No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Diabetic neuropathy: New strategies for treatment
Abstract
Current therapeutic possibilities can be divided into two groups: the pathogenetically oriented and the symptomatic therapy. One of the most important component of etiology-based treatment is the stabilization of glycemic control. Based on efficacy and safety data benfotiamine and alpha-lipoic acid should be considered as first choices among pathogenetically oriented treatments of diabetic neuropathy. Promising data were published about the aldose reductase inhibitor ranirestat. The symptomatic effect of antiepileptic drugs in diabetic painful neuropathy (DPN) is originated from several possible pharmacological properties. Pregabalin and gabapentin have the highest efficacy and the lowest frequency of adverse events among these drugs. Antidepressants also extensively used for symptomatic treatment in DPN. In the last years several studies were published about the benefial effect of duloxetine. Most likely combination therapy will be frequently applied in the future for the treatment of DPN, the optimal choice could be to combine pathogenetically oriented and symptomatic treatment.
... Diabetic neuropathy is a severe chronic complication of diabetes mellitus and is the most frequent form of neuropathy in the developed countries [1][2][3][4][5][6][7][8]. It affects 40-60% of the diabetic patients [6,9], representing a significant cause of morbidity and mortality [2,5,7,10]. Diabetic neuropathy is associated with a whole range of local and general complications that inflict important health care costs and reduce the patient's quality of life, with an overall major socio-economic impact. ...
... The most frequent form of diabetic neuropathy is the distal symmetrical polineuropathy [2,7,10], which is a gradual, diffuse, symmetrical impairment of the peripheral nerve fibers of the extremities [8,13]. Sensory, motor but also autonomic nerve fibers can be involved [6,14]. ...
... The clinical examination still remains fundamental in the diagnosis of diabetic neuropathy [2,10]. The vibratory, pressure, proprioceptive, tactile and thermo-algesic perception are investigated and the myotatic reflexes and the muscular force are evaluated. ...
Diabetic neuropathy is a major challenge for the healthcare system, being associated with multiple local and general complications which involve increased medical and socio-economic costs and an important reduction of the patient’s quality of life. In this paper we review the relevant aspects regarding the micro-morphological and pathophysiological changes in peripheral diabetic neuropathy, we summarize the main techniques used for diagnosis and staging of diabetic neuropathy and we discuss the biotechnological advances that were achieved in this field. Thus, recent developments in proteomics and in vivo investigation of cutaneous nerve structures provides promising data and could lead to the achievement of new biotechnological diagnostic strategies easy to implement, with a greater accuracy of results, which allow the diagnosis of early changes in diabetic neuropathy, in a stage in which the preventive and therapeutical measures have maximum efficiency, thus being able to contribute to the diminishing of the morbidity associated with the disease.
... In comparison to the above-mentioned enzymes, Aldose reductase is an enzyme for fructose formation from glucose, present in most parts of the body, and is convoluted in the catalyzation step of the polyol pathway. The action of this enzyme increases with the increasing level of glucose in the tissues of insulin-sensitive diabetic patients [11]. The aldose reductase inhibitor used in diabetic therapy is fidarestat [12]. ...
... .(11). 3D visualization, 2D visualization, and hydrophobic interactions of the binding framework of protein-ligand interactions of bestdocked compounds for Aldose Reductase (PDB ID: 1VJT). ...
Background
Plant species of the genus Daphne clasps a historical background with a potential source of bioactive phytochemicals such as flavonoids and daphnodorins. These compounds manifest a significant chemotaxonomic value in drug discovery. Their flair comprehensive pharmacological, phytochemical, biological, catalytic, and clinical utilities make them exclusively unique. This study was conducted to investigate the optimization and structure-based virtual screening of these peculiar analogs. The majority of the active constituents of medicines are obtained from natural products. Previously, before the invention of virtual screening methods or techniques, almost 80% of drugs were obtained from natural resources. Comparing reported data to drug discovery from 1981 to 2007 signifies that half of the FDA-approved drugs are obtained from natural resources. It has been reported that structures of natural products that have particularities of structural diversity, biochemical specification, and molecular properties make them suitable products for drug discovery. These products basically have unique chiral centers which increase their structural complexity than the synthesized drugs.
Background
Daphnodorins and their analogues are contemplated as pharmacologically significant scaffolds that have demonstrated numerous biological activities such as antifungal and insecticidal activities [17] antibacterial, cytotoxic, antiviral, anti-HIV activity, antioxidant activity [18], inhibitory activity against ∝-glucosidase and angiotensin II formation [19]. Recent pharmacological studies have manifested their efficient and versatile anti-inflammatory, anti-oxidant and protein glycation inhibition activities [20].
Method
This work aimed to probe the use of daphnodorins analogs for the first time as antidiabetic inhibitors based on significant features and to determine the potential of daphnodorin analogs as antidiabetic inhibitors through computational analysis and structure-based virtual screening. A dataset of 38 compounds was selected from different databases, including PubChem and ZINC, for computational analysis, and optimized compounds were docked against various co-crystallized structures of inhibitors, antagonists, and receptors which were downloaded from PDB by using AutoDock Vina (by employing Broyden-Fletcher-Goldfarb-Shanno method), Discovery studio visualizer 2020, PYMOL (Schrodinger). Docking results were further validated by Molecular dynamic simulation and MM-GBSA calculation. Quantitative structure-activity relationship (QSAR) was reported by using Gaussian 09W by intimating Density Functional Theory (DFT). Using this combination of multi-approach computational strategy, 14 compounds were selected as potential exclusive lead compounds, which were analyzed through ADMET studies to pin down their druglike properties and toxicity.
Objective
Optimized compounds were docked against various co-crystallized structures of antidiabetic drug targets using AutoDock Vina and Discovery studio. Using this approach, 14 compounds were selected as potential exclusive lead compounds, which were analyzed through ADMET studies to pin down their drugs-like properties and toxicity and subjected to measure significant parameters such as dipole moment, electronic energy, frontier molecular orbitals (FMO) energy, and the hardness of molecules by performing DFT.
Result
At significant phases of drug design approaches regular use of molecular docking has helped to promote the separation of important representatives from 38 pharmaceutically active compounds by setting a threshold docking score of -9.0 kcal/mol which was used for their exposition. Subsequently, by employing a threshold it was recognized that 14 compounds proclaimed this threshold for antidiabetic activity. Further, molecular dynamic simulation, MM-GBSA, ADMET, and DFT results screened out daphnegiralin B4 (36) as a potential lead compound for developing antidiabetic agents.
Method
Molecular docking, DFT, MD Simulation, ADMET
Conclusion
Our analysis took us to the conclusion that daphnegiralin B4 (36) among all ligands comes out to be a lead compound having drug-like properties among 38 ligands being non-carcinogenic and non-cytotoxic which would benefit the medical community by providing significant drugs against diabetes. Pragmatic laboratory investigations identified a new precursor to open new doors for new drug discovery.
Result
Hit to lead, out of 38 daphnodorins, 14 compounds were exclusively selected as lead compounds, and from these leads, one compound was chosen as a pre-eminent antidiabetic agent.
Conclusion
Hit to lead, out of 38 daphnodorins, 14 compounds were exclusively selected as lead compounds, and from these leads, one compound was chosen as a pre-eminent antidiabetic agent.
... In patients who develop diabetic neuropathy, alongside glycemic control, there are some medications that can be used as a supportive treatment for the relief of neuropathic pain and paraesthesia. Anti-epileptic drugs and anti-depressants are two groups of drugs that have been extensively used for the symptomatic treatment of diabetic neuropathy [11]. Gabapentine has been used for the treatment of chronic pain and peripheral neuropathy for decades. ...
... There are limited clinical studies on the treatment of allcause PN. In diabetic patients, glycemic control with BS lowering agents such as Metformin is the best known strategy for the prevention of developing PN [11]. However, the outcomes of studies, using Metformin as symptomatic treatment of diabetic neuropathy, is not consistent with pre-clinical studies. ...
Purpose: Despite the troublesome nature of Peripheral Neuropa-thy (PN) and the possibility of irreversible complications, there is still no approved strategy for the treatment of PN. However, some atypical analgesic agents such as gabapentin, pregabalin, and duloxetine have beneficial effects. Metformin is an anti-hyperglycemic agent which is widely used for the treatment of type 2 Diabetes Mellitus (DM). In addition to its blood sugar-lowering effect, many studies have suggested that Metformin has beneficial effect in the suppression of inflammation by many mechanisms. Regarding, several studies have been conducted on the effectiveness of Metformin in the prevention or controlling the symptoms of PN. The aim of this article is to review the potential effect of Metformin as an adjuvant for the treatment of PN with a focus on diabetic neuropathy and CIPN. Methods: In this paper, the researcher has conducted a search on PubMed and Scopus, and Web of Science for original articles and reviews published from 1993 until 2022, with the following keywords; Peripheral Neuropathy, Diabetic Neuropathy, Metformin and Post-Che-motherapy complications. Results: We identified 79 studies at the first step of search strategy. Finally, 17 studies were included, of which 12 were animal studies and 5 were human studies. Conclusion: In-Vitro and animal studies have shown beneficial effects of Metformin controlling the development of peripheral neuropa-thy. However, clinical results of using Metformin for symptomatic treatment of diabetic neuropathy is conflicting. Further clinical studies are needed to establish the effect of metformin on peripheral neuropathy. Citation: Moghaddam NS, Tebbi M, Borhaninia M, Gharibi S, Arasteh O, et al. Peripheral neuropathy: A review of mechanism based treatments with a focus on metformin as a possible choice.
... DN is variable, ranging from symptomatic to asymptomatic, but once established as neuropathy it is irreversible and may finally be disabling [14]. Therefore, early diagnosis of DPN is important for immediate interventions to decrease the associated complications and disabilities [15]. ...
... The frequency was higher in patients with disease duration more than 5 years (76.6%). This result is in agreement with other studies that reported a prevalence of 66% [15] and 62.5% [18]. Studies conducted at the time of diagnosis of diabetes reported a low prevalence of 7.5% [19] and 25% [20]. ...
Background Diabetic neuropathy is the most common complication of diabetes. We hypothesized that uncontrolled diabetes is associated with subclinical diabetic neuropathy that is influenced by duration of disease. Assessment of the prevalence and associated determining factors will be important for the prevention and treatment of neuropathy. Objective This aim of this study was to assess the frequency and determining factors of subclinical peripheral neuropathy in type 1 diabetic (T1DM) patients. Patients and methods The current hospital-based, case-control study was conducted at Zagazig University Hospitals. It included three age-matched and sex-matched groups. Each group comprised 30 participants: group A included diabetic patients with a duration of T1DM of 5 years or less; group B included patients with a duration of T1DM of more than 5 years; and the control group included normal healthy individuals. Clinical assessment was carried out to exclude symptoms and signs of neuropathy. Laboratory investigations including fasting and 2-h postprandial blood glucose level, glycosylated hemoglobin (HbA1c), lipid profile, liver function, kidney function, and nerve conduction studies were carried out for every participant. Results The frequency of subclinical neuropathy in group A and group B was 46.6 and 76.6%, respectively, and this difference was statistically significant (P=0.03). Univariate analysis revealed significantly higher levels of HbA1c, dyslipidemia, and nerve conduction parameters in group B compared with group A and the control group. Multivariate logistic regression analysis showed that duration of diabetes (P=0.02) and HbA1c (P=0.02) were the only independent factors associated with subclinical neuropathy. Conclusion The high frequency of subclinical neuropathy in diabetic patients highlights the importance of nerve conduction studies for the early detection of neuropathy in T1DM. © 2017 The Egyptian Journal of Neurology, Psychiatry and Neurosurgery.
... Некоторые виды биологически активных добавок (БАД) улучшают способность организма усваивать клетками инсулин. Известно, что лецитин, оказывают профилактическое действие снижении инсулиновых потребностей у диабетиков [4,5,6]. Лецитин входит в состав клеточных мембран, является эффективным эмульгатором жиров, растворителем и переносчиком холестерина, восстанавливает клетки легких и печени, стабилизирует желчь, принимает активное участие в функционировании мозга. ...
Analysis of the diet of patients with diabetes mellitus revealed a lack (4-5 g per day) in the consumption of lecithin. Theoretical and practical substantiation of the use of lecithin in food formulations with antidiabetic properties was carried out by computer chemistry methods by determining molecular properties and analyzing the electrostatic potential (EP) surface. It has been established that the molecules involved in the transport of glucose into the cell are electron acceptors. The molecular properties of the insulin receptor, insulin and glucose have been studied. The assessment of the action of lecithin on the insulin receptor was controlled by molecular docking. Based on the results of modeling, it was revealed that the interaction of these chemical compounds does not form strong complex compounds, the energy of the system increases, but insulin with glucose is not transported outside the receptor. It has been proven that the introduction of lecithin into the system promotes an increase in the activation of the system, since the potential energy of the complex increases by 387.3 kcal. To study the possibility of using lecithin as an additive in products subjected to heat treatment, the activation energy was compared with the energy state of the molecule during the action of temperature. With the help of Langevin dynamics and the method of controlling the amount of inorganic phosphorus (calorimetric method) in experimental samples of boiled sausages, the resistance of lecithin to heat treatment was confirmed.
... The primary complication of diabetes is untreatable, so the symptoms of the disease are treated rather than the complication itself [32]. The class of drugs known as tricyclic antidepressants and selective serotonin reuptake inhibitors is the first line of therapy for DPN, which consists of drugs such as amitriptyline, pregabalin, gabapentin, and duloxetine [33] Amitriptyline works by increasing noradrenergic and serotonergic neurotransmission due to the blocking of serotonin and norepinephrine transporters. One limitation of this medication presents is the potential side effects as it causes urinary retention, orthostatic hypotension, and sedation [32]. ...
