cognitive and psychomotor
impairments have been observed in neonates, infants and children in Europe,
both in mildly iodine-deficient areas and when maternal T4 concentrations
are low during pregnancy. (23) Currently, in some European countries, iodine
intake during pregnancy is considered insufficient and iodine supplementation is
recommended for pregnant women. (24) The period of iodine supplementation
is also very important. In a study examining 18-month-old babies, the cognitive
measurement score of the children of mothers who took iodine supplementation
in the first trimester was found to be higher than the children of mothers who
took supplements in the second and third trimesters. (25) A follow-up study of
122 mothers and children who received placebo, or 150 µg/day, or 300 µg/day
of iodine from birth to 12 months examined the neurocognitive development of
children. Cognitive scores were found to be higher in children whose mothers
took 150 µg iodine/day compared to children whose mothers took placebo; no
difference was found in language or motor development scores. There was also
no evidence of improved or delayed neurodevelopmental outcomes in children
whose mothers received 300 µg iodine/day. (26) According to the results of a
meta-analysis study; the development of the verbal IQ of the foetus is affected
by insufficient iodine concentration during early pregnancy until the onset of the
second trimester. (27)
Iodine concentrations should be monitored periodically in pregnant
women. (28) In a study conducted in Turkey, it was found that iodine deficiency
IODINE AND COGNITIVE DEVELOPMENT 85
becomes more pronounced in pregnant women as the trimester progresses. (29)
In a longitudinal study conducted in England, the iodine level of the mother was
examined in the first trimester of pregnancy and the cognitive performance of
the children of 646 mothers with iodine deficiency and 312 mothers with normal
iodine levels were evaluated. Verbal intelligence, reading ability and reading
comprehension levels of children born to mothers with mild and moderate
iodine deficiency were lower than those born to mothers with normal iodine
levels. (30) In a similar study, the grammar, writing, reading and literacy scores
of children born to mothers with mild and moderate iodine deficiency were
lower than those born to mothers with normal iodine levels. (31) In a study
conducted in Finland, using WHO criteria, it was shown that 60-70% of mothers
had iodine deficiency during and after pregnancy. In the same study, 29% of the
infants of these mothers were found to have iodine deficiency (UIC < 100 ug/L)
at 3 months of age. (32)
Cretinism results from severe, chronic iodine deficiency in the foetus and
affects the foetus. Mental impairment is a condition characterized by severe
stunting, delayed sexual maturation, motor spasticity, deaf-mutism, and other
physical and neurological abnormalities. If iodine deficiency persists throughout
the new-born, infant, and adult periods after the third trimester, the initial
irreversible brain damage may further increase and turn into endemic cretinism.
There are different types of cretinism. Sporadic and genetic cretinism are caused
by abnormal development or function of the foetal thyroid gland. Because
new-born screening tests are routinely performed and lifelong treatment with
T4 is required, this type of cretinism has almost been eliminated in developed
countries. Endemic cretinism is the most severe manifestation of iodine
deficiency. It occurs when iodine intake is below the critical level of 25 μg
per day. It usually affects populations living under conditions of severe iodine
deficiency. (33)
In a study conducted in Japan, the neurodevelopment of infants from birth
to one and three years of maternal iodine consumption during pregnancy was
examined. 56.7% of pregnant women were found to have insufficient iodine
intake. Low dietary iodine intake during pregnancy increased the risk of delayed
child neurodevelopment at one and three years of age. In addition, the increased
risk of neurodevelopmental delay in low iodine intake groups was found to be
more pronounced at 3 years of age than at 1 year of age. (34)
86 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
The global iodine nutrition scorecard was updated in 2021 by the Iodine
Global Network. Considering the most recent median UIC data from 194 WHO
member states, including Liechtenstein and Palestine, there is still an insufficient
intake of iodine in school-aged children and women of reproductive age. (35)
New evidence supports a lifetime perspective on childhood development with
negative early experiences having long-term physiological and epigenetic effects
on brain development and cognition. In this context, iodine greatly contributes
to the postnatal development and plasticity of neural tissues. (36).
A randomized, double-blind, placebo-controlled study in infants with
direct and indirect iodine supplementation (providing iodine supplementation
to nursing mothers); the effectiveness of iodine supplementation was compared
and it was concluded that indirect iodine supplementation was more effective.
(37) In areas with moderate to severe iodine deficiency without effective iodized
salt programs, therefore, iodine supplementation should be considered for
nursing mothers. (36)
Iodine deficiency in the new-born and childhood can cause irreversible
cognitive damage. (33) The thyroid gland of a new-born baby contains 0.1 mg
of iodine. For this reason, the baby should take iodine supplement after birth.
Mothers whose iodine deficiency continues after birth cannot provide enough
iodine to their babies with breast milk. As a result, neonatal hypothyrotrophinemia
also increases. (38)
The mental retardation caused by the effects of iodine deficiency on
the central nervous system during foetal development is irreversible once it
is established. In contrast, additional impairment resulting from persistence
of postpartum hypothyroidism and/or iodine deficiency may improve with
appropriate thyroid hormone replacement and/or iodine supplementation.
(39) In a trial of iodine supplementation and placebo in 310 children, iodine
supplementation significantly improved thyroid function and performance on
cognitive tests by reducing the prevalence of hypothyroxinaemia. (40)
In childhood and adolescence, iodine deficiency causes school failure
together with mental function deficiency. (41) A meta-analysis study of children
with insufficient iodine intake showed that intelligence scores were lower, from
6.9 to 10.2 points. (42) In a study conducted in Turkey in 2005 and investigating
urinary iodine excretion in 299 children aged 6-15 years, it was found that
17.87% of children had moderate or mild iodine deficiency in terms of iodine
intake. (43)
IODINE AND COGNITIVE DEVELOPMENT 87
The cheapest and most useful method for the prevention of iodine deficiency
is the iodization of salt. Significant progress has been made through national salt
iodization programmes. (44) For the prevention of iodine deficiency diseases
in Turkey, the “Prevention of Iodine Deficiency Diseases and Salt Iodization
Program” has been carried out in cooperation with the Ministry of Health of
the Republic of Turkey - UNICEF since 1994. (45) With the salt communiqué
prepared in 1998, it was ensured that all table salts were enriched with iodine.
According to this communiqué, table salt defines finely ground, iodine-enriched,
refined or unrefined processed salt that is offered directly to the end consumer.
It is mandatory to add potassium iodate at the rate of 25-40 mg/kg to salt. (45)
Ensuring adequate iodine intake is necessary to prevent problems caused
by iodine deficiency. Adequate iodine intake recommendations according to
WHO and IOM are shown in Table 2. (2, 46)
Iodine Requirements by Age and Population Groups
WHO
Recommendations
IOM
Recommendations
Up to 5 years old 90 mcg 1-8 years 90 mcg
6-12 years 120 mcg 9-13 years 120 mcg
12 years and
older 150 mcg Young adults and
non-pregnant adults 150 mcg
Pregnancy 250 mcg Pregnancy 220 mcg
Lactation 250 mcg Lactation 290 mcg
While the prevalence of severe and moderate iodine deficiency in Turkey
was 58% in 1997, it was found to be 28.2% in 2008. In this study including 30
provinces, iodine level is sufficient in 20 provinces. The frequency of household
use of iodized salt was found to be 89.9% in urban areas and 71.5% in rural
areas. Although iodine deficiency has decreased in the world and in Turkey, it is
still an important public health problem. (47)
Iodine is an important micronutrient for the development and maintenance
of brain structure and function through thyroid hormone. Iodine deficiency is
a global public health problem, and tackling it should be focused on diagnosis
and intervention at the community level rather than the individual. Ensuring
adequate iodine intake in the population will eliminate the need for specific
88 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
supplementation during pregnancy and lactation. (7) However, there is no
scientific evidence to support generalized iodine supplementation in mild to
moderate deficiency in pregnant and lactating women, preterm/term infants
and young children. (48) In addition, there are no randomized maternal iodine
supplementation studies with long-term follow-up data on the psychomotor and
mental development of infants in our country. In this way, it will be beneficial to
plan and conduct epidemiological studies.
1. Zimmermann MB. Research on iodine deficiency and goiter in the 19th
and early 20th centuries. The Journal of nutrition. 2008;138(11):2060-2063.
2. WHO, UNICEF. International Council for the Control of Iodine
Deficiency Disorders. Assessment of iodine deciency disorders and monitoring
their elimination: a guide for programme managers, 3rd edn Geneva: World
Health Organization. 2007;
3. Zimmermann MB. Iodine deficiency. Endocrine reviews. 2009;30(4):376-
408.
4. König F, Andersson M, Hotz K, Aeberli I, Zimmermann MB. Ten repeat
collections for urinary iodine from spot samples or 24-hour samples are needed
to reliably estimate individual iodine status in women. The Journal of nutrition.
2011;141(11):2049-2054.
5. Ahmed OM, El-Gareib A, El-Bakry A, El-Tawab SA, Ahmed R. Thyroid
hormones states and brain development interactions. International Journal of
Developmental Neuroscience. 2008;26(2):147-209.
6. Delange F. Iodine deficiency as a cause of brain damage. The Fellowship
of Postgraduate Medicine; 2001.
7. Redman K, Ruffman T, Fitzgerald P, Skeaff S. Iodine deficiency and the
brain: Effects and mechanisms. Critical reviews in food science and nutrition.
2016;56(16):2695-2713.
8. Hetzel B. Iodine deficiency disorders (IDD) and their eradication. The
Lancet. 1983;322(8359):1126-1129.
9. Zimmermann MB. Iodine deficiency in pregnancy and the effects of
maternal iodine supplementation on the offspring: a review. The American
journal of clinical nutrition. 2009;89(2):668S-672S.
10. Glinoer D. The regulation of thyroid function during normal pregnancy:
importance of the iodine nutrition status. Best practice & research Clinical
endocrinology & metabolism. 2004;18(2):133-152.
IODINE AND COGNITIVE DEVELOPMENT 89
11. Glinoer D. The regulation of thyroid function in pregnancy: pathways
of endocrine adaptation from physiology to pathology. Endocrine reviews.
1997;18(3):404-433.
12. Trumpff C, De Schepper J, Tafforeau J, Van Oyen H, Vanderfaeillie
J, Vandevijvere S. Mild iodine deficiency in pregnancy in Europe and its
consequences for cognitive and psychomotor development of children: a review.
Journal of trace elements in medicine and biology. 2013;27(3):174-183.
13. Liberman CS, Pino SC, Fang SL, Braverman LE, Emerson CH.
Circulating iodide concentrations during and after pregnancy. The Journal of
Clinical Endocrinology & Metabolism. 1998;83(10):3545-3549.
14. Dafnis E, Sabatini S. The effect of pregnancy on renal function:
physiology and pathophysiology. The American journal of the medical sciences.
1992;303(3):184-205.
15. Glinoer D. Iodine nutrition requirements during pregnancy. Thyroid.
2006;16(10):947-948.
16. Perez-Lopez FR. Iodine and thyroid hormones during pregnancy and
postpartum. Gynecological endocrinology. 2007;23(7):414-428.
17. Radaelli T, Cetin I, Zamperini P, Ferrazzi E, Pardi G. Intrauterine
growth of normal thyroid. Gynecological endocrinology. 2002;16(6):427-430.
18. Morreale de Escobar G, Jesus Obregón Ma, Escobar del Rey F.
Is neuropsychological development related to maternal hypothyroidism or
to maternal hypothyroxinemia? The Journal of Clinical Endocrinology &
Metabolism. 2000;85(11):3975-3987.
19. Calvo RM, Jauniaux E, Gulbis B, et al. Fetal tissues are exposed
to biologically relevant free thyroxine concentrations during early phases
of development. The Journal of Clinical Endocrinology & Metabolism.
2002;87(4):1768-1777.
20. Glinoer D, Delange F. The potential repercussions of maternal, fetal,
and neonatal hypothyroxinemia on the progeny. Thyroid. 2000;10(10):871-887.
21. Bernal J, Nunez J. Thyroid hormones and brain development. European
journal of endocrinology. 1995;133(4):390-398.
22. Oguz Kutlu A, Kara C. Iodine deficiency in pregnant women in the
apparently iodine‟ sufficient capital city of T urkey. Clinical Endocrinology.
2012;77(4):615-620.
23. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ. Neonatal
effects of maternal hypothyroxinemia during early pregnancy. Pediatrics.
2006;117(1):161-167.
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24. De Benoist B, McLean E, Andersson M, Rogers L. Iodine deficiency in
2007: global progress since 2003. Food and nutrition bulletin. 2008;29(3):195-
202.
25. Berbel P, Mestre JL, Santamaria A, et al. Delayed neurobehavioral
development in children born to pregnant women with mild hypothyroxinemia
during the first month of gestation: the importance of early iodine supplementation.
Thyroid. 2009;19(5):511-519.
26. Nazeri P, Tahmasebinejad Z, Pearce EN, et al. Does maternal iodine
supplementation during the lactation have a positive impact on neurodevelopment
of children? Three-year follow up of a randomized controlled trial. European
Journal of Nutrition. 2021;60(7):4083-4091.
27. Levie D, Korevaar TI, Bath SC, et al. Association of maternal iodine
status with child IQ: a meta-analysis of individual participant data. The Journal
of Clinical Endocrinology & Metabolism. 2019;104(12):5957-5967.
28. WHO, UNICEF, ICCIDD. Assessment of iodine deficiency disorders
and monitoring their elimination.
https://apps.who.int/iris/bitstream/handle/10665/43781/9789241595827_
eng.pdf;jsessionid=864A74456385CDACB3B8CBAC401714C5?sequence=1
Accessed 05.06.2020.
29. Mocan M, Erem C, Telatar M, Mocan H. Urinary iodine levels in
pregnant women with and without goiter in the Eastern Black Sea part of Turkey.
Trace elements and electrolytes. 1995;12(4):195-197.
30. Bath SC, Steer CD, Golding J, Emmett P, Rayman MP. Effect of
inadequate iodine status in UK pregnant women on cognitive outcomes in their
children: results from the Avon Longitudinal Study of Parents and Children
(ALSPAC). The Lancet. 2013;382(9889):331-337.
31. Hynes KL, Otahal P, Hay I, Burgess JR. Mild iodine deficiency during
pregnancy is associated with reduced educational outcomes in the offspring:
9-year follow-up of the gestational iodine cohort. The Journal of Clinical
Endocrinology & Metabolism. 2013;98(5):1954-1962.
32. Miles EA, Vahlberg T, Calder PC, et al. Iodine status in pregnant
women and infants in Finland. European Journal of Nutrition. 2022:1-9.
33. Hong L. The Role of Iodine in Cognitive Development in Children:
Should Iodine Supplementation for Children Be Mandated in the United States?
Topics in Clinical Nutrition. 2013;28(4):364-372.
34. Hisada A, Takatani R, Yamamoto M, et al. Maternal Iodine Intake and
Neurodevelopment of Offspring: The Japan Environment and Children’s Study.
Nutrients. 2022;14(9):1826.
IODINE AND COGNITIVE DEVELOPMENT 91
35. Network TIG. Global scorecard of iodine nutrition in 2020 in the general
population based on school-age children (SAC). 26.10.2022, 2022. Updated
07.05.2021. https://www.ign.org/cm_data/IGN_Global_Scorecard_2021_7_
May_2021.pdf. Accessed 26.10.2022.
36. Velasco I, Bath SC, Rayman MP. Iodine as Essential Nutrient during
the First 1000 Days of Life. Nutrients. 2018;10(3):290.
37. Bouhouch RR, Bouhouch S, Cherkaoui M, et al. Direct iodine
supplementation of infants versus supplementation of their breastfeeding
mothers: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes
Endocrinol. Mar 2014;2(3):197-209. doi:10.1016/s2213-8587(13)70155-4
38. Kurtoğlu S. İyot eksikliği sorununun değerlendirilmesi ve çözüm
yolları. Türk Pediatri Arşivi. 1997;32(3)
39. Van den Briel T, West CE, Bleichrodt N, van de Vijver FJ, Ategbo
EA, Hautvast JG. Improved iodine status is associated with improved mental
performance of schoolchildren in Benin. The American journal of clinical
nutrition. 2000;72(5):1179-1185.
40. Zimmermann MB, Connolly K, Bozo M, Bridson J, Rohner F, Grimci
L. Iodine supplementation improves cognition in iodine-deficient schoolchildren
in Albania: a randomized, controlled, double-blind study. The American journal
of clinical nutrition. 2006;83(1):108-114.
41. Ulu H. Gebe kadınlarda ve yenidoğan bebeklerinde idrarda iyot
düzeyleri ve tiroid fonksiyon testleri sonuçlarının değerlendirilmesi. Selçuk
Üniversitesi; 2012.
42. Bougma K, Aboud FE, Harding KB, Marquis GS. Iodine and mental
development of children 5 years old and under: a systematic review and meta-
analysis. Nutrients. 2013;5(4):1384-1416.
43. Barutçugil MB. Bakırköy bölgesi bir ilköğretim okulu öğrencilerinde
idrar iyot atılımı ve guatr prevalansı. T.C. Sağlık Bakanlığı Bakırköy Dr. Sadi
Konuk Eğitim ve Araştırma Hastanesi; 2005.
44. Pearce EN, Andersson M, Zimmermann MB. Global iodine nutrition:
Where do we stand in 2013? Thyroid. May 2013;23(5):523-8. doi:10.1089/
thy.2013.0128
45. SağlıkBakanlığı TC. Zeki Nesiller İçin İyotlu Tuz Kullanın. Updated
28.03.2016, https://www.saglik.gov.tr/TR,2693/zeki-nesiller-icin-iyotlu-tuz-
kullanin.html. Accessed 30.10.2022.
46. Trumbo P, Yates AA, Schlicker S, Poos M. Dietary reference intakes:
vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese,
92 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
molybdenum, nickel, silicon, vanadium, and zinc. Journal of the Academy of
Nutrition and Dietetics. 2001;101(3):294.
47. Dilek E, Dünyada TFİYH. Türkiye’de Güncel Durum. Türkiye
Klinikleri J Pediatr Sci. 2016;12(2):7-13.
48. Ley D, Turck D. Iodine supplementation: is there a need? Current
Opinion in Clinical Nutrition & Metabolic Care. 2021;24(3):265-270.
93
(Dr., DDS), İstanbul University Faculty of Dentistry,
Department of Oral Implantology
nazliaysesek@gmail.com
ORCID: 0000-0002-0752-5200
Diabetes mellitus is a disease that the body cannot balance the blood
glucose level. Glucose provides the energy which needed for daily
activities to human body. The glucose which is converted from the
nutrients by the liver enters the bloodstream and in healthy people, blood
glucose level is regulated by hormones, such as insulin. Insulin is produced by
the pancreas which also secretes some enzymes that play a role in the digestion.
Insulin allows glucose to get through the cells and used for energy. There are
two scenarios for the diabetes. The people with type 1 diabetes cannot produce
enough insulin. On the other hand, pancreatic b-cell dysfunction and varying
degrees of insulin resistance occurs in type 2 diabetes. Glucose cannot pass into
cells effectively and blood glucose level remains high as a result of diabetes.
This situation causes energy loss of the cells and damages some organs and
tissues (1-5).
Type 1 diabetes is an autoimmune disease which pancreas B cells cannot
produce enough insulin. Blockage of the glucose entrance causes to the increasing
the blood glucose level. This may lead to life-threatening hypoglycemic and
hyperglycemic results. Confusion, distraction, and coma may occur in the
hypoglycemic conditions. Hyperglycemia and prolonged absence of insulin lead
to ketoacidosis. In the absence of glucose, energy production is provided from
fats. Ketones make the blood acidic and lead to a decline in body functions. The
increase in ketones also causes ketoacidosis. Failure to improve this condition
causes coma and ultimately death (6-11).
94 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Type 2 diabetes is a complex endocrine and metabolic disorder which is
affected by the combination of genetic factors and environmental effects. Insulin
resistance and glucose intolerance occurs as a result of dysfunction of pancreatic B
cells and usually causes overweight and obesity (12-18). Overweight and obesity
cause an imbalance in certain hormone concentrations (such as increased leptin,
decreased adiponectin, and increased glucagon), leading to insulin resistance.
Concentrations of cytokines such as TNF-a and IL-6 increase. When insulin
secretion becomes insufficient to meet insulin resistance, glucose intolerance
progresses to type 2 diabetes. Chronic hyperglycemia, chronic non-ester fatty
acid accumulation, oxidative stress, inflammation and amyloid formation occurs
with decreased pancreatic B cell functions (19-21).
Diabetic ketoacidosis and hyperosmolar hyperglycemic state are the main
acute complications. While diabetic ketoacidosis usually observed in type 1
diabetes, non-ketosis hyperosmolar state (hyperosmolar hyperglycemic state)
observed in type 2 diabetes. Both disorders occur insulin absence. Glucagon,
catecholamines, cortisol, and growth hormone levels increase in diabetic
ketoacidosis and insulin deficiency. When glucagon levels compared to the
decreased insulin levels lead to gluconeogenesis, glycogenolysis and ketone
body conversion in the liver. Nausea and vomiting are common in diabetic
ketoacidosis. Central nervous system depression and lethargy can be seen in the
progression of the condition. The non-ketosis hyperosmolar state is mostly seen
in adults with type 2 diabetes. Common symptoms such as polyuria, orthostatic
hypotension, and various neurological symptoms may cause decreased mental
status, lethargy, decreased level of consciousness, paralysis, and coma (10,12)
Chronic complications are mainly divided into vascular and non-vascular.
Vascular complications are also divided into two groups which are microvascular
(retinopathy, neuropathy and nephropathy) and macrovascular (coronary
artery disease, peripheral vascular disorders and cerebrovascular diseases)
complications. Non-vascular complications include gastroporesis, sexual
dysfunction, and skin changes. Blindness, neuropathies that reduce mobility,
DIABETES AND COMPLICATIONS 95
cerebral and vascular problems occur as a result of chronic complications.
Treating these complications is much more difficult than controlling the disease.
Intracellular hyperglycemia causes failure in blood flow and increases vascular
permeability in the early stages of diabetes. The activity of vasodilators such
as nitric oxide decreases as a conclusion. The effect of vasoconstrictors such as
Angiotensin II and Endothelin-1 increases (22, 23).
2.1.Diabetic Retinopathy: Diabetic retinopathy occurs 75% of patients
with diabetes for more than 15 years and causes blindness. Diabetic retinopathy
is divided into two phases: non-proliferative and proliferative. The non-
proliferative phase occurs in the first decade of the disease or early in the second
decade. In the proliferative phase, neovascularization occurs in response to
retinal hypoxia. New vascular structures can rupture easily, causing bleeding,
fibrosis, and retinal detachments (23).
2.2.Neuropathy: Various degrees of neuropathy are seen in approximately
half of diabetic patients. These can be in the form of polyneuropathy,
mononeuropathy or autonomic neuropathy. In polyneuropathy; thickening
of axons and reduction of microfilaments. Constriction occurs in capillary
tubes containing small myelinated or unmyelinated C fibers. While these can
be caused by direct damage to the nerve parenchyma due to hyperglycemia,
they also occur due to neural ischemia caused by endothelial cell activation,
basal cell thickening, and microvascular anomalies due to monocyte adhesion.
Mononeuropathy is less common than polyneuropathy and includes dysfunction
of isolated cranial or peripheral nerves. Autonomic neuropathy can affect multiple
systems such as cardiovascular, gastrointestinal, genitourinary, sudomotor and
metabolic systems (24).
2.3.Nephropathy: Glomerular hemodynamic abnormalities are seen as a
result of glomerular hyperfiltration. Certain proteinuria, decreased glomerular
filtration rate and causes renal disease. As a result of microalbuminuria,
dysfunction occurs in the glomerular filtration apparatus. Another possible
mechanism explaining the increase in glomerulus permeability is the elevation
of renal VEGF level which is both an angiogenic and permeability factor (25).
2.4. Cardiovascular Morbidity and Mortality: There is an increase in
various cardiovascular diseases in diabetes patients. These are peripheral
vascular disease, congestive heart disease, coronary artery disease and
myocardial infarction. Absence of chest pain is remarkable and is common in
diabetic patients. Cardiac evaluation is indicated in patients undergoing major
surgical procedures.
96 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Despite evidence showing that microvascular complications are
reduced with improved glycemic control, macrovascular complications may
remain unchanged or even worsen. In addition to coronary artery disease,
cerebrovascular diseases can be seen at a high rate in diabetes patients. There is
an increased incidence of congestive heart failure in patients with DM (diabetic
cardiomyopathy). The etiology of this abnormality is likely multifactorial and
includes factors such as myocardial ischemia from atherosclerosis, hypertension,
and myocardial cell dysfunction secondary to chronic hyperglycemia (26).
2.5.Hypertension: Hypertension accelerates the complications of Diabetes
Mellitus, especially cardiovascular disease and nephropathy. Antihypertensive
drugs; It should be applied by determining the advantages and disadvantages by
considering the risk factor profile of the patient.
Conditions to consider associated with Diabetes Mellitus:
1) α -adrenal blockers significantly increase insulin resistance and
positively affect the lipid profile. α-blockers and thiazide diuretics increase
insulin resistance, negatively affect the lipid profile, and significantly increase
the risk of type 2 diabetes.
2) B-blockers are effective agents because of their potential to mask
hypoglycemic symptoms, and hypoglycemic events are rare when cardioselective
B1 agents are used.
3) Central adrenergic antagonists and vasodilators exhibit neutral behavior
on lipid and glucose.
4) Sympathetic inhibitors and α-adrenal blockers are associated with
orthostatic hypertension in diabetic patients with autonomic neuropathy.
5) Calcium channel blockers have a neutral effect on lipid and can reduce
cardiovascular morbidity and mortality in type 2 DM patients, especially in
elderly patients with systolic hypertension (27).
1. Barrett JC, Clayton DG, Concannon P, et al. Genome-wide association
study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat
Genet 2009; 41: 703e7
2. Wherrett DK, Daneman D. Prevention of type 1 diabetes.
EndocrinolMetabClin North Am. 2009; 38: 777e90
3. Colagiuri S, Lee CM, Wong TY, Balkau B, Shaw JE, Borch-Johnsen K.
Glycemic thresholds for diabetesspecific retinopathy: implications for diagnostic
criteria for diabetes. Diabetes Care. 2011; 34: 145–50.
DIABETES AND COMPLICATIONS 97
4. Prentki M, Nolan CJ. Islet 7 cell failure in type 2 diabetes. J Clin Invest.
2006; 116: 1802 12.
5. Defronzo RA. Banting Lecture. From the triumvirate to the ominous
octet: a new paradigm for the treatment of type 2 diabetes mellitus. 2009; 58:
773–95.
6. Thivolet C, Beta cells in type-1 diabetes: victims or activators of T cell
response. Diabetes Metab. (Paris) 2002; 28: 267–269.
7. Gillespie KM, Type 1 diabetes: pathogenesis and prevention. CMAJ.
2006; 175 (2): 165.
8. Narendran P, Estella E, Fourlanos S, Immunology of type 1 diabetes. Q.
J. Med. 2005; 98: 547–556.
9. Barclay L, Type 1 diabetes. new medical therapy: nmt briefs, 2005.
thomson centerwatch, www.centerwatch.com.
10. Weinman EO, Strisower EH, Chaikoff IL, Conversion of fatty acids to
carbohydrate: application of isotopes to this problem and role of the Krebs cycle
as a synthetic pathway. Physiol. Rev. 1957; 37: 252–272.
11. Figueiredo LF, Schuster S, Kaleta C, Fell DA, Can sugars be produced
from fatty acids? A test case for pathway analysis tools. Bioinformatics. 2009;
25 (1):152–158.
12. Stumvoll M, Goldstein BJ, van Haeften TW; Type 2 diabetes: principles
of pathogenesis and therapy. Lancet. 2005; 365: 1333–46.
13.Reaven GM, Role of insulin resistance in human disease. Diabetes.
1988; 37: 1595–607
14.Kahn SE, Hull RL, Utzschneider KM, Mechanisms linking obesity to
insulin resistance and type 2 diabetes. Nature. 2006; 444: 840–46.
15. Burcelin R, Knauf C, Cani PD, Pancreatic alpha-cell dysfunction in
diabetes. Diabetes Metab. 2008; 34 (suppl 2): 49–55.
16. Mulder H, Nagorny C, Lyssenko V, Groop L. Melatonin receptors in
pancreatic islets: good morning to a novel type 2 diabetes gene. Diabetologia.2009;
52: 1240–49.
17. Cooper MS, Stewart PM. 117-hydroxysteroid dehydrogenase type 1
and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome,
and inflammation. J ClinEndocrinolMetab. 2009; 94: 4645–54.
18. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1
receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Lancet. 2006; 368: 1696–705.
98 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
19. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H.
Glucosetoxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the
glutathione connection. Diabetes. 2003; 52: 581–87.
20. Hull RL, Westermark GT, Westermark P, Kahn SE. Islet amyloid: a
critical entity in the pathogenesis of type 2 diabetes. J ClinEndocrinolMetab.
2004; 89: 3629–43.
21. Marchetti P, Lupi R, Del Guerra S, Bugliani M, Marselli L, Boggi U.
The beta-cell in human type 2 diabetes. AdvExp Med Biol. 2010; 654: 501–14.
22. Ehses JA, Ellingsgaard H, Boni-Schnetzler M, Donath MY. Pancreatic
islet inflammation in type 2 diabetes: from alpha and beta cell compensation to
dysfunction. Arch PhysiolBiochem. 2009; 115: 240– 47.
23. Aiello LP, Gardner TW, King GL et al. Diabetic retinopathy. Diabetes
Care. 1998; 21: 143–56
24. Chen YD, Reaven GM. Insulin resistance and atherosclerosis. Diabetes
Rev. 1997; 5: 331–43
25. Ritz E, Orth SR: Nephropathy in patients with type 2 diabetes. N Engl
J Med. 1999; 341: 1127–33
26. Grundy SM, Benjamin IJ, Burke GL et al. Diabetes and cardiovascular
disease: A statement for healthcare professionals from the American Heart
Association. Circulation. 1999; 100: 1134–46
27.Barroso I, Gurnell M, Crowley VEF et al. Dominant negative mutations
in human PPARg associated with severe insulin resistance, diabetes mellitus and
hypertension. Nature. 1999; 402: 880–83.
99
(Dr), Afyonkarahisar State Hospital, Department of
Internal Medicine drsedatyildiz06@gmail.com
ORCID: 0000-0002-3817-8934
Diabetic ketoacidosis (DKA) is one of the most serious acute complications
of diabetes. DKA is the consequence of a total absence or relative (that
is, levels insufficient to supress ketone production) lack of insulin and
concomitant elevation of counter-regulatory hormones, usually resulting in the
triad of hyperglycaemia, metabolic acidosis and ketosis, often accompanied by
varying degrees of circulatory volume depletion.1
Although DKA is mostly seen in patients with type 1 diabetes (T1DM), it
can also be seen in patients with type 2 diabetes (T2DM) or those with gestational
diabetes.2 DKA may be the first sign of the disease in 20-25% of adult patients
with type 1 diabetes.2
1.1.Riskfactors
A precipitating event can usually be identified in patients with diabetic
ketoacidosis (DKA). The most common events are infection (often pneumonia
or urinary tract infection) and discontinuation of or inadequate insulin therapy.
Compromised water intake due to underlying medical conditions, particularly
in older patients, can promote the development of severe dehydration. In
addition, new-onset type 1 diabetes (20-25% in cases) may present with
DKA. Less common causes include cerebrovascular events, alcohol, cocaine
use, pancreatitis, myocardial infarction, trauma, burns, drugs that disrupt
carbohydrate metabolism (corticosteroids, thiazide group diuretics, adrenergic
agonists, antipsychotics, anticonvulsants, immune checkpoint inhibitors),
eating disorders (fear of weight gain and hypoglycemia, especially in young
100 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
girls with type 1 diabetes with a history of recurrent DKA), endocrinological
diseases distrupting carbohydrate metabolism (hyperthyroidism, acromegaly,
pheochromocytoma, Cushing’s syndrome).2
1.2.Pathophysiology
T1DM or T2DM, when there is absolute or relative insulin deficiency or
in times of acute illness, which is associated with an increase in the counter-
regulatory hormones. These alterations in hormone levels and the subsequent
inflammatory response form the basis of the pathophysiological mechanisms
involved in DKA. The changes in hormone concentrations lead to alterations in
glucose production and disposal, as well as increased lipolysis and ketone body
production. Intercurrent illness can lead to the production of counter regulatory
hormones leading to hyperglycaemia and the pro-inflammatory state resulting
from an infection precipitate DKA.1
1.3.Gluconeogenesisandhyperglycaemia
In diabetes mellitus, insulin deficiency leads to increased gluconeogenesis
(hepatic glucose production), which is simultaneously accompanied by impaired
glucose uptake and use in peripheral tissues3,4 resulting in hyperglycaemia.
In healthy individuals, ~20% of total endogenous glucose production also
comes from the kidneys as a result of a combination of gluconeogenesis and
glycogenolysis.5 Endogenous renal glucose production has been speculated to
be increased in DKA because data from the 1970’s suggest that the presence of an
acidosis increase renal glucose output, while impairing hepatic gluconeogenesis.6
In T1DM and T2DM, increased hepatic gluconeogenesis results from the
increased availability of gluconeogenic precursors such as lactate, glycerol
and several gluconeogenic amino acids including alanine, glycine and serine.
Furthermore, low insulin concentrations lead to catabolism of protein from
muscles, liberating amino acids that are gluconeogenic and ketogenic such as
tyrosine, isoleucine and phenylalanine, or purely ketogenic such as lysine and
leucine. Catabolism of isoleucine, lysine and tryptophan lead to the formation of
acetyl coenzyme A (acetyl CoA); catabolism of phenylalanine and tyrosine lead to
the formation of acetoacetate; and leucine leads to the production of β-Hydroxy-
β-methylglutaryl-CoA (HMG-CoA) — all of which feed into the production
of ketone bodies. High glucagon, catecholamine and cortisol concentrations
relative to insulin levels stimulate gluconeogenic enzyme activity, in particular
DIABETIC KETOACIDOSIS 101
phosphoenol pyruvate carboxykinase, fructose-1,6-bisphosphatase and pyruvate
carboxylase, all of which augment hyperglycaemia.7–9
1.4.Ketogenesis
The increase in counter-regulatory hormone concentrations associated with
severe insulin deficiency activates hormone-sensitive lipase in adipose tissue.
Lipolysis of endogenous triglycerides by this enzyme releases large quantities
of free fatty acids (FFAs) and glycerol into the circulation.10 These FFAs are
oxidized to ketone bodies in the hepatic mitochondria, a process mediated by
high glucagon concentrations. Glucagon reduces the hepatic concentrations of
malonyl CoA, which is the first committed intermediate in the lipogenic pathway.11
Malonyl CoA is also a potent inhibitor of fatty acid oxidation and inhibits the
enzyme, carnitine palmitoyl transferase 1 (CPT1). CPT1 regulates the uptake of
FFAs into the mitochondria for b-oxidation12, causing an accumulation of acetyl
CoA. Under normal circumstances, acetyl CoA enters the tricarboxylic acid
(TCA) cycle (also known as Krebs cycle) and, subsequently, the mitochondrial
electron transport chain to synthesize ATP. However, when acetyl CoA
production exceeds the levels that can be metabolized by the TCA cycle, two
molecules of acetyl CoA condense to form acetoacetyl-CoA, which can condense
with another acetyl CoA molecule to form β-hydroxy-β-methylglutaryl-CoA
(HMG-CoA). The enzyme HMG- CoA synthase is stimulated by glucagon and
inhibited by insulin, therefore, in times of fasting or insulin deprivation, the
enzyme actively produces HMG-CoA. HMG-CoA within the mitochondria is
lysed to form acetoacetate (as opposed to in the cytosol, where it is involved in
cholesterol synthesis), which can further spontaneously degrade to form acetone
or be metabolized to b- hydroxybutyrate.13
The acetone, acetoacetate and b-hydroxybutyrate constitute the three
ketone bodies produced by the liver. The exhaled acetone is what gives the
classic ‘fruity’ breath in people presenting with DKA. Concurrent with increased
ketone body production, the clearance of b-hydroxybutyrate and acetoacetate is
reduced. Acidosis occurs due to the buffering of the protons produced by the
dissociation of ketoacids that occurs at physiological pH. The reduced clearance
of ketones contributes to the high concentration of anions in the circulation,
which also contributes to the development of DKA.14
Accumulation of ketoacids leads to a decrease in serum bicarbonate
concentration and retention of these ‘fixed acids’ leads to the development of high
anion gap metabolic acidosis. The measure of acidity is important because as pH
102 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
falls <7.35, intracellular biological systems begin to fail, leading to irreversible
damage at ~pH <6.8. This low pH can lead to neurological dysfunction, leading
the coma, and if severe or prolonged enough, death.
2.1.Presentation
It is important to evaluate the symptoms and physical examination findings
in the diagnosis. Table 1 shows the signs and symptoms of DKA. DKA frequently
presents with a short history, with symptoms developing usually over a few
hours. These include the classic symptoms of polyuria , polydipsia and, in those
for whom DKA is the first presentation of diabetes, weight loss. Polyphagia has
been reported in children, but remains rare in adults.15 Gastrointestinal symptoms
such as nausea, vomiting and generalized abdominal pain are reported in >60%
of patients.16,17 Abdominal pain, sometimes mimicking an acute abdomen, is
especially common in children and in patients with severe metabolic acidosis.
Abdominal pain typically resolves during the first 24 hours of treatment and lack
of resolution of abdominal pain within this time frame should prompt a search
for other causes.17
Physical examination usually reveals signs of circulatory volume
depletion, including dry mucous membranes and tachycardia. Mental status
on admission varies from full alertness to lethargy and stupor, with <20% of
adults hospitalized showing loss of consciousness. As pH drops, respiratory
compensation for the metabolic acidosis, that is, excreting acidic carbon dioxide
in an attempt to maintain plasma pH, leads to Kussmaul respirations (a deep and
laboured breathing pattern) in individuals with DKA and the breath might have
a classic fruity odour owing to acetone exhalation.18
Signs and symptoms of diabetic ketoacidosis2
Weakness Tachycardia
Anorexia, nausea, vomiting Dryness of mucous membranes, decreased skin
turgor
Dry mouth, polydipsia, polyuria Hot and dry skin
Abdominal pain, cramps Dehydration, hypotension
Shortness of breath Tachypnea, Kussmaul respiration
Weight loss Abdominal tenderness
Clouding of consciousness Ketone odor in the mouth
Lethargy, mental blunting, coma
DIABETIC KETOACIDOSIS 103
Despite infection, most cases do not develop fever due to vasodilation.
Moreover, some patients with a poor prognosis are hypothermic.
In DKA, metabolic acidosis is often the major finding, while the serum
glucose concentration is generally below 800 mg/dL and often in the 350 to 500
mg/dL range.19–21 However, serum glucose concentrations may exceed 900 mg/
dL in patients with DKA, most of whom are comatose19,22, or may be normal
or minimally elevated (<250 mg/dL) in patients with euglycemic DKA (which
occurs more often in patients with poor oral intake, those treated with insulin
prior to arrival in the emergency department, pregnant women, and those who
use sodium-glucose co-transporter 2 [SGLT2] inhibitors).
2.2.Diagnosis
The diagnosis of DKA is based on the triad of hyperglycaemia, ketosis and
metabolic acidosis.23 In the course of DKA, metabolic acidosis with an increased
anion gap is usually present and the serum bicarbonate level is moderately to
severely decreased. In some cases, hyperchloremic metabolic acidosis may
develop within the first 8 hours of treatment.
2.3.ClinicalFollow-up
At hospital admission, immediate assessment of the haemodynamic state
and level of consciousness, together with measurement of blood glucose, blood
or urine ketones, serum electrolytes, venous blood gases and complete blood
count should be performed. As part of the rapid assessment of the individual,
precipitants for DKA should be sought, including an ECG to exclude acute
coronary syndrome and repolarization abnormalities (that is, peaked T waves)
due to hyperkalaemia.
The systemic effect of DKA in adults depends on the severity of the
acidaemia and circulatory volume depletion. There is an average of 5-7 liters of
fluid deficit in DKA. However, one of the drawbacks of the ADA classification
is that the degree of acidaemia is imperfectly correlated with the patient’s level
of consciousness.17
Since the serum Na+ level may initially decrease as a result of the
displacement of water into the extracellular space due to hyperglycemia, the
corrected Na+ level should be considered in the treatment. In some cases, the serum
Na+ level may be falsely low due to concomitant severe hypertriglyceridemia
(pseudohyponatremia).
104 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Intracellular potassium is decreased due to insulin deficiency. However, the
serum potassium value can be measured as normal or high due to reasons such
as leakage of potassium into the extracellular space, dehydration, hypertonicity,
acidosis, and renal failure. A low or lower limit of the first measured potassium
level should suggest a severe potassium deficiency. However, in a patient with
DKA who has a normal initial serum potassium value, it should be estimated
that intracellular potassium is low and will decrease further with insulin therapy
and correction of hyperglycemia.
Calcium, phosphate, and magnesium deficiencies can also be seen in DKA.
Although intracellular phosphate is low, phosphate level can be measured as
normal or increased due to different reasons such as leakage into the extracellular
fluid and dehydration.
During follow-up, serum electrolytes, glucose, urea, creatinine, osmolality
and blood pH should be evaluated every 2-4 hours. It is recommended to measure
arterial pH initially, but venous pH can be used for follow-up.
Insulin therapy and fluid and electrolyte replacement are the cornerstones
of DKA treatment. The aim is to correct acidaemia, restore normal circulatory
volume and normalize blood glucose concentrations and acid-base disturbances
to restore normal levels of inflammatory and oxidative stress markers24,25
(Table 2).
The goals of treatment in DKA/HHD
· regulating circulation volume and tissue perfusion
· bringing serum glucose and osmolality to normal limits
· clearing ketone bodies in urine and serum
· correcting electrolyte balance and to metabolic decompensation
· identifying and treating the causative factors
Once DKA is identified, management of the patient is twofold. The
precipitating stressors must be identified and treated, as must the serum glucose
level and the additional significant symptoms.
Careful monitoring of the patient’s response to DKA treatment and
appropriate adjustments in treatment based on this response are essential.
Monitoring should include tracking of blood pressure, pulse and respiratory rate
DIABETIC KETOACIDOSIS 105
as well as accurate documentation of fluid intake and output. For most patients,
glucose levels should be monitored hourly and electrolytes (sodium, potassium,
chloride and bicarbonate), urea nitrogen, creatinine and venous pH should
be measured every 2–4 hours. Levels of phosphate, calcium and magnesium
are measured less frequently (generally every 4–6 hours). There should be a
low threshold for moving individuals presenting with altered cognitive status
or severe metabolic derangement and those who fail to improve after initial
treatment to an intermediate care unit (high dependency) or critical care unit in
the hospital.16,26
Successful treatment of DKA is possible by maintaining fluid and electrolyte
balance, correcting hyperglycemia, and treating comorbid conditions.
3.1.Volumecorrection
Administration of intravenous fluid is the key to intravascular volume
correction, thereby improving renal perfusion. The concomitant decrease in
circulating counter-regulatory hormone concentrations also reduces insulin
resistance.27 In adults with DKA, the ADA and UK guidelines recommend normal
saline (0.9% sodium chloride solution, NS) for the initial fluid replacement.18,28
Patients with DKA typically need 3 to 6 L NS during the first few hours
after onset.29 The ADA recommends that 0.9% NS be administered intravenously
at 15 to 20 mL/kg/hr for 60 to 90 minutes.30 Others have recommended that 0.9%
NS be given intravenously at 15 mL/kg/hr for one hour, then at 7.5 mL/kg/hr for
2 hours, then at 3.75mL/kg/hr for the next 24 to 36 hours as long as the corrected
serum sodium isn’t elevated.31
After restoration of intravascular volume, the serum sodium concentration
and state of hydration assessed by blood pressure, heart rate and fluid balance
should determine whether the rate of normal saline infusion can be reduced to
250 ml/hour or changed to 0.45% sodium chloride (250–500 ml/h).21
3.2.Insulinadministration
In most adults with DKA, a continuous intravenous infusion of regular
(soluble) insulin is the treatment of choice. Routine treatment includes
administering regular insulin 0.1 to 0.15 units per kg IVP followed by a 0.1 unit/
kg/hr IV infusion.29
If the glucose level doesn’t drop by 50 to 100mg/dL every hour, the insulin
infusion rate should be doubled.32,33
106 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Once the hourly blood sugar measurements are less than 250 mg/dL, the
hourly rate of intravenous insulin should be reduced by half. Start an infusion
of 5% dextrose and 0.45% NS at 100to 150 mL/hr to replace the 0.9% (or
0.45%) NS infusion. The insulin infusion should continue until at least two of
the following outcomes occur: the anion gap is less than 14 mEq/L, the venous
pH is 7.3 or greater, or the bicarbonate level is greater than 18 mEq/L.29,32,33
3.4.Potassiumreplacement
At presentation, serum potassium concentrations are frequently normal or
slightly elevated in spite of total body deficits. As insulin treatment starts, ketone
production is suppressed, and the acidosis begins to resolve. In addition, insulin
drives potassium back into the cell, and the individual can become profoundly
hypokalaemic. Hypokalaemia occurs frequently despite aggressive potassium
replacement34,35 and frequent monitoring of potassium during the first few hours
of treatment is an essential part of managing DKA.21,36 Because of potentially
rapid shifts in potassium and the possible risk of developing cardiac arrhythmias,
continuous cardiac monitoring is recommended in all cases where potassium is
being administered at >10mmol/hr. The development of severe hypokalaemia (<2.5
mmol/l) was associated with increased mortality (OR 3.17; 95% CI 1.49–6.76).34
In patients who develop symptomatic hypokalaemia (muscle weakness and cardiac
arrhythmia), potassium replacement should be started and insulin administration
should be delayed until the potassium concentration has risen to >3.3mmol/l.
3.5.Bicarbonateadministration
For treating acidosis, if the pH is less than 6.9, the ADA recommends
adding 100 mmol of sodium bicarbonate (NaHCO3) to 400 mL sterile water
and administering the solution over two hours. If the pH is 6.9 to 7.0, 50 mmol
of NaHCO3 should be added to 200 mL sterile water and given over two hours.
The venous pH should be reevaluated every two hours. When the pH reaches
7.0, no further NaHCO3 need be administered. Because bicarbonate therapy
might increase the risk of hypokalaemia, slow the resolution of ketosis, cause
paradoxical increases in cerebral acidaemia due to an increase in tissue pCO2
and increase the risk of cerebral injury.37,38
3.6.Phosphatereplacement
Similar to potassium, serum phosphate concentrations are typically normal
at presentation but intracellular depletion is present and serum concentrations
DIABETIC KETOACIDOSIS 107
decline during DKA treatment. Phosphate replacement is necessary in those
with serum phosphate concentration <1.0– 1.5mg/dl (0.3–0.5mmol/l).21
Inclusion of phosphate in the infusion has been proposed to diminish the risk
of hypophosphataemia, which has been associated with severe complications in
some patients including rhabdomyolysis (breakdown of skeletal muscles), renal
failure, respiratory failure, arrhythmias and haemolytic anaemia.39–43. Phosphate
levels should be monitored during treatment at least every 4–6 hours, although
more frequent monitoring (every 2–3 hours) is recommended for those not
receiving phosphate replacement.
Complications due to uncontrolled diabetes cause a serious increase in
health expenditures, the intensity of health services and significant labor losses.
The first thing to do to deal with these complications is to inform people about
the disease correctly and to ensure that they reach the right treatment. Education
and the implementation of protocols might reduce lapses in treatment and are
a cost-effective way to reduce future risk of hospitalization for hyperglycaemic
emergencies.
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3. Miles JM, Rizza RA, Haymond MW, Gerich JE. Effects of Acute
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6. Exton JH. Gluconeogenesis. Metabolism. 1972;21(10):945-990.
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Insulin Deficiency on Glucose and Ketone Body Turnover in Man: Evidence
for the Primacy of Overproduction of Glucose and Ketone Bodies in the
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DIAB.29.11.926
10. McGarry JD, Woeltje KF, Kuwajima M, Foster DW. Regulation of
ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes
Metab Rev. 1989;5(3):271-284. doi:10.1002/DMR.5610050305
11. Foster DW. Malonyl-CoA: the regulator of fatty acid synthesis and
oxidation. J Clin Invest. 2012;122(6):1958-1959. doi:10.1172/JCI63967
12. Cook GA, King MT, Veech RL, Elizabeth’s Hospital S, Washington
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13. Laffel L. Ketone Bodies: a Review of Physiology, Pathophysiology
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7560(199911/12)15:6
14. Dhatariya K. Blood Ketones: Measurement, Interpretation, Limitations,
and Utility in the Management of Diabetic Ketoacidosis. Rev Diabet Stud.
2016;13(4):217. doi:10.1900/RDS.2016.13.217
15. Xin Y, Yang M, Chen XJ, Tong YJ, Zhang LH. Clinical features at
the onset of childhood type 1 diabetes mellitus in Shenyang, China. J Paediatr
Child Health. 2010;46(4):171-175. doi:10.1111/J.1440-1754.2009.01657.X
16. Umpierrez G, Korytkowski M. Diabetic emergencies - ketoacidosis,
hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol.
2016;12(4):222-232. doi:10.1038/NRENDO.2016.15
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17. Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic
crises. J Crit Care. 2002;17(1):63-67. doi:10.1053/JCRC.2002.33030
18. Fayfman M, Pasquel FJ, Umpierrez GE. Management of Hyperglycemic
Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State.
Medical Clinics of North America. 2017;101(3):587-606. doi:10.1016/j.
mcna.2016.12.011
19. Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB. Thirty
years of personal experience in hyperglycemic crises: diabetic ketoacidosis and
hyperglycemic hyperosmolar state. J Clin Endocrinol Metab. 2008;93(5):1541-
1552. doi:10.1210/JC.2007-2577
20. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with
hyperglycemia: clinical features, pathophysiology, renal function, acid-base
balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37
cases. Medicine. 1972;51(2):73-94. doi:10.1097/00005792-197203000-00001
21. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic
crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343.
doi:10.2337/DC09-9032
22. Morris LR, Kitabchi AE. Efficacy of low-dose insulin therapy for
severely obtunded patients in diabetic ketoacidosis. Diabetes Care. 1980;3(1):53-
56. doi:10.2337/DIACARE.3.1.53
23. Dhatariya KK. Defining and characterising diabetic ketoacidosis in
adults. Diabetes Res Clin Pract. 2019;155. doi:10.1016/J.DIABRES.2019.107797
24. McLarty DG, Kinabo L, Swai ABM. Diabetes in tropical Africa: a
prospective study, 1981-7. II. Course and prognosis. BMJ. 1990;300(6732):1107-
1110. doi:10.1136/BMJ.300.6732.1107
25. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory
Cytokines, Markers of Cardiovascular Risks, Oxidative Stress, and Lipid
Peroxidation in Patients With Hyperglycemic Crises. Diabetes. 2004;53(8):2079-
2086. doi:10.2337/DIABETES.53.8.2079
26. French EK, Donihi AC, Korytkowski MT. Diabetic ketoacidosis
and hyperosmolar hyperglycemic syndrome: review of acute decompensated
diabetes in adult patients. BMJ. 2019;365. doi:10.1136/BMJ.L1114
27. Waldhäusl W, Kleinberger G, Korn A, Dudczak R, Bratusch-Marrain
P, Nowotny P. Severe hyperglycemia: effects of rehydration on endocrine
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28. Waldhäusl W, Kleinberger G, Korn A, Dudczak R, Bratusch-Marrain
P, Nowotny P. Severe hyperglycemia: effects of rehydration on endocrine
derangements and blood glucose concentration. Diabetes. 1979;28(6):577-584.
doi:10.2337/DIAB.28.6.577
29. Uncontrolled diabetes mellitus - PubMed. Accessed September 29,
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DIACARE.25.2007.S1
31. Konick-McMahan J. Riding out a diabetic emergency. Nursing (Brux).
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32. KITABCHI AE, WALL BM. Management of Diabetic Ketoacidosis.
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33. Miller J. Management of diabetic ketoacidosis. Journal of emergency
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34. Pasquel FJ, Tsegka K, Wang H, et al. Clinical Outcomes in Patients
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35. Dhatariya KK, Nunney I, Higgins K, Sampson MJ, Iceton G. National
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36. Savage MW, Dhatariya KK, Kilvert A, et al. Joint British Diabetes
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39. Kutlu AO, Kara C, Cetinkaya S. Rhabdomyolysis without
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43. Shen T, Braude S. Changes in serum phosphate during treatment
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113
asanüseyin1 yşenur
1(Dr), Elbistan State Hospital, Clinic of Neurology, Kahramanmaras, Turkey
e-mail: hasanhuseyinkir@gmail.com
ORCID: 0000-0001-5496-7397
2(Dr), Necmettin Erbakan University, Meram Medical Faculty, Clinic of
Neurology, Konya, Turkey e-mail: aysnrnc@yahoo.com.tr
ORCID: 0000-0002-9791-425X
After the decreasing prevalence of poliomyelitis in the population,
Guillain-Barré Syndrome (GBS) has become the most common cause
of acute diffuse flaccid paralysis (incidence: 1-2/100.000)(1). GBS is
a polyneuropathy characterized by rapidly developing diffuse weakness due to
inflammatory damage of peripheral nerves. Inflammation is associated with a
monophasic autoimmune process and leads to demyelination of nerves.
Incidence is lower in childhood than in other age groups however there is a
relative increase especially after 50 years of age(2). Unlike many other
autoimmune diseases, GBS is 1.5 times more common in men than women(3).
It usually occurs in people who do not have any other disease. But it could be
associated with another systemic or autoimmune disease. There are some
subgroups that differ from each other sometimes by clinical aspects and
sometimes more by laboratory characteristics (Table 1). The term GBS is
practically used for this most common classic inflammatory demyelinating
form of the disease. Because this form is seen in approximately 90% of GBS
cases in the Western countries(4). In this section, this form will be mentioned.
114 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
. Classification of Guillain-Barré
Syndromes((EP Bosch and BE Smith, modified)(5)
Acute inflammatory demyelinating polyradiculoneuropathy
Acute motor axonal neuropathy
Acute motor-sensory axonal neuropathy
Acute motor-sensory axonal neuropathy
Pharyngeal-cervical-brachial
Paraparetic
Facial paralysis
Pure oculomotor
Functional variants of GBS
Acute pandysautonomia
Pure sensorial GBS
Ataxic GBS
2.1.Clinic
Most patients have an event such as an upper respiratory tract or
gastrointestinal tract infection, surgery, or vaccination within 1-4 weeks before
the onset of GBS symptoms. The target of immune attack in Acute Inflammatory
Demyelinating Polyradiculoneuropathy (AIDP) is the myelin of the peripheral
nerve.
GBS is classically monophasic and all symptoms usually resolve in 1-2
weeks. In about half of the cases, the weakness starts in the feet and legs and
spreads to the trunk and arms in a few days (ascendant spread). Weakness
begins simultaneously in the legs and arms in 1/3 of the cases, and firstly in the
arms in 12% (6). Indeed few times, a muscle weakness that goes beyond the
general distribution pattern defined for polyneuropathy syndrome and is evident
in the proximal extremities is seen. The accompanying sensory complaints in
approximately 80% of the patients are generally in the background and include
paresthesia at the extremities or, rarely, back, waist and leg pains. Pain due to
nerve root inflammation may be the first symptom of the disease and may begin
before muscle weakness in 1/3 of cases.
Neurological examination reveals widespread loss or reduction of tendon
reflexes, in addition to muscle weakness in the identified areas. However, rarely,
tendon reflexes can be found to be normal at the beginning of the disease and
especially only in motor and axonal forms. Objective sensory findings are mostly
limited to mild superficial hypoesthesia at the extremities or reduced vibration
and joint position sense.
GUILLAIN-BARRÉ SYNDROME 115
Respiratory failure requiring mechanical ventilation develops in 10-30% of
cases(7). Cranial nerve palsies occur in half of the patients, most commonly facial
paralysis. Oropharyngeal muscle weakness develops in half of the cases, and eye
movement paralysis develops in 10-20%. Uncommonly, papilledema can be seen
and is associated with very increased CSF protein (>200 mg/dL). Autonomic
nervous system disorders occur in 38 to 70 percent of patients and are more
common in patients with severe motor weakness and respiratory failure (8,9).
Autonomic signs and symptoms include ECG changes (T wave abnormalities,
ST segment depression, QRS widening, QT prolongation and various heart
blocks), cardiac arrhythmias (sinusal tachycardia, bradycardia, ventricular
tachycardia, atrial flutter, atrial fibrillation and asystole), orthostatic hypotension
and hypertensive crisis, less frequently transient urinary retention, sweating
disorders, and paralytic ileus(8). Severe and persistent sphincter defect should
be considered as a criterion that excludes the diagnosis of GBS. The factors that
support and exclude the diagnosis of GBS are discussed in Table 2.
Diagnosis of typical Guillain-Barré Syndrome (PA van Doorn et al,
modified)(10)
Progressive weakness in both arms and legs (might start with weakness only in the legs)
Areflexia (or decreased tendon reflexes)
Features that strongly support diagnosis
Mild sensory symptoms or signs
Pain (often present)
Autonomic dysfunction
Cranial nerve involvement, especially bilateral weakness of facial muscles
Relative symmetry of symptoms
Typical electrodiagnostic features
High concentration of protein in CSF
Progression of symptoms over days to 4 weeks
Persistent bladder or bowel dysfunction
Slow progression with limited weakness without respiratory involvement (consider subacute
inflammatory demyelinating polyneuropathy or CIDP)
Bladder or bowel dysfunction at onset
Marked persistent asymmetry of weakness
Sharp sensory level
Severe pulmonary dysfunction with limited limb weakness at onset
Polymorphonuclear cells in CSF
Fever at onset
Increased number of mononuclear cells in CSF (>50×106 /L)
Severe sensory signs with limited weakness at onset
CSF: Cerebrospinal fluid, CIDP: Chronic inflammatory demyelinating
polyradiculoneuropathy
Features required for diagnosis
116 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Muscle weakness usually completes its progression in terms of severity
and distribution within 1-3 weeks (50% of cases reach maximum muscle
weakness in 1 week, 80% in 3 and 90% in 4 weeks)(11). Four to eight weeks
of progression occasionally called subacute inflammatory demyelinating
polyradiculoneuropathy (SIDP). Acquired demyelinating polyneuropathy
cases that progress for more than two months should be considered as chronic
inflammatory demyelinating polyradiculoneuropathy (CIDP)(12). Fulminant
form is observed in patients who progress to respiratory failure within 24-48
hours. After pause of progression, the disease passes into plateau phase of
2-4 weeks followed by a slow recovery period. Deterioration may occur
during or shortly after treatment with intravenous immunoglobulin (IVIg) or
plasmapheresis in approximately one-quarter of patients.
In 75% of cases with GBS, complete or almost complete improvement
in weakness occurs within one year at the latest. Only pathological fatigue and
mild weakness at the ends may remain as sequelae. In approximately 20% of
the cases, severe neurological sequelae remain and approximately one out of
every 6-7 cases cannot walk unaided(13). Despite the increase in intensive
care facilities and new treatment methods, mortality rate of GBS is 3-7%(14).
Mortality in patients who become ventilator dependent is approximately 20
percent. Death is often due to ventilation complications, cardiac arrhythmias,
pulmonary embolism, and sepsis. Scales (Erasmus GBS Outcome Score- EGOS)
are used to determine prognosis. Especially old age, a history of pre-diarrhea,
and reaching the most severe level of weakness in less than 2 weeks were found
to be poor prognostic signs(Table 3). Modified EGOS scale can be beneficial
that determine the prognosis in the first week in cases with GBS(15).