Diabetes mellitus is the global epidemic of the 21st century affecting millions worldwide. Usually, patients with long-standing type one diabetes (T1D) or type two diabetes (T2D) tend to develop complications. A common complication is the degenerative of the nerves in the peripheral nervous system (PNS). This complication is known as distal symmetric polyneuropathy or just diabetic neuropathy. A variety of symptoms can be experienced with this complication, including pain and numbness. One characterization of this complication is the sensory loss that begins in the lower extremities and spreads substantially to the fingers and hand. There is no clear mechanism for how this happens in diabetic patients. Studies have shown that nerve damage from this complication can be due to oxidative stress, sorbitol accumulation, and advanced glycation end products (AGEs). Some of the most common medications being provided for diabetic neuropathic pain (DNP) include amitriptyline and desipramine. Other medications also include gabapentin and duloxetine. There are noninvasive options, such as acupuncture, that could provide beneficial data if rigorous studies are conducted. A number of new studies are being completed to identify more effective treatments for this condition.
... Risk factors for neuropathy include poor glucose control, advanced age, duration of diabetes, impaired lipid levels, and high blood pressure. Diabetes has been identified as the most important risk factor for neuropathy (5). It has been reported that approximately 66 and 59% of patients with type 1 and type 2 diabetes tend to develop neuropathy, respectively (6). ...
Background & Objective: Diabetic neuropathy pain is a common pain condition that has a major negative impact on health-related quality of life. However, despite many studies, it remains difficult to treat neuropathic pain. This study aimed to compare the efficacy of duloxetine with high tone power therapy (HTPT) in diabetic peripheral neuropathic pain. Materials & Methods: The study is a single-centre, phase III clinical trial comparing the effect of HTPT versus treatment with duloxetine in diagnosed diabetic neuropathy patients between October 2019 to December 2020. In the case group, the HTPT was used with a four-second duration for 30 minutes daily. This treatment was continued twice a week for 10 sessions. The control group received duloxetine (30 mg/m2 once a day). The treatment response was assessed based on the VAS score. Results: The results showed that in both groups, there was a significant reduction in pain severity. In HTPT group, the average pain decreased from 7.36 to 4.6 and in duloxetine group from 7.7 to 4.8. During 8 measurements after the intervention; decrease in VAS score was higher in HTPT group (5.6) than in duloxetine group (6.5) in the first and fourth times after the intervention (P-Value=0.01). Further analysis demonstrated a positive correlation between pain severity and age so that, the pain also increases with advancing age. Conclusion: The results of the present study showed that both duloxetine and high tone therapies are safe and effective methods for neuropathic pain relief.
... Amitriptyline, citalopram, gabapentin, pregablin, and oxycodone have often used to cure pain, but only duloxetine and pregablin have actual evidence for the intervention of painful peripheral diabetic neuropathy. [45] Dhingra et al. ...
Herbal drugs, plant medicine, and agricultural medicine are all synonyms for the use of plants as medicine. In comparison to conventional medicine, the medicative use of herbal drugs in the treatment of various diseases such as hyperglycemia has an ancient legacy. Hyperglycemia is one of the major global health interests. Hyperglycemia, also known as diabetes mellitus, is a prevalent matter of public health that is still difficult to manage. Uncontrolled diabetes or sustained hyperglycemia has the potential to cause severe health problems such as renal failure, loss of sight, heart disease, and lower-limb deformities, all of which make a significant contribution to diabetes incidence and death. Herbal drugs are one of the treatment options to manage and prevent diabetes along with its associated complications. Nevertheless, the choice of herbs may be influenced by a number of aspects, including the level of diabetes development, the types of comorbid conditions that the patients have, accessibility, price, and the clinical efficacy of the herbs. This study concentrates on the naturally-derived therapies that play a role in the management of this distressing disorder-diabetes, together with their biological causes for blood glucose reducing properties and herbal supplements that have already been introduced into the market for therapeutic intervention of diabetes.
... This opinion coincides with actual knowledge in drug treatment of neuropathy (during the last years). Moreover, contemporaneous studies prescribe a combination of symptomatic and pathogenetically oriented therapy [35]. ...
The Declaration of Montréal of the International Pain Summit of the International Association for the
Study of Pain (IASP) identifies that chronic pain is a serious chronic health problem and access to
pain management is a fundamental human right. The objective of current work was to formulate
principles of physical analgesia or physical modalities for pain reduction and to present basic methods
and mechanisms. We consider pain management as an important part of rehabilitation algorithms in
patients with neurologic and rheumatologic diseases, orthopedic and traumatic conditions.
Keywords: Pain; physical analgesia; electrotherapy; physiotherapy
... Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication of T2DM,results in decreased sensation, poor mobility, and high risk of foot ulceration and amputation [1][2][3]. Várkonyi et al [4]. and Sugimoto et al. [5]. ...
Background: A high plasma level of small dense low-density lipoprotein cholesterol (sdLDL-C) is one of the key features of diabetic dyslipidemia. However, the relationship between sdLDL-C and diabetic peripheral neuropathy (DPN) has not been investigated. Therefore, we measured sdLDL-C in patients with type 2 diabetes mellitus (T2DM) ± DPN, determined the factors affecting sdLDL-C levels, and characterized the relationship between sdLDL-C and DPN in T2DM.
Methods: sdLDL-C was measured in the T2DM patients with (n=702) and without (n=780) DPN and the characteristics of these two groups were compared. Correlation analysis was used to identify factors associated with sdLDL-C levels. Finally, multiple regression analysis was used to further characterize the relationship between sdLDL-C and DPN in patients with T2DM.
Results: The serum sdLDL-C levels were higher in T2DM patients with DPN than in those without. sdLDL-C positively correlated with systolic blood pressure, diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, urinary microalbumin–creatinine ratio, and urinary microalbumin in T2DM patients with DPN (P=0.017, P<0.001, P<0.001, P<0.001, P=0.005, and P=0.002, respectively) and negatively correlated with high-density lipoprotein cholesterol (P=0.01). Furthermore, sdLDL-C was independently associated with DPN in patients with T2DM (odds ratio=5.857, 95% confidence interval [CI]: 2.60–13.20, P<0.001). Receiver operating characteristic analysis was performed to identify the optimal cut-off value of sdLDL-C for the prediction of DPN, which was found to be 0.985 mmol/L (area under the curve=0.571; 95% CI: 0.541–0.600; sensitivity, 64.8%; specificity, 47.7%, P<0.001).
Conclusions: sdLDL-C was increased in T2DM patients with DPN and was found to be an independent predictor of the presence of DPN.
... The pathological basis for DM neuropathy includes both metabolic, vascular and immune pathogenesis models [5]. Experimental models of metabolic pathogenesis of neuropathy postulate that severe hyperglycemia can produce reduction in nerve conduction velocity and axonal shrinkage. ...
... Despite the continuing and increasing incidence of DPN, nowadays, there is no specific treatment able to stop DPN progression and prevent the formation of foot ulcers (FU). Furthermore, the palliative drugs commonly used, such as antiepileptics, antidepressants, and opioids, are symptomatic treatments with untoward side effects; thus, they are not recommended as long-term treatments [5]. The main difficulty in generating a comprehensive treatment for DPN is due to its highly complex and multifactorial etiology [6]. ...
Background:
Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus.
Methods:
Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated.
Results:
Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer.
Conclusions:
Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.
... In diabetic patients, due to an increased glucose concentration in tissues that are not susceptible to insulin, the activity of aldose reductase causes polyol to penetrate through the cell membrane less easily and accumulate. This causes osmotic damage and leads to retinopathy and neuropathy [71]. ...
... 37 On the other hand, current therapies for PDN aim to mask symptoms and do not influence the course of neuropathy; while pathogenetic treatments targeting the underlying molecular and cellular mechanisms involved in PDN, may delay, stop, or reverse the progression of neuropathy and may also alleviate pain. 38 Despite the fact that the etiology of diabetic neuropathy has remained unclear, strong and growing evidence supports the important roles of mitochondrial dysfunction, OTS, and neuroinflammation in neuronal damage in diabetic patients. The dysregulation in these pathways by structural and functional changes at the level of both peripheral and central nervous systems can impair normal neuronal process, resulting in pain generation and maintenance. ...
Purpose
Painful diabetic neuropathy (PDN) is a variant of diabetic peripheral neuropathy which is highly prevalent and distressing in diabetic patients. Despite its high burden, the optimal treatment of PDN has remained a clinical challenge. To explain the emergence and maintenance of PDN, increasing attention has been focused on dimensions of inflammation and oxidative toxic stress (OTS). Accordingly, the aim of this study was to investigate the effects of oral N-acetylcysteine (NAC), an agent with known anti-oxidant and anti-inflammatory effects, as an adjunct therapy in patients suffering from PDN.
Patients and methods
113 eligible patients with type 2 diabetes suffering from PDN were randomly assigned to either the pregabalin + placebo or pregabalin + NAC group for 8 weeks (pregabalin at a dose of 150 mg per day, NAC and matched placebo at doses of 600 mg twice a day). Mean pain score was evaluated at baseline, week 1, 2, 4, 6, and 8 of the study based on the mean 24 hr average pain score, using an 11-point numeric rating scale (NRS). As secondary efficacy measures, mean sleep interference score (SIS) resulting from PDN, responder rates, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety were also assessed. Additionally, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.
Results
Ninety patients completed the eight-week course of the study. The decrease in mean pain scores and mean sleep interference score in pregabalin + NAC group was greater in comparison with pregabalin + placebo group (p value<0.001 in both conditions). Moreover, more responders (defined as ≥50% reduction in mean pain score from baseline to end-point) were observed in the pregabalin + NAC group, in comparison with pregabalin + placebo group (72.1% vs 46.8%). More improvement in PGIC and CGIC from baseline to the end of the study was reported in pregabalin + NAC group. Oral NAC had minimal adverse effects and was well tolerated in almost all patients. Furthermore, in respect to OTS biomarkers, adjuvant NAC significantly decreased serum level of MDA and significantly increased serum levels of SOD, GPx, TAC, and TTG.
Conclusion
The pattern of results suggests that compared to placebo and over a time period of 8 weeks, adjuvant NAC is more efficacious in improving neuropathic pain associated with diabetic neuropathy than placebo. Ameliorative effects of NAC on OTS biomarkers demonstrated that NAC may alleviate painful symptoms of diabetic neuropathy, at least in part by its antioxidant effects.
... Az alfa-liponsav hatékonyságát szabadgyök-fogó aktivitása, antioxidáns hatása magyarázza. 60,61,62 Klinikai hatékonyságát több randomizált, kontrollált tanulmányban igazolták. 63,64,65,66,67,68,69,70 A hazai gyakorlatban a naponta kis infúzióban adott parenteralis kezelést a súlyosabb panaszok kezelésében, a per os kezelést széles körben hasznosítjuk. ...
... 11 Hence diagnosis of DPN (Diabetic Peripheral Neuropathy) early is important for intervention to decrease this complication and disability. 12 It is difficult to diagnose DPN early by clinical methods because of the minor alteration in nerve function. Hence, NCS (Nerve Conduction Study) is being used widely for evaluation and prediction of DPN. 13 The present study revealed 26% of type 1 diabetes who were free from symptoms and signs of DPN had subclinical neuropathy. ...
BACKGROUND
The most important and hidden microvascular complication of diabetes mellitus is diabetic neuropathy. Uncontrolled and
prolonged hyperglycaemia is associated with subclinical neuropathy in type 1 diabetes mellitus. Assessment of this complication
early will be important in prevention of foot complications that occur due to subclinical peripheral neuropathy. The aim of the
study is to evaluate the prevalence of subclinical peripheral neuropathy in patients with type 1 diabetes.
METHODS
75 patients who were diagnosed and treated as type 1 diabetes attending the OP of Department of Diabetology- Govt. Mohan
Kumaramangalam Medical College and Hospital, Salem, were included in this study during the period of January 2018 to August
2018. The study was conducted after getting ethical committee approval of our institution. The study group consists of 43 males
and 32 females. The age at onset, duration of diabetes mellitus, anthropometric measurements, clinical neurological examination
and glycaemic assessment were done and recorded. Subclinical peripheral neuropathy was assessed using nerve conduction
study at the Department of Neurology at GMKMC, Salem.
RESULTS
Abnormal nerve conduction was found in 20 patients with 2 patients of diabetes duration less than 5 years, 18 patients had
duration more than 5 years. Subclinical Peripheral neuropathy has been found in 20 patients out of 75 type 1 DM study
population (26%).
CONCLUSIONS
Peripheral neuropathy is a major disabling and reversible complication of diabetes mellitus. Neurological assessment is
recommended to detect subclinical neuropathy in asymptomatic type 1 diabetes mellitus. Nerve conduction study which is
considered as the gold standard method is helpful for early detection of peripheral neuropathy.
... Based on the polyol pathway hypothesis, several clinical and experimental studies tried aldose reductase hibitors (ARIs) as therapy of DN. 147 ARIs inhibit the conversion of glucose to sorbitol(Figure 1), inhibiting the accumulation of sorbitol and myoinositol in the nerve cells.41,42 However, some ARIs (zenarestat, sorbinil, and tolrestatand) were associated with adverse effects, and others (zopolrestat and ponalrestat) did not have satisfactory therapeutic results.151,155 Ongoing trials on new ARIs suggest they are more effective in the prevention of progression of painful DN.51 ...
Diabetic neuropathy (DN) is a common long‐term complication of type 1 (T1D) and type 2 (T2D) diabetes mellitus, with significant morbidity and mortality. DN is defined as impaired function of the autonomic and/or peripheral nervous system, often subclinical, particularly in children and adolescents with T1D. Nerve conduction studies (NCS) and skin biopsies are considered gold‐standard methods in the assessment of DN. Multiple environmental and genetic factors are involved in the pathogenesis of DN. Specifically, the role of metabolic control and glycemic variability is of paramount importance. A number of recently identified genes, including the AKR1B1, VEGF, MTHFR, APOE, ACE genes, contribute significantly in the pathogenesis of DN. These genes may serve as biomarkers to predict future DN development or treatment response. In addition, they may serve as the basis for the development of new medications or gene therapy. In this review the diagnostic evaluation, the pathogenesis and the associated genetic markers of DN in children and adolescents with T1D are presented.
... Diabetic neuropathy symptoms are sometimes unnoticed, unregistered, underdiagnosed, and undertreated by physicians. DPN is the most common form (Cathelijne et al., 2015;Várkonyi & Kempler, 2008). DPN is often experience pain and hyperalgesia, both of which were developed as a result of damage or dysfunction of the system that signals pain. ...