Table 3. Poor prognostic factors in Guillain-Barré Syndromes (6,16)
1. Older age (>50–60)
2. Rapid onset before presentation (<7 days)
3. Ventilator dependency
4. Severely reduced distal CMAP amplitudes (<20% lower limit of normal)
5. Preceding infection with Cytomegalovirus
6. Preceding diarrheal illness or Campylobacter jejuni
7. Erasmus GBS outcome score at 2 weeks ≥ 5
a. Ventilator dependence, or
b. Bedbound or chairbound and elderly (>60), or
c. Bedbound or chairbound and preceding diarrheal illness
CMAP: Compound muscle action potential
GUILLAIN-BARRÉ SYNDROME 117
2.2.Pre-diseaseeventsandPathogenesis
As noted above, up to two-thirds of patients with GBS have a history of
respiratory or gastrointestinal infection 1-3 weeks prior to the disease(17). The
most common infectious agent is Campylobacter jejuni. Epstein-Barr virus,
Cytomegalovirus (CMV), Haemophilus influenzae and Mycoplasma pneumoniae
are known to be associated with GBS. GBS following C. jejuni infection mostly
progresses with motor symptoms and axonal involvement. In addition, these
cases show slower recovery and have a worse prognosis with increased disability
rates(18). Although cases of GBS accompanied by coronavirus disease 2019
(COVID-19) and zika virus infections have been reported, the existence of a
direct causal relationship between them has not yet been clarified(19). Other
events reported to precede GBS are vaccinations (influenza, rabies, tetanus and
diphtheria toxoids, oral poliomyelitis vaccine), surgical interventions, and the
use of certain drugs (streptokinase, suramin, gangliosides, and heroin). Studies
have shown that the risk of developing GBS associated with vaccination is not
greater than the risk of developing GBS associated with influenza(20).
Pathological changes have many variable forms according to GBS
subtype. In AIDP, the focal inflammatory response occurs against peripheral
myelin or myelinating Schwann cells. The main histopathological findings in
the form of AIDP are mononuclear inflammatory infiltration in the endoneurium
and segmental demyelination in nerve fibers. Although these lesions are seen
all over the peripheral nerves from nerve roots to distal intramuscular nerve
branches, mostly motor roots and proximal plexus segments are involved.
It is accepted that the pathological processes leading to GBS are initiated
by autoantibodies formed against antigens in the structure of peripheral nerves.
Antiganglioside antibodies have been shown in the blood of patients with GBS
at a very high rate (approximately 60%). Gangliosides are found in layers called
“lipid rafts” in peripheral nerve membranes and play a role in maintaining
membrane integrity. Some antibodies do not bind to individual gangliosides,
but to new conformational epitopes formed by different ganglioside complexes.
2.3.LaboratoryFindings
The clinical diagnosis of GBS is supported by the results of diagnostic tests
such as cerebrospinal fluid (CSF) and electrodiagnostic studies(21). Lumbar
puncture is performed for CSF evaluation in all patients. Electrodiagnostic
studies and imaging are performed in patients with atypical symptoms and when
initial CSF evaluation is not diagnostic. These diagnostic tests can also help rule
out alternative diagnoses(22).
118 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
2.3.1.RoutineLaboratoryExaminations
Erythrocyte sedimentation rate, leukocyte count and CK level may be a
slight increase. Hyponatremia due to inappropriate ADH release may occur.
2.3.2.CerebrospinalFluid
Protein level increased. In general, cell isn’t observed (albuminocytological
dissociation). Protein increase due to disruption of the blood-Cerebrospinal
Fluid (CSF) barrier usually occurs after 48 hours (more specifically the first
week) and peaks at 3-4 weeks. At the end of the first week, while 66% of the
cases have high CSF protein, the CSF protein level never rises in about 10%
(23). The number of cells in the CSF generally does not exceed 10 mononuclear
cells per mm3 (rarely, 50/mm3 mononuclear cells can be seen). In a case of
GBS with CSF pleocytosis, other diagnostic possibilities such as leptomeningeal
malignant diseases, Lyme disease, HIV infection or poliomyelitis should be
considered.
2.3.3.ElectrophysiologicalStudies
Nerve conduction studies may be normal in the early days of GBS. In
87% of patients with AIDP, abnormal findings are found on electrophysiological
examination in the first 5 weeks(5). Characteristic findings of demyelination are
observed in motor nerve conduction examination of patients with AIDP long
latency F response or failure to receive F response, prolongation of distal latency,
slow conduction velocity and conduction blocks, and disperse response. Sural
preservation in sensory conduction study (sural sensory conduction normal,
median and ulnar sensory conduction abnormal) is an important finding in GBS
electrophysiology. In axonal forms, reduction in CMAP and SAP amplitudes
without demyelination findings and spontaneous activity in needle EMG in the
advanced period are detected. A single ENMG examination couldn’t distinguish
the axonal and AIDP forms of GBS at an early stage. Therefore, it is recommended
to repeat the electrophysiological examination within 1-2 weeks(24).
2.4. Treatment
2.4.1. Management
Patients with GBS should be followed in neurology intensive care units or
intermediate intensive care units. It should be followed closely and, if
necessary, monitored, especially in terms of respiration, bulbar functions
and autonomic disorders. Pulmonary function assessment is priority. If vital
GUILLAIN-BARRÉ SYNDROME 119
capacity decreases rapidly and/or falls below 15 ml/kg and/or negative
inspiratory pressure falls below 60 cm H2O, the patient should be intubated
immediately and mechanically ventilated before hypoxemia develops. Patients
who cannot swallow their secretions and/or cough adequately due to bulbar
weakness should also be evaluated for intubation. Patients with significant
dysphagia should be fed with a nasogastric tube. Tracheostomy should be
performed for intubation longer than two weeks. Although there is
improvement in respiratory functions in an intubated patient, extubation should
not be rushed and waited for a while. Autonomic functions, especially cardiac
rhythm and TA should be closely monitored. When hypotension or
hypertension develops, aggressive treatment should not be used, and long-
acting drug use should be avoided.
Pain is a distressing symptom in patients with GBS and may be difficult
to manage. Antidepressant and antiepileptic drugs, tramadol and mexiletine
can be used for radicular and neuropathic pain that does not respond to
NSAIDs. Deep vein thrombosis in the legs and associated pulmonary
embolism is one of the important causes of mortality in patients with GBS.
From the first moment, a protective dose of heparin or low molecular weight
heparin should be given. Passive exercises from an early period may contribute
clinical improvement.
2.4.2. Immunotherapy
Plasmapheresis (PLEX) or IVIG is used in the immunological treatment of
GBS(1). Multicenter controlled studies have shown that if these treatments are
applied within the first 2-4 weeks from the onset of the disease, they provide a
significantly faster recovery than those who do not receive treatment, and there
is no significant difference between the efficacy of these two treatment options
(25). Earlier initiation of treatment (first 2 weeks) provides a higher effect. The
choice between PLEX and IVIG depends on local availability, patient
preference, risk factors, and contraindications (26).
Plasmapheresis is usually performed with the aim of changing a total of 5
plasma volumes in 5 sessions over a 2-week period. While 2 sessions of
plasmapheresis are sufficient in mild cases, it has been shown that 4 sessions
of plasmapheresis are required for moderate and severe patients, and that
severe patients do not provide an additional benefit from 2 additional sessions
of plasmapheresis (6 in total) (27). Plasmapheresis requires a good venous
120 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
access route (such as a central venous catheter) and is a treatment method that
can only be applied in large medical centers. Patients with cardiovascular
instability and autonomic dysfunction couldn’t tolerate these treatment
regymes, also these are very difficult to be aplied in children. Severe side
effects such as sepsis are more common. For these reasons, IVIG, which is
easier to apply, finds widespread use(28).
IVIG is administered by administering a total dose of 2 g/kg in daily
doses of 0.4 g/kg over 5 days. Less than 10% of patients experience mild side
effects such as flu symptoms, headache, chemical meningitis, nausea, and
fatigue. These can be prevented by administering antiallergics such as
diphenhydramine, paracetamol and low-dose corticosteroids before treatment.
Serious side effects are very rare. These include anaphylactic reaction (mainly
seen in patients with IgA deficiency, therefore immunoglobulin A levels
should be checked before treatment), renal failure (more common in patients
with renal disease, a pre-treatment evaluation of kidney function is
appropriate) and thromboembolic complications(29). It has been shown that
combining plasmapheresis and IVIG treatments has no superiority over their
individual application(6). Corticosteroids are generally ineffective in GBS.
The combined use of IVIG and corticosteroids was also not more beneficial
than IVIG alone(30). A summary of the principles regarding the monitoring
and treatment of cases with GBS is given in Table 4.
Table 4. GBS treatment (IR Bella, modified) (31)
Clinical Status Follow-up and Treatment
Mild GBS Hospitalisation
Walking independent, no
respiratuar dysfunction
Observation
Plasmapheresis or IVIG (consider).
Walking with support, no
respiratuar dysfunction
If possible, take patient to the intensive care unit,
otherwise keep in a place where VC can be measured
frequently and access to intensive care facilities is
relatively easy
Follow-up ABG
IVIG or plasmapheresis (4 session)
No walking, mild
respiratuar dysfunction
Take patient to the intensive care unit
Follow-up VC closely
Follow-up ABG
Entubation criteria:
VC <15 ml/kg, or VC tends to decrease within 4-6 hours,
Oropharyngeal paresis and aspiration
Respiratuar distress ndings and VC 15 ml/kg.
IVIG or plasmapheresis (4 session)
No walking, respiratuar
dysfunction needs
mechanic ventilation
Take patient to the intensive care unit
Autonomic nervous system dysfunction observation
Fluid replacement for hypotension
Short-acting beta-blockers can be used for resistant
hypertension
Frequently turn over in bed for decubitus ulcer and
compression neuropathies, position changes
Physical therapy
IVIG or plasmapheresis (4 session)
ABG: arterial blood gas, IVIG: intravenuos immunoglobulin,
VC: vital capasity.
GUILLAIN-BARRÉ SYNDROME 121
3. Conclusion
After the decreasing prevalence of poliomyelitis in the population, Guillain
Barré Syndrome has become the most common cause of acute diffuse flaccid
paralysis (incidence: 1-2/100.000)(1). In approximately 20% of the cases,
severe neurological sequelae remain and approximately one out of every 6-7
cases can not walk unaided(13). Despite the increase in intensive care facilities
and new treatment methods, mortality rate of GBS is 3-7%(14).
Plasmapheresis or IVIG is used in the immunological treatment of GBS(1).
Multicenter controlled studies have shown that if these treatments are applied
within the first 2-4 weeks from the onset of the disease, they provide a
significantly faster recovery than those who do not receive treatment, and there
is no significant difference between the efficacy of these two treatment
options. Earlier initiation of treatment (first 2 weeks) provides a higher
effect(26).
In conclusion, although GBS is a rare disease in the community, it carries
a substantial risk of disability and death. Considering that early initiation of
treatment provides a higher effect, it is important that clinicians know
the diagnosis, treatment and management of the Guillain-Barré syndrome.
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14. van den Berg B, Bunschoten C, van Doorn PA JB. Mortality in
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127
II
(Asst.Prof. Dr.), Karadeniz Technical University,
Medical Faculy, Department of Cardiology
mursel61@yahoo.com
ORCID: 0000-0003-0245-2038
Syncope is a symptome characterised by sudden and transient loss of
consciousness (TLOC) of relatively short duration with spontaneous
complete recovery. (1) Syncope is caused by inadequate cerebral blood
flow, most often the result of an abrupt drop of systemic blood pressure. TLOC
is a broader definition that includes syncope. The term of syncope should not be
used for clinical features of other non-syncope causes of loss of consciousness,
such as seizure, head trauma, or apparent loss of consciousness (pseudosyncope).
Syncope can be caused by benign or life-threatening conditions (Table 1.) and is
a common reason for visiting the emergency depatment (ED). Often, the primary
responsibility of the ED clinician is to identify which patients are at high risk for
adverse outcomes. In most cases the underlying cause of the syncope episode
may not be clearly identified in the ED. This chapter will discuss how to evaluate
and manage patients presenting to the ED with syncope.
The incidence of syncope depends on the population being evaluated. Due
to the changes in the definition and because different patient populations were
evaluated, the frequency of syncope in the literature is less than it is and a clear
assessment could not be made. (2) Studies of syncope report prevalence rates
estimated to be 32%-41% in the general populationas and 35% with recurrent
syncope. (3-5) Syncope is more common in women. (6) The first syncope
episode is common around twenties and a sharp increase in incidence after 70
128 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
years of age. (7) Older institutionalized patients have a 7% annual incidence of
syncope, a 23% overall prevalence, and a 30% two-year recurrence rate. (8)
Syncope is defined as a temporary, self-limited loss of consciousness that
usually leads to falling. The underlying mechanism is transient global cerebral
hypoperfusion due to systemic arterial pressure. Decreased venous filling is
usually the main factor contributing to decreased cardiac output. Other factors,
such as bradyarrhythmias or tachyarrhythmias, can also cause impaired cardiac
output and trigger syncope. This is more common in conditions such as left
ventricular dysfunction, severe valvular disease, obstructive cardiomyopathy,
volume depletion, and abnormal vascular reactivity. Inappropriate vasodilation
and inadequate venous return are the main causes of reflex syncope. Decreased
capacity to increase vascular resistance during the upright position is critical in
orthostatic hypotension.
The primary responsibility of the emergency clinician is to assess whether
a life-threatening cause of syncope exists and to ensure appropriate management
and regulation. Cardiac syncope, acute hemorrhage, pulmonary embolism, and
acute cerebrovascular events are the most important causes to consider. conditions
that mimic TLOC/syncope like seizures, sleep disturbances, accidental falls,
and some psychiatric conditions should be also considered.
Syncope could be the initial complaint in 5-12% of patients with acute
myocardial infarction (MI) and is related to arrhythmia or pump failure. (9)
Vasovagal reactions, bradyarrhythmia, and atrioventricular blocks can be caused
by ischemia. Ventricular tachycardia (VT) and bradyarrhythmias secondary to
myocardial ischemia are infrequent causes of syncope. (10) While polymorphic
VT and VF are common during acute ischemic conditions, monomorphic VT is
common for chronic ischemia.
4.2.Cardiacarrhythmias
Cardiac arrhythmias can cause syncope if the heart rate is too slow or too
fast to allow for adequate cardiac output and maintenance of systemic arterial
SYNCOPE IN THE EMERGENCY DEPARTMENT 129
pressure. Bradycardia from prolonged sinus pauses, high-grade atrioventricular
(AV) block or termination of atrial tachyarrhythmia can cause syncope. Similarly,
syncope or a near-syncopal condition may occur at the onset of a tachycardia
episode in which the decrease in cardiac output is not adequately compensated
by vascular constriction. The diagnosis of arrhythmic etiology for syncope is
often difficult, as most are paroxysmal and infrequent. Long-term ambulatory
ECG monitoring is usually required for diagnosis.
4.2.1.AVblock: Complete or Mobitz type II second-degree AV block can
trigger syncope. First-degree and Mobitz type I (Wenckebach) second-degree
AV blocks are usually benign and not associated with syncope.
4.2.2.Cardiacpauses: Cardiac pauses may be caused by intrinsic or drug-
induced sinus pauses or prolonged recovery times after spontaneous termination
of an episode of fast tachycardia.
4.2.3. Ventricular tachyarrhythmias: Syncope from VT occurs most
often in the case of structural heart disease, particularly coronary heart disease.
Patients with cardiomyopathies (eg, hypertrophic and dilated cardiomyopathy,
arrhythmogenic right ventricular cardiomyopathy (ARVC)) are also prone to VT
occurring with syncope. Congenital or acquired long QT syndrome can cause
torsades de pointes, an unusual form of VT. Rare genetic cardiac ion channel
diseases such as Brugada syndrome and catecholaminergic polymorphic VT
(CPVT) also should be considered as differential diagnoses of syncope. Syncope
is a relatively common presentation in Brugada syndrome (BrS), an inheritable
primary arrhythmia syndrome. Considered one of the J wave syndromes, BrS
has several clinical and genetic similarities with early repolarization syndrome
(ERS). (11)
4.2.4. Supraventricular tachyarrhythmias: Supraventricular tachyar-
rhythmias are rarely associated with syncope. Syncope may occur more often
in relatively fast tachycardias or at the onset of tachycardia or during exercise.
4.3.Structuralcardiac or cardiopulmonarydisease: Heart failure with
low ejection fraction, severe aortic stenosis, hypertrophic cardiomyopathy, atrial
myxoma, pulmonary embolus, pulmonary hypertension, pericardial tamponade,
and acute aortic dissection are common causes of syncope and emergency
consults.
4.3.1. Aortic stenosis: Syncope in patients with aortic stenosis is often
associated with exertion. Aortic stenosis presents with syncope if the valve is
critically stenotic. (12). Although it is mostly seen in the elderly, it can also be
seen in young people in the case of bicuspid aortic valve.
130 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
4.3.2. Hypertrophic cardiomyopathy: Syncope occurs due to dynamic
left ventricular outflow tract (LVOT) obstruction. LVOT obstruction may
be exacerbated by postural changes, hypovolemia, or medications. In these
patients, the cause of syncope is often ventricular arrhythmias or decreased
cardiac output.
4.3.3. Other causes: Pulmonary embolism, severe pulmonic stenosis,
pulmonary arterial hypertension, and atrial myxomas are other rare causes of
syncope due to obstruction of blood flow. (13)
4.4. Cerebrovascular disease: Atherosclerotic disease of the cerebral
arteries is not a cause of true syncope, but stroke and episodes of transient
ischemia cause focal neurological deficits that do not heal rapidly and completely.
4.5.Reexsyncope: Reflex syncope is a condition in which a reflex response
causes vasodilatation and/or bradycardia leading to systemic hypotension and
cerebral hypoperfusion with TLOC. Types of reflex syncope include vasovagal
syncope, situational syncope, and carotid sinus syncope.
4.6. Orthostatic (postural) hypotension: Orthostatic syncope most
commonly occurs following a transition from a lying or sitting position to a
standing position. Orthostatic hypotension, defined as a decrease in systolic blood
pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg in
standing upright. The major causes of orthostatic hypotension associated with
syncope are decreased intravascular volume due to inadequate fluid intake and
excessive fluid loss. Drugs are other important cause of orthostatic syncope.
Antihypertensive drugs like alfa and beta blockers, nitrates are often related
with syncope especially in older patients.
4.7.Otherconditions
4.7.1. Neurologic syncope: Syncope could be the only sign of some
neurological disorders like subarachnoid hemorrhage, transient ischemic attack,
subclavian steal syndrome, epilepsy, and complex migraine headache. a history of
non-syncope episodes featuring neurologic deficits, possibly including diplopia,
vertigo, focal weakness, or numbness is often. Syncope can be misinterpreted
as a seizure because many patients with TLOC experience brief convulsive
episodes secondary to cerebral hypoperfusion, especially if bystanders or objects
are holding them upright. Syncope can usually be distinguished from a seizure
by the shortness of the convulsions; epileptic aura, urinary or fecal incontinence,
absence of tongue biting; and the absence of a true postictal phase (typically five
minutes or longer)).
SYNCOPE IN THE EMERGENCY DEPARTMENT 131
4.7.2. Psychiatric syncope: Anxiety and panic disorders can cause
situational syncope ofttimes. Emergency clinicians must be cautious when
attributing syncope to psychiatric causes. Patients with hypoxia, inadequate
cerebral perfusion, or other medical conditions may appear confused or anxious.
Patients with psychiatric syncope are generally young, without cardiac disease,
and complain of multiple episodes. (14)
4.7.3.Drug-inducedlossofconsciousness: Drugs of abuse and alcohol
can cause a temporary loss of consciousness, but often these patients show signs
of toxicity and do not spontaneously return to normal neurological function
soon after regaining consciousness. Alcohol can also impair vasoconstriction,
causing symptomatic orthostasis. (14)
4.7.4.Metabolic: Metabolic causes of syncope include hypoglycemia and
hypoxia. Electrolyte abnormalities due to kidney damage or other conditions
can precipitate arrhythmic syncope.
The first problem is determining whether the episode was due to syncope
or some other cause of real or apparent TLOC. Detailed history and physical
examination are very important for differential diagnoses. However, in emergency
conditions, a definite diagnosis may not be revealed. The most critical issue to
be decided in the emergency department should be risk stratification.
5.1.History:The clinical features characterizing TLOC are usually derived
from history taking from patients and eyewitnesses. History and physical
examination are sufficient to diagnose in approximately half of the patients.
Specific signs and symptoms are important to determine high risk for serious
outcomes, particularly sudden death. (16)
5.1.1.Age: Vasovagal syncope is more common in young people. However,
if there is exertional syncope, and a family history of sudden death, arrhythmic
causes should also be considered. Again, pathological physical examination
findings should suggest a structural disorder. Risk of adverse outcomes
incereases with age. (17) Coronary artery disease, aortic stenosis, pulmonary
embolism is the most common causes in olders. Also autonomic dysfunction,
orthostasis, and multiple medications are commom among older patients. Age is
also important for risck stratification.
5.1.2. Associated symptoms and triggers: Associated symptoms can
provide important diagnostic clues. Chest pain may indicate acute coronary
132 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
syndrome or pulmonary embolism. Dyspnea raises concern for pulmonary
embolism or heart failure. Accompanying palpitations suggest arrhythmia.
Headache and neurological symtopms may indicate a neurological cause.
Vasovagal syncope generally precedes and often includes symptomes such as
warmth, nausea, vomiting and diaphoresis, either just prior to or shortly after
the event. It is also helpful to question vasovagal triggers. Triggers commonly
associated with vasovagal syncope include strong physical or emotional stress,
voiding, defecation, coughing, swallowing, and prolonged standing in a warm
environment.
5.1.3. Position: Fainting associated with vasovagal syncope is often
associated with prolonged standing. Although very rare, vasovagal syncope in
the sitting or supine position can occur. Arrhythmic syncope can be considered
in such situations.
5.1.4.Durationofsyncope: Measuring the duration of a syncope event is
often difficult because patients are unconscious and events are often unwitnessed.
Reflex syncope attacks are of very short duration and resolve quickly when
lying down, but syncope longer than four or five minutes should raise concern
for other causes.
5.1.5. Exertional syncope: Syncope with exertion raises the possibility
of arrhythmia or cardiac outflow obstruction (eg, aortic stenosis, hypertrophic
cardiomyopathy, pulmonary embolisn or pericardial tamponade). Detailed
physical examination and imaging should be considered.
5.1.6. Medications: A review of the patient’s medications may reveal
the cause of syncope. This is particularly important with older adult patients.
Medications often implicated include calcium channel blockers, beta blockers,
alpha blockers, nitrates, antiarrhythmics, diuretics (affecting volume status and
electrolyte concentrations), and medications affecting the QTc interval (eg,
antiarrhythmics, antipsychotics etc)
5.1.7.Priorepisodes: A history of syncopal episodes may be of value. A
single episode or multiple episodes over many years suggests a benign etiology.
Several episodes over a short period of time in someone with no history of
syncope suggest a more significant cause, such as dysrhythmia.
5.1.8. Family history: A family history of unexplained sudden death,
dysrhythmia, or early cardiovascular disease places patients at increased risk for
cardiac syncope
5.1.9. Associated injury: Acute loss of consciousness may result in
significant events. like motor vehicle accidents, fractures, and hemorhage.
SYNCOPE IN THE EMERGENCY DEPARTMENT 133
These conditions are observed more frequently in patients without prodrome
symptoms.
The examination should focus on vital signs;
blood pressure measurements, pulses, cardiac, pulmonary, abdominal, rectal,
and skin signs. Any new focal neurologic findings suggest a primary central
nervous system lesion. Most patients with syncope will have normal physical
examination findings. (18)
6.1.Vitalsigns: Transient bradycardia or hypotension occurs during most
episodes of syncope. Abnormal vital signs usually return to normal during
evaluation in the emergency department. Persistent abnormal vital signs are of
concern and should be investigated. Upper extremity differences in heart rate
or blood pressure may be the sign of aortic dissection. Low oxygen saturation
or tachypnea are common with cardiac failure or pulmonary embolism.
Orthostatic vital signs should be obtained. The patient should lie on their back
for five minutes before the first set is achieved. After the patient has been
standing for three minutes, vital signs are taken again and compared with the
initial measurements. (19) A drop in systolic blood pressure of 20 mmHg or
more or an increase in heart rate of 20 beats per minute or more are compatibble
with orthostatic hypotension. If available, pacemakers or wearable devices can
be used in diagnosis by evaluating the records of vital signs at the time of the
event.
6.2. Cardiac examination: Auscultation of the heart may reveal a rate
that is either abnormal or irregular. Murmurs and extra heart sounds may be
diagnostic for structural heart diseases like aortic stenosis and HOCM. The
presence of an implantable pacemaker should be noted as malfunction may lead
to syncope.
6.3.Lungexamination: Auscultation of the lungs may reveal abnormal
sounds consistent with heart failure or other pathologies (eg, pulmonary
embolism, cardiac ischemia).
6.4.Neurologicalexamination: By definition, patients with syncope return
to basic neurological function. A thorough examination should be performed to
identify any subtle focal abnormalities suggestive of stroke.
6.5. Rectal examination: Rectal examination with the stool guaiac test
can identify some patients with gastrointestinal bleeding who may present with
syncope.
6.6. Intraoral examination:Tears on the lateral surface of the tongue
suggest a seizure
134 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
After the initial evaluation by history and physical
examination, some tests are required to confirm the diagnosis of syncope and
exclusion of differential diagnosis.
7.1. Electrocardiogram: Practice guidelines suggest that all patients
presenting with syncope should receive an electrocardiogram (ECG). (20). ECG
should be evaluated immediately at admission to the emergency department.
patients should be followed up continuously in order to record the arrhythmias
that may recur during the follow-up. Any abnormalities in ECG suggests
a cardiac problem, and further investigation is needed. evidence of cardiac
arrhythmia or ischemia as the cause of syncope should be assessed with the
ECG. A list of ECG features associated with arrhythmia is found in Table 4. (21)
ECGs of patients with pacemakers should be evaluated by a cardiologist, and
even the functions of the device should be controlled with a programmer.
Clinical and electrocardiographic (ECG) features of
patients with syncope at high risk of an arrhythmic cause
Persistent sinus bradycardia <40 beats per minute or sinus pauses >3 seconds in an
awake patient
Third-degree (complete) AV block, Mobitz II second-degree AV block
Significant structural heart disease or CAD ()
Preexcited QRS complexes, suggesting Wolff-Parkinson-White syndrome
VT or paroxysmal supraventricular tachycardia with rapid ventricular rate
Long or short QT intervals
Right bundle branch block pattern with ST elevation in leads V1 to V3 (Brugada
syndrome)
Pacemaker or implantable cardioverter-defibrillator malfunction with cardiac pauses
Alternating left and right bundle branch block
Negative T waves in right precordial leads and epsilon waves suggestive of
arrhythmogenic right ventricular cardiomyopathy
7.2. Laboratory evaluation: There is no clear evidence for routine
laboratory screening in patients with syncope. However, routine kidney and liver
tests, blood count, electrolyte levels should be evaluated. For such conditions as
myocardial infarction, pulmonary embolism, troponin and d- dimer should be
performed.
SYNCOPE IN THE EMERGENCY DEPARTMENT 135
7.3. Neurologic studies: Patients with a history of transient ischemic
attack, stroke, or new-onset seizure, or suspected on physical examination,
require further evaluation. Patients without historical or examination features
suggestive of neurological disease do not need further neuroimaging. Despite
the low diagnostic yield of brain imaging, clinicians continue to overuse head
computed tomography and magnetic resonance imaging in the evaluation
of patients with syncope. An electroencephalogram may be useful in some
situations where distinguishing syncope from seizure is clinically difficult. (22)
7.4. Echocardiography: While not immediately available in most
emergency departments, echocardiography is helpful in identifying the
presence of structural heart disease and is being performed at the bedside by
more emergency room physicians. For patients with suspected heart disease,
echocardiography serves to confirm or refute the suspicions in equal proportions
and plays an important role in risk stratification. Echocardiography identifies the
cause of syncope in very few patients when no more tests are needed (i.e. severe
aortic stenosis, obstructive cardiac tumours or thrombi, pericardial tamponade,
or aortic dissection).
The most important tasks for the emergency clinician faced with a syncope
patient are to identify and manage life-threatening problems and to differentiate
between patients safe for discharge and those who require immediate
investigation and in-hospital management. The risk classification recommended
by the ESC guideline is shown in the Table 2. The risk stratification flowchart is
also shown in Figure 1. (21) Treatment is based upon the underlying cause. In
most conditions treatment includes only prevention for recurrences, preventing
falls and sometimes death.
8.1.Immediatetreatment
The immediate treatment of a patient with syncope includes; laying
down the patient supine, with legs elevated if possible, assessing vital signs to
distinguish cardiac arrest from syncope. For patients who are hypotensive but
lack bradycardia, fluid resuscitation must be the first approach to subsequent
treatment. Patients with symptomatic bradycardia or high-grade AV block
atropine and if not sufficient followed by temporary cardiac pacing are the initial
treatments. Dobutamine or isoproterenol infusion may help to increase heart rate
if atropin is ineffective and temporary pacing is not available.
136 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
. High and low-risk features in patients with syncope at
initial evaluation in the emergency department
High
risk
Majör Minor
- New onset of chest discomfort, breathlessness,
abdominal pain, or headache
- Syncope during exertion or when supine
-Sudden onset palpitation immediately followed
by syncope
- No warning symptoms or
short prodrome (<10 s)
- Family history of SCD at
young age
- Syncope in the sitting position
Low
risk
- Associated with prodrome typical of reflex syncope
- After sudden unexpected sight, sound, smell, or pain
- After prolonged standing or crowded, hot places
- During a meal or postprandial
- Triggered by cough, defaecation, or micturition
- With head rotation or pressure on carotid sinüs
- Standing from supine/sitting position
High
risk
- Severe structural or coronary artery disease
Low
risk
- Long history of recurrent syncope with low-risk features with the same
characteristics of current episode
- Absence of structural heart disease
High
risk
- Unexplained systolic BP in the ED<90 mmHg
- Suggestion of gastrointestinal bleeding on rectal examination
- Persistent bradycardia (<40 bpm) in awake state and in absence of physical training
- Undiagnosed systolic murmur
Low
risk
- Normal examination
High
risk
Major Minor
- ECG changes consistent with acute ischemia
- Mobitz II second and third degree AV block
- Slow AF
- Persistent sinüs bradicardia or repetitive
sinoatrial block or sinüs pauses >3 seconds in
awake state and in the absance of physical training
- Bundle branch block, intraventricular
conduction disturbance, ventricular hypertrophy
- Sustained and non-sustained VT
- Dysfunction of an implantable cardiac device
- Type 1 Brugada pattern
- QTc>460 ms in repeated 12-lead ECGs
indicating LQTS
- Mobitz type I second degree
AV block and
– First degree AV block with
markedly prolonged PR interval
- Asymptomatic inappropriate
mild sinüs bradicardia or slow
AF
- Paroxysmal SVT or AF
- Preexited QRS (WPW)
- Short QTc interval (<340 ms)
- Atypical Brugada patterns
- Negative T waves in right
precordial leads, epsilon waves
suggestive of ARVC
Low
risk
-Normal ECG
SYNCOPE IN THE EMERGENCY DEPARTMENT 137
Emergency department risk stratification flow chart
8.2.Treatmentofrecurrences:Patient education is important to prevent
recurrent syncope and to reduce the risk of traumatic injury and even death.
If possible, triggers should be addressed directly, such as cough uppression in
cough syncope, micturition in the sitting position, etc. Increased intake of oral
fluids is also advised. Prolonged standing should be avoided. Patients should
be educated to recognize early symptoms and take action to avert syncope and
reduce the risk of injury. If the symptoms are mild, the patient may perform a
physical counterpressure maneuver while moving safely to a seated or supine
position, which should terminate the episode. If the symptoms are severe, the
patient should move directly to a supine position. In either case, they should
remain in a safe, gravitationally neutral position long enough to be sure that all
of the warning symptoms have subsided. Patients with vasovagal syncope and
prodromal symptoms should be taught how to perform physical counterpressure
maneuvers. The rationale for these maneuvers is to reduce venous pooling
and thus improve cardiac output. Some examples of these maneuvers are leg-
crossing, handgrip, and arm tensing. Careful avoidance of agents that lower BP,
i.e. any antihypertensive agents, nitrates, diuretics, neuroleptic antidepressants,
or dopaminergic drugs, is key in the prevention of recurrence of syncope.
Additional treatment may be necessary in patients with severe forms when
very frequent syncope alters quality of life; when recurrent syncope without, or
with a very short, prodrome exposes the patient to a risk of trauma; and when
syncope occurs during a high-risk activity. The general framework of treatment
is based on risk stratification and the identification of specific mechanisms when
possible (Figure 2).
138 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
The general framework of treatment
In most cases the prognosis of the patient with syncope is
directly related to the underlying etiology and the underlying comorbidities.
Those with an underlying cardiovascular cause are at higher risk for sudden
death and all-cause total mortality rates than those with a noncardiovascular
cause. Overall mortality in the cardiovascular group after five years of follow-up
has been reported to approach 50 percent, with a 30 percent incidence of death
in the first year. (25) A major problem in determining the true mortality rate in
patients with syncope is that most individuals with TLOC do not seek medical
advice. It is suspected that most individuals have a low recurrence rate of syncope
and an excellent long-term survival in the absence of underlying cardiac disease
or channelopathy (eg, long QT syndrome, Brugada syndrome). (26) Underlying
cardiac disease substantially increases mortality risk. Outpatients never admitted
for their episodes may be at lesser risk for recurrence and have a more benign
long-term prognosis than those requiring hospitalization.
Syncope is a common clinical problem, which is one of
the many causes of transient loss of consciousness (TLOC). Syncope patients
often present to emergency department first. The most important step of the
first evaluation here is the risk classification. The highest mortality risk occur
when syncope is associated with underlying cardiac disease. Syncope in the ED
should remain an area of focus given the high cost associated with ED visits, and
the impact that ED clinicians have on decisions related to hospital admissions.
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141
1
1(Dr.), Balıkesir University, Medicine Faculty,
Physiology Department, Balıkesir, Turkey
e-mail: hasanmonica@hotmail.com
ORCID: 0000-0002-3729-1863
2(Asst.Prof. Dr.) Kırşehir Ahi Evran University,
Medicine Faculty, Physiology Department, Kırşehir, Turkey
e-mail: sdakocak@gmail.com
ORCID: 0000-0003-1183-4847
Metabolic syndrome (MetS), abdominal obesity starting with insulin
resistance, glucose intolerance and It is a fatal endocrinopathy
combined with systemic disorders such as diabetes mellitus,
dyslipidemia, hypertension and coronary artery disease (1). Instead of metabolic
syndrome, insulin resistance syndrome, syndrome X, poly metabolic syndrome,
fatal quartet, and civilization syndrome is used also medical terminology (2).
Long-term (one year) multidisciplinary therapy via physicians, nutritionist,
physiologists, psychologist showed that beneficial effect on metabolic
disorders (3).
Anxiety disorders are one of the most common mental illnesses (4).
Anxiety Disorder Is associated with metabolic Syndrome in some studies (5, 6).
While anxiety was not observed in patients with metabolic syndrome in some
clinical studies, depression was observed to be significant (7). Some authors
argue that anxiety occurs as a by-product of coexistence with depression (8).
According to a systematic review and meta-analysis, there is an association
between anxiety and metabolic syndrome (9).
Some of the different applications used to trigger off MetS in animals
include dietary regimes, genetic modification and drugs administration (10).
Anxiety-like behaviors are conditional or unconditional examined by animal
142 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
anxiety tests (11). It is the most frequently preferred anxiety test to induce
natural and unconditional anxiety in rodents (12). Because of the variety of
metabolic syndrome models in this study, anxiety-like behaviors were only
examined in the elevated plus maze test. Conditional or unconditional anxiety
tests applied other than the elevated plus maze test were excluded. The changes
in anxiety-like behavior in the generated tables only include the results from the
elevated plus maze.
The new environment triggers anxiety-like behaviors in the subject who is
taken from the cage and placed in the new environment. The height in the test
setup is the second factor affecting anxiety-like behaviors. Subject exposed to
height exhibits sheltering behavior from the open arms of the maze to the closed
arm. Therefore, the time spent in the open arm and the number of entries into the
open arm are reduced. An increase in stretch-attend posture posture due to stress
can also be observed in the open arm (11). Furhermore head dipping behavior
(Exploratory behavior) decrease adversly in the open arm (13).
An increase in anxiety like behavior was clearly observed in some of
the analyzed studies (14, 15).In some studies, some behavioral patterns were
negatively affected, while others were not (16 ,17, 18).
There are also studies that show no change in the elevated plus maze (19,
20). Rebolledo-Solleiro et al reported that metabolic rats displayed anxiety
like behaviors in the open field test and marble burying test in same study
(19). According to Santos et al, 2017, anxiety lile behaviors were increased
in metabolic syndrome rats under restraint stress but non- stressed metabolic
syndrome’s rat not (20).
Metabolic syndrome can also be seen in polycystic ovary syndrome
patients. One of the polycystic ovary syndrome model is dehydroepiandrosterone
(DHEA)-induced rodent model (21). Polycystic female rats induced by
5α-dihydrotestosterone exhibited anxiety like behavior in elevated plus
maze (22).
Although the general result of the studies is towards an increase in anxiety-
like behaviors, the underlying mechanisms have not been fully elucidated. More
preclinical studies are needed regarding anxiety and metabolic syndrome.
THE STATE OF ANXIETY-LIKE BEHAVIORS IN ANIMALS WITH METABOLIC SYNDROME 143
Table 1: Elevated plus maze parameters
Behavior patterns and unit Describtion
Open arm time
(time or %)
Risky area and trigger off anxiety
like behavior.
Open arm entrance
(number or %)
Risky area and trigger off anxiety
like behavior.
Head dipping
(number)
exploratory behavior
Stretcg-attend- postüre
(number)
Stress inudced posture
Table 2: Metabolic Syndrome Model Results in the Elevated Plus Maze
Study Metabolic
Syndrome Model
Animal Behavior parameters Result
Dinel et al,
2011 (15)
Genetic db/db mice Open arm time (%)↓,
Open arm entrance ↓
ALB ↑
Ressler et al,
2015 (17)
High Fat Diet+
dihydrotestosterone
female Long-
Evans rats
Open arm time (%)↓,
Open arm entrance ↔
ALB ↔, ↑
Rebolledo-
Solleiroet al,
2017 (19)
High Sucrose Diet Male rats Open arm time ↔, Open
arm entrance (%)↔
ALB↔
Santos et al,
2018 (20)
high refined
carbohydrate-
containing diet
Male
BALB/c
mice
Open arm time(%)↔,
Open arm entrance (%)↔
ALB↔
Ribeiro et al,
2020 (18)
High Fructose Diet Male Wistar
Rat
Open arm time↔
Open arm entrance↓
Stretch-attend posture↑
ALB↔, ↑
Coêlho et al,
2021 (16)
Monosodium
L-glutamate (MSG)
Male swiss
mice
Open arm entrance ↔
Rearing number ↓
ALB↔, ↑
Bayram et al,
2022 (14)
High Sucrose Diet Male Wistar
Albino rat
Open arm time↓
Open arm entrance↓
Stretc-attend posture↑,
head dipping behavior ↓
ALB ↑
ALB: Anxiety-like behavior, ↑: increase, ↓: decrease, ↔: not change
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İki Hastanesinde Metabolik Sendrom Riski ve Anksiyete İlişkisinin
Değerlendirilmesi Evaluation of the Relation between Metabolic Syndrome and
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syndrome: a systematic review and meta-analysis of epidemiological studies.
Psychoneuroendocrinology. 2017;77:112-121.
10. Wong SK, Chin K-Y, Suhaimi FH, Fairus A, Ima-Nirwana S. Animal
models of metabolic syndrome: a review. Nutrition & metabolism.
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11. Çalışkan H, Fırat A, Zaloğlu N. Şartsız Hayvan Anksiyete Testleri.
Ankara Sağlık Hizmetleri Dergisi. 16(1):35-40.
12. Korte SM, De Boer SF. A robust animal model of state anxiety:
fear-potentiated behaviour in the elevated plus-maze. European journal of
pharmacology. 2003;463(1-3):163-175.
13. Caliskan H, Akat F, Tatar Y, et al. Effects of exercise training on anxiety
in diabetic rats. Behavioural brain research. 2019;376:112084.
14. Bayram P, Billur D, Kizil S, Caliskan H, Can B. Alterations in
hippocampal neurogenesis and hippocampal insulin signaling pathway in rat with
metabolic syndrome. Iranian Journal of Basic Medical Sciences. 2022;25(11)
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15. Dinel A-L, Andre C, Aubert A, Ferreira G, Laye S, Castanon N.
Cognitive and emotional alterations are related to hippocampal inflammation in
a mouse model of metabolic syndrome. PloS one. 2011;6(9):e24325.
16. Coêlho CFF, Souza ILS, Chagas VT, et al. Myricetin improves
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in male mice. Food & Function. 2021;12(8):3586-3596.
17. Ressler IB, Grayson BE, Ulrich-Lai YM, Seeley RJ. Diet-induced
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syndrome in a rodent model. American Journal of Physiology-Endocrinology
and Metabolism. 2015;308(12):E1076-E1084.
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147
(Asst. Prof. Dr.), Karamanoğlu Mehmetbey University, Faculty of Health
Sciences, Department of Physiotherapy and Rehabilitation
e-mail: mlselcuk@hotmail.com
ORCID: 0000-0002-9915-3829
The eye, which is the least growing organ after birth, is called oculus in
Latin and ophthalmus in Greek. A pair of eyes has about 70% of the
receptors in the whole body. In addition, 1/3 of all afferent nerve fibers
going to the central nervous system come out of the eye. In birds, the eye is
highly developed according to their lifestyle, habitat and physical activity. Their
visual acuity is excellent and color vision is well developed. It is believed that
most birds, with the exception of birds that hunt at night, can detect light in the
ultraviolet spectrum. The visual organ consists of the eyeball (bulbus oculi),
located in the orbit, and the accessory structures of the eyeball such as extraocular
muscles, orbital fascia, eyelids, eyelashes, eyebrows, orbital fat tissue, and tear
system (1,2).
The eyeball (Bulbus oculi) is classified into three different types according
to its shape in poultry. The eye is “flat” in flat-headed diurnal birds such as
domestic chickens, “spherical” in sparrows and wider-headed diurnal birds
hunting during the day, and “tubular” in nocturnal birds hunting at night (3).
It consists of two parts, formed by the intertwining of two spheres of different
diameters, the smaller part of which remains outside. The anterior part of the
small sphere, called the cornea, is transparent and forms 1/6 of the bulbus oculi.
The posterior part, which forms 5/6 of it, belongs to the large sphere and is not
transparent. The anterior most prominent point of the eyeball is called the polus
148 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
anterior. This forms the central part of the cornea. The most protruding part at
the back is called the pole posterior. The straight line connecting the outer part
of these two protruding parts is called axis bulbi externus, and the straight line
connecting their inner faces is called axis bulbi internus. The line starting from
the pole anterior and ending in the fovea centralis of the retina is called the axis
opticus (4,5).
2.1.EyeLayers
The bulbus oculi is composed of three layers: tunica fibrosa bulbi, tunica
vasculosa bulbi and tunica interna bulbi. Tunica fibrosa bulbi consists of two
parts, the cornea anteriorly and the sclera posteriorly. The sclera is made of fibrous
tissue with a hard structure and is not transparent. It forms 5/6 of the eyeball
and maintains the shape of the eyeball and its volume by resisting intraocular
pressure (6). The thickness of the sclera becomes thinner from the posterior to
the equator. In front of the equator, the thickness of the repeat increases due
to the adhesion of the tendons of the muscles that move the eye. The anterior
part of the sclera, that is, the part covered by the eyelids, is covered by the
conjunctiva. The outer surface of its posterior part is in contact with the inner
surface of the vagina bulbi (Tanon capsule), which separates the bulbus oculi
from the orbita. There is a loose connective tissue called the lamina episcleralis
within this range. In poultry, the distal part of the sclera bordering the cornea
contains bone plates called anulus ossicularis sclerae, which are located in about
14 scleral rings like fish scale. This structure strengthens the bulbus oculi and
forms the origin of the striated muscles that provide accommodation. The inner
surface of sclera is brown and corrugated. Cilar vessels and nerves are located
in these grooves (1,3). The inner face is attached to the lamina suprachoroidea,
the outermost layer of the choroidea. On its posterior side, there is a perforated
area called the lamina cribrosa sclerae, through which the fibers of the n. opticus
pass. This is its weakest area, and the nerve fibers forming the n. opticus, a. and
v. centralis retina pass from here. Where N. opticus emerges from the sclera, this
layer extends over the nerve, forming a fibrous sheath, and then continues as the
dura mater. The sclera continues anteriorly with the cornea, and at the junction
of these two structures there is an outer groove, sulcus sclerae. In cross section of
the eye, the anterior margin of the sclera appears as two leaves, between which
the thin edge of the cornea is inserted. In the inner part of this fork, there is lig.
pectinatum anguli iridocornealis, which is made of connective tissue to which
m. ciliaris is attached with lig. pectinatum. This structure separates the camera
EYE ANATOMY AND PECTEN OCULI 149
anterior from the sinus venosus sclera (schlemm’s canal), which carries the
humor aquosus in the camera anterior bulbi into the venous circulation (4,5,7).
The cornea is the transparent part of the outer layer of the eye and forms
the anterior 1/6 of the eyeball. It has no blood vessels except its periphery. Its
nutrition is by diffusion from the tissue fluid circulating in the spaces between
the lamellae. It has many free nerve endings. If the ratio of the surface area of
the cornea to that of the sclera increases, there will be more light transmission
(1,5). Nocturnal (night active) animals have larger cornea than diurnal (day
active) animals. The most protruding anterior part of the convex anterior surface
(facies anterior), which is in contact with the eyelids, is called vertex cotneae.
Its concave posterior surface (facies posterior) limits the camera anterior. The
thin peripheral edge of the cornea is called the limbus corneae. This place inserts
into the groove formed by the anterior edge of the sclera. When viewed from the
front, the cornea is slightly flattened from above to the back (8).
Tunica vasculosa bulbi is a layer with a lot of vascularization and loose
connective tissue rich in fibroblasts, macrophages, mast cells, plasma cells,
collagen and elastic fibers between blood vessels and consists of three parts (7).
These are choroidea, corpus ciliare and iris. Choroidea, a thin layer very rich
in vessels, lies in the 5/6th of the bulbus oculi and extends to the ora serrata
by laying the inner surface of the sclera. Although the dark brown choroidea
adheres more firmly to the sclera in the part where the n. opticus enters, it is
loosely attached in the remainder. Between the outer surface and the sclera is
a space called spatium perichoroideale. This range contains connective tissue,
nerves, and vessels that are loosely attached to the sclera. The inner surface is
firmly attached to the retina. In the posterior outer and outer part of this face,
just above the discus nervi optici, there is a bright and colorful region called the
tapetum lucidum. Since this formation reflects the light falling on it, it gives the
animal the opportunity to see better in the dark (2,5). Tapetum lucidum cells
reflect the incoming light, allowing the receptor cells to be stimulated a second
time with the same light. This gives a very good view even in minimal light. The
reflected light moves forward and passes out through the pupil. Reflected light
is the reason why animals’ eyes shine when light hits them at night. Choroidea
consists of four layers from outside to inside. These are lamina suprachoroidea,
lamina vasculosa, lamina choroidocapillaris, lamina basalis (1,9).
The corpus ciliare is the part of the middle layer that extends from the ora
serrata to the outer edge of the iris. Its main structure is m. ciliaris and connective
tissue. The peripheral ends of the fibrae zonulare, which hang the lens, attach
150 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
to the corpus ciliare and cover the thin pigment layer of the retina (pars ciliaris
retinae) on its inner surface. On the inner surface of the corpus ciliare, there
are plicae ciliares starting from the ora serrata and extending radially towards
the iris. A few of these folds combine to form thicker projections called the
processus ciliaris, which run in the same direction. The ring formed by arranging
the plica ciliaris side by side is called orbicularis ciliaris. The ring formed by
the processus ciliaris in a radial fashion is called corono ciliaris. Fibers called
fibrae zonulares begin from the processus ciliaris, extending towards the lens
and holding it in place. These fibers are involved in the accommodation of the
eye with the m. ciliaris (10,11). Processus ciliaris are structures rich in blood
vessels. The humor secreted from here flows into the camera posterior bulbi
between the anterior surface of the aquosus lens and the posterior surface of
the iris, and passes from the pupil to the camera anterior bulbi. Then it comes
to the angulus iridocornealis, which is the junction of the iris and cornea,
and passes through the trabecular tissue in the sclera and pours into the sinus
venosus sclerae (schlemm’s canal). M. ciliaris consists of smooth muscle fibers
contained within the corpus ciliaris. In mammals, it starts from the reticulum
trabeculare and extends in four different directions. These fibers are named
fibrae meridionale (brücke muscle), fibra longitudinales, fibra radiales and fibra
circulares (müller muscle) according to their directions. In domestic birds, mm.
ciliares are transversely striped, consisting of two or three segments. The outer
part is the Crampton’s muscle. This muscle originates from the connective tissue
covering the bony layers of the anulus ossicularis sclerae. Behind this muscle is
the Brücke muscle (5,12).
The iris, meaning rainbow, is located behind the cornea as a circular
formation. The color of the iris in poultry is dependent on breeding and age.
In the middle is a round hole called the pupil. It is one of the three parts of the
tunica vasvasculosa bulbi and is located between the cornea and the lens or in
front of the lens. It has two edges, an outer and an inner. Its outer edge attaches to
the corpus ciliare. This edge is called the margo ciliaris. Its inner edge delimits a
hole in the middle of the organ, called the pupil, which varies in shape according
to the species. This edge, which limits the pupil, is called the margo pupillaris
(4,13). The iris has two faces, one anterior and the other posterior. Its anterior
surface is called facies anterior, and this face facing the cornea also forms the
posterior wall of the camera anterior bulbi. On this face, there is a narrow ring
near the pupil, called the anulus iridis minor. On the outside of this narrow ring,
there is another wider light colored ring, which is called the anulus iridis major.
EYE ANATOMY AND PECTEN OCULI 151
The folds on the same face, close to and parallel to the margo pupillaris, are also
called plicae iridis. The posterior aspect of the iris is called facies posterior. It is
the inner face facing the lens and is concave (1,2,8).
Tunica interna bulbi is the innermost light-sensitive layer of the eyeball.
This layer, also called the retina, thins towards the ora serrata. Its outer surface is
in contact with the choroidea and its inner surface with the vitreous membrane,
and it is also thin in the discus nervi optici and macula. The retina consists
of two layers, the stratum pigmentosum and the stratum nervosum (2,14). The
pars pigmentosa is a pigment layer that covers the entire inner surface of the
tunica vasculosa. The pars nervosa extends from the discus nervi optici to the
ora serrata on the inner surface of the pars pigmentosa. The part of the retina
from discus nervi optici to ora serrata is called pars optica retinae. This is the
part of the eye that actually sees. The invisible part in front of the ora serrata,
between the processus ciliaris and the posterior aspect of the iris, is called the
pars ceca (caeca) retinae. The part of the pars ceca retinae that covers the corpus
ciliare is called the pars ciliaris retinae, and the part that covers the posterior
surface of the iris is called the pars iridica retinae. Unlike mammals, poultry
has pecten oculi, which originates from the retina due to its development and
cellular structure (5,12,15).
The retina is soft, translucent and has a purplish color in vivo because
of the rhodopsin. A round, yellow colored area is seen in the posterior part
of the retina. This area that receives the best light is called macula lutea in
humans and area centralis rotunda in animals. The depression in the middle
of the macula is called the fovea centralis. In addition, discus nervi optici is
seen in the part where the n. opticus pierces the retina. This part differs from
one species to another (1,2). The depression in the middle of the discus nervi
optici is called excavatio disci. A. and v. centralis retinae passes through this
part. It is also known as the blind spot because there are no photosensitive
receptors in this part. The retina is the only place where the artery can be
seen directly. Pars optica retiae contains bacillus and cone cells, bipolar,
multipolar ganglion and amacrine cells from outside to inside. The retina of
domestic mammals is mostly rod-shaped, while the retina of domestic birds
mostly has cone-shaped cells. Rods are the photoreceptor cells responsible for
black and white vision, and cones are responsible for color vision. Rods are
highly sensitive to light and are used for night vision, while cones provide the
best daytime vision. The axons of the multipolar ganglion cells also extend
towards the papilla nervi optici and form the n. opticus. The retina consists of
152 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
two layers, the outer stratum pigmentosum and the inner stratum nervosum.
Histological sections from the choroidea to the corpus vitreum show that it
consists of ten layers (2,16).
2.2.Camerabulbi
There are three cameras in the eye: camera anterior bulbi, camera posterior
bulbi, and camera vitrae bulbi. The camera anterior bulbi is bounded anteriorly
by the posterior surface of the cornea, posteriorly by the anterior surface of the
iris, and where the pupil is located, by the middle part of the anterior surface of
the lens. It is filled with humor aquosus. The part where it joins the corpus ciliares
and iris is called the angulus iridocornealis. On the outer wall of this corner is
the sinus venosus sclerae (schlemm’s canal) (1,17). The camera posterior bulbi
is located between the iris, lens, corpus vitreum, and corpus ciliare. Since the
middle part of the anterior surface of the lens is in contact with the pupil and its
surroundings, the camera posterior bulbi is a narrow gap between the peripheral
parts that are not in contact. The lens, corpus vitreum, processus ciliaris and
attached fibra zonularis are located posterior to the camera posterior bulbi. On
the anterior side, it limits the peripheral part of the posterior surface of the iris that
does not come into contact with the lens. The pupil connects the camera anterior
et posterior bulbi to each other 4,5. The camera vitrae bulbi is the part behind the
retina, corpus ciliare and lens and forms the internal cavity in the bulbus oculi.
It is filled with a substance called the corpus vitreum. The corpus vitreum is the
largest of the refracting structures and fills the camera vitrae bulbi behind the
ora serrata. The semi-gelatinous corpus vitreum is transparent. The depression
in front of it is called fossa hyaloidea and the lens fits here. In the middle of the
corpus vitreum is a canal extending from the discus nervi optici to the middle
of the posterior surface of the lens. This canal is called canalis hyaloideus. In
the fetus, a. hyaloidea passes through this channel. The gelatinous fluid inside
the corpus vitreum is called the humor vitreus, and the surrounding membrane
is called the membrana vitrae. There are no blood vessels in the corpus vitreum.
For this reason, its nutrition is supplied by the vessels of its neighbor retina and
processus ciliaris (2,16). It is a colorless liquid mostly water secreted by the
humor aquosus processus ciliaris. It first fills the camra posterior bulbi, then
passes through the pupil to the camera anterior bulbi. Finally, it passes through
the angulus iridocornealis and is absorbed by the villi pectinati and empties into
the sinus venosus sclerae (schlemm canal). Therefore, it mixes with the venous
circulation system (3,13,18).
EYE ANATOMY AND PECTEN OCULI 153
1.3.Lens
The lens, which is in the form of a convex lens, is located between the iris
and the corpus vitreum. The anterior aspect of the lens is called facies anterior
and the posterior aspect is called facies posterior. The edge joining these convex
faces is called the equator. The posterior face is more convex than the anterior
(1,2,14). The most prominent points on the anterior and posterior face are called
the polus anterior and pollus posterior. The imaginary line connecting both
poles is called the axis. The lens is surrounded by a transparent and flexible
membrane. This capsule is called capsula lentis. The lens tissue that completely
fills it is called substnatia lentis. The lens is suspended on the processus ciliaris
via the fibra zonulares (5,17). Although the capsula lentis is tearable, it is quite
flexible. When it is torn for any reason, it immediately folds on itself with its
inner side facing out. The posterior surface of the lens sits on the fossa hyaloidea
on the anterior surface of the corpus vitreum. The anterior surface, on the other
hand, touches the edges of the pupil in the middle part, but does not contact the
periphery, and the camera posterior bulbi is located between the iris and the iris
(8,16).
The central part of the lens of the eye is composed of the nucleus lentis.
The outer part is surrounded by cortex lentis and is harder than the inner part.
The anterior surface of the lens is covered with a single cubical epithelium.
These epithelial cells retain their shape only on the anterior surface of the lens
and grow lengthwise as they approach the equator. In the sun, they take the form
of a thin, long fiber. These fibers, called Fibrae lentis, go around the equator
and dive deep into the opposite face and lose their nuclei. As a result of new
fibers replacing old ones and wrapping them from the outside, lamellae called
radii lentis are formed. The spaces between these fibers that keep the lens in its
normal position are called spatia zonularia (5,14,18).
The pecten oculi is a highly vascular and pigmented structure unique to the
bird’s eye, not found in other vertebral species except birds (19). It originates
above the papilla n. optici and has a pincer-like shape. The pecten oculi humour
enters the vitreous in a convoluted fashion, but does not extend to the lens. The
glial cell network is covered by a comb and contains numerous blood vessels.
The pecten oculi is thought to supply the retina, which is devoid of vessels, with
oxygen and other nutrients (14,20). It is assumed to have a primary function
154 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
in maintaining intraocular pressure (21). It plays a role in reducing intraocular
glare, adjusting the blood and retinal fluid barrier, providing vascular circulation
in the retina, light absorption, bird direction assurance, warming the bird’s eye
in cold weather and stabilizing the vitreous body (22).
Three morphological species of pecten oculi are recognized as conical,
winged and pleated types. Conical type has been reported only in brown kiwifruit
(Apteryxmantelli). It is found in winged ostriches (Struthio camelus) and rhea
(Rhea americana). The pleated form is common in most birds such as quail,
black kite, galah, vulture, wild duck, pigeon and forest crow (14,20). The size
of the pecten depends on the visual requirements of the bird, so diurnal active
bird species have a relatively large and highly complex pecten oculi with many
folds, whereas nocturnal active bird species have a relatively small, simple, and
low pile number pecten oculi (15).
Although the eye, as an organ of vision, has similar structures in all living
things with its general anatomy, it shows species-specific differences. Birds
have one of the most detailed visual systems of any animal species. Differences
in eye axis are observed in birds, especially depending on whether they are
nocturnal or diurnal. In this section, the general anatomy of the eye and pecten
oculi, which is found only in vertebrate animals, are mentioned.
1. Diesem C. Organ of vision. In: Getty R, Sisson S, eds. Sisson and
Grossman’s the Anatomy of the Domestic Animals. 1975:226-245.
2. Dyce KM, Sack WO, Wensing CJG. Textbook of veterinary anatomy-E-
Book. Elsevier Health Sciences; 2009.
3. Pearson R. The avian eye and vision. In: Pearson R, ed. The avian brain.
New York: Academic Press; 1972.
4. Arıncı K, Elhan A. Anatomi. Güneş kitap evi; 2001.
5. Dursun N. Veteriner anatomi. Medisan yayınevi; 2008.
6. Noyan A. Fizyoloji. Meteksan; 1993.
7. Junqueira L, Carneiro J. Temel histoloji. McGraw-Hill companies; 2003.
8. Reece W. Functional anatomy and physiology of domestic animals.
Wiley-Blackwell; 2012.
9. Sancak B, Cumhur M. Fonksionel anatomi. ODDÜ Yayınları; 2004.
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10. Jones MP, Pierce Jr KE, Ward D. Avian vision: a review of form
and function with special consideration to birds of prey. Journal of exotic pet
medicine. 2007;16(2):69-87.