Type 2 diabetes mellitus (T2DM) has multigenetic and environmental interactive factors. Although diabetic neuropathies (DPN) are the most common, but at the same time, the least recognized and understood long‐term complication of diabetes. This study aimed to investigate the association of IL‐4 VNTR gene polymorphism with T2DM complicated with neuropathy in Egyptian subjects. This is a case control study including 102 T2DM Egyptian patients, plus 188 unrelated healthy individuals as controls. They were evaluated for variable number tandem repeat (VNTR); 70 base pair repeats located in the intron 3; of IL‐4 gene using the PCR technique. Homozygote frequency of the three‐repeat allele (A1/A1) genotype of IL‐4 VNTR was nearly equal among diabetic cases and controls (60.8% vs. 62.2%, respectively). Heterozygous frequency of (A1/A2) genotype was higher among controls compared to cases (33.5% vs. 19.6%, respectively) but not statistically significant. The (A2) allele had a significantly higher frequency in diabetic cases compared to controls (29.3% vs. 21.0%, respectively) while the (A1) allele had lower frequency but not significant one (70.7% vs. 79.0%, respectively). Comparing cases complicated with diabetic neuropathy vs. noncomplicated cases regarding their polymorphic IL‐4 (VNTR) genotypes revealed a nonsignificant lower frequency of (A1A1) genotype (57.1% vs. 65.1%, respectively, p = .57) with a higher combined (A2A2 + A1/A2) genotype frequency (42.9% vs. 34.9%, respectively). Only two haplotypes (A1) & (A2) of IL‐4 (VNTR) gene were recognized among Egyptian population; (A2) allele may influence in diabetes but not its complication (neuropathy) among Egyptian diabetic patients.
... Iako su za liječenje DPN dostupni različiti lijekovi i nefarmakološki modaliteti koji ublažuju subjektivne tegobe, još uvijek ne postoji specifičan terapijski pristup koji bi usporio progresiju ovog stanja. Terapijski potencijal alfalipoinske kiseline (ALK) u tretmanu DPN primarno je povezan sa njenim antioksidantnim svojstvima, s obzirom na to da se smatra da je upravo oksidacioni stres jedan od glavnih patofizioloških mehanizama nastanka ednotelijalne disfunkcije i oštećenja endotela krvnih sudova kod pacijenata sa dijabetesom [12,13] Figure 2. The average value of Toronto-CSS before and after treatment DISKUSIJA Rezultati navedenog istraživanja pokazuju da je kombinovana primjena ALK i fizikalne terapije efikasna u smanjenju subjektivnih simptoma i znakova (mjerenih TSS-4 i Toronto CSS) kod pacijenata oboljelih od DPN. ALK je potentni antioksidans koji se koristi u liječenju simptomatske DPN u mnogim prospektivnim, placebo-kontrolisanim studijama [16][17][18][19][20]. U Sidnej studiji (SYDNEY 1 trial), parenteralna primjena ALK (600mg), tokom 3 sedmice, kod pacijenata sa simptomatskom DPN je bila povezana sa smanjenjem pozitivnih neuropatskih senzornih simptoma mjerenih TSS i Skorom neuropatskih oštećenja (Neuropathy Impairment Score-NIS), kao i sa poboljšanjem jedne komponente nervne provodljivosti (latence suralnog nerva) [16]. ...
... In addition to the neurological impact of B vitamin deficiencies, vitamins B1, B6, and B12 have been shown to exert anti-inflammatory and analgesic effects in animal models of chemical, electrical and thermal stimulation-induced pain. In clinical evaluations, the B-vitamins have been successfully used to address painful conditions such as carpal tunnel syndrome, lumbago, and neuropathies [42,[63][64][65][66][67][68][69][70]. ...
Vitamins B1, B6 and B12 are members of a group of water-soluble organic vitamins with important structural and functional roles in the human body. This updated literature review examines the physiological and biochemical properties of these B vitamins.
... Antioxidants have been more and more discussed as an adjuvant therapy in various oxidative stress-associated diseases [12][13][14]. There are an increasing number of studies showing that oxidative stress may also be involved in the pathogenesis of glaucoma [2][3][4][5]. ...
Aims: Glaucoma is a chronic eye disease, which is associated with progressive optic neurodegeneration and concomitant visual field defects. Besides an elevated intraocular pressure, recent studies have suggested that other risk factors such as oxidative stress may play an important role in the pathogenesis of glaucoma. The goal of this study was to examine the effects of oral micronutrients on the antioxidant status in glaucoma patients. Study Design: randomized, placebo-controlled, double-masked pilot study. Place and Duration of Study: Ophthalmological Clinic Oculus Parter-Bucharest,
... Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent sensorimotor polyneuropathy associated with metabolic and microvessel alterations which innervates almost all systems, and even organs, via affecting pain fibers, motor neurons, and the autonomic nervous system [1]. DPN is considered to be the most common form of diabetic neuropathy, and it affects nearly 50 % of type 2 diabetic mellitus (T2DM) patients and poses both health and economic burdens to affected individuals and society [2,3]. DPN damages the quality of life for its severe clinical manifestations including loss of ability to sense pain, gradual absence of temperature sensation, and developing neuropathic pain, which begins in the lower limbs, initially affecting the toes and then spreading upward [4]. ...
Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) 677 C>T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C>T and ACE I/D polymorphisms and DPN found in various types of electronic databases. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (ORs) and its corresponding 95 % confidence interval (95 % CI) were calculated. We used STATA statistical software (version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D>I mutation (OR = 1.43, 95 % CI 1.12–1.83, P = 0.004) and MTHFR 677 C>T mutation (OR = 1.43, 95 % CI 1.08–1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P < 0.05). Subgroup analysis by country indicated that the MTHFR 677 C>T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D>I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta-analyses support the view that the MTHFR and ACE genes might play an important role in the development of DPN.
... Oxidative stress generates many of the pathophysiologic changes found in T2DM [16]; furthermore, free radical excessive production is involved in axonal degeneration and segmental demyelinization found in T2DM patients with DPN [17,18]. Mitochondrial biogenesis is a complex process that involves more than 100 proteins coded by the nucleus and requires coordination with synthesis of 13 proteins coded by mitochondrial DNA. ...
Diabetic polyneuropathy (DPN) pathophysiologic findings include loss of multifocal and focal nerve fibers secondary to axonal degeneration and segmental demyelization due to oxidative stress and mitochondrial dysfunction induced by chronic hyperglycaemia.
Aim: To evaluate the effect of ubiquinone, ezetimibe/simvastatin and rosuvastatin on mitochondrial function in patients with diabetic polyneuropathy.
Methods: A randomized, double-blinded, placebo-controlled clinical trial was performed in patients with type 2 Diabetes Mellitus (T2DM) who had DPN, glycated haemoglobin (HbA1c) <12% (108 mmol/mol), previous exclusion of other type of neuropathy. Ninety-eight persons with T2DM were enrolled allocated 1:1:1:1 to either placebo, ubiquinone 400 mg, ezetimibe/simvastatin 10/20 mg or rosuvastatin 20 mg for 16 weeks. Primary outcomes were F0F1-ATP hydrolysis, erythrocyte and sub-mitochondrial platelet membrane fluidity. Results were expressed as mean ± SD or SEM and percentages.
Results: F0F1-ATP hydrolysis levels in healthy controls were 236.80±118.42 nmol/PO4; all patients with T2DM exhibited an increase, but only rosuvastatin demonstrated an improvement with baseline 463.37±47.07 nmol/PO4 vs. after 340.61±37.80 nmol/PO4 treatment (p<0.05). Plasma and sub-mitochondrial membrane fluidity did not experience any significant changes.
Conclusions: Rosuvastatin was found to improve mitochondrial function by reducing F0F1-ATP hydrolysis. No changes in sub-mitochondrial platelets particles or erythrocytes ghosts were found.
Submitochondrial platelet membrane fluidity in HS had 0.38 ± 0.03 Ie/Im, with increase in treatment groups; placebo control group had 0.68 ± 0.05 Ie/Im (p < 0.01 vs. HS), ubiquinone 0.64 ± 0.04 Ie/Im (p < 0.01 vs. HS), ezetimibe/simvastatin 0.68 ± 0.04 Ie/Im (p < 0.01 vs. HS), and rosuvastatin 0.65 ± 0.05 Ie/Im (p < 0.01 vs. HS); however, no statistical difference between treatment groups was found (p = 0.675, Kruskal-Wallis). After 16-week treatment there was no significant change in any group, those with placebo had 0.93 ± 0.14 Ie/Im (p = 0.426, baseline vs. final), ubiquinone 0.90 ± 0.13 Ie/Im (p = 0.057, baseline vs. final), ezetimibe/simvastatin 0.76 ± 0.08 Ie/Im (p = 0.670, baseline vs. final), and rosuvastatin 0.96 ± 0.12 Ie/Im (p = 0.092, baseline vs. final), without difference between groups (p = 0.780, Kruskal-Wallis). There is a significant difference in submitochondrial membrane fluidity when compared with healthy controls, probably because of underlying pathophysiologic changes in patients with diabetes, which cannot be resolved with short-time treatment (Figure 2C).
... Néanmoins, les mécanismes exacts par lesquels se développe une neuropathie n'ont pas encore été totalement élucidés (Nakamura et al., 2001). Les thérapies actuelles s'attaquent soit à la pathogenèse de la maladie soit aux symptômes de celle-ci (Varkonyi and Kempler, 2008). Quant à la pathogenèse de cette maladie, différentes hypothèses existent et elles impliquent le métabolisme glucidique ou la vascularisation (Nakamura et al., 2001). ...
Le diabète est une maladie associée à une perturbation du métabolisme glucidique et représentent un problème de santé publique majeur. L'importante majorité des patients présente un diabète de type 2.Les complications les plus courantes sont vasculaires. Chez le diabétique, l'angiogenèse est défectueuse et paradoxale. La microangiopathie qui survient lors du diabète modifie le microenvironnement de la moelle osseuse et entraine egalement des problemes de cicatrisation alors qu'une angiogenèse exacerbé est responsable de pathologie telle que la rétinopathie ou la néphropathie diabétique.Les cellules souches mésenchymateuses (CSMs) sont connues pour leur potentiel de différenciation et de libération de facteurs paracrins, qui sont impliqués dans la régénération tissulaire. Les mécanismes qui associent le microenvironnement et les fonctions des CSMs dans un contexte diabétique restent actuellement méconnus. Le diabète peut modifier les caractéristiques des CSMs et le microenvironnement diabétique peut influencer la fonctionnalité de CSMs transplantées tout autant que leurs effets autocrins et/ou paracrins sur les cellules environnantes. L'étude du potentiel de CSMs diabétiques et du microenvironnement diabétique sur de CSMs pourrait alors avoir d'importantes implications cliniques. L'objectif primaire de cette étude est de caractériser l'impact du diabète sur la fonctionnalité et le potentiel angiogènique de CSMs à l'aide du modèle de rat dit Zucker Diabetic Fatty (ZDF) qui développe spontanément le diabète de type 2 et les complications vasculaire qui l'accompagne.
... Complex B vitamins, specifically thiamine (B1) and cyanocobalamin (B12), have been shown to be of clinical use in some painful diseases, derived from their effects on the central nervous system, synthesis, and secretion of serotonin in several brain areas [6], blocking metabolic pathways related to oxidative stress [7], as well as their effects on the nitric oxide/guanosine monophosphate cyclic (NO/GMPc) pathway [8], among other mechanisms. Synergy of these vitamins with other drugs, for example, gabapentin, allows for reducing recommended doses of these vitamins as monotherapy, achieving greater reduction effects on pain intensity with less AE occurrence. ...
. Painful diabetic neuropathy (PDN) is a prevalent and impairing disorder. The objective of this study was to show the efficacy and safety of gabapentin (GBP) plus complex B vitamins: thiamine (B1) and cyanocobalamine (B12) compared to pregabalin in patients with moderate to severe intensity PDN.
Method
. Multicenter, randomized, blind study. Two hundred and seventy patients were evaluated, 147 with GBP/B1/B12 and 123 with PGB, with a 7/10 pain intensity on the Visual Analog Scale (VAS). Five visits (12 weeks) were scheduled. The GBP/B1 (100 mg)/B12 (20 mg) group started with 300 mg at visit 1 to 3600 mg at visit 5. The PGB group started with 75 mg/d at visit 1 to 600 mg/d at visit 5. Different safety and efficacy scales were applied, as well as adverse event assessment.
Results
. Both drugs showed reduction of pain intensity, without significant statistical difference (
P
=
0.900
). In the GBP/B1/B12 group, an improvement of at least 30% on VAS correlated to a 900 mg/d dose, compared with PGB 300 mg/d. Likewise, occurrence of vertigo was lower in the GBP/B1-B12 group, with a significant statistical difference,
P
=
0.014
.
Conclusions
. Our study shows that GPB/B1-B12 combination is as effective as PGB. Nonetheless, pain intensity reduction is achieved with 50% of the minimum required gabapentin dose alone (800 to 1600 mg/d) in classic NDD trials. Less vertigo and dizziness occurrence was also observed in the GBP/B1/B12 group. This trial is registered with ClinicalTrials.gov
NCT01364298
.
... Aldose reductase inhibitors (ARIs) have been researched over many years for their use in treating diabetic complications, but although animal studies have provided promising results, clinical trials in search of an optimal ARI for humans continues (197)(198)(199)(200)(201)(202)(203)(204)(205)(206). Only Epalrestat is currently on the market in Japan to treat DPNassociated symptoms (198,207,208). ...
Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual.
... One of the main problems with the use of these drugs is the adverse events (AEs), which sometimes limits the possibility of using the recommended dose in clinical trials. The B complex vitamins, specifically thiamine (B1) and cyanocobalamin (B12) have demonstrated utility in some painful conditions by having effects on the central nervous system, in the synthesis and secretion of serotonin in several brain areas [3], by blocking three metabolic pathways related to oxidative stress [4] and also its effects on nitric oxide-GMPc path [5], among other mechanisms. The synergism these vitamins produce with other drugs, for example gabapentin, would reduce the recommended dose as monotherapy achieving a greater effect in reducing pain intensity with reduced occurrence of AEs [6]. ...
... Z tego względu stosowana jest ona nie tylko w leczeniu neuropatii, lecz także retinopatii oraz nefropatii [23]. Według Kemplera benfotiamina -obok ALA -powinna być lekiem pierwszego rzutu w leczeniu przyczynowym neuropatii cukrzycowej ze względu na dużą skuteczność oraz małą ilość działań niepożądanych [24]. ...
Diabetic neuropathy is one of the most frequent complications
of diabetes mellitus and the most frequent etiological
factor of diabetic foot formation. Prevalence is estimated even
to 90% depending on the duration and the type of the diabetes.
Neuropathy negatively affects quality of life, lead to pain, loss of
sensation, muscle weakness and skin ulcers. The effects are higher
risk of infections, amputations and progressive disability. Therefore,
it is so important to find an effective treatment to protect the
peripheral nerves from degenerative effects of diabetes. To date,
management of diabetic neuropathy is based on symptomatic treatment,
glycemic control and reduction of risk factors. Satisfactory
pathogenic treatment is not yet available. In this article was presented
review of the new researches on the neuroprotective treatment
with the most promising effect based on understanding of
pathogenesis of diabetic neuropathy.
Key words: diabetic foot | diabetic neuropathy | neuroprotection
... Unlike the current treatment options for diabetic neuropathy, Epalrestat is Oral anti diabetic agent, Aldose reductase inhibitor which is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycemic conditions epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the onset complications of diabetes mellitus [1][2][3][4]13 . Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity, and vibration threshold compared with baseline and placebo in diabetic neuropathy 6 . ...
Pubicon Abstract Experiments were conducted on Epalrestat 50 mg tablet which is antidiabetic drug that is used for the treatment peripheral diabetic neuropathy as well as diabetic neuropathy. Six study which were coded as F-1, F-2, F-3, F-4, F-5&F-6 were conducted to optimize the formulation to find out the better formulation that exhibits good systemic bioavailability. The active material of this formulation was collected from Cangzou senary Chemical S. & T. Co., Ltd., China. The local agent of this active is ASN Corporation. All of these formulations conducted in accordance with strong cGMP guidelines. The first three formulations were done through direct compression method but last two, formulated through wet granulation method. Then coating operation was performed for the formulation-05 to ensure good aesthetic value and taste and also to protect the drug from moisture. Then certain quality control tests (e.g. Thickness, Individual weight, Hardness, Friability Disintegration and dissolution) were carried out for the formulation-05, the final formulation. The assay content of Epalrestat were calculated by UV-instrumental method which was developed for getting convenient and cost effective result. Test was carried out at 400 nm wavelength .The dissolution test of six tablets of the final formulation were also performed and the result of dissolution test performed through dissolution test apparatus-п (paddle method) with phosphate Buffer (PH=7.2) with 75 Rotation per minute and it exhibited better result that ensure good bioavailability by means of enhanced dissolution property.
... Alpha-lipoic acid is an effective agent in the pathogenetically oriented treatment of diabetic neuropathy [ 88 ], and its beneficial effects on the cardiovascular manifestations of autonomic neuropathy have been proved [ 89 ]. These data may support the theory that the autonomic neuronal fibers that are responsible for gastroparesis might respond to alpha-lipoic acid treatment, but no studies have yet been organized to explore this possible effect. ...
The regulation of gastrointestinal motility mainly involves the smooth muscle, neural (extrinsic and intrinsic), and hormonal elements, the glial cells, and the interstitial cells of Cajal. An orchestrated function of all these components is required for the appropriate propulsive movement of the food in the gastrointestinal tract. Gastroparesis, a pathological slowing-down of gastric emptying, is a result of the damage to the tissue elements involved in the regulation of motility. Gastroparesis is one of the well-known complications of long-standing diabetes mellitus. Although it is rarely a life-threatening complication, it has a deteriorating effect on the quality of life, leads to unpredictable oscillation of the blood glucose level, and increases the time required for the absorption of food and medicines. This review describes the clinical characteristics of diabetic gastroparesis and summarizes the organic and functional motility abnormalities caused by this complication. Finally, the currently available and potential future therapeutic approaches are summarized.
... however, the exact mechanisms by which the neuropathy develops have not yet been elucidated [59]. the current therapeutic possibilities in neuropathy are divided into two groups, pathogenetically oriented therapy and symptomatic therapy [86]. Pathogenetically oriented therapy may delay, stop, or reverse the progression of the neuropathy, and thereby alleviate symptoms. ...
We overviewed the pathophysiological features of diabetes and its complications in obese type 2 diabetic rat models: Otsuka Long-Evans Tokushima fatty (OLETF) rat, Wistar fatty rat, Zucker diabetic fatty (ZDF) rat and Spontaneously diabetic Torii (SDT) fatty rat. Pancreatic changes with progression of diabetes were classified into early changes, such as islet hypertrophy and degranulation of β cells, and degenerative changes, such as islet atrophy and fibrosis of islet with infiltration of inflammatory cells. Renal lesions in tubuli and glomeruli were observed, and nodular lesions in glomeruli were notable changes in OLETF and SDT fatty rats. Among retinal changes, folding and thickening were interesting findings in SDT fatty rats. A decrease of motor nerve conduction velocity with progression of diabetes was presented in obese diabetic rats. Other diabetic complications, osteoporosis and sexual dysfunction, were also observed. Observation of bone metabolic abnormalities, including decrease of osteogenesis and bone mineral density, and sexual dysfunction, including hypotestosteronemia and erectile dysfunction, in obese type 2 diabetic rats have been reported.
... Administration of benfotiamine in diabetic patients having thiamine defi ciency markedly ameliorated neuropathic symptoms and neutralized the damaging eff ects of hyperglycaemia on neuronal vascular cells [ 69 ] . Benfotiamine has been recently suggested to be considered as a fi rst choice of nutritional supplement in preventing the progression of diabetic neuropathy based on its effi cacy and safety data [ 70 ] . ...
Diabetic neuropathy is a prevalent, disabling disorder. Currently, the only treatments available to patients with diabetic neuropathy are glucose control and pain management. B vitamin present neuroprotective effects, which are suggested to be related to their analgesic action in various models of neuropathic pain. According to our literature knowledge there is no report about antinociceptive effects of thiamine as benfotiamine and opioids together in diabetic mice. The purpose of this study was to determine the effects of benfotiamine on the antinociception produced by mu-opioid receptor agonist fentanyl in diabetic mice. The effects of benfotiamine on antinociception produced by fentanyl in diabetic mice were studied in 4 groups. Antinociceptive effect was determined with tail flick, hot plate and formalin test. Our results showed that, mu-opioid agonist fentanyl in benfotiamine applied diabetic group caused more potent antinociceptive effect than in diabetic group without benfotiamine treatment. In brief benfotiamine supplement in diet did not bring out antinociceptive effect itself, but during development of STZ diabetes, benfotiamine replacement increased the antinociceptive effect of fentanyl in mice tail-flick test. This effect is probably due to the replacement of benfotiamine efficiency occuring in diabetes mellitus. Finally, we suppose that oral benfotiamine replacement therapy may be useful to ameliorate analgesic effect of mu-opioid agonists on neuropathic pain in diabetic case.
Cél: A diabéteszes neuropathia összefüggésben van a cukorbetegek morbiditásának és összmortalitásának növekedésével. Tisztázatlan azonban ezeknek a kimeneteli eseményeknek az alakulása attól függően, hogy a neuropathia kezelése a szövődmény patomechanizmusát befolyásoló oki terápiával vagy csak tüneti gyógyszeres kezeléssel történik. Módszerek: A retrospektív (2009–2019) adatbázis-elemzésben olyan cukorbetegek szerepeltek, akik diabéteszes neuropathia miatt alfa-liponsav adásával végzett oki terápiában, vagy csak tüneti gyógyszeres kezelésben részesültek. A klinikai események alakulását a propensity score matching módszer szerint illesztett, egymással összehasonlítható két betegcsoportban vizsgáltuk. A kockázati arány (HR: hazard ratio) alakulását és az éves eseménygyakoriságot állapítottuk meg, illetve szenzitivitási elemzéseket végeztünk. Eredmények: Az alfa-liponsavval (vs. tüneti szerekkel) kezelt betegcsoportban a HR értéke előnyösebben alakult az alábbi kimeneti események vonatkozásában: akut miokardiális infarktus (HR: 0,73, 95%-os CI: 0,60–0,89, p=0,0016), stroke (HR: 0,71, 95%-os CI: 0,62–0,82, p<0,0001), szívelégtelenség miatti hospitalizáció (HR: 0,72, 95%-os CI: 0,66–0,78, p<0,0001), daganatos betegségek (HR: 0,83, 95%-os CI: 0,76–0,92, p=0,0002), összmortalitás (HR: 0,55, 95%-os CI: 0,49–0,61, p<0,0001). Az alsó végtagi amputáció terén különbség nem mutatkozott a két betegcsoport között (HR: 1,05, 95%-os CI: 0,89–1,25, p=0,5455). Az összefüggések hasonlóan alakultak akkor, ha az események éves gyakoriságát vizsgáltuk. Az elvégzett szenzitivitási elemzések támogatták az alapelemzésben talált eltérések valódiságát. Következtetések: A retrospektív adatbázis-elemzésünk eredményei szerint a diabéteszes neuropathia miatt alfa-liponsav adásával végzett oki terápia (vs. tüneti gyógyszeres kezelés) a kardio- és cerebrovaszkuláris morbiditás, a daganatos betegségek és az összhalálozás kockázati arányának csökkenésével állt összefüggésben. A hipotézist generáló eredményeink további vizsgálatokat igényelnek.
Aims:
Diabetic neuropathy is associated with increased risk of morbidity and all-cause mortality. It is unclear whether these outcomes differ in patients with diabetic neuropathy treated with pathogenetically oriented vs symptomatic pharmacotherapies.
Methods:
We performed a retrospective (2009-2019) database analysis of patients treated with pathogenetically oriented alpha-lipoic acid (ALA) or symptomatic pharmacotherapies for diabetic neuropathy. We investigated clinical outcomes in propensity score matched patients in Hungary. Changes in hazard ratios and annualized event rates were assessed and sensitivity analyses performed.
Results:
Hazard ratios favored treatment with ALA vs symptomatic pharmacotherapies regarding acute myocardial infarction (HR 0.73, 95%CI: 0.60-0.89, p = 0.0016), stroke (HR 0.71, 95%CI: 0.62-0.82, p<0.0001), hospitalization for heart failure (HR 0.72, 95%CI: 0.66-0.78, p<0.0001), cancer events (HR 0.83, 95% CI: 0.76-0.92, p = 0.0002) and all-cause mortality (HR 0.55, 95% CI: 0.49-0.61, p<0.0001), but not for lower limb amputation (HR 1.05, 95%CI: 0.89-1.25, p = 0.5455). This association was supported by results of evaluating annual event rates and sensitivity analyses.
Conclusions:
This retrospective database analysis revealed a lower occurrence of cardio- and cerebrovascular morbidity, cancer events and all-cause mortality in patients with diabetic neuropathy treated with pathogenetically oriented ALA vs symptomatic pharmacotherapies. This hypothesis-generating result requires further investigations.
Advances in the treatment of neurodegenerative diseases (NDs) are nominal. Currently available therapies are merely symptomatic treatments that cannot prevent the development of the disease. Several herbs have been found very useful for managing neurological diseases. There are immense possibilities to discover a more successful line of ND treatment. Phytochemicals from medicinal plants may play a vital role in maintaining the chemical balance of the brain by affecting the capacity of receptors for the major inhibitory neurotransmitters. A few plants have already gained popularity for the potential treatment of NDs. This volume highlights the therapeutic role of medicinal plants and their scientific validation for improving neuronal health. It presents 15 chapters that cover the herbal treatment of NDs, including Parkinson's disease and Alzheimer's disease. The contents cover a range of pharmaceutical agents like sirtuins, berberine, rosmarinic acid and resveratrol. The book serves as a reference for pharmacology and herbal medicine scholars as well as healthcare workers interested in information about alternative and complementary therapies for neurological disorders.
Advances in the treatment of neurodegenerative diseases (NDs) are nominal. Currently available therapies are merely symptomatic treatments that cannot prevent the development of the disease. Several herbs have been found very useful for managing neurological diseases. There are immense possibilities to discover a more successful line of ND treatment. Phytochemicals from medicinal plants may play a vital role in maintaining the chemical balance of the brain by affecting the capacity of receptors for the major inhibitory neurotransmitters. A few plants have already gained popularity for the potential treatment of NDs. This volume highlights the therapeutic role of medicinal plants and their scientific validation for improving neuronal health. It presents 15 chapters that cover the herbal treatment of NDs, including Parkinson's disease and Alzheimer's disease. The contents cover a range of pharmaceutical agents like sirtuins, berberine, rosmarinic acid and resveratrol. The book serves as a reference for pharmacology and herbal medicine scholars as well as healthcare workers interested in information about alternative and complementary therapies for neurological disorders.
Ethnopharmacological relevance: Previously before the invention of virtual screening methods or techniques almost 80% of drugs were obtained from natural resources or compounds obtained from these sources. Plant species of the genus Daphne have historical background as a source of bioactive phytochemicals such as flavonoids including daphnodorins which have been found to possess significant chemotaxonomic value in drug discovery.
Aim of the study: Their comprehensive pharmacological, phytochemical, biological, various catalytic activities and clinical uses have prompted us to conduct the optimization and structure based virtual screening of its potent analogues. The aim of this work is to investigate the use of daphnodorins analogues for the first time as anti-diabetic inhibitors on the basis of significant features by computational analysis.
Materials and methods: A dataset of 38 compounds was selected from authentic database i.e., PubChem and ZINC database for computational analysis and quantitative structure activity relationship (QSAR). Optimized compounds were docked against various co-crystallized structures of inhibitors, antagonists and receptors were downloaded from PDB by implicating AutoDock Vina, Discovery studio 2020, PYMOL (Schrodinger). After performing molecular docking compounds of desired threshold were analyzed by ADMET studies through Swiss ADMET, ADMET SAR, ADMET lab and ProTox-II for investigating their drug-like nature. Elaboration of electronic structures of hit compounds was carried out using Gaussian 09W by intimating Density Functional Theory (DFT).