11. De Stefano M, Mugnaini E. Fine structure of the choroidal coat of the
avian eye. Anatomy and embryology. 1997;195(5):393-418.
12. Türkmenoğlu İ, Dursun N. Evcil kuşların anatomisi. Medisan Yayınevi;
2004.
13. Yıldırım M. Resimli sitematik anatomi. Nobel Tıp kitapevi; 2013.
14. Carvalho CMd, Rodarte-Almeida ACdV, Santana MIS, Galera PD.
Avian ophthalmic peculiarities. Ciência Rural. 2018;48
15. Abumandour MM, Bassuoni NF, Hanafy BG. Ultrastructural studies
of the pecten oculi of the Garganey (Anas querquedula, Linnaeus 1758) and the
Eurasian common moorhen (Gallinula chloropus chloropus, Linnaeus 1758).
Microscopy Research and Technique. 2021;84(9):1967-1976.
16. Land MF, Nilsson D-E. Animal eyes. OUP Oxford; 2012.
17. Kahle W, Helmut L, Werner P. Taschenatlas der Anatomie. Georg
Thieme Verlag; 1985.
18. Fails AD, Magee C. Anatomy and physiology of farm animals. John
Wiley & Sons; 2018.
19. Gültiken ME, Yıldız D, Onuk B, Karayiğit MÖ. The morphology of the
pecten oculi in the common buzzard (Buteo buteo). Veterinary Ophthalmology.
2012;15:72-76.
20. Dayan MO, Ozaydın T. A comparative morphometrical study of the
pecten oculi in different avian species. The Scientic World Journal. 2013;2013
21. Ferreira TAC, Turner Giannico A, Montiani‟ Ferreira F. Hemodynamics
of the pectinis oculi artery in American pekin ducks (Anas platyrhynchos
domestica). Veterinary ophthalmology. 2016;19(5):409-413.
22. Elghoul M, Morsy K, Abumandour MM. Ultrastructural
characterizations of the pecten oculi of the common ostrich (Struthio camelus):
New insight to scanning electron microscope–energy dispersive X‟ ray analysis.
Microscopy Research and Technique. 2022;85(5):1654-1662.
157
13
1(Pharmacist) Arhavi State Hospital, Artvin, Turkey.
baltacionu98@gmail.com,
ORCID: 0000-0002-0186-1844
2(Pharmacist) Cukurova University, Faculty of Pharmacy, Adana, Turkey.
seydadnmzz@gmail.com ,
ORCID: 0000-0002-2240-0238
3(Assoc. Prof. Dr.) Department of Basic Pharmaceutical Sciences, Faculty of
Pharmacy, Cukurova University, Adana, Turkey,
c.yamali@yahoo.com, cyamali@cu.edu.tr,
ORCID: 0000-0002-4833-7900
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most
popular medications sold in pharmacies. They are used for acute
or chronic inflammation including arthritis, rheumatoid arthritis,
osteoarthritis, muscle, and joint injuries, post-operative pain, and headache. (1,
2) Considering that some NSAIDs, such as ibuprofen and aspirin, which are
considered safe, are available over-the-counter in most countries, it is clear that
their use is high in the world.(3)
NSAIDs work by suppressing the prostaglandin production process, which
is believed to be critical in the development of inflammation, pain, and fever.
NSAIDs inhibit prostaglandin synthesis from arachidonic acid and exert their
effects through the cyclooxygenase (COX) enzyme inhibition pathway.(4)
COX-1 and COX-2 enzymes provide the synthesis of prostaglandins in tissues.
NSAIDs inhibit the formation of prostaglandins from arachidonic acid via COXs
pathway.(5, 6) In addition, a new type of COX-3 enzyme, which is the molecular
158 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
target of Paracetamol was reported and it has catalytic and structural features of
COX-1 and COX-2. COX-3 is presents in large amounts in the cerebral cortex
and heart and is affected by Paracetamol and similar drugs.(7)
The regions of enzymes in cells are different from each other. While
COX-1 enzyme is present in large of tissues, COX-2 enzyme is synthesized in
the injured tissues by stimulation of inflammatory cytokines. COX-1 enzyme
has a role in platelet function, coagulation, setting of renal blood flow, protection
of gastric mucosa, bone metabolism, etc.(2, 8, 9) The main COX enzymes differ
from each other in structure. While COX-1 has Ile523, COX-2 has Val523 in
the active site of the enzyme. Val523 creates a cavity in the wall of COX-2
enzyme’s channel that leads to forming a side pocket affecting the binding site
of many selective drugs compared to COX-1 enzyme.(10-12) Several NSAIDs
in the clinic are given in Figure 1. It is necessary to develop selective COX-2
enzyme inhibitors with reduced side effects including gastrointestinal and
cardiovascular adverse effects.
The formula of the well-known NSAIDs
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 159
1.1.COX-2enzymeasapotentialtargetfordierentdiseases
It has been reported that chronic
inflammation mediated by prostaglandin E2 may be a reason for cancer, since
elevated COX-2 levels may promote the carcinogenesis process. Prostaglandin
E2 has also the capacity to depress the immune system by inhibiting natural
killer cells.(13-15) As a result, particular COX-2 inhibitors can be considered as
possible anticancer drug candidates.
Clinical trials have
shown that the level of COX-2 in the Alzheimer’s patient is significantly higher
compared to the control group. Additionally, it has been claimed that consistent
NSAID use halts the progression of Alzheimer’s disease.(16, 17)
: Celecoxib and
risperidone, which were used in a double-blind trial, were found to offer
symptomatic improvement for schizophrenia.(18) In vivo and clinical trials have
shown that COX-2 inhibitors are effective in treating schizophrenia in its early
stages. Studies on rats have demonstrated that serotonin levels in the frontal and
temporoparietal cortex rise after receiving COX-2 enzyme inhibitors.(19-21)
Therefore, it is thought to be favorable to utilize COX-2 inhibitors in the study
of neurological diseases.
Zarghi et al. designed and reported COX-2 inhibition of ketoprofen
analogs. Potent compounds 8a and 8b with the azido pharmacophore group
(Figure 2) exhibited promising inhibition potency compared to celecoxib.
IC50 values of compound 8a were 65.55 μM (COX-1) and 0.057 μM (COX-2)
while compound 8b had IC50 values >100 μM and 0.077 μM, respectively. IC50
values of Celecoxib were 24.3 µM and 0.06 µM. According to enzyme-ligand
interaction studies of 8a and 8b with COX-2, the azido group bonded strongly
to the active site of the enzyme by its interactions with Arg-513. The findings
indicate that 2-aryl-4-carboxyl quinoline is a pharmacophore structure for the
development of potent COX-2 inhibitors.(22)
160 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Chemical structures of the most potent compounds 8a, 8b, 3b
Arfaie et al. designed 1,2,3-triaryl-2-propen-1-one derivatives. Compound
3b (Figure 2) showed the remarkable inhibition effect and selectivity on COX-2
(IC50 = 0.07 µM) and COX-1 (IC50 = 14.27 µM). IC50 values of celecoxib were
0.06 µM (COX-2) and 24.3 µM (COX-1). According to the results, the form of
propenone and its substituents affected COX-2 inhibition.(23)
Eren et al. reported in vitro COX inhibitory activities of 2-oxo-5H-furan,
2-oxo-3H-1,3-oxazole, and 1H-pyrazole structures (Figure 3). Compound 6b
has been reported as a potent COX-1 enzyme inhibitor with high selectivity
against COX-1 enzyme (IC50 = 0.325 µM for COX-2; IC50 = 0.061 µM for
COX-1). Reference drug indomethacin’s IC50 values were IC50 = 0.537 µM
(COX-2) and IC50 = 0.069 µM (COX-1). Moreover, compound 11c potently
and selectively inhibited COX-2 enzyme with an IC50 = 0.011 µM. According
to molecular docking findings, a useful scaffold for the subsequent development
of strong and selective COX-2 inhibitors has been presented by appropriately
substituting 1H-pyrazole with the benzoxazole structure.(24)
Chemical structures of compounds 6b, 11c, 10d, 10e
COXs inhibitory properties of compounds derived from 3-methyl-2-
phenyl-1 substituted indoles were described by Abdellatif et al. They investigated
the methanesulfonyl derivatives compound 10d and compound 10e (Figure 3)
which showed promising biological effects on COXs. 10d inhibited COX-2 (IC50
= 7.98±1.91 µM) and COX-1 (IC50 = 32.23 ± 2.36 µM). 10e inhibited COX-2
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 161
(IC50 = 1.65 ± 1.02 µM) and COX-1 (IC50 = 42.36 ± 2.45 µM). The reference
drug indomethacin inhibited COX-2 (IC50 = 11.36±1.6 µM) and COX-1 (IC50 =
0.63 ± 0.02 µM). Compounds 10d and 10e were revealed to have IC50 values
that made them highly selective COX-2 enzyme inhibitors than the standard
indomethacin. The molecular docking and bioassays demonstrated that the
compounds bearing a methyl sulfonyl group conferred selectivity for COX-2.
The selectivity may have been enhanced by three hydrogen bond interactions
between this group and COX-2.(25)
Sabakhi et al. reported the chemical synthesis of 1,4-dihydropyridine
derivatives. Compound 5e (Figure 4) had the highest selectivity index. 5e
inhibited COX-2 (IC50 = 0.59 µM) and COX-1 (IC50 = 30.7 µM) while celecoxib
had IC50 = 0.06 µM (COX-2) and IC50 = 24.3 µM (COX-1). According to the
molecular docking results, the methyl and ethoxycarbonyl groups interact
more strongly with COX-2 enzyme’s secondary binding site (Arg513, Phe518,
Gly519, and His90), providing selective inhibition of COX-2 enzyme.(26)
Chemical structures of compounds 5e and 6a
Shahrasbi et al. studied imidazo[2,1-b]thiazole-bearing compounds as
selective and strong COX-2 inhibitors. Compound 6a (Figure 4) was identified
as a remarkable COX-2 inhibitor. 6a inhibited COX-2 (IC50 = 0.08 µM) and
COX-1 (IC50 = >100 µM). Celecoxib inhibited COX-2 with an IC50 = 0.06
µM and COX-1 with an IC50 = 24.3 µM. According to molecular docking
experiments, the size and type of the amine on the imidazo[2,1-b]thiazole had a
positive impact on the potency and selectivity against COX-2.(27)
El-Sayed et al. reported new arylhydrazone derivatives and 1,5-diphenyl
pyrazoles with anti-inflammatory properties and COX inhibitory. Compounds
2f, 5, 6a, and 6d (Figure 5) attracted attention with the effects on COX-2 enzyme.
2f inhibited COX-2 (IC50 = 0.45 µM) and COX-1 (IC50 = >50 µM). Compound 5
inhibited COX-2 (IC50 = 0.55 µM) and COX-1 (IC50 = >50 µM). Compound 6a
162 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
inhibited COX-2 (IC50 = 0.45 µM) and COX-1 (IC50 = >50 µM). Compound 6d
inhibited COX-2 (IC50 = 0.45 µM) and COX-1 (IC50 = >50 µM). The selectivity
index was found between 90-110 against COX-2. The side pocket selectivity
in COX-2 enzyme’s active site was increased by the aryl hydrazide structure,
according to the molecular docking data. Pyrazoles with the proper substitutions
can interact with polar areas including Gln192 and Arg513 in the side pocket,
increasing their selectivity for COX-2 enzyme.(28)
Chemical structures of compounds 5, 6a, 6d, 2f, 2b
Zarghi et al. were designed 1,3-benzdiazinan-4-one derivatives. Compound
2b (Figure 5) inhibited COX-2 (IC50 = 0.07 µM) and COX-1 (IC50 = 40.1 µM)
while celecoxib inhibited COX-2 with an IC50 = 0.06 µM and COX-1 enzyme
with an IC50 = 24.30 µM. Although compound 2b was weaker than celecoxib,
its selectivity was higher. Compound 2b’s selectivity index was 572.8, while
celecoxib’s was 405. The enzyme inhibitory activity are both influenced by
the structure and size of the substitution made at the C-2 or N-3 locations of
the 1,3-benzdiazinan-4-one structure according to molecular docking studies.
Furthermore, substances with a methyl sulfonyl group in the para position of
the C-2 phenyl ring were more specific for COX-2. In addition, potency and
selectivity were improved by substituting appropriate groups like -F and -OMe
at the para position of the N-3-phenyl ring.(29)
Zargh et al. designed 5,5-diarylhydantoin derivatives as COXs inhibitors.
Compound 4 (Figure 6) inhibited COX-2 (IC50 = 0.077 µM) and COX-1 (IC50
= >100 µM. Celecoxib inhibited COX-2 with an IC50 = 0.06 μM and COX-1
with an IC50 = 24.30 μM. Compound 4’s selectivity was >1298 while reference
drug celecoxib’s was 405. Molecular docking studies revealed that the p-methyl
sulfonyl group on the C-5 phenyl ring was directed to the COX-2 enzyme’s side
pocket and increased selectivity.(30)
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 163
Chemical structures of compounds 4, 8d and 8a
El-Sayed et al. reported COXs inhibitory potencies of pyrazole and
pyrazolines. Compound 8d (Figure 6) has been reported to be a promising
COX-2 inhibitor. Compound 8d inhibited COX-2 (IC50 = 0.26 µM) and COX-1
(IC50 = >50 µM). Diclofenac also inhibited COX-2 with an IC50 = 1.1 µM and
COX-1 with an IC50 = 0.22 µM while celecoxib inhibited COX-2 with an IC50
= 0.28 µM and COX-1 with an IC50 = >50 µM. The selectivity of compound
8d was found higher than the reference celecoxib. Similar to celecoxib, the
molecular interactions of 8d demonstrated their effect by binding to the side
pocket of the COX-2 enzyme. The trifluoromethyl moieties of compound 8d
were discovered to penetrate deeper into the side pocket of the COX-2 enzyme,
forming strong hydrogen bonds with Gln192 and Arg513. This study found that
appropriately substituted triarylpyrazole-type compounds inhibited COX-2 and
had a high anti-inflammatory activity.(31)
Al-Suwaidan et al. synthesized benzenesulfonamide derivatives.
Compound 8a (Figure 6) showed strong COX-2 inhibition and high anti-
inflammatory effect. 8a inhibited COX-2 (IC50 = 0.10 µM) and COX-1 ( IC50
= >100 µM). Diclofenac inhibited COX-2 (IC50 = 4.2 µM) and COX-1 (IC50
= 0.25 µM) while celecoxib inhibited COX-2 with an IC50 = 0.26 µM and
COX-1 with an IC50 = >100 µM. In comparison to celecoxib and diclofenac,
compound 8a has been found to have better anti-inflammatory efficacy and
higher COX-2 enzyme inhibition. Investigations of compound 8a’s interactions
with the enzyme concerning COX-2 were conducted. It was revealed that the
sulfonamide group in compound 8a’s structure entered the COX-2 enzyme’s
side pocket deeply and made hydrogen bonds with the amino acids Gln192,
Phe518, and Arg513. According to reports, compound 8a and celecoxib had
similar binding properties.(32)
Kim et al. reported 1H-methyl-pyrrole-2,5-dione derivatives as COX
inhibitors. The most potent compound 9d (Figure 7) inhibited COX-2 with an
IC50 = 0.006 µM and COX1 with an IC50 = >1.0 µM. IC50 values of reference
164 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
celecoxib were IC50 = 0.072 μM (COX-2) and IC50 = >1.0 μM (COX-1) while
ibuprofen had IC50 = 30 μM (COX-2) and IC50 = 26 μM (COX-1). The findings
show that compound 9d had a stronger COX-2 inhibition than the standard
celecoxib. Compound 9d improved COX-2 side pocket contact by establishing
hydrogen bonds with the sulfonamide group, Arg499, Phe504, Ile503, Gln178,
and Leu338 proteins.(33)
Chemical structures of compounds 9d, 6a, 10a, 10b, 10e, 10f
Alanazi et al. reported cyclic imide compounds with their COXs inhibition
and other bioactivities. Compound 6a (Figure 7) was identified as COX-2
inhibitor. IC50 values of 6a were IC50 = 0.18 µM (COX-2) and IC50 = 120.3 µM
(COX-1). Celecoxib had IC50 = 0.26 µM (COX-2) and IC50 = >100 µM (COX-
1) while diclofenac had IC50 = 1.1 µM (COX-2) and IC50 = 4 µM (COX-1).
Compound 6a’s selectivity index was 668.3 while celecoxib’s index was 384.6.
Investigations into the molecular interactions of 6a with the COX-2 enzyme
were investigated. According to report, the methoxy groups of chemical 6a form
bonds with the amino acids His90, Arg513, and Gln192 and settle deep inside
the side pocket of the COX-2 enzyme.(34)
Abdellatif et al. reported anti-inflammatory, ulcerogenic, and COXs
inhibition of 1,2-diaryl-4-substituted-benzylidene-5-4H-imidazolone
derivatives. Compounds 10a, 10b, 10e, and 10f (Figure 7) had higher selectivity
towards COX-2 than celecoxib. Compound 10a inhibited COX-2 (IC50 = 0.42
µM) and COX-1 (IC50 = 4.52 µM), compound 10b inhibited COX-2 (IC50 = 0.62
µM) and COX-1 (IC50 = 6.74 µM). Compound 10e inhibited COX-2 (IC50 =
0.52 µM) and COX-1 (IC50 = 4.52 µM). Compound 10f inhibited COX-2 with
an IC50 = 0.86 µM and COX-1 with an IC50= 7.86 µM. IC50 values of celecoxib
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 165
were 0.84 µM (COX-2) and IC50 = 7.23 µM (COX-1). Comparing the four
substances to ibuprofen and celecoxib, it was discovered that they were much
less ulcerogenic.(35)
Mohamed et al. reported COXs inhibition studies of oxazolone and
triazinon derivatives. Compounds 3c (IC50 = 0.024 µM), compound 3e (IC50
= 0.019 µM), compound 4d (IC50 = 0.011 µM), compound 4g (IC50 = 0.014
µM) were found as COX-2 inhibitors. IC50 of celecoxib was IC50=0.05μM.
Compounds 3c, 3e, 4d, and 4g (Figure 8) showed remarkable enzyme inhibition
potency than the reference drug.(36)
Chemical structures of compounds 3c, 3e, 4d and 4g
Abdelgawad et al. evaluated pyrazole-hydrazones as COX and lipoxygenase
(LOX) inhibitors. Compounds 4a and 4b (Figure 9) selectively inhibited COX-2
enzyme. Compound 4a had IC50 = 0.67 µM (COX-2) and IC50 = 5.64 µM (COX-
1) values. Compound 4b had IC50 = 0.58 µM (COX-2) and IC50 = 6.12 µM
(COX-1) values. Reference drug celecoxib inhibited COX-2 enzyme at IC50
= 0.87 µM and COX-1 enzyme at IC50 = 7.7 µM. In addition, compounds 4a
and 4b exhibited higher LOX enzyme inhibitory properties than zileuton. The
interactions of 4a and 4b with the enzyme were investigated. According to the
findings, pyrazole groups formed H-bonds in the active site of COX-2 receptor,
which helped to contribute to the selective inhibition of COX-2 enzyme.(37)
Chemical structures of compounds 4a and 4b
166 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Moussa et al. designed a series of thioquinazolinone series as COXs
inhibitors. Compounds 3h (Figure 10) was the most potent COX-2 inhibitor
(IC50 = 0.11 µM). Favorable interactions between compound 3h and COX-2
enzyme’s side pocket were observed.(38)
Chemical structures of compounds 3h, 17b, 18 and 3d
Tageldin et al. evaluated COXs inhibition effects of pyrazolo[3,4-d]
pyrimidines. Compounds 17b and 18 (Figure 10) showed promising inhibition
effects. 17b inhibited COX-2 (IC50 = 0.22 µM) and COX-1 (IC50 = 2.74 µM).
Compound 18 inhibited COX-2 with an IC50 = 0.69 µM and COX-1 with
an IC50 = 5.88 µM. IC50 values of celecoxib were IC50 = 0.78 µM (COX-2)
and IC50 = 5.46 µM (COX-1). The compounds 17b and 18 demonstrated
tolerable gastrointestinal safety.(39) In the next study, they reported different
pyrazolo[3,4-d]pyrimidines with their bioactivities. Compound 3d (Figure 10)
was found as a potent and selective COX-2 inhibitor with an IC50 = 0.11 µM.
Additionally, it has been demonstrated that this class of drugs has a favorable
gastrointestinal profile and potent anti-inflammatory effects.(40)
Ren et al. reported enzyme inhibitory and cytotoxic effects of diaryl
pyrazoles. Compound e9 (Figure 11) was distinguished among them due to
its remarkable bioactivities. e9 inhibited COX-2 (IC50 = 0.23 ± 0.02 µM) and
COX-1 (IC50 = 47.48 ± 2.73 µM) similarly to reference drug celecoxib. The
chemical interactions between e9 and the enzyme COX-2 were investigated. By
using Van der Waals contacts, compound e9 strongly bound to the side pocket
of the COX-2 enzyme than celecoxib. The findings suggest that compound e9’s
selective COX-2 enzyme inhibition and antiproliferative properties may make it
a suitable candidate for cancer treatment.(41)
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 167
Chemical structure of compound e9
Labib et al. revealed isoindoline hybrids as a promising class of compounds.
In comparison to celecoxib (IC50 = 0.09 µM), compounds 10b, 10c, 11a, 11d,
13, and 14 (Figure 12) demonstrated COX-2 inhibition in the range of IC50 =
0.11-0.18 µM. The majority of the compounds exhibited notable central and/or
peripheral analgesic efficacy. Investigations were done into how the produced
substances interacted with the amino acid residues in the COX-2 active region.
While the presence of a hydrogen acceptor group mimicking the aminosulfonyl
pharmacophore, such as the methoxy group at 11d and the acetyl group at 13,
improved the compounds’ ability to inhibit enzymes, the aminosulfonyl group
at the para position of the phenyl ring also contributed to the activity for
compounds (10c, 14).(42)
Chemical structure of compounds 10b, 10c, 11a, 11d, 13 and 14
168 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Kaur et al. investigated inhibitory effects of benzamides towards COXs.
Compound 3b (Figure 13) was discovered to be the most effective COX-2
inhibitor. IC50 values of 3b were IC50 = 0.14 µM (COX-2) and IC50 = 4.40 µM
(COX-1). IC50 values of ibuprofen were IC50 = 1.8 µM (COX-2) and IC50 = 1.42
µM (COX-1) while celecoxib had IC50 = 0.15 µM (COX-2) and IC50 = 6.20 µM
(COX-1) values. In addition, compound 3b showed higher anti-inflammatory
activity than ibuprofen. Studies have shown that the ulcerogenic activity of
compound 3b is lower than that of ibuprofen. The molecular interactions of
compound 3b were investigated against COX-2 enzyme. The interaction with
the COX-2 enzyme involved the crucial function of the benzoxazole ring.
Furthermore, the insertion of electron-withdrawing groups to the ortho and para
locations of the phenyl ring improved the compounds’ activity.(43)
Chemical structure of compounds 3b, 5g, and 5m
Movahed et al. evaluated pyrazino[1,2-a]benzimidazole derivatives in
terms of COX-2 enzyme inhibition, anticancer, and antiplatelet aggregation
activities. Compound 5g (Figure 13) showed the strongest COX-2 enzyme
inhibition. IC50 values of compound 5g were IC50 = 0.07 µM (COX-2) and IC50 =
55.7 µM (COX-1) (Selectivity index = 795.7). Celecoxib inhibited COX-2 with
an IC50 = 0.06 µM and COX-1 with an IC50 = 24.3 µM (Selectivity index = 405).
When compared to the reference drug, the compound 5g demonstrated effective
and selective COX-2 inhibition. In addition, compound 5m (Figure 13) against
COX-2 enzyme was the strongest compound in terms of selectivity index > 909.
The reference drug cisplatin inhibited MCF-7 cancer cells by 76.2% at a dose
of 10 μM, whereas the compound 5m inhibited MCF-7 cancer cells by 74.8% at
the same concentration. These findings showed that compounds that selectively
inhibit the COX-2 enzyme may exhibit strong cytotoxicity.(44)
The COX-1/COX-2 enzyme inhibition, anti-inflammatory, and ulcerogenic
activities of pyrazolo-pyrimidinones and pyrazolo-triazolo-pyrimidinones were
assessed by Tageldin et al. The most potent compounds 2c, 6a, 8, and 12 (Figure
14) had IC50 in the range of 0.29-0.74 µM. The anti-inflammatory activity of
these substances was also greater than celecoxib’s.(45)
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 169
Chemical structure of compounds 2c, 6a, 8 and 12
Ahmed et al. evaluated pyridazinone and pyridazine derivatives in terms
of COX enzyme inhibitory activity. Compound 3g (Figure 15) inhibited COX-2
with an IC50 = 43.84 ± 1.1 µM and COX-1 enzyme with an IC50 = 505.01 ±
16.5 µM. The reference drug celecoxib inhibited COX-2 enzyme with an
IC50 = 73.53 ± 2.59 µM, and COX-1 enzyme with an IC50 = 873.44 ± 19.47
µM. In comparison to celecoxib and indomethacin, compound 3g displayed a
better GI safety profile. Studies using molecular docking have demonstrated
that compound 3g interacts more strongly than celecoxib with the binding site
pocket of the COX-2 enzyme. Compound 3g’s sulfonamide group established
hydrogen bonds with the amino acids His 90 and Arg 513 in the COX-2 side
pocket, and further hydrogen bonds formed with Ser 530 and Tyr 385 over two
methoxy groups.(46)
Health et al. evaluated thiazolylhydrazine-methyl sulfonyl derivative
compounds in terms of COX inhibition. Compound 3a (Figure 15) had an IC50 =
0.140 ± 0.006 µM (Selectivity index = > 714.286) towards COX-2. IC50 values
of references were as follows; celecoxib IC50 = 0.132 ± 0.005 µM, ibuprofen
IC50 = 5.326 ± 0.218 µM, nimesulide IC50 = 1.684 ± 0.079 µM towards COX-
2. Investigations on compound 3a’s interactions with COX-2 were conducted.
Studies using molecular modeling have revealed that compound 3a interacted
with COX-2 enzyme similarly to celecoxib.(47)
Chemical structure of compounds 3g, 3a and 3f
170 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Shaaban et al. reported a group of pyrazoloquinazoline derivatives as COX
and 5-LOX inhibitors. IC50 values of compound 3f (Figure 15) were IC50 = 488.2
± 21.2 µM (COX-2), IC50 = 1.485 ± 34.8 µM (COX-1), and IC50 = 0.6 ± 0.02
µM (5-LOX). Celecoxib inhibited COX-2 enzyme with an IC50 = 95.02 ± 3.8
µM, COX-1 enzyme with an IC50 = 187.8 ± 13.2 µM. Zileuton inhibited 5-LOX
enzyme at IC50 = 0.8 ± 0.03 µM. Compound 3f had higher COX-2 enzyme
selectivity than celecoxib. The interactions of compound 3f with the enzyme
and bioassay results showed that compound 3f could be a leading structure for
designing novel agents.(48)
Alfayomy et al. evaluated pyrimidine-5-carbonitriles as COXs inhibitors.
10c, 10j, and 14e (Figure 16) had enzyme inhibitory potency in the range of IC50
values 0.042-0.081 μM. When the ulcerogenic potential of these substances was
examined, compound 10j displayed superior safety to celecoxib, but compounds
10c and 14 exhibited minor lesions. Compared to rofecoxib and celecoxib, these
substances demonstrated a comparable interaction with the hydrophobic side
pocket of the COX-2 enzyme. In addition to interacting with Arg513 in the side
pocket, the 4-chlorophenyl of compound 10c and the 2,6-dichlorophenyl of
compound 10j also contributed to interactions with the proteins Ala516, Ile 517,
Phe518, and Gln192.(49)
Chemical structure of compounds 14e, 10j and 10c
Sakr et al. reported quinazolinone-based compounds and their ulcerogenic,
anti-inflammatory, anticancer, and COXs enzyme inhibitions. Compounds 4a
(IC50 = 12.68 ± 0.11 µM for COX-1 and IC50 = 0.04 ± 0.08 µM for COX-2 ) and
7c (IC50 = 14.73 ± 0.13 µM for COX-1 and IC50 = 0.037 ± 0.20 µM for COX-2)
(Figure 17) showed similar anti-inflammatory activity compared to ibuprofen
and celecoxib, but more potent than indomethacin. The mean edema inhibition
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 171
was 45.37% for compound 7c and 47.18% and 47.60% for the reference drugs
ibuprofen and celecoxib, respectively. When tested on HT29 cells that express
COX-2, compounds 4a and 7c showed partial cytotoxic activity. Against the
enzyme COX-2, interactions between compound 7c and compound 4a were
examined. In the COX-2 enzyme’s active region, compound 4a created an extra
hydrogen bond with Ala527, and compound 7c created two hydrogen bonds
with Val523 and Arg120. Compounds 4a and 7c may be candidates for further
studies.(50)
Chemical structure of compounds 4a and 7c
Abdellatif et al. reported indomethacin analogs with their ulcerogenic
effects and COXs inhibitions. It has been reported that compound 4b (Figure
18) was a potent and selective COX-2 enzyme inhibitor with IC50 values IC50
= 0.09 µM (COX-2) and IC50 = 0.57 µM (COX-1). Celecoxib had IC50 = 0.89
µM (COX-2) and IC50 = 3.14 µM (COX-1) values. However, histopathological
studies showed that compound 5 (Figure 18) was a promising candidate because
compound 4b induced moderate lesions in the stomach. Results were also
corroborated by interactions between compounds and the COX-2 enzyme.(51)
Osmaniye et al. reported COX-2 enzyme inhibitors having N-acyl
hydrazone structure. IC50 of compound 3j was 0.143 ± 0.006 µM while celecoxib
had IC50 = 0.132 ± 0.005 µM towards COX-2. Compound 3j (Figure 18) had
similar COX-2 inhibition as the reference drug. Investigations of the COX-2
enzyme’s interactions with 3j were also conducted. It has been demonstrated
that the polar side pocket of the COX-2 enzyme interacts with the methyl
sulfonyl group linked to the N-acyl hydrazone group. Additionally, the Gln512
amino acid in the side pocket of the COX-2 enzyme formed a second interaction
(halogen bond) with the chlorine atom in the second position on the phenyl ring,
strengthening the binding.(52)
172 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Chemical structures of compounds 4b, 5, 3j
Abdellatif et al. reported 1,2,4 triazoles as selective COX-2 inhibitors.