Results: At significant phases of drug design approaches regular use of molecular docking has helped to promote the separation of important representatives from 38 pharmaceutically active compounds and 14 compounds were selected as lead compounds which were analyzed through ADMET studies for identifying their drug like properties and toxicity. Dataset of these 14 hit compounds was subjected for measuring significant parameters such as dipole moment, electronic energy, energy of Frontier Molecular Orbitals (FMO) and hardness of molecules by performing DFT as a result, one compound was selected as lead compound for anti-diabetic agent.
Background: Since serum uric acid is a controllable and modifiable factor in diabetic patients, identifying the risk factors and accelerating the incidence of neuropathy in these patients plays an important role, and can reduce its level, and the patient's disability, as well as additional therapeutic costs for the patient and the health system in the country. Method: In this retrospective cohort study conducted at the Golestan Hospital in 2015-2017, the study population was 100 type 2 diabetic patients based on NCS of 54 patients with polyneuropathy. First, the demographic data on clinical examinations, lab tests, and uric acid levels in these patients were recorded on a checklist. Then, in 2017, patients were reassessed for clinical investigations and lab tests, and all data entered on the previous checklist. Finally, all the data were analyzed using the SPSS v23. Results: The mean age of patients with polyneuropathy was 51.77 years, and there was a significant relationship between age, BMI and duration of diabetes with neuropathy, but there was no significant difference in gender, smoking and hypertension. The mean serum level of uric acid in the two years ago was 3.85 mg/dl, and at the time of the study, it was 4.18±1.55 mg/dl. There was no significant difference in serum levels of this substance after two years of follow up in patients with polyneuropathy (P=0.139). The incidence of polyneuropathy was reported by NCS findings of 54%. In other words, 54% of diabetic patients developed diabetic polyneuropathy for two years. Conclusion: Polyneuropathy is a common complication in diabetic patients, and the serum levels of uric acid over time cannot have a significant effect on the incidence of this disorder.
Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes mellitus and may cause pain, decreased motility, and even amputation. Diabetic neuropathy includes multiple forms, ranging from discomfort to death. Prognosis of diabetic neuropathy is an uphill task as it remains silent for several years after the onset of diabetes. Hyperglycemia, apart from inducing oxidative stress in neurons, also leads to activation of multiple biochemical pathways which constitute the major source of damage and are potential therapeutic targets in diabetic neuropathy. A vast array of molecular pathways, including polyol pathway, hexosamine pathway, PKCs signaling, oxidative stress, AGEs pathway, PARP pathway, MAPK pathway, NF-κB signaling, hedgehog pathways, TNF-α signaling, cyclooxygenase pathway, interleukins, lipoxygenase pathway, nerve growth factor, Wnt pathway, autophagy, and GSK3 signaling may be accounted for the pathogenesis and progression of diabetic neuropathy. Although symptomatic treatment is available for diabetic neuropathy, few treatment options are available to eliminate the root cause. The immense physical, psychological, and economic burden of diabetic neuropathy highlights the need for cost effective and targeted therapies. The main aim of this review is to highlight the putative role of various mechanisms and pathways involved in the development of diabetic neuropathy and to impart an in-depth insight on new therapeutic approaches aimed at delaying or reversing various modalities of diabetic neuropathy.
Lanostanes are a group of tetracyclic triterpenoids derived from lanosterol. They have relevant biological and pharmacological properties, such as cytotoxicity, immunomodulation, and anti-inflammation. Some of them also have interesting effects on metabolism and anti-infectious properties. This review will compile chemical data, biological effects, and mechanisms on the most relevant lanostanoids isolated from fungi, such as those from Ganoderma lucidum, Poria cocos, Laetiporus sulphureus, Inonotus obliquus, Antrodia camphorata, Daedalea dickinsii, and other.
Diabetic neuropathy is a major long term problem allied with diabetes that can cause serious disability and also death. Fifty to seventy five percent of all ulcerations and non trauma amputations are a consequence of diabetic neuropathy. Epalrestat, duloxetine and epalrestat with methylcobalamine are widely used to overcome neuronal damage. This study was designed to evaluate the efficacy of these three drug regimens. Material and methods: Patients included in this study were experiencing pain because of diabetic neuropathy for more than 6 months but not more than 5 years. Results: From 236 subjects with diabetic neuropathy included in the study, 181 patients concluded final analysis. 55 patients dropped from the study (14, 23 and 18 patients from duloxetine, epalrestat+methylcobalamine combination and epalrestat respectively). Mean pain score was reduced from 5.01±1.99 (severe pain) at first visit to 2.86±2.10 (moderate pain) in the epalrestat group, from 6.41±1.73 (severe pain) at first visit to 2.38±1.58 (mild pain) in the duloxetine group and from 5.86±1.76 (severe pain) to 2.88±1.91 (mild pain) in the epalrestat with methylcobalamine group. Conclusion: We conclude that duloxetine was significantly more effective than epalrestat and epalrestat in combination with methylcobalamine in relieving diabetic neuropathic pain.
AimsTo investigate the protective effect of acetagastrodin on visual electrophysiology in patients with early-stage diabetes. MethodsA prospective, randomized, controlled, double-blind trial was conducted. Subjects who were randomly assigned to either the treatment group or the control group were orally administered acetagastrodin or placebo, respectively, for 6 months. The quantity, mean amplitude and mean latency of oscillatory potentials (OPs) wavelets at baseline and 6 months were measured on electroretinogram (ERG), in all subjects. ResultsA total of 92 right eyes in 92 patients with type 2 diabetes, who were diagnosed for the first time, were enrolled. Each group consisted of 46 cases (46 eyes). There was no significant difference in baseline characteristic between treatment and control groups at baseline, but quantity in treatment group was more than that in control group at 6 months (P = 0.001). The mean amplitude of OPs was reduced in the control group 6 months later compared with treatment group (P = 0.001). As to mean latency of OPs, statistical difference was also detectable between the treatment group and control group 6 months later (P < 0.001). No statistical differences were found in hemoglobin between both groups at 6 months (P > 0.05). Conclusions
Electrophysiological changes would go on worsening even hemoglobin was under control during the initial stage of diabetes. Acetagastrodin treatment may be an effective treatment to protect retinal neurons against such functional impairment during the early stages of diabetes.
Lanostanes are a group of tetracyclic triterpenoids derived from lanosterol. They have relevant biological and pharmacological properties, such as cytotoxicity, immunomodulation, and anti-inflammation. Some of them also have interesting effects on metabolism and anti-infectious properties. This review will compile chemical data, biological effects, and mechanisms on the most relevant lanostanoids isolated from fungi, such as those from Ganoderma lucidum, Poria cocos, Laetiporus sulphureus, Inonotus obliquus, Antrodia camphorata, Daedalea dickinsii, and other.
Background: Peripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy.
Method: The current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity. The article also highlights the therapeutic significance of maintaining a healthy mitochondrial environment in neuronal cells via pharmacological management in context of peripheral neuropathies.
Results: Aberrant cellular signaling coupled with changes in neurotransmission, peripheral and central sensitization are found to be responsible for the pathogenesis of variant toxic neuropathies. Current research reports have indicated the possible involvement of mitochondria mediated redox imbalance as one of the principal causes of neuropathy aetiologies. In addition to imbalance in redox homeostasis, mitochondrial dysfunction is also responsible for alterations in physiological bioenergetic metabolism, apoptosis and autophagy pathways.
Conclusions: In spite of various etiological factors, mitochondrial dysfunction has been found to be a major pathomechanism underlying the neuronal dysfunction associated with peripheral neuropathies. Pharmacological modulation of mitochondria either directly or indirectly is expected to yield therapeutic relief from various primary and secondary mitochondrial diseases.
Diabetic neuropathy is one of the most frequent and serious complications in patients with diabetes mellitus, of which about 16-26 % suffer from painful symptoms. Clinical diagnosis must distinguish between asymptomatic and symptomatic manifestations of diabetic neuropathy. Treatments are based on those that normalize blood glucose levels, those that target the pathogenetic mechanisms of nerve damage, and those that relieve symptoms. Although improving blood glucose control has been found to reduce the risk of developing diabetic neuropathy, or hindering its progression, in type 1 diabetic patients, its significance in type 2 diabetic patients is less clear. Despite the fact that several different molecular pathways in the development of diabetic nerve damage have been identified in recent years, only alpha-lipoic acid is currently registered as a treatment of diabetic neuropathy in Europe. In the past, there was only limited scientific evidence as to the efficacy of drugs used in the treatment of neuropathic pain. For many years, mainly tricyclic anti-depressants, carbamazepine, gabapentin, or opioids were the standard medications. More recently, significant pain relief has been reported in clinical trials using agents such as the dual-selective serotonin noradrenalin re-uptake inhibitor, duloxetin, and a modulator of the voltage-dependent calcium channel, pregabalin.The aim of this review is to provide a scientific update on the latest treatments for diabetic neuropathy.
Wernicke encephalopathy (WE) is a cause of rapidly progressive but reversible dementia due to deficit of thiamine (the B1 vitamin). In developed countries, WE is principally described in chronic alcoholism; however, it can also develop in other, probably underestimated and undiagnosed, nonalcoholic conditions. The nonalcoholic conditions causing reduced intake (malnutrition, reduced or absent absorption) or increased consumption of thiamine can be physiologic (aging) or pathologic. Abdominal surgery for cancer is an underestimated cause of atypical WE leading to high morbidity and mortality in which the diagnosis is often missed or delayed. Alongside acute neurological emergence, chronic deficit of thiamine may contribute to the neurodegenerative process leading to senile dementia and Alzheimer's disease. This chapter provides an overview of (1) the main metabolic effects of thiamine in specific brain areas; (2) the natural history of WE in patients who have undergone abdominal surgery for cancer; (3) the mechanisms linking thiamine deficiency to Alzheimer's disease; and (4) alternative causes of rapidly progressive dementias that should be differentiated from atypical WE.
Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of MTHFR 677 C > T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C > T and ACE I/D polymorphisms and DPN found in various types of electronic databases. STROBE quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (OR), and its corresponding 95 % confidence interval (95%CI) were calculated. We used STATA statistical software (Version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D > I mutation (OR = 1.43, 95%CI 1.12-1.83, P = 0.004) and MTHFR 677 C > T mutation (OR = 1.43, 95%CI 1.08-1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P < 0.05). Subgroup analysis by country indicated that the MTHFR 677 C > T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D > I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C > T and ACE I/D polymorphisms with DPN patients presented in this meta-analyses support the view that the MTHFR and ACE genes might play important roles in the development of DPN.
Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) are common type 2 diabetes complications with a large inter-individual variability in terms of clinical manifestations and severity. Our aim was to evaluate a possible involvement of genetic polymorphisms in miRNA regions in the susceptibility to DPN and CAN. Nine polymorphisms in miRNA genes were studied in a sample of 132 type 2 diabetes patients (T2D) analysed for DPN and 128 T2D patients analysed for CAN. A genotype–phenotype correlation analysis was performed. The T allele of rs11888095 single nucleotide polymorphism (SNP) in MIR128a was significantly associated with a higher risk (ORadj = 4.89, P
adj = 0.02), whereas the C allele of rs2910164 SNP in MIR146a was associated with a lower risk to develop DPN (ORadj = 0.49, P
adj = 0.09), respectively. A multivariate logistic regression analysis confirmed that both SNPs contribute to DPN (p < 0.001 and p = 0.01 for MIR128a and MIR146a, respectively). MIR128a SNP significantly contributed also to DPN score (p = 0.026). Rs895819 SNP in MIR27a was significantly associated with a higher risk to develop early CAN (P
adj = 0.023 and ORadj = 3.43). The rs2910164 SNP in MIR146a showed a protective effect respect to early CAN (P
adj = 0.052, ORadj = 0.32) and to confirmed CAN (P
adj = 0.041, ORadj = 0.13). The same SNP resulted significantly associated with a lower CAN score and a higher E/I (p = 0.002 and p = 0.003, respectively). In conclusion, we described associations of MIR128a and MIR146a SNPs with DPN susceptibility and of MIR146a and MIR27a SNPs with CAN susceptibility. This is the first study showing that genetic variability in miRNA genes could be involved in diabetic neuropathies susceptibility.
OBJECTIVES—We aimed to determine whether ranirestat, an aldose reductase inhibitor, maintains the improved nerve function observed in patients with diabetic sensorimotor polyneuropathy (DSP) after completing a 12-week nerve biopsy study.
RESEARCH DESIGN AND METHODS—Patients with mild to moderate DSP, as determined by the presence of sural nerve responses, were enrolled in a double-blind, placebo-controlled biopsy trial and randomized to placebo or 5 or 20 mg/day ranirestat for 12 weeks. Patients completing this biopsy study were offered a 48-week extension at the same ranirestat dose or at 5 mg/day ranirestat if they were originally treated with placebo. Electrophysiological tests, the Toronto Clinical Neuropathy Score, and vibration perception thresholds (VPTs) were performed at entry and at 12 (end of the biopsy study) and 60 (end of the 48-week extension) weeks.
RESULTS—Peroneal motor nerve conduction velocity (NCV) improved in the 20-mg/day group following 60 weeks of treatment. Sural and median sensory NCV improved after both 12 and 60 weeks of treatment with 20 mg/day. VPT improved after 60 weeks of treatment with 20 mg/day. Ranirestat was well tolerated with no difference in adverse events between the 5- and 20-mg/day groups.
CONCLUSIONS—Twenty milligrams ranirestat per day improves NCV and VPT following 60 weeks of administration. The improved sensory nerve function observed after 12 weeks of therapy was maintained at 60 weeks, and improved motor nerve function was observed at 60 weeks.