Compounds 4a, 6a, and 7a (Figure 19) had remarkable activity compared to the
reference drug celecoxib. In addition to having edema inhibition capability that
was superior to celecoxib and indomethacin. According to the molecular docking
findings, these substances had a stronger binding affinity for the proteins in the
COX-2 enzyme’s side pocket and improve selectivity.(53)
Chemical structures of compounds 4a, 6a and 7a
Prostaglandins are produced in the body when there is an infection, and
they can lead to several unpleasant conditions like pain, fever, and inflammation.
Prostaglandins are often produced via the COX enzyme pathway in the body,
which indicates that we can eliminate prostaglandin’s negative effects by
blocking this mechanism. Drugs that inhibit the COX enzyme have been used
in the clinic for many years. It has been established that there are many COX
enzyme types with distinctive functions. Particularly in the stomach mucosa,
RECENT DRUG DEVELOPMENT STUDIES ON NOVEL AND SELECTIVE COX-2 INHIBITORS 173
the COX-1 enzyme has a protective function. Because of this, excessive COX-1
inhibition is undesirable, and it also has side effects on the gastrointestinal system.
Selective COX-2 inhibition is required to prevent these adverse effects. COX-1
and COX-2 have some structural variations. Compared to COX-1, COX-2 has
a bigger side pocket. This side pocket enables the creation of specific drugs
that target the COX-2 enzyme. COX-2 has been regarded as the primary target
enzyme in the prevention of inflammation.
This review states that research on selective COX-2 enzyme inhibitors is
ongoing due to the severe gastrointestinal and cardiovascular side effects of
currently available COX inhibitors. The compounds described here, which have
a variety of heterocyclic systems and functional groups, may be used to develop
novel COX-2 enzyme inhibitors as potential non-steroidal anti-inflammatory
pharmaceutical candidates. Additionally, numerous studies have mainly focused
on the part COX-2 plays in the development of several illnesses, including
cancer, Alzheimer’s disease, and other neurological disorders.
This review was prepared within the scope of the graduation report prepared
Onur Baltacıoğlu under the supervision of Assoc. Prof. Dr. Cem Yamalı.
CY (Supervisor): Design and organization of the study. Manuscript design,
preparation, editing.
OB: Collecting data, searching literatures.
SD: Preparing figures, editing references, formatting.
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179
rem1urçin
1(Asst. Prof. Dr.) Erzincan Binali Yıldırım University, Faculty of Pharmacy
e-mail: irem.bozbey@erzincan.edu.tr
ORCID: 0000-0002-9290-938X
2(Asst. Prof. Dr.) Erzincan Binali Yıldırım University, Faculty of Pharmacy
e-mail: burcin.turkmenoglu@erzincan.edu.tr
ORCID: 0000-0002-5770-0847
Drug repurposing (drug repositioning, reprofiling or re tasking) is done
for the discovery of new indications by repositioning the drug. This
method is used to ensure that FDA-approved clinically used drug
molecules or unlicensed drugs are used as new therapeutic agents. The aim is to
adapt or expand the indication of the drug during the drug development phase
(1). The main advantage of this method is that the risk of failure is lower; less
likely to fail safety for new use as existing drug is already known to be safe
(2). In addition, new drug candidates must go through many different stages,
including disease state and target identification, preclinical study, toxicity study,
formulation, clinical trial, approval process, and marketing. This method is
becoming more and more attractive because it takes a long time to develop new
drugs, is expensive, and allows drugs to be reused (3).
Azoles are the most widely used antifungals in clinical practice. Azole
antifungals exert their effects by inhibiting the synthesis of fungus ergosterol
(4). The first approved antifungal drugs were compounds bearing the imidazole
ring. These drugs have serious side effects such as poor oral absorption,
inability to cross the blood-brain barrier, and liver and gastrointestinal system
180 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
complications. For these reasons, new compounds have been developed using
the triazole ring instead of imidazole as the azole. Fluconazole was introduced in
1990 and provided many advantages over imidazole derivatives. Subsequently,
many drugs have been developed that contain a triazole ring in their structure
(5-7). Currently, there are about 40 azole-containing drugs and drug candidates
that can be classified (6, 8, 9).
Alzheimer’s disease (AD) is a neurodegenerative disease whose
prevalence and incidence increase with advancing age. It is expected to increase
more in the coming years in the population aged 65 and over worldwide
(10-12). Cholinesterase inhibition is a hypothesis of great importance for
symptomatic treatment in Alzheimer’s disease. Acetylcholinesterase (AChE)
and butyrylcholinesterase (BChE), known as cholinesterase enzymes, are
enzymes responsible for the hydrolysis of acetylcholine in the synaptic cleft.
The purpose of cholinergic inhibition is to prevent hydrolysis of acetylcholine
and to ensure that it is present in the synaptic gap at an adequate level. There are
cholinesterase inhibitor drugs used in the clinic for this purpose (13-16). One of
the drugs approved for the treatment of AD, Donepezil has aroused great interest
for researchers.
Due to the insufficient activity of the cholinergic system, Donepezil inhibits
cholinesterase and may alleviate neuronal degeneration (17, 18).
In this study, triazole ring structure azole antifungal drugs used in
the treatment of systemic fungal infections, different indication studies for
Alzheimer’s disease, which still has no definitive treatment, were carried
out in silico methods. In a literature study, an azole library was evaluated
against acetylcholinesterase and butyrylcholinesterase using in vitro and in
silico methods (19). Fluconazole, Itraconazole, Voriconazole, Ravuconazole,
Posaconazole, Eficonazole and Isavuconazole drug active ingredients, which are
in triazole antifungal structure, were used in our study. The interactions of these
drugs with AChE enzyme by in silico methods were investigated and compared
with Donepezil drug active ingredient.
In this study, molecular docking studies were applied with in-silico
approaches. Donepezil, which is effective in AChE and BChE enzymes, was
taken as a reference compound and drugs containing azoles with triazole
ring structure (Fluconazole, Itraconazole, Voriconazole, Ravuconazole,
Posaconazole, Eficonazole and Isavuconazole) were examined.
DRUG REPURPOSING STUDY FOR TRIAZOLE RING BEARING AZOLE ANTIFUNGALS . . . 181
2.1.MolecularDockingStudies
Schrödinger 2021-2 software (Schrödinger Release 2021-2: Glide, LLC
New York, USA) (20) was used in molecular docking studies. Molecular
docking examinations were applied according to the order in the specified steps.
Donepezil, Fluconazole, Itraconazole,
Voriconazole, Ravoconazole, Posaconazole Eficonazole and Isavuconazole
compounds were optimized using the LigPrep wizard (Schrödinger Release
2021-2: LigPrep) (21) utility of the Schrödinger 2021-2 software (22, 23).
Crystal structures of proteins with which
compounds will interact were obtained from the Protein Data Bank (https://
www.rcsb.org/). PDB ID:4EY7 (24) was used for AChE crystal structure and
4BDS was used for BChE crystal structure. The crystal structures obtained from
the protein database were prepared separately with the “Protein Preparation
Wizard” (25) module of the Schrödinger 2021-2 software, respectively.
viainsilico After ligands and
proteins were prepared one by one with intermediate modules, both docking
score values and binding sites were determined by interacting with the ligand
placement wizard. The method used in molecular docking was also applied as in
previous studies (23, 26).
2.2.MM-GBSA
Molecular mechanical energies combined with the Poisson-Boltzmann or
generalized Born and surface area continuous solving (MM/GBSA) method are
popular approaches to estimate the free energy of attachment of small ligands
to biological macromolecules (27). According to the MM-GBSA method, the
binding value of the complex can be determined by calculating the free binding
energy (ΔGBind) between the ligand and the target.
The OPLS-2005 force field and VSGB solvent model of Prime MM/GBSA
(Schrödinger Release 2021-2: Prime) (28) were used to calculate ΔGBind energy
values. MM-GBSA analysis was applied to calculate the free binding energies
of the indicated compounds with both AChE and BChE enzymes, respectively.
3.1.MolecularDockingStudies
Molecular docking studies were performed to determine the binding
parameters of Donepezil, Fluconazole, Itraconazole, Voriconazole,
182 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Ravuconazole, Posaconazole, Eficonazole and Isavuconazole compounds. The
best results determined for compounds in molecular docking studies were
obtained with in silico approaches. Crystal structures PDB ID:4EY7 (24) for
AChE and PDB ID:4BDS (29) for BChE were used.
The binding parameter values as a result of the binding interactions of
these compounds with the AChE and BChE crystal structures are presented in
Table 1.
First of all, the binding parameter values of Donepezil, which is used as
the reference compound in Table 1, obtained in silico were examined. Docking
score, XP GScore and Glide energy values of Donepezil interacted with AChE
crystal structure are -15.837, -15.840, -49.514, respectively. Likewise, the
docking score, XP GScore and Glide energy values of Donepezil in BChE were
determined as -6.820, -6.824, and -44.119, respectively. When these values are
taken as a reference, it can be said that Eficonazole has the closest values for
AChE. Molecular docking result parameter values of Eficonazole compound
were calculated as Docking Score, XP Gscore, Glide energy values -11,707,
-11.737, -48.868 for AChE. For the BChE crystal, Posaconazole, which has
better binding values than the reference drug Donepezil, was found remarkable
in Table 1. Docking Score, XP Gscore and Glide energy values of the
Posaconazole compound were calculated as -7.189, -7.207, -62.656,
respectively, by molecular docking method.
Binding parameter values of compounds interacting
with AChE and BChE crystal structures in molecular docking.
-7.534 -7.534 -66.524 -4.913 -4.913 -36.071
-7.911 -7.933 -64.732 -4.646 -6.618 -55.530
-8.670 -8.670 -46.734 -6.174 -6.174 -34.700
-8.432 -8.432 -58.117 -1.532 -1.532 -48.065
-8.171 -8.188 -66.856
-3.719 -5.496 -37.800
-9.944 -9.944 -55.424 -4.310 -4.310 -46.907
DRUG REPURPOSING STUDY FOR TRIAZOLE RING BEARING AZOLE ANTIFUNGALS . . . 183
When the binding parameter values of the compounds examined in Table
1 were not sufficient, they were compared with Donepezil by examining the
amino acids in the binding site.
. (A) 2D interaction diagram of Eficonazole compound with
AChE (PDB ID:4EY7 (24)) crystal structure. (B) 2D interaction diagram
of Donepezil reference compound with AChE (PDB ID:4EY7 (24)) crystal
structure.
When the 2D interaction diagram of donepezil reference compound
in Figure 1(B) was examined, it was determined that Phe 295 had hydrogen
bonding, Trp 286 amino acid had π-π bond, and Trp86 amino acid had π-π bond
interaction. In Figure 1 (A), it is seen that the Eficonazole compound is located
right inside the AChE crystal structure and interacts with important amino acids.
It is presented in Figure 1(A) that Phe337, Phe 338, Trp86 and Eficonazole, which
are important amino acids for AChE crystal structure, make π-π interaction and
also π-cation interaction with Asp74.
184 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
. (A) 2D interaction diagram of Posaconazole compound with
BChE (PDB ID:4BDS (29)) crystal structure. (B) 2D interaction diagram
of Donepezil reference compound with BChE (PDB ID:4BDS (29)) crystal
structure.
In Figure 2, 2D interaction diagrams of Posaconazole and Donepezil
compounds interacted with the BChE crystal structure are presented. In Figure
2(B), it was determined that Donepezil had hydrogen bond interactions with the
amino acid Hip438, π-cation interactions with Tyr332 and π- π interactions with
Trp82. According to Tables 1 and 2, when the interactions of Posaconazole, which
is the most active in BChE, were examined in Figure 2(B), it was determined
that it had π- π interaction with Trp82, hydrogen bond interaction with Gln71,
and hydrogen bond with Tyr128 and Glh197 amino acids.
3.2.MM-GBSA
Both the binding parameter values, and the binding sites of the compounds
examined by in silico approaches were investigated. In addition, GBind and
complex energy values with the MM-GBSA method are shown in Table 2.
Considering the ΔGBind, complex energy values of donepezil, which is active
in AChE and BChE, respectively, in Table 2, it was determined that -86.28,
-22656.367 and -60.32 -22909.067 kcal/mol were calculated.
DRUG REPURPOSING STUDY FOR TRIAZOLE RING BEARING AZOLE ANTIFUNGALS . . . 185
ΔGBind and complex energy values of compounds interacting with
AChE and BChE crystal structures in MM-GBSA method.
-50.43 -22630.248 -34.43 -22901.055
-87.16 -22620.762 -68.05 -22894.522
-42.56 -22696.744 -33.39 -22962.041
-75.12 -22754.721 -50.50 -23005.466
-71.63 -22598.932
-40.49 -22881.916
-57.95 -22694.322 -38.05 -22910.690
When the other compounds discussed in Table 2 are examined, the ΔGBind
and complex energy values for the Eficonazole compound for the AChE crystal
structure are -68.79, -22660.836, respectively. It was determined that the
Posaconazole compound in the BChE crystal structure had a better ΔGBind and
complex energy values (-69.14, -22882.798) than Donepezil.
In this study, the efficacy of azole antifungal derivatives carrying triazole
ring against cholinesterase enzymes was investigated by in silico approaches.
Inhibitory properties against AChE and BCh were compared with the drug
Donepezil as a reference. While it was determined that Eficonazole could be
effective for AChE, it was determined that Posaconazole compound had better
binding parameter values for BChE than Donepezil.
Authors would like to thank Erzincan Binali Yıldırım University, Basic
Sciences Application and Research Center (EBYU-EUTAM) for the Schrödinger
Maestro 2021-2 program.
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II
BANUTUFANKOÇAK1&SERHATSİREKBASAN
1(M.D.), T.C. Health Ministry, Erenkoy Mental Health and
Neurology Training and Research Hospital, Istanbul, Turkey
ORCID: 0000-0002-6435-0785
2(Assoc. Prof.), Department of Medical Laboratory Techniques,
Eldivan Vocational School of Health Services,
Çankırı Karatekin University, Çankırı, Turkey
e-mail: serhats@karatekin.edu.tr
ORCID: 0000-0001-7967-3539
Vaccine hesitancy is people’s reluctance to accept a proven safe and
effective vaccine available to them to protection against an infectious
disease (1). This hesitation has existed since vaccines were first
developed and poses an ongoing threat to global public health. Historically, anti-
vaccine discourse has a long history dating back to the first smallpox vaccination
(2). So that, anti-vaccine articles on vaccination studies on smallpox which is the
most common and crucial disease at that time, increased the hesitations about
vaccination even more (Figure 1).
Prejudices against vaccination have contributed to the re-emergence of
previously eradicated diseases such as polio and measles and increase vaccine
preventable deaths. Vaccine hesitancy is increasingly becoming a global
challenge in threatening public health. The World Health Organization (WHO)
declared this situation as one of the top 10 threats to global health in 2019 (3-5).
While the concerns and factors driving vaccine hesitance have changed
over time, many are similar to those in the past. Among them; vaccines are
ineffective or cause disease, vaccines are used by companies to make a profit,
vaccines contain dangerous substances, the harms of vaccines are hidden by
the authorities, natural immunity is better than vaccine-induced immunity,
etc. statements are often included. Vaccine hesitancy is generally complex and
context-specific. In other words, this hesitation varies according to time, place
and vaccines. Other factors associated with vaccination hesitancy include living
190 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
in a rural area, lower income, female gender, lower education, and vaccine costs
(1, 6, 7).
A cartoon illustrated by English caricaturist James Gillray in 1802.
In this cartoon, showing that cowpox pustules used to vaccinate against
smallpox will cause cow-like appendages from different parts of people’s
bodies (James Gillray - British Cartoon Prints Collection - Library of
Congress)
However, in 1998 Lancet report by Andrew Wakefield, a British physician,
and his team of 12 colleagues suggested a link between the measles, mumps,
and rubella (MMR) vaccine and the development of inflammatory bowel
disease and autism (The Lancet retracted the Wakefield et al. paper in 2010)
has opened the doors of fear of vaccines to the fullest. Over the next 20 years,
epidemiological studies have consistently found no evidence of a link between
MMR vaccine and autism, but it has further reinforced human vaccine concerns.
In addition, although there is epidemiological research evidence that there is
no association between childhood vaccines containing thimerosal and autism,
concerns continue about pediatric mercury exposure (8-10).
With the increase in internet use, online platforms and social media in
our digital world have become a source where health-related information
can be easily reached by everyone. This has also allowed widespread access
to misinformation. With the founding of Google in 1998 and the subsequent
launch of other social media platforms such as Facebook, Twitter, YouTube, and
VACCINE HESITANCY: A GLOBAL THREAT 191
Instagram, the spread of true or false information about vaccines accelerated
(Figure 2). Especially during pandemics, there has been an abundance of
information from many sources, including social media, called an infodemic
(9, 11, 12).
Timeline of Key Events Prompting Vaccine Hesitancy and
Milestones in the Expansion of Social Media and Digital Technology
(adapted from Larson et al., 2022)
Without a doubt, one of the most effective strategies to contain the
COVID-19 pandemic is vaccination. Considering the dynamic and changing
nature of vaccine hesitancy, it can be said that this rate has increased especially
in the context of the COVID-19 pandemic. As a result, the post-pandemic world
today is more challenging and more effort is needed to build confidence in
vaccination programs. Apart from this, it is also very important to inform the
public about the importance of vaccines, to disseminate the correct information
to all communities and to prevent the spread of false information.
192 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
1. MacDonald NE; SAGE Working Group on Vaccine Hesitancy. Vaccine
hesitancy: Definition, scope and determinants. Vaccine. 2015;33(34):4161-
4164.
2. Leask J. Vaccines — lessons from three centuries of protest. Nature.
2020;585(7826):499-501.
3. Joslyn MR, Sylvester SM. The Determinants and Consequences of
Accurate Beliefs About Childhood Vaccinations. Am Polit Res. 2017;47(3):628-
649.
4. World Health Organization. Ten threats to global health in 2019.
[Internet]. Available from: https://www.who.int/news-room/spotlight/ten-
threats-to-global-health-in-2019. (accessed 04 November 2022)
5. Dubé E, MacDonald NE. Vaccine acceptance: barriers, perceived risks,
benefits, and irrational beliefs. In: The vaccine book. Amsterdam: Elsevier;
2016. pp. 507-528.
6. Farhart CE, Douglas-Durham E, Lunz Trujillo K, Vitriol JA. Vax
attacks: How conspiracy theory belief undermines vaccine support. Prog Mol
Biol Transl Sci. 2022;188(1):135-169.
7. Lazarus JV, Wyka K, White TM, Picchio CA, Rabin K, Ratzan SC,
Parsons Leigh J, Hu J, El-Mohandes A. Revisiting COVID-19 vaccine
hesitancy around the world using data from 23 countries in 2021. Nat Commun.
2022;13(1):3801.
8. Motta M, Stecula D. Quantifying the effect of Wakefield et al.
(1998) on skepticism about MMR vaccine safety in the U.S. PLoS One.
2021;16(8):e0256395.
9. Larson HJ, Gakidou E, Murray CJL. The Vaccine-Hesitant Moment. N
Engl J Med. 2022;387(1):58-65.
10. Hurley AM, Tadrous M, Miller ES. Thimerosal-containing vaccines
and autism: a review of recent epidemiologic studies. J Pediatr Pharmacol Ther.
2010;15(3):173-181.
11. Galagali PM, Kinikar AA, Kumar VS. Vaccine Hesitancy: Obstacles
and Challenges. Curr Pediatr Rep. 2022:1-8.
12. Sirekbasan S, Suzuk S. YouTube as an information source during the
COVID-19 outbreak: a cross sectional study of Turkish video content. J Health
Sci Med. 2021;4(3):340-343.
193
1
1(Asst. Prof. Dr.), Sivas Cumhuriyet University Faculty of Pharmacy,
Department of Pharmaceutical Botany
e mail: hulya1177@yahoo.com.tr
ORCID: 0000-0001-8154-0874
2(Pharmacist), Sivas Cumhuriyet University Faculty of Pharmacy
e mail: camliogluderya91@gmail.com
ORCID: 0000-0002-5952-914X
Psychoactive plants; In the human mind, perception can be defined as
plants with simple or complex structures that affect the living mind
and consciousness that produce mood-state changes. Hundreds of
psychoactive plants are known to exist. (1) These plants act by affecting neurons,
putting pressure on the sympathetic and parasympathetic nervous system or
hormones. The use of these herbs in small amounts can be stimulating, mood-
altering, euphoria, and the use of high doses can lead to serious consequences up
to death. (2) Most psychoactive plants have been used in cultural and religious
rituals and daily routines for therapeutic purposes and to create a fun and joyful
environment, albeit temporary.
Psychoactive plants; It is classified in many ways according to its
chemical structure, the type of secondary metabolite contained in it, and the
effects it creates on the living body. These plants can cause pharmacological
and psychological effects in different ways. In general, psychoactive plants
194 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
are classified as anxiolytics, euphoriates, stimulants, antidepressants, and
hallucinogens according to the effect they have on the living body. A plant can
also be in more than one class. (3)
1.1.Banisteriopsiscaapi(Spruce ex Griseb.) Morton
The species Banisteriopsis caapi is the main component of a drink called
Ayahuasca, which is used by the indigenous people of the Amazon basin in
both social and religious ceremonies. (4) The leaves of the Psychotria viridis
bush, which contain N,N-dimethyltryptamine (DMT), and the roots of the
Banisteriopsis caapi vine, which are abundant in beta-carbolin harmala
alkaloids, are typically used to make this psychedelic beverage. (5)
Ayahuasca users have reportedly experienced experiences including inner
tranquility, joy, interaction with plant and animal spirits, and even communion
with a higher power. (6, 7) The perception of time alters, causing users to feel as
though time is moving faster or slower or that they have traveled through time.
Temporary side effects of ayahuasca that are not entogenic can include tremors,
nausea, vomiting, diarrhea, autonomic imbalance, hyperthermia, sweating,
motor dysfunction, drowsiness, relaxation, vertigo, dizziness, and muscular
spasms, depending on the dose. (5)
1.2.TabernantheibogaBaill.
The main active ingredient of Tabernanthe iboga plant is ibogaine.
Ibogaine was first isolated from the West African shrub and root bark that grew
in the Congo and Angola. (8) This plant, which is about 3 or 4 m high, is found
in the wild and is also grown around its native huts. Locals have discovered
that root bark has a powerful stimulant and aphrodisiac effect, increases the
strength of muscles and improves sexual abilities. (9) The aphrodisiac effect of
ibogaine lasts for 2 days. (3) Traditionally, hallucinogen has been used by locals
to suppress hunger and fatigue. This herb in high doses can cause convulsions
and paralysis. (10)
Examples of the autonomic nervous system effects of ibogaine on the
living body are the formation of visual hallucinations in person, insomnia,
dry mouth, too much sweating, increased pulse, tremor, enlargement of the
pupils. (3)
SOME EXAMPLES OF PSYCHOACTIVE PLANT SPECIES 195
1.3. Lophophora williamsii (Lem. ex Salm-Dyck) J.M.Coult.
(Peyote Cactus)
Mescaline (3,4,5-trimethoxyphenethylamine), the main component of
the species Lophophora williamsii, has been used for thousands of years in
religious rituals and for medicinal purposes by North American natives due
to its psychedelic properties. It is a naturally occurring alkaloid. (11) It is still
legally used today by the Indian Church in religious ceremonies traditionally
held at night and lasting about 12 hours. (12) In addition, both cactus and mainly
mescaline are consumed illegally. (13)
Although they exhibit different chemical properties, all hallucinogens
usually produce similar psychological effects. However, mescaline and peyote
have some distinctive features. Shortly after application, hallucinations and
excessive sensitivity to sound appear. (14) Light and colors are pronounced,
appear bright and intense. Typically, hallucinations can last longer than 10-12
hours. (15) Symptoms of mescaline poisoning include hyperreflexia, tachycardia,
agitation, muscle stiffness, ataxia, seizures, midria fog, sialoure, hyperthermia.
(13, 16)
1.4.PsilocybemexicanaHeim
In 1957, psilocybin was isolated from the fungus Psilocybe mexicana. In
the examinations carried out from those years to the present day, it has been
determined that psilocybin and psilocin are present in the composition of more
than 75 different mushroom species. These mushrooms are also called magic
mushrooms. (17)
Psilocybin was first synthesized by Hofmann. Clinical studies in the 1960s
and 1970s showed that psilocybin produced an altered mood. Psilocybin and
psilocin are known to cause changes in thought, time, space and self-concepts,
along with subjective symptoms such as marked changes in perception and
mood. (18) Many effects can be observed in individuals using psilocybin from
laughing crises to the emergence of deep philosophical thoughts, from the
increase in artistic abilities such as painting and music to the change in the flow
of time. (3)
196 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
The physiological, visual, cognitive, auditory, multi-sensory and
transpersonal effects that magic mushrooms have on the living body (19)
PHYSIOLOGICAL EFFECTS Mild sedation, physical euphoria, runny nose,
mydriasis, hypersalivation, increase in body
temperature
VISUAL EFFECTS Color saturation, sharpness of vision,
perspective distortion, perception of brightly
colored shapes, and both closed and open-eyed
figures and eyes
COGNITIVE EFFECTS Increased empathy, simultaneous different
emotional states, loss of ego, lack of time
consciousness
AUDITORY EFFECTS Enhancement or distortion of the sound
MULTIPLE SENSORY EFFECTS Synesthesia
TRANSPERSONAL EFFECTS An increase in emotion and spirituality
1.5.CannabissativaL.
Cannabis sativa L. (Cannabaceae) can grow in different habitats and
altitudes. Cannabis has a rich history of medical use dating back to fairly
ancient times. The cultivation and use of hemp dates back to 5000 to 6000 years
ago. (20) Secondary substances known as “cannabinoids” or, more precisely,
“phytocannabinoids” are a characteristic of all cannabis plants. Trichomes,
which are primarily made from female hemp, yield more than 100 distinct
phytocannabinoids. (21)
Because of its multi-faceted effect on humans, different forms of use of
cannabis, such as marijuana (tobacco-like), have been used for recreational,
religious, spiritual, and medical purposes for thousands of years. For example,
cannabis has been used in the Middle East to treat epilepsy. There are also
records of its use during funeral rites in western China BC. Patients who have
multiple sclerosis, cancer, or AIDS can utilize products containing THC to
relieve their pain, nausea, and vomiting. Cannabis has the potential to treat a
wide range of illnesses, including Tourette’s syndrome, post-traumatic stress
disorder, and sleep difficulties. For this reason, it is removed from the list of
prohibited substances in many countries and its use for medical and recreational
purposes is tried to be legalized. (21)
SOME EXAMPLES OF PSYCHOACTIVE PLANT SPECIES 197
Known medicinal uses of cannabis (22, 23)
Amyotrophic lateral sclerosis Glaucoma Multiple sclerosis
Alzheimer Hepatit C Osteoporosis
Diabetes HIV Itch
Dystonia Hypertension Rheumatoid Arthritis
Fibromyalgia Incontinence Sleep apnea
Disorders of the Gastro-intestinal tract MRSA Tourette’s syndrome
People who use cannabis have many physical and mental changes.
Examples include;
Altered senses (for example, seeing brighter colors)
Altered perception of time
Changes in mood
Abnormal bodily movement
Challenges in reasoning and solving problems
Poor memory
Hallucinations (when taken in high doses)
Delusions (when taken in high doses)
Psychosis (the risk is highest with regular use of high-potency cannabis)
Breathing problems
Tachycardia
Child development issues both during and after pregnancy
Temporary hallucinations
Temporary paranoia. (24)
1.6.PapaversomniferumL.
Opium (Papaver somniferum L.) is a CNS depressant and narcotic
analgesic. It is not hallucinogenic. It exerts its effects through specific opiate
receptors mu, delta, kappa, nosiseptin receptors. Opium contains morphine,
codeine and tebain, as well as papaverine and noskapin (isoquinolins). (25, 26)
There are many examples of the use of opium in history. Examples include
evidence that its seeds were consumed at the end of the Stone Age, doctors in
Egypt and Mesopotamia used poppy water with prayers, spells, talismans and
religious rituals, Helen of Troy added opium to wine to cheer up her guests, and
198 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
the poppy fields in Turkey during the Ottoman Empire spread over hundreds of
kilometers. (27)
Milk and latex obtained from the opium plant contain 12% morphine
alkaloid. This resulting morphine has been used for centuries as a poppy or
poppy tincture. Another derivative of opium alkaloids is heroin. Heroin is used
as an analgesic. (3)
Opium smoking causes many physiological and pharmacological effects.
Sedation, nauseousness, vertigo, vomiting, constipation, physical dependency,
tolerance, and respiratory depression are a few of these. Constipation and nausea
are the most frequent ones, and there is no tolerance building up to them. (28)
Although it does not cause sharp hallucinations, it has analgesic, hypotensive
and antidiarrheal effects. It can also cause a dreamlike condition. (25, 26) Opium
and some alkaloids have the potential to be seriously addictive. (3)
1.7. Erythroxylum coca Lam.and Erythroxylum
novogranatense(Morris) Hieron.
Cocaine is a tropane alkaloid derived from the coca plant
(Erythroxylum coca Lam. ve Erythroxylum novogranatense (Morris)
Hieron.) native to Western South America. The coca plant has been
cultivated for thousands of years, and 2000-year-old mummies have been
found in Nazca, Peru, with small bags used for coca leaves in their hands.
Coca leaves have shown interest in Europe due to their psychoactive
properties, and with the discovery of methods of extracting and concentrating
the alkaloid cocaine, cocaine use became more common in Europe towards the
19th century. (29) In the 19th century, cocaine was incorporated into a number
of pharmaceutical and consumer products, such as Coca-Cola and cigarettes.
(30)
The cocaine plant is an elongated shrub form that can grow up to 2-3
meters in height. The leaves are laid out in thin layers and dried in the sun.
Then they are packed in sacks for transportation. To maintain the quality of
cocaine, the leaves should be kept dry. Depending on the species and location
grown, the leaf contains about 0.3-1.5% cocaine.
While a loud or abrupt change in emotion is what is meant by cocaine
intoxication, there are other side effects as well, such as strong euphoria, a
quick heartbeat, elevated blood pressure, and more active motor and speech
functions. Additionally, there is an increase in attentiveness, hostility, anxiety,
aggressiveness, alertness, poor judgment, and emotional instability. Greater
behavioral complexity or repetitive habits (such as touching one’s nose or
SOME EXAMPLES OF PSYCHOACTIVE PLANT SPECIES 199
forehead) are seen in heavy users. In any acute consumption, a high dosage
of cocaine that results in an overdose can be linked to medical issues such
cardiac arrhythmia-related mortality, seizures, hyperthermia, dehydration, and
local vasoconstriction that causes myocardial infarction or paralysis. Physical
examination results are less frequent or diagnostic in cocaine users. Tachycardia,
elevated blood pressure, and motor agitation are seen in acute users. Regular
nosebleeds and/or an eroded nasal septum can occur in heavy intranasal users.
The typical signs of chronic needle usage in the arms, legs, or neck are present
in injection users. (31)
3.8.MandragoraofficinarumL.
Mandragora ocinarum L., is a perennial plant that is a member of the
Solanaceae family and is widely found in the Mediterranean region, including
Greece. The species, also called mandrake grass, has oval leaves, a thick and
erect root, bell-shaped flowers, and yellow or orange fruits. (32) It is even called
“man’s grass” because the appearance of plant roots resembles a human being.
Mandragora species have been one of the most famous medicinal plants in
western culture throughout written history. This view has been clearly expressed
by several authors in such statements as “Of all the medicinal herbs used in the
ancient and medieval world, none of them has been looked upon with as much
fear and amazement as mandrake.” (33)
The unique names of mandrake give away the particular medical use of
this plant. The Greek names for this plant are fistulóriza and fistulóchorto, which
translate to “hemostatic-acting root” and “healing root,” respectively. (34) The
stem has a human-like shape (anthropomorphic). It alludes to sexuality and
reproduction symbolically. (35, 36)
Among the main tropane alkaloids in mandrake are hyocyanamine and
scopolamine (also known as hyosine). These tropane alkaloids have been shown
to exhibit psychedelic and hallucinogenic effects and to be muscarinic receptor
antagonists, which results in a parasympatholytic effect. Chronic spasms, a rapid
pulse, tachycardia, enlarging of the pupil, suppression of saliva production,
respiratory arrest, and coma can all result with larger dosages of these drugs.
Mandrake is therefore regarded as being exceedingly harmful and at the level of
a chemical that alters consciousness. (37)
Mandrake is said to have aphrodisiac properties. At least 136 chemical
compounds were discovered in Mandrake fruit in one research, and it was
hypothesized that the primary components, which were only discovered in
200 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
mature fruits and were absent from unripe fruits, may be to blame for the fruit’s
distinctive flavor, odor, and aphrodisiac effects. (38) Mandrake has never been
pharmacologically confirmed to have aphrodisiac effects, yet it is nevertheless
used for this purpose in many nations today, particularly in the Balkans and the
Southeast Mediterranean. (39)
Mandrake is probably the most famous of the so-called “magical” plant
species in history, and that is why it appears in many areas of literature. (40) The
magical powers attributed to Mandrake, both good and bad, have made him a
formidable object. Among the people, Mandrake was considered an entity with
open ties to the forces of the underworld. (41, 42)
3.9.PeganumharmalaL.
The plant is widely found in Central Asia, North Africa and the Middle
East and is used as a medicinal plant. (43, 44) The dried capsules are mixed
with other ingredients and burned as a talisman against the “evil eye” among
Iranians. (43)
The alkaloids found in P. harmala also have some role in the
pharmacological effects of the plant. (45) Harmaline was first isolated by
Goebel from the seeds and roots of the plant. (46) Harmaline is found in many
plants such as Banisteriopsis caapi (Malpighiaceae) in addition to P. harmala.
It is also one of the components of Ayahuasca, a hallucinogenic drink drunk
by Amazonian tribes in rituals. (47) This plant contains harmaline alkaloid as
well as harmine alkaloid. Harmine and harmaline alkaloids contain monoamine
oxidase inhibitors. (3)
3.10.ArtemisiaabsinthiumL.
It is a shrub-like perennial plant, growing up to 80 cm in height. In some
habitats it even reaches a height of 1.5 m. The whole plant contains a large
number of feathers and has an intense, pungent odour. (48) A. absinthium leaves
contain feathers/glandular trichomes that secrete essential oil and hairs that
have a protective function. These protect the plant against high temperatures
and prolonged drought. (49)
A. absinthium is a species that is currently grown in Brazil, the USA, and
Southern Europe. The start of the harvest season coincides with the emergence
of the first blossoms. Cut leafy branches and base leaves are left with woody
remnants. Many times a year, harvesting can be done. The essential oil of
SOME EXAMPLES OF PSYCHOACTIVE PLANT SPECIES 201
A. absinthium is significantly impacted by the drying process. It has been
shown that even a small amount of air heating can alter the oil’s organoleptic
characteristics. The harvested plant shouldn’t also be spread out in a thick layer
because it will cause it to dry out much more slowly. Drying should be done at
room temperature in drying rooms or airy, shaded areas. (50)
Wormwood has long been known for its very bitter flavor. The expression
“bitter as wormwood” is used in Polish. This species was characterized by
Dioscorides (1st century AD) and Theophrastus (4th–3rd century BC) as
“ápsinthos,” which is Greek for “unpleasant” or “ápinthos,” unfit for drinking.
(51) In addition to its distinctive bitterness, wormwood also has a central
nervous system stimulant effect that, depending on the amount, can even
result in epileptic convulsions and hallucinations. This feature has been known
about since ancient times. (52) Wormwood, which is often used as a tincture,
is mentioned in Dioscorides’ book ‘De Materia Medica’ as having warming,
astringent, and invigorating qualities as well as being useful against poisons. (53)
Pliny (1st century AD) also recommended Absinthium as a hypnotic, laxative,
menstruation trigger, healer of “fistulas in the eyes”, and even cosmetically.
He also stated that his ash, combined with a rose ointment, darkened the hair.
(54) This plant’s ritual use in funeral rituals and the exorcism of bad spirits
is due to the same strong fragrance it emits when burned. (55) According to
the recommended traditional use, the leaves are used to lower fever, while the
flowers help with diseases of the stomach and helminthiasis. Tincture of A.
absinthium has been evaluated as a tonic and digestive aid. (48)
To support the long-standing usage of A. absinthium for the treatment of
memory problems and poor focus, a research was done. The study looked at
the chemicals isolated from A. absinthium’s ability to bind to muscarinic and
nicotinic receptors because it is known that cholinergic receptors are involved
in cognitive processes. The efficacy of two sets of harvested plants’ ethanol
extracts to remove [3H]-(N)-nicotine and [3H]-(N)-scopolamine from receptors
was tested using a homogenate of human cortical brain cells. According to
the study, A. absinthium has a significant affinity for muscarinic and nicotinic
receptors, which means that products derived from the plant may have beneficial
effects. (56)
202 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
3.11.SalviadivinorumEpling & Jativa-M.
(A) Salvia divinorum plant (B) Characteristic flower structure
(C) Dry leaf specimens (57)
Salvia divinorum, a plant belonging to the Labiatae family, is indigenous to
a tiny area of Oaxaca, Mexico. S. divinorum may be cultivated indoors or in any
humid, semi-tropical climate, just like cannabis. The herb has been utilized for
generations by the shamans of the Mazatec Indians of Oaxaca to treat conditions
including diarrhea, migraines, rheumatism, and anemia as well as for prophetic
and religious purposes. The panzón de Borrego sickness, which is semi-magical,
was also treated with it. Fresh S. divinorum leaves are either chewed or crushed
and ingested in a combination for ethnomedical purposes. (58) Due to its
distinct psychomimetic properties, S. divinorum, sometimes known as Salvia,
has recently attracted more interest for its recreational usage. S. divinorum is
frequently marketed as a risk-free, accepted substitute for hallucinogens like
cannabis, LSD, and mescaline. (58, 59)
The main active ingredient of S. divinorum is the neoclerodan diterpene
Salvinorin A. (58) The reported Salvinorin A content in the dried leaf samples
was found to be 0.89-3.70 mg. The concentration of Salvinorin A in leaves
collected from individual plants can vary significantly. (60)
In vitro and in vivo studies have shown that Salvinorin A is a selective
and potent agonist of k-opioid receptors (KOR), more effective than the two
prototype KOR agonists, U69,593 or U50,488. Salvinorin A is the only KOR
agonist found in S. divinorum and has no structural similarity to any known
hallucinogen. (58, 61)
Sublingual doses of Salvinorin A have not been found to be psychoactive in
humans. (62) On the other hand, when inhaled, Salvinorin A shows psychoactive
effects in just minutes. (58, 63)
SOME EXAMPLES OF PSYCHOACTIVE PLANT SPECIES 203
Inhalation of evaporated smoke of Salvinorin A is considered to be the most
effective method for causing psychoactive effects in humans. It gives people
a cannabis-like experience. In people, visual hallucinations, changes in bodily
form in objects, time and space perception disorders, intense but short-term
psychedelic-like effects, altered state of consciousness, auditory hallucination,
dream-like experience, increase in sensory and aesthetic appreciation, spiritual
experiences, acute psychosis and paranoid, temporary language disorder,
psychomotor agitation can occur. (63)
Psychoactive plants can be classified in many ways according to their
chemical structure, the type of secondary metabolites contained in them,
and the effects they have on the living body. Psychoactive plants can cause
pharmacological and psychological effects in different ways.
Psychoactive compounds mimic neurotransmitters that are responsible
for chemical communication across synapses between neurons. (64) Many
psychoactive compounds or foreign substances entering the body can easily bind
to receptors thanks to their complex and three-dimensional structures and cause
a number of changes in the body. (3) Although these compounds are not exactly
the same, due to their compatible chemical structure, they can bind to specific
neurotransmitter receptor sites, increase their activity, suppress or otherwise alter
them. For example, mescaline, the active alkaloid of peyote cactus, is structurally
similar to the neurotransmitter noradrenaline (also known as norepinephrine).
Since both are derivatives of the phenylethylamine compound, mescaline can
mimic noradrenaline by binding instead of noradrenaline. (64)
In general, psychoactive plants, which are included in the human mind as
plants used for pleasure with their narcotic and hallucinogenic effects, are used
for medicinal purposes with many secondary metabolites they contain.
In this study, briefly, information about the effects of psychoactive plants
on the living body and the most commonly used psychoactive plant species,
the active substances of these species and the mechanisms of action of these
active substances are reviewed. In conclusion, it should be noted that these plant
species, which are first thought to be used in shamanic ceremonies, have many
active components that need to be identified, and these components may have
many therapeutic aspects that need to be discovered in the scientific world.
204 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
1. Rätsch C. The Encyclopedia of Psychoactive Plants: Ethnopharmacology
and Its Applications. Rochester, USA: VT: Park Street Press; 2005.
2. Tanker, N., Koyuncu, M., Coskun, M. Pharmaceutical Botany Textbook.
VI. Press. Turkey: Ankara University. Pharmacist. Fac. Publications, 2019: 123.
3. Sayın, H. Psychoactive Plants. Turkey: Tantra Academy; 2016.
4. Hay, M. The Colonization of the Ayahuasca Experience. JSTOR Daily,
2020; 20.
5. Gable R.S. Risk assessment of ritual use of oral N, Ndimethyltryptamine
(DMT) and harmala alkaloids Addiction; Psychedelic Medicine (Vol 2): New
evidence for hallucinogenic substances as treatments. 2007;102(1):24–34.
6. Riba J, Rodríguez-Fornells A, Urbano G, et al. Subjective effects and
tolerability of the South American psychoactive beverage Ayahuasca in healthy
volunteers. Psychopharmacology, 2001; 154(1): 85-95.
7. Shanon B. Altered temporality. Consciousness Studies. 2001;8(1):35-
58.
8. Maciulaitis R, Kontrimaviciute V, Bressolle F. M., & Briedis, V. Ibogaine,
an anti-addictive drug: pharmacology and time to go further in development. A
narrative review. Human & experimental toxicology, 2008; 27(3), 181-194.
9. Pope, H.G. Tabernanthe iboga: an African narcotic plant of social
importance. Econ Bot. 1969; 23: 174-184.
10. Strubelt S, Maas U. The near-death experience: a cerebellar method to
protect body and soullessons from the Iboga healing ceremony in Gabon. Altern
Ther Health Med. 2008; 14(1): 30–4.
11. El-Seedi H.R., De Smet, P.A., Beck O, Possnert G, Bruhn J.G. Prehistoric
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209
1(Dr.), Department of Food Hygiene and Technology, Faculty of
Veterinary Medicine, Firat University, Elazig, Turkey
ORCID: 0000-0002-0824-1672
2(Prof.Dr.), Department of Food Hygiene and Technology, Faculty of
Veterinary Medicine, Bingol University
ORCID: 0000-0001-5933-9971
*Corresponding author: E-mail: p.demir@rat.edu.tr
One of the fundamental principles of leading a healthy life is adequate
and balanced nutrition. Foods that meet the energy, protein, vitamin and
mineral needs are divided into four main groups as foods providing this
balance. It is extremely important for living beings to consume healthy foods
to grow, develop, sustain their life; protect, improve and develop their health
and increase their quality of life. The place and importance of milk and dairy
products both in the food pyramid and in leading a healthy lifestyle is beyond
doubt. Milk is an important source of animal protein that contains almost all
of the essential nutrients required for growth and development. However,
since raw milk has a short shelf life, it should be subjected to heat treatment at
appropriate temperatures and time periods as soon as possible or converted into
more durable products. Cheese is a dairy product that has quite an important
place among dairy products and has a wide variety. The main reasons for this
are that most of the nutrients in milk are concentrated in cheese, cheese has a
long shelf life, and the milk can also be transformed into cheese in a short time
period with different processing methods in seasons and regions where raw milk
is abundant (1).
210 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Cheese is a dairy product consumed fresh or after ripening, obtained
by coagulating whole milk, cream, partially or completely skimmed milk,
buttermilk or some or all of these with appropriate proteolytic enzymes known
as rennet and/or harmless organic acids, separating the whey, shaping the clot
and salting it (2). The Food and Agriculture Organization’s (3) Codex of General
Standards for Cheese (4) defines cheese as “a semi-soft, hard or extra-hard
product obtained from milk, ripened or unripened, semi-soft, hard or extra-hard,
which can be coated and where the whey does not exceed the amount of milk”.
According to the Turkish Language Association (5), cheese is defined as “a food
made from milk by solidifying with yeast and has many types”. Cheese, which
is obtained from butchery mammals whose milk is consumed, is a popular
foodstuff in our country. When cheese is produced from raw milk, it contains
phosphorus, calcium, high quality protein, riboflavin (vitamin B2) and vitamin
A. Cheese also contains essential fatty acids (linoleic, linolenic and arachidonic
acid) and essential amino acids in sufficient and balanced amounts (6). As the
amount of fat in cheese increases, the amount of aroma increases as a result of
the separation of fat into its components. Therefore, the higher the fat content of
the cheese, the higher the aroma will be. In addition, since fat-soluble vitamins
such as A, D, E and K do not undergo any change during cheese making, they
increase in direct proportion to the fat content of the cheese. The higher the fat
content, the higher the amount of carotene. Water-soluble vitamins are partly in
cheese and partly in whey. Vitamin C, which is present in small amounts in milk,
passes completely into the whey during cheese making. Therefore, its amount in
cheese is quite low. The lactose content in cheese is also very low. Calcium and
phosphorus ratio in cheese is at the desired level (7).
Another important fact about the cheese in terms of nutrition is that it has
a high biological value but a low marketing price. Another feature that increases
the value of cheese is that the yeast (pepsin) used in the production process
continues its activities in the stomach and therefore it is easily digestible and can
help digest other foods as well (8, 9).
When we look at its etymological origin, the word “peynir” (cheese)
has passed into modern Turkish from the Persian word “panīr”, which means
made from milk. It came into English from the Latin “caseus”. It is thought
that the origin of this word comes from the root “kwat” in Indo-European
languages, which means fermenting-sourdough (10). Cheese comes from the
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 211
Latin word “formaticus” meaning “made in a mold”. The Italians used the word
formaggio, the French first used formage, formaige, fourmage, frommaige and
finally fromage. The words “cheese” in English, “käse” in German, “kaas” in
Dutch, “questo” in Spanish, “queijo” in Portuguese, “formatge” in Catalan
originate from the Latin word “coagulum” meaning coagulation and “caseus”
meaning cheese (10, 11). Cheese, which is also defined by various names in
other countries, is known to be called “chiz”, which is known as “excellent
thing” in Urdu, the common language in the geography where many languages
are spoken when the Indian Peninsula was under the sovereignty of the Great
Mongol-Turkish Empire. It is called “sir” in Russia, “sirene” in Bulgaria, “sajt”
in Hungary, “ser” in Poland, “brinza” in Romania, “ost” in Sweden, “juusto” in
Finland, “tiri” in Greece, “cebbene” in Arabia (2, 4, 11-14).
When researching the information on the use of the word “peynir” in pure
Turkish, we can see that it was first used by the Uyghur Turks (750 A.D.). The
cheese obtained by leaving the milk to its own state and developing its acidity
is called “eksimik” or “kesik” in the folk language. In the Divanu Lügati’t-Türk
written by Kashgarli Mahmud between 1072-1074 (1072 A.D.), it is pointed
out that “milk is creamed”. In this work, it is known that fresh cheese is called
“udma” or “udhıtmanın” (derived from the word udhıt, which means to put to
sleep, to solidify, to keep waiting with yeast). “Udh” means cattle, oxen. It is
also stated that a type of cheese made from sour milk was called “sogut” in the
Karluk dialect and some Turkmen tribes migrating to Anatolia still use the same
name. The word peynir entered Turkish from Persian during the migration from
Central Asia. Among the words “benir”, “penir”, “beynir”, which first appeared
in the Turkish vocabulary of the Egyptian Mamluks, “penir” was used by
Turkmens when they passed through Iran on their westward march or when they
settled in Anatolia. “Nan-ü penîr” means bread and cheese, “penîr’i gercek”
means fatty cheese and “penîr-i teras” means grated cheese. In the language
spoken by the Kipchaks (Kumans), a Turkish tribe that lived in the Ukrainian
steppes in the twelfth century, it is also expressed as “benir”. In Chagatai, the
written language of Eastern Turkic in the fifteenth century, the word “pendir”
is used. Like Chagatais, Azerbaijanis also frequently use the word “pendir” or
“penir”. In addition, the word peynir is used in Dede Korkut tales (such as tası
peynir gibi ditti / südi peyniri bol gibi), which are considered to be 12th and 13th
century works (2, 14-17).
During the Seljuk period, cheese was known as “udıtma” and/or “udhıtma”.
The Uyghur term “udhıtmak” is still used today in some villages in Ankara
212 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
province as a term expressing the coagulation of milk. In addition, the oldest
word for cheese is known as “bıslak”. Originating from the Turkish “pis-, bis-”,
this word is still used in Anatolian folk language (Karachay tribe around Konya
and Afyon Emirdağ). This word was also used by the Mongols to refer to cheese.
This word was first found in the Turkish dictionaries of Mamluk Turks (Ibni
Mühenna Lügat) and in ancient Anatolian inscriptions. In this dictionary, there
are some Turkish words such as “ciet, cıkıt, irimcik” meaning cheese. The word
“Irimcik” was used in Mamluk period for milk that coagulates during the heat
treatment applied to make yogurt, while in Central Asian dialects this word
means cheese. In addition to these, the fact that the Central Asian Turks use the
words “agırımsık” or “akermisik” for white cheese is an indication that it means
cheese and that our history of white cheese dates back to very ancient times (14,
16, 18).
In Yusuf Has Hacip’s work “Kutadgu Bilig” written in the eleventh century,
there is also information about the food culture of the Turks. Dry yogurt (kurut)
and cheese types are also mentioned in the said work. In particular, it is known
that they call the type of cheese obtained by draining and drying the degreased
yogurt “kurut”. This type of cheese, brought to Anatolia by the Turks of Central
Asia, was called “black kurut”, while in Iran it was called “kashk black” or “tarf
black”. Today, in many regions of Anatolia, this cheese made from skim milk
or yogurt is called “kesk”, “kesük”, “quiche”, “kes” or “cökelek» (14, 19-20).
There is no precise information on how, where and when cheese was first
made. According to many rumors, there are different opinions on this subject.
According to R.W. Menges, the first cheese production was obtained by an
Arab traveler by chance while carrying milk in a sheepskin bag made of sheep’s
stomach, while some historians such as Herodotus, Hippocrates and Strabo
state that cheese was first made by the Scythian Turks (600-200 B.C. Southern
Russia) from mare’s milk, presumably after souring it. It has been reported that
Scythians lived in the steppes north of the Black Sea (VII century BC-IV century
BC) and that traces of cheese were found in bags made of goat or sheep skins
encountered in ice-covered graves in these regions. According to Kosikowski,
communities known as Turkish and Mongolian ancestors produced fermented
products from goat milk during their migration from Asia to Europe (14, 21-22).
Although there is no concrete evidence other than this information, it is reported
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 213
that cheese was first seen 8000-8500 years ago in lower Mesopotamia, that is, in
the Neolithic Period (Polished Stone Age), when some plants and animals were
domesticated, in the “Fertile Crescent” between the Euphrates and Tigris rivers
(today’s Iraq), or that it was accidentally found by shepherds in the Indus valley
(today around Karachi) as a result of milk souring and coagulating while being
transported in bags made of goat skin. Figures on a stone relief dating back to
3500-3100 B.C. in Mesopotamia, now on display in the Baghdad Museum, show
that the Sumerians (4000 B.C.) were well acquainted with milk technology. It is
believed that Akkadians and Sumerians used nearly 200 types of cheese (2, 14,
19, 23-24).
In the Torah and ancient Hebrew, the importance of cheese is emphasized
by stating that the place known as the running field in Jerusalem was established
near the “Plain of the Cheese Makers”. It is stated that the raw milk to be processed
into cheese was filled into a bag said to be made of goat skin, a piece of rumen
was left in it, which curdled the milk, after the milk in the bag coagulated, they
broke up the clot by hand, left these curdled pieces of milk in other bags, then
dried the pieces taken out of the bag in the open air, crushed them well in a bowl,
mixed them with salt and ate them. Although the Torah states that it is forbidden
to leave organ parts in goat’s milk, it says that it’s not considered “makruh” to eat
cheese made by this way. Therefore, the Jews named the edible cheese “kosher”,
which means “permissible”. It is thought that the name of kashar cheese may
have originated from this Hebrew word (13, 14, 17).
Although the Greeks and Romans (1000 BC) also made different types of
cheese, there is not much information about them. They only mentioned these
cheeses as sheep or goat cheeses. Cheese was not only the food of the lower and
middle classes in the Greeks and Romans, but also the food of the noble class.
It is reported that the noble class consumed cheese made from sheep’s milk. It
is said that cheese was among the gifts that the Hellenes offered to their gods
on Mount Olympus. It is also mentioned that in the Olympics organized by the
Greek site states, athletes ate cheese to strengthen themselves (13, 19).
In the Middle Ages, monasteries and feudal principalities made important
contributions to the development of cheese technology and cheese variety. It is
alleged that the name of the cheese variety called “Munster” comes from the
monastery. Cheese was also used as medicine in the treatment of many diseases
during this period (26).
Cheese first became known in the American geography with the immigration
from Europe in the early seventeenth century. Since the immigrants settled only
214 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
on the Atlantic coast during this period, cheese was known as a food specific to
this region. Due to the economic crisis that broke out in Switzerland in the early
nineteenth century, the poor and unemployed Swiss people migrated to the state
of Wisconsin, and cheese making became widespread in the interior regions of
the American geography. The first cheese factory was established in the USA in
1851 and the second in England in 1899 (13, 14, 25-26).
It is mentioned that some of the types of cheese consumed today were
already produced during the period of the principalities. In the “Tabiat-name”
written by Tutmacı, a Turkish poet on behalf of Aydınoğlu Umur Bey in the
fourteenth century, it is stated that there are fresh cheese and deleme (teleme)
cheese types. In Evliya Celebi’s Seyahatname, which is an important source
about the Ottoman world in the seventeenth century, it is written that there are
400 artisans producing cheese in Istanbul and cheese types such as Kaskaval
Cheese, Kesme Cheese and Teleme Cheese (22).
It is known that Turks were dealing with cheese before their migration to
Anatolia. The fact that cheese was the main food of the soldiers of Attila the
Hun, who was at war with the Romans, is an indication that cheese making was
widely known among the Turks in those years. In addition, the stories of Dede
Korkut that mention the cheese and the document called “Bostan, written by
Sadi of Shiraz, who lived in the twelfth century, described cheese as “a sacred
food” are among the important documents. It is also stated that Karacaoğlan,
one of our folk poets, used the word cheese a lot in his poems (2, 14, 16). It is
stated that in the foundation times of the Ottoman Empire, cheese was among
the gifts that Osman Gazi Bey’s tribes presented to the Bilecik beys who kept the
remaining belongings while returning from the plateau. It is known that there
were many types of cheese (fresh lor, fresh dil, fresh cayir, Mudurnu, Sumu,
Karaman, Sofya, Esme, Midilli, Teleme, white cheese, Cimi Tulum, İzmir
Tulum, Rumeli Tulum, fresh Kashkaval, Balkan Kashkaval) brought to Istanbul
in 1502 during the reign of Beyazıt II (16).
It is stated that, while the milk was being transported in the skin bag, cheese
formation took place with the development of acidity under the influence of
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 215
temperature and separation of the curd from the water during agitation. Today,
cheese production has gained diversity with the combination of technology and
modernization of traditional methods. In many countries, as in Turkey, there are
still types of cheese that are traditionally produced and offered for sale in the
world market. Cheese diversity depends on type of animal (cow, sheep, goat’s
milk cheese), clotting method (acid, yeast cheeses), heat treatment of milk (raw,
pasteurized cheese), fat content (full fat, fatty, low fat, fat-free cheese), structure
(very hard, hard, soft cheeses), salt ratio (salty, unsalted cheeses), additives
(various herbs and spices, melting salts, cheeses made by supporting mold
growth), ripening time (fresh, semi-ripened, ripened cheeses) (27). The socio-
cultural development and change levels of societies are among the important
factors affecting diversity. Cheese is a part of the culture of the society in which
it belongs. In Turkey, it is stated that there are more than 25 local and regional
cheese varieties depending on the breed of animal from which milk is obtained,
regional and climatic differences and traditional and technological processes
applied (28).
Cheese is the most diverse and globally recognized dairy product. It is a
known fact that there is an absolute link between the number of cheese types
and the consumption habits of nations. There are more than 4000 types of cheese
worldwide and more than 150 types of cheese in Turkey. The production of
cheese varies from year to year, and according to the data of the Turkish Statistical
Institute (TÜİK) for 2021, a total of 763,266 tons of cheese was produced (29).
The fact that cheese, whose raw material is only milk, has so many varieties is
due to many differences such as the type of milk used, the type of yeast used,
the way of processing the clot, the processing method, the fat ratio, the ripening
process and conditions, and the salting method (30).
The variety of cheeses may vary according to countries and even regions
within countries. For example; Brie, Camembert and Maroilles in France;
Cheddar cheese in Cheddar Village in England; Edam and Gouda cheeses in
the Netherlands; Gamalost cheese in Norway; Emmental cheese in Switzerland
are among the world cheeses (2). The most produced cheese types in terms
of tonnage in our country are white, kashar, tulum, gruyere, mihalic, lor and
cökelek cheeses. In addition to these, there are about 20 local cheese types
produced regionally to meet family needs and produced with primitive methods.
Traditional cheese types produced in our country are shown in Table 1 (13, 17,
27, 31-33).