Context
Nerve growth factor is a neurotrophic factor that promotes the survival
of small fiber sensory neurons and sympathetic neurons in the peripheral nervous
system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy
as treatment for peripheral neuropathy in experimental models and phase 2
clinical trials.Objective
To evaluate the efficacy and safety of a 12-month regimen of rhNGF in
patients with diabetic polyneuropathy.Design
Randomized, double-blind, placebo-controlled phase 3 trial conducted
from July 1997 through May 1999.Setting
Eighty-four outpatient centers throughout the United States.Patients
A total of 1019 men and women aged 18 to 74 years with either type 1
or type 2 diabetes and a sensory polyneuropathy attributable to diabetes.Interventions
Patients were randomly assigned to receive either rhNGF, 0.1 µg/kg
(n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week
for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and
48 weeks.Main Outcome Measures
The primary outcome measure was a change in neuropathy between baseline
and week 48, demonstrated by the Neuropathy Impairment Score for the Lower
Limbs, compared between the 2 groups. Secondary outcome measures included
quantitative sensory tests using the CASE IV System, the Neuropathy Symptom
and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global
symptom assessment, as well as nerve conduction studies and occurrence of
new plantar foot ulcers. Patients also were evaluated for presence of adverse
events.Results
Among patients who received rhNGF, 418 (83%) completed the regimen compared
with 461 (90%) who received placebo. Administration of rhNGF was safe, with
few adverse events attributed to treatment apart from injection site pain/hyperalgesia
and other pain syndromes. However, neither the primary end point (P = .25) nor most of the secondary end points demonstrated a significant
benefit of rhNGF. Exceptions were the global symptom assessment (P = .03) and 2 of 32 comparisons within the PBQ, which showed a modest
but significant benefit of rhNGF (P = .05 for severity
of pain in the legs and P = .003 for 6-month symptoms
in the feet and legs).Conclusion
Unlike previous phase 2 trials, this phase 3 clinical trial failed to
demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy.
Figures in this Article
Nerve growth factor (NGF) is a protein that plays a major role in the
development and maintenance of the peripheral nervous system. Nerve growth
factor selectively promotes the survival of small fiber sensory neurons that
mediate pain, temperature sensation, and sympathetic neurons.1
Nerve growth factor is expressed in target tissues innervated by responsive
neurons, where it binds to specific high-affinity receptors and is retrogradely
transported back to the neuronal cell body.2
Recent data suggest that reduced availability of NGF may play a significant
role in the pathogenesis of diabetic polyneuropathy. In animals with diabetes
mellitus, retrograde axonal transport of NGF is impaired,3- 5
and levels of NGF messenger RNA are reduced in neuronal target tissues.6 In patients with diabetes mellitus, levels of NGF
are reduced in skin biopsy specimens. Furthermore, the diminished levels of
NGF in the skin correlate with decreased skin axon-reflex vasodilatation,
suggesting that reduced availability of NGF from the target tissue leads to
early dysfunction of small fiber neurons.7
Systemic administration of NGF prevents manifestations of neuropathy in rodent
models of toxic8- 9 and diabetic
polyneuropathy.10 That loss of NGF might contribute
toward the pathogenesis of diabetic polyneuropathy plus the demonstrated ability
of exogenous NGF to prevent experimental neuropathy provided a compelling
rationale for testing NGF administration in clinical studies.
Two randomized, placebo-controlled trials of recombinant human NGF (rhNGF)
administered to patients with polyneuropathy were initiated. In a phase 2
trial of 250 patients with diabetic polyneuropathy, improvements in signs
and symptoms were seen after treatment with rhNGF, 0.1 or 0.3 µg/kg,
subcutaneously, 3 times per week for 6 months.11
A second phase 2 trial of 270 patients with human immunodeficiency virus (HIV)–associated
sensory neuropathy demonstrated significant improvements in neuropathic pain
following 18 weeks of treatment with rhNGF, 0.1 or 0.3 µg/kg, twice
a week.12 Recombinant human NGF was well tolerated
with the exception of self-limited injection site hyperalgesia and other pain-related
syndromes. This article reports the results of a large randomized, double-blind,
placebo-controlled, phase 3 study of rhNGF administered to patients with diabetic
polyneuropathy to determine safety and efficacy during a 12-month period.
The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy.
A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms.
Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group.
The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy.
Although its exact mode of action is not known, gabapentin appears to have a unique effect on voltage-dependent calcium ion channels at the postsynaptic dorsal horns and may, therefore, interrupt the series of events that possibly leads to the experience of a neuropathic pain sensation. Gabapentin is especially effective at relieving allodynia and hyperalgesia in animal models. It has been shown to be efficacious in numerous small clinical studies and case reports in a wide variety of pain syndromes. Gabapentin has been clearly demonstrated to be effective for the treatment of neuropathic pain in diabetic neuropathy and postherpetic neuralgia. This evidence, combined with its favourable side-effect profile in various patient groups (including the elderly) and lack of drug interactions, makes it an attractive agent. Therefore, gabapentin should be considered an important drug in the management of neuropathic pain syndromes.
Considerable evidence implicates impaired nitric oxide (NO) generation in the pathogenesis of diabetic neuropathic pain. We therefore conducted a pilot study to examine the effects of isosorbide dinitrate (ISDN), a NO donor with local vasodilating properties, in spray form in the management of chronic neuropathic pain.
The study was of double-blind, randomized, placebo-controlled, and two-period cross-over design. After a 2-week run-in period, 22 diabetic patients (13 men, 20 with type 2 diabetes, age [mean +/- SE] 63.7 +/- 1.8 years, duration of diabetes 9.1 +/- 1.5 years, duration of painful neuropathy 2.6 +/- 0.4 years) were randomized to receive ISDN or placebo sprays for 4 weeks, exchanging their treatment for a further 4 weeks after a 2-week wash-out period. The patients administered the spray to both feet before bedtime. Biweekly pain and other sensory symptoms were assessed using a visual analog scale (VAS) and the Lickert scale, respectively.
ISDN spray reduced overall neuropathic pain (P = 0.02) and burning sensation (P = 0.006). No treatment difference was observed with other sensory modalities (hot/cold sensation, tingling, numbness, hyperesthesia, and jabbing-like sensation). At study completion, 11 patients (50%) reported benefit and wished to continue using the ISDN spray, 4 (18%) preferred the placebo spray, and the remaining 7 (32%) were undecided.
ISDN spray offers an alternative and effective pharmacological option in relieving overall pain and burning sensation in the management of painful diabetic neuropathy. The potential of ISDN spray in alleviating other specific sensory symptoms associated with diabetic peripheral neuropathy merits further study.
Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria.
The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin.
The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79).
A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.
Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.
The pathogenesis of painful diabetic neuropathy remains unknown. As a consequence we still do not have any effective, rational treatments and a greater understanding of the mechanisms is urgently required. Previous studies have shown no consistent morphological differences in the nerves of patients with and without painful neuropathy. The aim of this study was to compare epineurial haemodynamics in patients with chronic painful and painless neuropathy.
The techniques of microlightguide spectrophotometry and fluorescein angiography were used to measure epineurial intravascular oxygen saturation and blood flow respectively. Eleven patients with painful and eight with painless neuropathy were studied, with the groups matched carefully in terms of severity of neuropathy and diabetes control.
Intravascular oxygen saturation was higher in the painful neuropathy group compared to those without pain (median 73.8% vs 67.7%, respectively; p=0.021). Fluorescein rise time was also faster in those with painful symptoms (median 18.3 s vs 53.6 s; p=0.046) indicating higher epineurial blood flow in these subjects.
These results indicate that there are distinct differences in haemodynamics within the epineurium of the sural nerve in subjects with painful and painless neuropathy. Haemodynamic factors could therefore have an important role in the pathogenesis of neuropathic pain and might offer further insight into potential treatments for this distressing condition.
In the October 2002 issue of Diabetes Care , we reported (1) the benefit of isosorbide dinitrate (ISDN) in the treatment of painful diabetic neuropathy. This stance was based on the speculation that the impaired nitric oxide (NO) generation might play a role in the pathogenesis of neuropathic pain through defects in local vasodilatation. This was a double-blind, randomized, placebo-controlled, two-period, crossover design study of 22 diabetic patients. The ISDN spray reduced overall neuropathic pain ( P = 0.02) and burning sensation ( P = 0.006). Fifty percent of the patients reported improvement in their quality of life and wanted to continue the ISDN spray. Since then, this publication has received considerable interest, with numerous inquiries from clinicians and …
Erythropoietin (EPO) possesses generalized neuroprotective and neurotrophic actions. We tested the efficacy of recombinant human EPO (rhEPO) in preventing and reversing nerve dysfunction in streptozotocin (STZ)-induced diabetes in rats. Two days after STZ [60 mg/kg of body weight (b.w.), i.p.], diabetic animals were administered rhEPO (40 microg/kg of b.w.) three times weekly for 5 weeks either immediately (preventive) before or after a 5-week delay (therapeutic) after induction of hyperglycemia or at a lower dose (8 microg/kg of b.w. once per week) for 8 weeks (prolonged). Tail-nerve conduction velocities (NCV) was assessed at 5 and 11 weeks for the preventive and therapeutic schedule, respectively. Compared to nondiabetic rats, NCV was 20% lower after 5 weeks in the STZ group, and this decrease was attenuated 50% by rhEPO. Furthermore, the reduction of Na(+),K(+)-ATPase activity of diabetic nerves (by 55%) was limited to 24% in the rhEPO-treated group. In the therapeutic schedule, NCV was reduced by 50% after 11 weeks but by only 23% in the rhEPO-treated group. rhEPO treatment attenuated the decrease in compound muscle action potential in diabetic rats. In addition, rhEPO treatment was associated with a preservation of footpad cutaneous innervation, as assessed by protein gene product 9.5 immunostaining. Diabetic rats developed alterations in mechanical and thermal nociception, which were partially reversed by rhEPO given either in a preventative or therapeutic manner. These observations suggest that administration of rhEPO or its analogues may be useful in the treatment of diabetic neuropathy.
The primary purpose of this investigation was to determine whether AS-3201, a new aldose reductase inhibitor, penetrates the sural nerve and inhibits sorbitol and fructose accumulation in patients with diabetic sensorimotor polyneuropathy (DSP). An additional aim was to determine whether any changes in nerve function would manifest with AS-3201 therapy.
Patients with mild to moderate DSP based on nerve conduction studies were randomized into one of three treatment groups in a double-blind fashion: placebo or AS-3201 at 5 or 20 mg/day. After 12 weeks of administration, the sural nerve was biopsied for measurement of sorbitol, fructose, and AS-3201.
At baseline, no important clinical, electrophysiological, or laboratory differences were found between the three groups. The nerve sorbitol concentration of 3.14 x 10(-2) nmol/mg wet nerve in patients in the placebo group was inhibited by 65 and 84% in patients on AS-3201 at 5 and 20 mg/day, respectively (P < 0.001). Fructose levels were similarly inhibited. Sensory nerve conduction velocities improved by > or = 1 m/s (P < 0.05).
AS-3201 penetrates the sural nerve and inhibits sorbitol accumulation in patients with DSP. Additional studies are needed to confirm the electrophysiological suggestion that AS-3201 delays progression or leads to regression of DSP.
Because alpha-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms.
Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test.
At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P < 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy.
Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.
We evaluated frozen databases from two 52-week randomized placebo-controlled clinical diabetic neuropathy trials testing two doses of acetyl-L-carnitine (ALC): 500 and 1,000 mg/day t.i.d.
Intention-to-treat patients amounted to 1,257 or 93% of enrolled patients. Efficacy end points were sural nerve morphometry, nerve conduction velocities, vibration perception thresholds, clinical symptom scores, and a visual analogue scale for most bothersome symptom, most notably pain. The two studies were evaluated separately and combined.
Data showed significant improvements in sural nerve fiber numbers and regenerating nerve fiber clusters. Nerve conduction velocities and amplitudes did not improve, whereas vibration perception improved in both studies. Pain as the most bothersome symptom showed significant improvement in one study and in the combined cohort taking 1,000 mg ALC.
These studies demonstrate that ALC treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy.
Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study.
Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (+/-SD) follow-up of 7.3+/-0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory.
At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors.
This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension.
Glycemic control is the only treatment for diabetic neuropathy. The emphasis must be on prevention. Identifying risk factors for diabetic neuropathy may allow modification of these risk factors and decrease the incidence of diabetic neuropathy in patients with diabetes. The authors studied 1,172 patients with type I diabetes mellitus from 31 centers involved in the European Diabetes (EURODIAB) Prospective Complication Study. From 1989 to 1991, neuropathy was assessed at baseline and at follow up (1997 to 1999). Mean follow up was 7.3 ± 0.6 years. Patients were evaluated with a standardized protocol, including autonomic function tests, quantitative sensory testing, and clinical evaluation. In addition, serum lipids and lipoproteins, urinary albumin excretion rates, and glycosylated hemoglobin were measured in a core laboratory.
Avanir Pharmaceuticals in the US is developing a fixed-dose combination of dextromethorphan (30mg), a weak NMDA antagonist/sigma 1 agonist, and quinidine (30mg), a cytochrome P450-2D6 (CYP2D6) enzyme inhibitor [AVP 923, Neurodex]. Quinidine sustains therapeutic levels of dextromethorphan over a 12-hour dosing schedule by inhibiting oxidative first-pass metabolism of the drug, and is used in the combination product at 2.55.0% of its normal daily therapeutic dose. A rolling NDA for the treatment of emotional lability has been initiated, and phase II trials with dextromethorphan/quinidine for the treatment of neuropathic pain have been completed.Avanir is exploring partnering opportunities for dextromethorphan/quinidine in Europe and Japan. Prospective partners would carry out development and commercialisation in the licensed territory. Additionally, a co-promotion partner for the US is sought.Avanir Pharmaceuticals sublicensed this formulation of dextromethorphan from IriSys Research and Development. Avanir has exclusive rights to develop, manufacture and market dextromethorphan/quinidine for four potential indications: emotional lability, neuropathic pain, chronic cough and weaning drug-dependent patients from narcotics and antidepressants. Avanir will make milestone payments to Irisys upon US FDA acceptance of filing, marketing approval, and royalties based on product sales.Medison Pharma (Israel) has obtained development, marketing and distribution rights to the dextromethorphan/quinidine combination for the treatment of emotional lability in patients with multiple sclerosis in Israel.Avanir will fund all clinical development of the dextromethorphan/quinidine combination for the treatment of emotional lability. The phase II clinical trials with dextromethorphan/quinidine for the treatment of neuropathic pain have been completed. Results indicated that the combination significantly improved pain scores in patients with diabetic neuropathy. Phase III trials in this indication are expected to begin in 2005. Avanir has been issued with six patents in the US regarding dextromethorphan/quinidine and has a total of 14 pending applications, 12 of which are in Europe.