216 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Types of cheese produced in Turkey
Abaza cheese
Hendek, Bilecik, Bursa, Düzce, Adapazarı,
Kocaeli, Bolu, Sinop, Canakkale
Acı cheese Giresun
Adıyaman Pazarcık Köy cheese Adıyaman
Adıyaman Basma cheese Adıyaman
Afyon Tulum cheese Afyonkarahisar
Aho cheese
Araklı, Sürmene (Trabzon), Cimen, Balağot
highlands (Gümüshane), Bayburt
Akcakatık cheese Isparta and surrounding areas
Aladağ Köy cheese Ağrı
Antep Sıkma cheese Gaziantep and Kahramanmaras surrounding areas
Armola cheese Seferihisar (İzmir)
Ayas Ovma cheese / Ayas
Basma cheese Ayas (Ankara)
Ayran Kırması cheese
Doğu Karadeniz Bölgesi (Eastern Black Sea
Region)
Ayran cheese Rize
Balkabağı Küp cheese Adapazarı, Doğancay, Hendek, Arifiye
Basma cheese Adıyaman
Batman Kozluk Kok cheese Batman
White cheese Edirne
Bez Kashar cheese Mut
Bez Tulum cheese Konya (Ereğli)
Biberli Cökelek Akdağmadeni (Yozgat)
Cabalti Cökeleği İnebolu (Kastamonu)
Cacık (Otlu Cökelek) cheese Siirt, Hakkâri, Van, Bitlis
Cami Boğazı Trabzon
Carra cheese Hatay
Camur cheese İzmir-Tire
Canak (Testi) cheese Yozgat (Sorgun, Boğazlayan, Sefaatli, Yerköy)
Cayır cheese Manisa
Cepni Tulum cheese Akcabelen (Konya),
Cerkes cheese
Sinop, Bolu, Düzce, Canakkale (Biga), Balıkesir
(Gönen), Hendek, Adapazarı, Bursa
Ciğleme cheese Tokat, Kayseri
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 217
Cihanbeyli Küflü cheese Konya (Cihanbeyli, Karapınar, Ereğli)
Cimi cheese Antalya, Akseki, Serik, Manavgat
Cimi Tulum cheese Antalya (Akseki, Serik, Manavgat)
Civil (Tel) cheese Erzurum, Ağrı, Kars, Ardahan, Mus
Coban cheese Yenisehir (Bursa)
Cömlek cheese Kayseri, Kırsehir, Nevsehir, Cankırı, Aksaray
Cürük cheese Artvin
Deve Dili cheese Kars
Dil cheese
İc Anadolu Bölgesi’nde (The İnterior Anatolia
Region), Hatay
Divle Tulum cheese Divle (Karaman), Konya-Ereğli
Dolaz (Tort) cheese Isparta and surrounding areas
Dövme cheese Hakkâri
Eğirdir Taze Kelle cheese Isparta and Eğirdir
Eksi (Siyah) cheese Cankırı
Eksimik cheese Ordu, Samsun, Giresun (Tüm Karadeniz)
Eridik cheese Yusufeli (Artvin)
Ereğli Bez Tulumu Ereğli (Konya)
Eritme cheese Endüstri
Erzincan (Savak)Tulum cheese Erzincan, Tunceli, Bingöl, Elâzığ
Erzurum Civil cheese Erzurum
Erzurum Kerti cheese Erzurum
Erzurum Tortum Pismis cheese Erzurum
Erzurum Sünme cheese Erzurum
Ezme cheese Hatay
Gaziantep Tulum cheese Gaziantep
Giresun Acı cheese Giresun
Gorcola cheese Artvin (Savsat), Ardahan (Posof)
Gödelek cheese Niğde
Gölbası Tulum cheese Gölbası (Ankara)
Gravyer cheese Kars
Ham Cökelek Silifke
Hellim cheese Kıbrıs
Herki cheese Hakkari (Semdinli)
Hınıs cheese Erzurum
İmansız cheese Trabzon
218 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
İspir Kuru cheese Erzurum
İspir Kurun cheese Erzurum
İvriz Tulum cheese Konya Ereğlisi
İzmir Tulum cheese İzmir
Kadina (Kadine) cheese
Camlıhemsin, Yukarıkavrun, Cat, Elevit, Cicekli,
Ayder Yaylaları (Rize)
Karabük cheese Safranbolu, Yenice, Eskipazar (Karabük)
Karaman Tulumu Karaman (Ermenek)
Karasar Tulumu Beypazarı (Ankara)
Kargı Tulum cheese Karadeniz Bölgesi
Karın Kaymağı cheese
Pasinler, Aybastı, Gümüshane (some villages),
Siirt, Sarıkamıs
Kars Kashar Kars, Ardahan
Kars Cecil cheese Kars
Kartal cheese İslâhiye
Kaynamıs cheese Hatay
Kayseri Cömlek cheese Kayseri
Kazıklı cheese Milas
Keci sepet cheese Karaburun
Kelle cheese Kahramanmaras province and in its district
Kesmük cheese Cankırı and surrounding areas
Kes Ordu, Giresun, Burdur
Kırklareli cheese Kırklareli
Kırktokmak cheese Milas
Kirlihanım Ayvalık
Kolete (koleti, goloti, kolot,
kolo) cheese Artvin, Trabzon, Rize, Bayburt
Konya Küflü cheese Konya
Kopanisti Cesme and Karaburun villages
Kozluk Kok cheese Batman
Köcer (Göcer) cheese Siirt
Kurci Erzurum, Rize, Bayburt
Kuru Ezme cheese Aydın
Kuru Cökelek İzmir and Aydın in districts,
Küflü cheese Konya
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 219
Külek (Varella) Cheese
Trabzon, Araklı, Tonya, Caykara, Posof, Of, Rize,
Artvin
Künefe cheese Urfa, Antep, Adana
Küp cheese Sivas, Sürmene, Yalvac (Isparta)
Küp Cökeleği Tokat
Küpecik cheese Ayas, Cankırı
Lor The East and Marmara Region
Lorlu Kashar Kırığı Bayburt
Malatya cökeleği Malatya
Malatya Kelle cheese Malatya
Maras Parmak cheese Kahramanmaras
Mengen cheese Mengen (Bolu)
Mezele cheese Trabzon (Sürmene)
Mihalic cheese Bursa, Balıkesir, Canakkale
Minzi cheese Trabzon, Rize, Artvin,
Minzi Kurut Trabzon
Motal cheese Mus, Bulanık
Oğma cheese Trabzon, Artvin
Olaman Ordu
Otlu cheese Diyarbakır-Kars-Siirt-Van, Hakkari, Bitlis
Otlu Cacık cheese Va n
Otlu Lor cheese Van
Ovma ve Basma Ankara (Ayas)
Örgü cheese Diyarbakır
Örme cheese Bayburt
Pesküten Sivas
Pestigen Elazığ, Bingöl, Tunceli, Erzurum
Posa cheese Bodrum
Sacak cheese Selim, Sarıkamıs, Hanak, Damal
Sepet cheese Burhaniye, Karaburun, Foca, Cesme, Ayvalık,
Sepet Loru Ayvalık
Sırvakta Loru Bursa, Balıkesir
Siirt Otlu cheese Siirt
Su (Sulu) cheese Trabzon
Sürk (Sürke) Hatay
220 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Süller Tuluk cheese Denizli
Sünme Hatay
Süt Kırması Trabzon and its surroundings
Sütcüler tortusu Isparta
Sütlü cheese Antalya, Mersin
Safak cheese Erzincan
Savak cheese Elazığ, Tunceli, Bingöl
Sor cheese Savsat (Artvin)
Sor Loru Kars
Urfa Beyaz cheese Sanlıurfa
Urfa Topak cheese Sanlıurfa
Tekne cheese Artvin
Tel cheese Erzurum and Kars
Telli Peynir Sürmene, Akcabat (Trabzon), Artvin
Telli Kremalı Peynir Artvin (Yusufeli)
Testi cheese Antalya
Tomas (Serto) cheese Tunceli, Bingöl, Elazığ ve Mus
Tonya Kashar Tonya (Trabzon)
Tonya cheese Tonya (Trabzon), Yusufeli (Artvin)
Topak cheese Sanlıurfa
Trabzon Cami Boğazı Trabzon
Trakya Kashar Kırklareli, Tekirdağ, Edirne
Tulum Kashar Dumanlı (Tokat), Vakfıkebir, Sürmene (Trabzon)
Tulum Kesi Akseki, Manavgat, Korkuteli
Türkmen Sacak Ardahan
Varil cheese Trabzon
Vartu Keci cheese Mus (Varto)
Yalvac Küp cheese Yalvac
Yaprak cheese Hakkâri
Yayla cheese Trabzon, Artvin
Yer cheese Trabzon
Yörük cheese Antalya, Denizli, Isparta, Burdur, Toroslar, Gönen
Yumme cheese Artvin
Yusufeli küflü köylü cheese Sarıgöl (Artvin-Yusufeli)
Yüksekova cirek cheese Hakkari
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 221
Turkey is a very rich country in terms of traditional foods with its
geographical location, rich natural resources, historical and cultural heritage. It
is thus one of the few countries in the world with high potential for Geographical
Indication (GI) (33-37). Geographical Indications (GI) are signs that indicate
products originating from a specific region or identified with the region of origin
with a certain quality, reputation or other characteristics (37-38). Geographical
Indications are registered as a sign of origin or designation of origin in the
Industrial Property Law No. 6797 dated 22.12.2016, which replaced the Decree
Law No. 555, in parallel with the European Union practices. Traditional
product name protection is not a Cİ, but a tradition that is protected. “Protected
Designation of Origin” (PDO): Products originating from a region, territory with
defined geographical boundaries or, in exceptional cases, from a country, which
derive all or their essential characteristics from the natural and human elements
specific to this geographical area, and whose production, processing and other
operations all take place within the boundaries of this very geographical area.
“Protected Geographical Indication” (PGI): It defines products, at least one of
the production, processing and other operations of which is carried out within
the boundaries of the designated geographical area (36, 38). The cheeses with
geographical indications in Turkey are shown in Table 2. In the world, Parmesan
cheese (in the provinces of Parma, Reggio Emilia, Modena and Mantua in Italy
and along the banks of the Po and Reno rivers) and Grana Padano cheese (in
some regions along the banks of the Po and Reno rivers in Italy) are among the
cheeses with geographical indications. In Turkey, the cheeses with geographical
indications are shown in Table 2 (36).
222 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
Cheeses with geographical indication in Turkey
Antakya Carra Cheese
Hatay province; Antakya, Arsuz, Belen, Yayladağ,
Altınözü and Reyhanlı districts
Antakya Sürkü (Cökeleği) and
Moldy Sürkü
Hatay province
Antep Sıkma Cheese Gaziantep province
Bolu Kes Cheese
Bolu province Göynük, Mengen and Mudurnu
districts, Sakarya province Taraklı districts and
Bilecik province Gölpazarı districts
Diyarbakır Örgü (Braided)
Cheese
Diyarbakır province and districts
Edirne White Cheese Turkey borders
Erzincan (Savak)Tulum cheese Erzincan province and its districts
Erzurum Civil and Moldy
Cheese
Erzurum province and its districts
Ezine White Cheese
Ezine, with Bayramic and Ayvacık districts, Serbetli,
Etili, Ahlatlıburun, Kücüklü, Alibeyköy, Söğütalan,
Karacaören, Kursunlu and Kirazlı villages
Gümüshane Deleme Cheese Gümüshane province
Hellim Cheese Kıbrıs island
Karaman Divle Obruk Tulum
Cheese Karaman province Ayrancı district
Kars Kashar Kars and Ardahan provinces and its districts
Kırklareli White Cheese Kırklareli province
Malkara Aged Kashar Cheese Tekirdağ province Malkara district
Manyas Kelle Cheese
Balıkesir province Manyas, Bandırma and Gönen
districts
Maras Parmak (Finger)/Sıkma
Cheese Kahramanmaras province
Pınarbası Uzunyayla Cerkes
Cheese Uzunyayla platosu
Sakarya Abhaz (Abaza) Cheese Sakarya province
Urfa Cheese Sanlıurfa province
Vakfıkebir Külek Cheese Trabzon province
Van Otlu (Herby) Cheese Van and Hakkari provinces
Yozgat Canak Yozgat
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 223
6.1.AntepSıkmaCheese
Antep Sıkma is a type of cheese made from the milk of small cattle (sheep,
goat or a 1:1 mixture of these) grazing in the pastures of Gaziantep province.
This is one of the types of cheese made by boiling the curd, is consumed fresh
or kept in brine. Known as “pisken” or “kelle” in the region, this cheese is
easily dispersible in the mouth, leaves a squeaking sensation in the mouth when
chewed, flexible, non-porous, homogeneous, smooth, firm, does not crumble
when cut, gray-white in color and semi-hard. This cheese, which is also rich in
flavor components, has a spherical shape with a diameter of about 6-10 cm (23,
39-43).
6.2.AntakyaCarraCheese
Antakya Carra cheese is produced from the milk of cows or goats fed
with herbs rich in medicinal and aromatic plants (about 2000 species) and
endemic species (280) growing within the designated geographical borders. A
layer of cheese, a layer of salt, and a layer of cökelek cheese with zahter or
black cumin added to it are placed in a jug called carra (glazed/unglazed). After
3-4 days, the mouth of the jug is plastered with a special mortar and ripened
under the ground for about 3 months. The distinctive features of this cheese
come from the mountain thyme known as “zahter” in the region, black cumin
and the pottery used for packaging (23, 44-45). Depending on the season and
animal breed, Antakya Carra cheese is white-cream in color, hard and brittle,
salty and rich in aroma components (45-47). At the same time, more than 60
volatile compounds were detected in this cheese and characterized in terms of
3-methyl-2-butanol, ethyloctanoate, 2-isobutyl-3- methoxypyrazine, propanoic,
butanoic, 3-methylbutanoic, hexanoic and octanoic acids (45).
6.3.AntakyaSürkü(Cökeleği)andMoldySürkü
Antakya Sürkü (Cökeleği) is obtained from cow›s milk with increased
acidity or by boiling buttermilk. It is a type of orange colored and conical
shaped cökelek cheese that contains bitter, sour and salty flavors, obtained by
adding salt, pepper paste and optionally various spices (such as black pepper,
red pepper, cumin, coriander, mint, mahlep and ginger) together with wild
thyme collected from the mountains, known as «zahter» in the region (41, 43,
47-49).
224 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
6.4.AntakyaMoldySürkü(Cökeleği)
Antakya Moldy Sürkü is a separate type of moldy cheese obtained as a
result of the natural molding and ripening of Antakya Sürkü. During the ripening
process, the cheese undergoes changes in appearance, taste and smell. However,
unlike other moldy cheeses, Antakya Moldy Sürkü is consumed after the molds
are removed from the surface (50). While a hard crust is observed on the outside,
industrial production is not yet in question for this type of cökelek cheese, whose
color changes from dark red to brown (36).
6.5.BoluKesCheese
Bolu Kes cheese is a traditional Turkish cheese that has been produced
and consumed in Central Asia and Anatolia for centuries. This type of cheese,
which has many varieties with different characteristics (such as leather kes, gök
(moldy) kes, dry kes, yellow kes and fresh kes) varying according to the region
where it is produced (such as Bitlis, Bolu, Hatay, Giresun, Kars and Van), the
producer and consumer preference, is a salty and hard-structured cökelek cheese
with a distinctive taste, smell, aroma and color (matte-white), low fat content,
usually produced from cow’s milk in May and June. The most important
distinguishing feature of Bolu kes cheese is the use of strained yogurt made
from partially skimmed cow’s milk in its production and its longer shelf life due
to its production technology (salting and drying) (51-52).
6.6.DiyarbakırÖrgü(Braided)Cheese
Diyarbakır örgü cheese is a type of brined cheese with high fat content,
homogeneous, plastic curd, elastic structure, semi-hard, distinctive taste and
aroma, high nutritional value and shaped like a braid. This cheese, which can
be separated into threads by hand, has a shiny appearance and its color is cream
white or slightly yellowish (39, 53-54). This cheese, which is made from sheep’s
milk in the spring time, can also be produced from a mixture of goat and cow’s
milk. The distinguishing features of Diyarbakır örgü cheese stem from the use
of milk obtained from special sheep breeds (Karakas, Karacadağ, Zom and Ivesi
sheeps of the Akkaraman variety) that are fed with various grasses in pastures
with rich vegetation and the production method that requires a great deal of skill.
The most important distinguishing feature is that it is shaped like a pigtail, its
taste and smell are between white cheese and kashar cheese, and there are no
physical defects such as crusting and pore formation (36, 43). Diyarbakır örgü
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 225
cheese is similar to white cheese in terms of composition and to kashar cheese
in terms of production technology. Although this cheese is usually made from
raw sheep’s milk in spring, goat and cow’s milk and their mixtures can also be
used in its production (41, 54).
6.7.EdirneWhiteCheese
Edirne white cheese is a yellowish-white colored and rectangular shaped
brined type of white cheese made from milk (cow, sheep and goat) obtained
from dairy animals (cow, sheep and goat) fed by the vegetation under the
influence of the deltas formed by the Tunca, Meric, Arda and Ergene rivers of
Edirne Province and the climate specific to the region. Edirne white cheese is
produced by brine method or tinning method. One of the most important points
in the production of white cheese, which is salted and ripened in brine, is that the
cheese has a flat and non-porous structure. The distinctive feature of this cheese,
which has its own unique structure, taste and smell, is the geographical region
where it is produced as well as the type of milk in the region, the use of different
yeast and salt. It is the most widely consumed geographically indicated cheese
in our country (23, 26, 43, 55).
6.8.ErzincanTulumCheese
Erzincan tulum cheese is the most well-known and consumed type among
tulum cheeses. It is Turkey’s first cheese with a certificate of registration. Erzincan
Tulum cheese is “made from the milk of Karaman sheep fed in the highlands of
Erzincan (Munzur, Cimen, Cayırlı, Tercan and Kemah Oluk), which has 90-100
different kinds of plant richness” (56-58). It is also known as “Savak” cheese in
Tunceli, Erzincan and Elazığ provinces. It is pressed into jerry cans or skin bags
with Kemah salt and ripened in caves for about 1 year (23). The sheep’s milk,
rennet, Kemah salt, production method and packaging in goat skin bags are the
distinguishing features of this tulum cheese. Thus, it appears as a white-cream
colored, high fat content, fragile, homogeneous structured and delicious cheese
with a distinctive acidic, buttery and rancid taste, easily melting in the mouth
(26, 59).
6.9.ErzurumCivilCheese
Erzurum civil cheese is produced under names such as Cecil cheese,
string cheese, yarn cheese and pull cheese in the Eastern and Northeastern
226 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
parts of Turkey, especially in Erzurum, where acid, rennet and heat treatment
are used together (60-61). Although containing high levels of protein, calcium
and phosphorus, it has a low fat content (62). According to the Geographical
Indication (GI) registration certificate, Erzurum Civil cheese is defined as “a type
of local cheese classified as fat-free or low-fat cheese produced by obtaining the
milk from animals fed with various nutritious grasses in the pastures between
the high mountains of Erzurum province, passing it through separators and
removing the fat, and then acidifying the remaining skim milk at a certain level,
fermenting it with liquid sirden rennet and heating it, mixing and kneading the
clot and then hanging it on hangers to form a string in the mass”. It is consumed
both fresh and brined (63- 64).
6.10.ErzurumMoldyCivilCheese(GöğermisCheese)
Erzurum Moldy Civil Cheese (Göğermis Cheese); Erzurum Civil cheese
is a ripened cheese with a unique flavor obtained by shredding Erzurum Civil
cheese and mixing it with lor cheese or by putting Civil cheese in plastic drums
suitable for food packaging, removing the water and letting it naturally mold.
It is also known as göğermis (turned green) cheese or moldy lor cheese. This
cheese, produced by being put on materials such as wood and leather as well
as plastic materials, is molded in blue-green color (60, 64-67). It is an aromatic
cheese type that has an important place in the breakfast culture of Erzurum
province and its surroundings, is known all over Turkey, has a flavor similar to
the Roquefort cheese of France, is perceived as a fatty variety due to the effect of
biochemical reactions during ripening although it is produced from skim milk,
has been investigated in all aspects with projects supported by TÜBİTAK and
all its properties revealed, whose strains of Penicillium roqueforti have been
identified as starter molds. (60, 68-69).
6.11.EzineCheese
It is the most produced and consumed white cheese type in Turkey, with
the highest economic value. It is a geographically indicated cheese among
the white cheese varieties that are widely produced in almost every region of
our country, especially in the Aegean, Marmara, Thrace and Central Anatolia
regions (70-71). This full-fat brined type white cheese is produced from a
mixture of cow’s milk (maximum 25%), sheep’s milk (35-45%) and goat’s milk
(minimum 40%) obtained from animals fed with natural endemic vegetation
(such as sage, oregano, thyme, marjoram and hairy mint) and water resources in
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 227
the geographically demarcated regions located in the northern and western parts
of the Kaz Mountains; with a white to light yellow color, medium hardness,
non-fragile structure, few and small diameter pores in its mass (26, 43, 72-74).
Ezine cheese has a “creamy” taste and aroma due to milk fat and “baked milk”
taste and aroma due to the heat treatment applied. The milk or milk mixture
used, the yeast prepared from calf sirden in whey, the sea salt used and different
production methods constitute the distinctive features of Ezine cheese. The
milk obtained from special animal breeds (Tahirova, Sakız, Dağlıc breed sheep,
Holstein breed cows and Karakeci and Turkish Saanen goat breed) between
March and July is used in the production of this cheese (72). Starter culture and
calcium chloride (CaCI2) are not used in its production (74).
6.12.GümüshaneDelemeCheese
Gümüshane Deleme Cheese is a homogeneous, non-porous, slippery, semi-
hard cheese with a slightly sour taste and high milk flavor, which can melt when
heated, which is obtained by boiling the cökelek cheese produced by curdling/
coagulation of cow›s milk with naturally increased acidity with fat milk and
kneading and shaping it after pre-treatments (75).
6.13.HellimCheese
Hellim (Halloumi) cheese is a semi-hard traditional cheese type specific
to Cyprus and is also widely produced in Eastern Mediterranean countries
(76). The cheese is available in the market in two forms: fresh and mature
halloumi. Fresh halloumi is a double-layered, yellowish-white colored, easy-
to-slice, semi-hard and elastic cheese obtained by the production method
specific to the region with the addition of rennet to milk. Mature Halloumi,
on the other hand, is a double-layered, yellowish-white, easy-to-slice, semi-
hard and firm cheese obtained by maturing fresh Halloumi cheese in salty
whey brine. Halloumi cheese’s distinctive characteristics stem from the use of
raw or pasteurized sheep, goat and cow’s milk and mixtures thereof, obtained
from dairy animals fed on the rich vegetation of Cyprus, and its characteristic
production method (77).
6.14.KaramanDivleObrukTulumCheese
Tulum is a type of cheese that is widely produced and consumed after white
cheese in our country and has many varieties such as Cimi, Divle, Erzincan and
228 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
İzmir tulum cheeses. Tulum cheese is mostly produced in small family-type
enterprises (78). Karaman Divle Obruk tulum is a type of cheese that is offered
for consumption after the teleme cheese made with a mixture of cow (10%),
sheep (80%) and goat (10%) milk obtained from animals fed in the highlands
and pastures within the borders of Ayrancı district of Karaman province (fed
with roughage such as dried alfalfa, hay, etc. in seasons when they cannot go out
to pasture) is pressed into goat or lamb skin bags and ripened in Divle sinkhole
for 5-6 months. Its distinguishing feature from other cheeses is that the cheeses
pressed into the skin bags have a unique mold flora, blue, then white and then
brick red colored mold fungi develop after ripening, and it is ripened at 4ºC and
80% relative humidity in a cave called “obruk” (sinkhole), which is a natural
cold storage (39, 79-80).
6.15.KarsKashar
Kashar is the most produced and consumed semi-hard or hard cheese type
in our country after white cheese. The production methods of this cheese vary
according to regions. In our country, it is produced in many provinces such as
Kars, Tekirdağ, Edirne, Kırklareli, Kocaeli, Mus, Erzurum and Trabzon (81).
Kars Kashar, the most well-known of these, is a type of cheese with a distinctive
taste, smell, aroma and color, which can be consumed fresh or ripened, and
which can be produced by mixing sheep and goat milk with cow’s milk, although
it is generally made from cow’s milk grazing on pastures with rich vegetation
between May and August in Kars and Ardahan provinces. Fresh Kars kashar
(in the pre-ripening stage) is whitish in color and tastes slightly salty, bland and
reminiscent of milk when it comes first out of the mold, but within a week, it
turns yellowish with a crust. Aged kashar (after 3 months of ripening), on the
other hand, is harder, slightly salty, more aromatic and easily dispersed in the
mouth (41, 82). The most important feature distinguishing Kars kashar from
other kashars is that its color, which is close to white when fresh, turns yellow
after a week. Another distinguishing feature is the milk used in its production.
Kashar cheese is produced from the milks obtained from animals that feed on
endemic plants and grasses in the region (23, 83).
6.16.KırklareliWhiteCheese
Kırklareli white cheese is a type of cheese produced from a mixture of
milks obtained from cows (15-30%), sheeps (30-45%) and goats (25-45%)
which are grown in the pastures and meadows of Kırklareli and fed with grasses,
including endemic species, and consumed by ripening in oil and brine (84-85).
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 229
6.17.MalkaraAgedKasharCheese
Malkara Aged Kashar cheese is a hard, cylindrical, fully ripened cheese
with a distinctive taste, smell, aroma (terpene-derived components such as alpha
pinene and calarene from green forages are dominant) and color (straw yellow),
made from the milk of cows, sheeps and goats grazing on pastures with rich
vegetation (especially Lathyrus L., clover and thyme, which are native to the
region) in April and July in Malkara district. The most important distinguishing
characteristic of this cheese is that it is produced from the milk of animals fed
with high levels of grasses with various flavors originating from the vegetation
of the region. Sensory-wise, it has a salty, umami and sour taste; cooked,
creamy-milk fat, sulfur, PAS, rancid, animal-like, yeast/mold, fruity and nutty
aroma (10, 41, 86).
6.18.ManyasKelleCheese
Manyas Kelle cheese is a type of full-fat or half-fat hard cheese made with
cow’s and sheep’s milk or a mixture of these milks obtained from animals fed
with the natural vegetation and water resources of Manyas District of Balıkesir
province, with a hard rind 2-3 mm thick, yellow-white color, without cracks,
porous structure, unique taste and aroma (slightly acidic and salty), ripened in
brine (87). Manyas Kelle cheese, which has been produced from raw sheep milk
in Balıkesir and Bursa provinces for 250 years, also goes by different names
such as Mihalic, Maglıc and Mahlıc (88-89).
6.19.MarasParmak/SıkmaCheese
It is a local type of cheese whose curd is boiled, homogeneous, non-porous,
not easily disintegrating, low-salted, white colored, called “parmak” (finger) or
sıkma cheese because of its finger-shape, produced in Kahramanmaras and its
surroundings (90). Although it can be considered in the same group with many
other cheese varieties because it is shaped during the boiling of the cheese curd
and preserved in brine, it is in fact a typical local cheese variety thanks to its
origin, milk quality, external and internal qualities and shaping method (91).
6.20.PınarbasıUzunyaylaCerkesCheese
Pınarbası Uzunyayla Cerkes cheese is a traditional type of cheese produced
by coagulating the milk obtained from cows or sheeps grazing in the plateaus and
pastures at 1600-2000 altitude in Uzunyayla plateau with fermented whey at the
boiling point and dried in the wind. This semi-hard cheese has a smooth texture,
230 INTERDISCIPLINARY MEDICINE AND HEALTH SCIENCES CONCEPTS . . .
white-straw yellow color depending on the drying conditions, is oily, hard rind,
slightly salty, with a slightly sour and cooked taste and basket appearance (92).
6.21.SakaryaAbhaz(Abaza)Cheese
Sakarya Abkhaz (Abaza) cheese is a type of ripened cheese that has been
shaped by the culture of the Abkhaz people settled in Sakarya province 700 years
ago, has the characteristics between Kashar cheese and dil (string) cheese, has
a fibrous structure, amber yellow color, and its appearance is usually braided.
The distinctive features of the cheese are due to the rennet (sirden) used in its
production, different seasonings (optionally black cumin and thyme) and the
traditional production method (93).
6.22.UrfaCheese
Urfa cheese is produced in the Southeastern Anatolia Region, especially in
and around Sanlıurfa, using mostly sheep and goat milk (94-95). This is a type of
local cheese that has become increasingly popular in recent years. Urfa cheese is
a semi-hard cheese produced from sheep milk and ripened in brine (96).
6.23.VanOtlu(Herby)Cheese
Otlu cheese is a type of cheese that has been produced and consumed in
Eastern and Southeastern Anatolia regions of our country (Van, Diyarbakır, Siirt
and Ağrı) for many years and is mostly produced in Van province (39, 97-98).
Van Otlu cheese is made from sheep, cow or goat’s milk or a mixture of these,
with the addition of about 20-25 herbs called Sirmo, Mendi, Thyme, Siyabo,
Wild mint and Heliz, which grow in the region and surrounding provinces (47,
97, 99), with a color ranging from white to yellowish due to the differences in the
milk and herbs used, delicious (dominating garlic and thyme aroma), consumed
fresh after salting or ripened in brine, semi-hard and flat, shiny looking cheese
(39, 100). The most important feature of the herbs used in production is that
they have antimicrobial effect against coliform group bacteria. In addition, it is
reported that the unique color, taste, smell and appearance of the cheese are due
to the herbs in question (101). This traditional cheese is similar to white cheese
in terms of production method and structure, but has different characteristics
due to the presence of endemic herbs in its structure. Van Otlu cheese, which is
made in the spring time, is produced in two different ways in terms of salting
method: “brined” or “dry salted”. There are differences between the two types
regarding the structure and appearance (39, 98).
CHEESE, HISTORY AND DIVERSITY IN TURKISH CULTURE 231
6.24.VakfıkebirKülekCheese
Vakfıkebir Külek cheese is a traditional type of cheese obtained by pressing
the cheese and cökelek cheese produced from cow’s or sheep’s milk tightly in
layers in wooden containers named külek and ripening them under the ground
or in hazelnut shells. The distinctive characteristics of this cheese stem from the
traditional sirden rennet used in its production and the pots made of spruce trees
used for packaging (102).
6.25.YozgatCanakCheese
Yozgat Canak cheese is a low-ripened and half-fat cheese with a unique
taste and aroma, made from cow, sheep and goat milk fed with the natural
vegetation and water resources of Yozgat center and its districts. As the name
suggests [canak meaning bowl], this cheese is ripened by pressing it into an
earthen bowl and then burying it in sand. It is important that the buried sand is
moist and humid during the ripening phase (43, 103, 104).
The Turks have changed their homeland frequently throughout the world
and spread over a wide area and have been under the influence of many cultures.
The different civilizations they have lived in have created a cheese culture that
has changed from Central Asia to the present day. Cheese, which is consumed
with pleasure in our country as well as all over the world, is a durable dairy
product with a wide variety and it is as well an indicator of the cultural richness of
our country. Although there are many cheeses recorded in Turkey, many of them
are in danger of extinction. While some cheeses are produced locally, others are
recognized throughout the country. In our country, it is of great importance to
obtain Geographical Indication (GI) in order to classify and standardize cheeses
according to the region or area where they are produced. This will ensure that
our traditional cheeses are produced at a certain standard in the food sector,
encourage other local cheeses to obtain the GI mark and thus our traditional
cheese varieties will be introduced to the world.
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