Objectives – To evaluate the efficacy and tolerability of topiramate in patients with painful diabetic polyneuropathy.
Materials and methods – Patients with moderate to extreme pain (0–4 Categorical Pain Scale score ≥ 2) were randomized to placebo or topiramate (100, 200, or 400 mg/day) in three similar double-blind trials. The primary efficacy analysis was pain reduction from final visit to baseline in the 100-mm Visual Analog Scale (VAS) for the intent-to-treat populations.
Results – After 18–22 weeks of double-blind treatment, pain reductions were numerically greater with topiramate in two studies but differences between topiramate and placebo in VAS scores or in the secondary efficacy endpoints did not reach statistical significance in any of the three studies. Across all studies, 24% of topiramate-treated patients and 8% of placebo-treated patients discontinued due to adverse events; groups did not differ in the occurrence of serious adverse events.
Conclusion – These studies did not find topiramate to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy. Several design features may have precluded the studies from having sufficient sensitivity to differentiate effective and ineffective treatments. The study design and results are instructive for other investigators designing future clinical studies in neuropathic pain.
Aims To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study.
Methods The study involved the examination of randomly selected Type I (insulin-dependent) diabetic patients from 31 centres in 16 European countries. Neuropathic symptoms and two tests of autonomic function (changes in heart rate and blood pressure from lying to standing) were assessed and data from 3007 patients were available for the present analysis. Autonomic neuropathy was defined as an abnormality of at least one of the tests.
Results The prevalence of autonomic neuropathy was 36% with no sex differences. The frequency of one and two abnormal reflex tests was 30% and 6%, respectively. The R–R ratio was abnormal in 24% of patients while 18% had orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on standing. Significant correlations were observed between autonomic neuropathy and age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been identified from the study: the strong relationship of autonomic neuropathy to cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05) and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was related to the presence of cardiovascular disease (P < 0.0001). All analyses were adjusted for age, duration of diabetes and HbA1c. However, data have been only partly confirmed by logistic regression analyses. Frequency of dizziness on standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had problems with bladder control.
Conclusion Cardiovascular reflex tests, even in the form of the two tests applied, rather than a questionnaire, seem to be appropriate for the diagnosis of autonomic neuropathy. The study has identified previously known and new potential risk factors for the development of autonomic neuropathy, which may be important for the development of risk reduction strategies. Our results may support the role of vascular factors in the pathogenesis of autonomic neuropathy.
Diabet. Med. 19, 900–909 (2002)
Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy.
Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months.
Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05).
These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.
To evaluate the cost and effectiveness of intensive insulin therapy for type 2 diabetes on the prevention of diabetes complications in Japan, we performed economic evaluation based on a randomized controlled trial. A total of 110 patients with type 2 diabetes were randomly assigned into two groups, a multiple insulin injection therapy (MIT) group or a conventional insulin injection therapy (CIT) group, and were followed-up for 10 years. Economic evaluation (cost-consequences analysis) was applied to evaluate both health and economic outcomes. As outcome measures for effectiveness of intensive insulin therapy, the frequency of complications, such as retinopathy, nephropathy, neuropathy, macrovascular event, and diabetes-related death, was used. For estimating costs, a viewpoint of the payer (the National Health Insurance) was adopted. Direct medical costs associated with diabetes care during 10 years were calculated and evaluated. In a base case analysis, all costs were discounted to the present value at an annual rate of 3%. Sensitivity analyses were carried out to assess the robustness of the results to changes in the values of important variables. MIT reduced the relative risk in the progression of retinopathy by 67%, photocoagulation by 77%, progression of nephropathy by 66%, albuminuria by 100% and clinical neuropathy by 64%, relative to CIT. Moreover, MIT prolonged the period in which patients were free of complications, including 2.0 years for progression of retinopathy (P<0.0001), 0.3 years for photocoagulation (P<0.05), 1.5 years for progression of nephropathy (P<0.01) and 2.2 years for clinical neuropathy (P<0.0001). The total cost (discounted at 3%) per patient during the 10-year period for each group was $30310 and 31525, respectively. The reduction of total costs in MIT over CIT was mainly due to reduced costs for management of diabetic complications. Our results show that MIT is more beneficial than CIT in both cost and effectiveness. Therefore, MIT is recommended for the treatment of type 2 diabetic patients who require insulin therapy as early as possible from the perspective of both patients and health policy.
The diabetic state, in both humans and experimental animals, is associated with oxidative stress. Lipid peroxidation of nerve membranes has been suggested as a mechanism by which peripheral nerve ischemia and hypoxia could cause neuropathy. Lipoic acid (LA) is a powerful inhibitor of iron-dependent lipid peroxidation and reactive oxygen species. The treatment of diabetic peripheral and cardiac autonomic neuropathy with LA is based on good clinical and experimental evidence.
To investigate the magnitude of the oxidative stress, serum ceruloplasmin (Cp) and lipid peroxide (Lp) levels were measured in 10 patients with diabetic neuropathy, before and 70 days after treatment with single dose of 600 mg LA/day. For other 12 healthy age- and sex-matched control subjects the serum Cp and Lp levels were evaluated.
Our results show that hyperglycemia is a factor for an increase in serum ceruloplasmin in patients with diabetic neuropathy compared to healthy subjects (p < 0.0001). High serum ceruloplasmin (Cp) level in patients with diabetes may be related to antioxidant defense. The treatment of diabetic neuropathy with LA does not affect significantly the serum Cp activity. The serum Lp levels after LA administration were significantly lower (p < 0.005) than those before treatment.
The antioxidant therapy with LA improves and may prevent diabetic neuropathy. This improvement is associated with a reduction in the indexes of lipid peroxidation. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia autooxidation.
Capsaicinoids are molecules derived from chili peppers. They are best known for their pungency, producing mild to intense spice upon ingestion. It has long been known that peppers possess unusual qualities. Historically, they were burned in war rituals, and used to stimulate appetite. In 1997, a gene that encoded for a receptor specific for capsaicinoids was identified. Called VR1, this fatty acid receptor is present only on C fibers, and when activated produces desensitization or degeneration of the sensory afferent. Today, capsaicinoids are being studied as effective treatments for a number of sensory nerve fiber disorders, including pain associated with arthritis, cystitis, human immunodeficiency virus, and diabetic neuropathy.
Diabetic polyneuropathy is a serious complication in patients with diabetes mellitus. In addition to the maintenance of a sufficient metabolic control, alpha-lipoic acid (ALA) (Thioctacid, Asta Medica) is known to have beneficial effects on diabetic polyneuropathy although the exact mechanism by which ALA exerts its effect is unknown. In order to study the effect of ALA on microcirculation in patients with diabetes mellitus and peripheral neuropathy one group of patients (4 female, 4 male, age 60+/-3 years, diabetes duration 19+/-4 years, BMI 24.8+/-1.3 kg/m2) received 1200 mg ALA orally per day over 6 weeks (trial 1). A second group of patients (5 female, 4 male, age 65+/-3 years, diabetes duration 14+/-4 years, BMI 23.6+/-0.7 kg/m2) was studied before and after they had received 600 mg ALA or placebo intravenously over 15 minutes in order to investigate whether ALA has an acute effect on microcirculation (trial 2). Patients were investigated by nailfold video-capillaroscopy. Capillary blood cell velocity was examined at rest and during postreactive hyperemia (occlusion of the wrist for 2 minutes, 200 mmHg) which is a parameter of the perfusion reserve on demand. The oral therapy with ALA resulted in a significant decrease in the time to peak capillary blood cell velocity (tpCBV) during postocclusive hyperemia (trial 1: 12.6+/-3.1 vs 35.4+/-10.9 s, p<0.05). The infusion of ALA also decreased the tpCBV in patients with diabetic neuropathy (trial 2: before: 20.8+/-4,5, ALA: 11.74+/-4.4, placebo: 21.9-5.0 s, p<0.05 ALA vs both placebo and before infusions) indicating that ALA has an acute effect on microcirculation. Capillary blood cell velocity at rest (rCBV), hemodynamic parameters, hemoglobinA1c and local skin temperature remained unchanged in both studies. These results demonstrate that in patients with diabetic polyneuropathy ALA improves microcirculation as indicated by an increased perfusion reserve on demand. The observed effects are apparently acute effects. With the restriction of the pilot character of this investigation the findings support the assumption that ALA might exert its beneficial effects at least partially by improving microcirculation which is likely to occur also at the level of the vasa nervorum.
The objective of this study was to evaluate the efficacy and safety of tramadol in a 6-month open extension following a 6-week double-blind randomized trial.
Patients with painful diabetic neuropathy who completed the double-blind study were eligible for enrollment in an open extension of up to 6 months. All patients received tramadol 50-400 mg/day. Self-administered pain intensity scores (scale 0-4; none to extreme pain) and pain relief scores (scale -1-4; worse to complete relief) were recorded the first day of the open extension (last day of the double-blind phase) and at 30, 90, and 180 days.
A total of 117 patients (56 former tramadol and 61 former placebo) entered the study. On the first day of the study, patients formerly treated with placebo had a significantly higher mean pain intensity score (2. 2+/-1.02 vs. 1.4+/-0.93, P<0.001) and a lower pain relief score (0. 9+/-1.43 vs. 2.2+/-1.27, P<0.001) than former tramadol patients. By Day 90, both groups had mean pain intensity scores of 1.4, which were maintained throughout the study. Mean pain relief scores (2. 4+/-1.09 vs. 2.2+/-1.14) were similar after 30 days in the former placebo and former tramadol groups, respectively and were maintained for the duration of the study. Four patients discontinued therapy due to ineffective pain relief; 13 patients discontinued due to adverse events. The most common adverse events were constipation, nausea, and headache.
Tramadol provides long-term relief of the pain of diabetic neuropathy.
The objective of this study was to compare the efficacy and tolerability of gabapentin and amitriptyline monotherapy in painful diabetic neuropathy. This was a 12-week, open-label, prospective, randomized trial. Twenty-five type-II diabetic patients with pain attributed to diabetic neuropathy and a minimum score of 2 on a pain intensity scale ranging from 0 (no pain) to 4 (excruciating pain) were randomized to receive either gabapentin, titrated from 1,200 mg/day to a maximum of 2,400 mg/day, or amitriptyline, titrated from 30 mg/day to a maximum of 90 mg/day. Both drugs were titrated over a 4-week period and maintained at the maximum tolerated dose for 8 weeks. The main outcome measures were weekly pain intensity and paresthesia intensity, measured on two categorical scales. Thirteen patients received gabapentin and 12 received amitriptyline. All 25 patients completed the trial. Gabapentin produced greater pain reductions than amitriptyline (mean final scores were 1.9 vs. 1.3 points below baseline scores; P = 0.026). Decreases in paresthesia scores also were in favor of gabapentin (1.8 vs. 0.9 points; P = 0. 004). Adverse events were more frequent in the amitriptyline group than in the gabapentin group: they were reported by 11/12 (92%) and 4/13 (31%) of patients, respectively (P = 0.003). Side effects were the main limiting factor preventing dose escalation. Gabapentin produced greater improvements than amitriptyline in pain and paresthesia associated with diabetic neuropathy. Additionally, gabapentin was better tolerated than amitriptyline. Further controlled trials are needed to confirm these preliminary results.
To study the efficacy of lamotrigine in relieving the pain associated with diabetic neuropathy.
The authors randomly assigned 59 patients to receive either lamotrigine (titrated from 25 to 400 mg/day) or placebo over a 6-week period. Primary outcome measure was self-recording of pain intensity twice daily with a 0 to 10 numerical pain scale (NPS). Secondary efficacy measures included daily consumption of rescue analgesics, the McGill Pain Questionnaire (MPQ), the Beck Depression Inventory (BDI), the Pain Disability Index (PDI), and global assessment of efficacy and tolerability.
Twenty-four of 29 patients (83%) receiving lamotrigine and 22 of 30 (73%) patients receiving placebo completed the study. Daily NPS in the lamotrigine-treated group was reduced from 6.4 +/- 0.1 to 4.2 +/- 0.1 and in the control group from 6.5 +/- 0.1 to 5.3 +/- 0.1 (p < 0.001 for lamotrigine doses of 200, 300, and 400 mg). The results of the MPQ, PDI, and BDI remained unchanged in both groups. The global assessment of efficacy favored lamotrigine treatment over placebo, and the adverse events profile was similar in both groups.
Lamotrigine is effective and safe in relieving the pain associated with diabetic neuropathy.
There is growing evidence that idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and polyneuropathy in patients with diabetes mellitus (DM) that meets the electrophysiological criteria for CIDP (DM-CIDP) have many similarities.
To evaluate whether DM-CIDP responds to intravenous immunoglobulin (IVIG) therapy.
Twenty-six patients (mean [SD] age, 64 [8.9] years; age range, 40-80 years) with type 2 DM (n = 25), who met the electrophysiological criteria for CIDP, were given IVIG therapy (400 mg/kg body weight per day for 5 days) in a prospective open-label pilot study. All patients had quantitative evaluation using the Neuropathy Impairment Score at baseline and at the end of 4 weeks from the initiation of IVIG therapy.
The mean Neuropathy Impairment Score improved significantly from baseline (mean [SD], 61.5 [26.0] points) to the end of the fourth week (33 [29.6] points; P<.00l). This clinically significant improvement occurred in 21 (80.8%) of the 26 patients. Conduction block occurred in 11 (42.3%) of the 26 patients; improvement in the Neuropathy Impairment Score was more frequent in patients who had a conduction block (11 of 11 patients) than in those who did not (10/15 [66.7%]; P =.03). Adverse reactions to IVIG included reversible renal dysfunction in 3 patients, flulike symptoms in 5, headache in 5, and chest pain and shortness of breath in 1.
Although IVIG therapy seemed to improve DM-CIDP in this uncontrolled trial, a controlled trial is required for confirmation of our findings.
Topical treatment with capsaicin cream has been shown to be successful in the treatment of different symptomatic nerve disorders like diabetic neuropathy. Conflicting data exist on the effect of capsaicin on nerve function and neurovascular control especially in patients with diabetic neuropathy. The aim of this pilot study was to investigate the impact of topical capsaicin application on small nerve fibre function and neurovascular control. Capsaicin cream was applied to the feet of 13 patients with symptomatic diabetic neuropathy over a period of 8 weeks. Before and during the treatment period, we investigated the total symptoms score, the vibration, thermal (heat and cold) and pain perception thresholds, and the neurovascular responses to heat and acetylcholine stimuli. In addition, the serum plasma levels of substance P, a neurotransmitter of nociceptor C-fibres, were measured. A significant improvement in total symptoms score was observed during topical capsaicin treatment (18.3+/-3.2 vs. 14.3+/-3.3; p<0.05). An improvement in the heat perception threshold was also found (12.7+/-0.4 degrees C vs. 11.4+/-0.7 degrees C: p<0.05), while other sensory nerve fibre functions remained unchanged. No significant change in neurovascular control was observed, neither after mild thermal injury nor after stimulation with acetylcholine. Serum substance P levels increased after initiation of topical capsaicin treatment (72.9+/-5.8 pg/ml vs. 81.7+/-5.0 pg/ml; p<0.05), but returned to baseline levels during further treatment (77.4+/-8.3 pg/ml: n.s.). In conclusion, topical treatment with capsaicin cream over a period of 8 weeks in patients with symptomatic diabetic neuropathy is effective without adverse effects on nerve fibre function or neurovascular control.
The authors investigated the impact of IVIg as first line treatment of diabetic patients suffering from chronic inflammatory demyelinating polyneuropathy (CIDP) concomitant with distal symmetric axonal polyneuropathy. Nine patients with these clinical and electrophysiological features were treated with IVIg (0.4 g/Kg/day for 5 days). Clinical and electrophysiological evaluations were performed before and after treatment. Following IVIg treatment there was no significant improvement in clinical deficit. However, there was a significant and persistent decrease in the Rankin scale score and an improvement in the demyelinating feature on nerve conduction studies. Our findings suggest that IVIg had small but detectable beneficial effects on diabetic patients with CIDP and a high degree of axonal damage.
Elevated protein kinase C activity has been linked to the vascular and neural complications of diabetes. The aim of the present study was to examine the involvement of the beta-isoform of protein kinase C in abnormalities of neuronal function, neural tissue perfusion and endothelium-dependent vasodilation in diabetes, by treatment with the selective inhibitor LY333531 (10 mg.kg(-1).day(-1)). Diabetes was induced in rats by streptozotocin; the duration of diabetes was 8 weeks. Nerve conduction velocity was monitored, and responses to noxious mechanical and thermal stimuli were estimated by the Randall-Sellito and Hargreaves tests respectively. Sciatic nerve and superior cervical ganglion blood flow were measured by microelectrode polarography and hydrogen clearance. Vascular responses were examined using the in vitro mesenteric bed preparation. An 8-week period of diabetes caused deficits in sciatic motor (20%) and saphenous nerve sensory (16%) conduction velocity, which were reversed by LY333531. Diabetic rats had mechanical and thermal hyperalgesia. LY333531 treatment did not affect mechanical thresholds, but corrected thermal hyperalgesia. Sciatic nerve and superior cervical ganglion blood flow were both reduced by 50% by diabetes; this was almost completely corrected by 2 weeks of LY333531 treatment. Diabetes caused a 32% reduction in vasodilation of the mesenteric vascular bed in response to acetylcholine, mediated by nitric oxide and endothelium-derived hyperpolarizing factor. When the former was abolished during nitric oxide synthase inhibition, an 80% diabetic deficit in the remaining relaxation was noted. LY333531 treatment attenuated the development of these defects by 64% and 53% respectively. Thus protein kinase C beta contributes to the neural and vascular complications of experimental diabetes; LY333531 is a candidate for further study in clinical trials of diabetic neuropathy and vasculopathy.
Objective:
To outline the modes of action of topiramate and to examine the theoretical reasons as to why topiramate may alleviate neuropathic pain. Results of animal and human studies in the use of topiramate for treating pain are reviewed, together with case studies describing situations where topiramate was effective when other treatments have failed.
Conclusions:
Topiramate acts on neuronal transmission in at least five ways: by modulating voltage-gated sodium ion channels, potentiating gamma-aminobutyric acid inhibition, blocking excitatory glutamate neurotransmission, modulating voltage-gated calcium ion channels, and by inhibiting carbonic anhydrase. This review suggests that there are good theoretical reasons for a trial of topiramate in patients with neuropathic pain where conventional medical treatments have failed. Although not currently licensed for treating pain, topiramate should be considered before invasive methods of pain relief are contemplated. Most of the side effects of topiramate are dose dependent, but by starting medication with a low dose (</=25 mg/d) that is gradually titrated upward, tolerance is much more easily achieved.
Studies have demonstrated that proinsulin C-peptide stimulates the activities of Na(+),K(+)-ATPase and endothelial nitric oxide synthase, both of which are enzyme systems of importance for nerve function and known to be deficient in type 1 diabetes. The aim of this randomized double-blind placebo-controlled study was to investigate whether C-peptide replacement improves nerve function in patients with type 1 diabetes. Forty-nine patients without symptoms of peripheral neuropathy were randomized to either 3 months of treatment with C-peptide (600 nmol/24 h, four doses s.c.) or placebo. Forty-six patients (15 women and 31 men, aged 29 years, diabetes duration 10 years, and HbA(1c) 7.0%) completed the study. Neurological and neurophysiological measurements were performed before and after 6 and 12 weeks of treatment. At baseline the patients showed reduced nerve conduction velocities in the sural nerve (sensory nerve conduction velocity [SCV]: 50.9 +/- 0.70 vs. 54.2 +/- 1.2 m/s, P < 0.05) and peroneal nerve (motor nerve conduction velocity: 45.7 +/- 0.55 vs. 53.5 +/- 1.1 m/s, P < 0.001) compared with age-, height-, and sex-matched control subjects. In the C-peptide treated group there was a significant improvement in SCV amounting to 2.7 +/- 0.85 m/s (P < 0.05 compared with placebo) after 3 months of treatment, representing 80% correction of the initial reduction in SCV. The change in SCV was accompanied by an improvement in vibration perception in the patients receiving C-peptide (P < 0.05 compared with placebo), whereas no significant change was detectable in cold or heat perception. In conclusion, C-peptide administered for 3 months as replacement therapy to patients with early signs of diabetic neuropathy ameliorates nerve dysfunction.
Background:
Current symptomatic treatments for painful peripheral neuropathy in diabetes have variable efficacy in individual patients. Amongst other chemical transmitters involved in pain reception, the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor is involved in nociception. Amantadine was recently shown to act as a non-competitive antagonist of NMDA and may be effective in the treatment of neuropathic pain in patients with cancer. We have looked at the benefit of amantadine infusion in diabetic patients with painful peripheral neuropathy.
Methods:
Seventeen patients with diabetes (nine men) completed this double-blind randomized crossover placebo-controlled trial of intravenous amantadine. The average age was 58.4 (sd 11) years, with duration of diabetes of 21.1 (8.7) years and duration of painful peripheral neuropathy symptoms of 29.1 (24) months. All analgesics except paracetamol were stopped for 4 weeks prior to the study. Infusions were carried out on a weekly basis with amantadine being administered intravenously as a single 200-mg infusion. The Neuropathy Symptom Score (NSS), together with visual analogue scales, were used to assess current pain intensity (VAS-P) pre-therapy and 1 week later VAS-P was repeated together with a visual analogue scale used to assess relief in pain (VAS-R) and the Physicians Global Evaluation (PGE) score used to assess response to therapy.
Results:
Pre-therapy, the NSS was 6.8 (6.3-7.4) at baseline, remaining unchanged at 6.6 (5.8-7.4) after placebo (P = 0.33), but fell to 4.6 (3.4-5.8) after amantadine (P = 0.003 vs. baseline and P = 0.02 vs. placebo). The baseline perception of pain was scored as 7.8 cm (7.3-8.3), with no difference following placebo, at 8.2 cm (7.7-8.6) (P = 0.34), but following amantadine it fell to 6.2 cm (4.9-7.8) (P = 0.01 compared with pre-therapy, P = 0.003 compared with placebo). The perception of relief from pain following placebo was only 0.2 (-0.2 to +0.6) but following amantadine was 10-fold better at 1.9 (0.8-3.1) (P = 0.016). The PGE assessment of pain relief was -0.3 (-0.5 to 0) for placebo and following amantadine was 0.8 (0.1-1.5) (P = 0.006).
Conclusions:
Our study has shown that intravenous amantadine is beneficial in reducing the pain of painful peripheral neuropathy, with an effect sustained for at least 1 week after an infusion.
Background:
Pain is one of the most common reasons for seeking medical attention, and neuropathic pain is among the most common types of pain. Despite its prevalence, neuropathic pain is often underrecognized and inadequately treated. Many cases are refractory to the medications traditionally used for pain, such as nonsteroidal anti-inflammatory drugs. Tricyclic antidepressants are considered first-line agents for neuropathic pain, but their use is limited by unwanted side effects and a risk of cardiovascular mortality.
Objectives:
The goals of this article were to review data on the efficacy and tolerability of gabapentin in the treatment of neuropathic pain in adults and to determine the optimal dosing schedule.
Methods:
Randomized controlled studies of gabapentin for neuropathic pain were identified through a search of PubMed and MEDLINE from 1966 to the present using the search terms gabapentin, randomized, placebo, and pain. Abstracts of identified articles were screened for study size (>100 patients per treatment arm) and use of appropriate efficacy measures. A separate review based on information provided by the manufacturer of gabapentinaand clinical trial Web sites was conducted to ascertain whether there had been any other relevant industry- or government-sponsored trials. The manufacturer provided additional unpublshed study data.
Results:
Data from 5 randomized, placebo-controlled trials were included in the review, 1 of which has not yet been published. Gabapentin was effective in the treatment of painful diabetic neuropathy, postherpetic neuralgia, and other neuropathic pain syndromes. It relieved symptoms of allodynia, burning pain, shooting pain, and hyperesthesia. Adverse effects were typically mild to moderate and usually subsided within approximately 10 days from the initiation of treatment. Based on available data, it appears that treatment should be started at a dose of 900 mg/d (300 mg/d on day 1, 600 mg/d on day 2, and 900 mg/d on day 3). Additional titration to 1800 mg/d is recommended for greater efficacy. Doses up to 3600 mg/d may be needed in some patients. The effective dose should be individualized according to patient response and tolerability.
Conclusion:
At doses of 1800 to 3600 mg/d, gabapentin was effective and well tolerated in the treatment of adults with neuropathic pain.
Peripheral neuropathy commonly develops in patients with advanced chronic renal failure. The uremic neuropathy is often subclinical and detectable only by electrophysiological studies. Receptors to erythropoietin (EPO) have been described on non-hematopoietic cells including neuronal cells.
In order to evaluate the effect of five months' EPO therapy on polyneuropathy in predialytic patients, nerve conduction studies (NCS) were done in 46 anemic predialytic patients without neurological complaints. In 22 (twelve non-diabetic and ten diabetic) neuropathy was detected and these patients were included in the study. After five months of subcutaneous EPO therapy NCSs were repeated.
Hemoglobin increased significantly (p=0.0001) with no significant increase in plasma creatinine. Motor nerve conduction velocity (MNCV) and compound muscle action potentials (CMAP) of the ulnar nerve were normal before EPO therapy and at the end of the study. MNCV of the median, peroneal and tibial nerves improved significantly (p<0.05). CMAP of the median nerve rose significantly, to the normal range (p=0.01). Sensory nerve conduction velocity (SNCV ) and sensory nerve action potentials (SNAP) were reduced in all sensory nerves and did not improve. The improvement in non-diabetic patients was better than in diabetic patients. No significant correlation was found between the increase in hemoglobin and the improvement in MNCV.
Subcutaneous EPO therapy improved motor polyneuropathy in uremic patients, especially non-diabetic individuals. The improvement in MNCV may reflect remyelination. This non-hematopoietic effect may be related to some direct action through EPO receptors on peripheral neuronal cells.
Opioid treatment has played a limited role in the management of diabetic neuropathy, in part because of concerns about the responsiveness of neuropathic pain to opioid treatment. This controlled study evaluated the efficacy and safety of controlled-release (CR) oxycodone in subjects with moderate to severe pain due to diabetic neuropathy.
This multicenter, randomized, double-blind, placebo-controlled, parallel-group study included 159 subjects with moderate to severe pain due to diabetic neuropathy. Treatment began with either one 10-mg tablet of CR oxycodone (n = 82) or identical placebo (n = 77) every 12 hours. Doses could be increased every 3 days to a maximum of 6 tablets (60 mg CR oxycodone) every 12 hours. Treatment lasted up to 6 weeks. The primary efficacy variable was overall average daily pain intensity during study days 28 to 42.
At an average (SD) dose of 37 (21) mg per day (range 10 to 99 mg/d), CR oxycodone provided more analgesia than placebo (p= 0.002) in the intent-to-treat cohort. From days 28 to 42, overall average daily pain intensity (least squares mean +/-SE), rated in subject diaries on a numeric scale of 0 (no pain) to 10 (pain as bad as you can imagine), was 4.1 +/- 0.3 in subjects given CR oxycodone and 5.3 +/- 0.3 in placebo-treated subjects. Overall, 80 (96%) of 82 subjects given CR oxycodone and 52 (68%) of 77 subjects who received placebo reported adverse events. The most common adverse events in the CR oxycodone group were opioid related.
In this 6-week trial, CR oxycodone was effective for the treatment of moderate to severe pain due to diabetic neuropathy. Adverse events were typical of opioid-related side effects.
Tricyclic antidepressants (TCA) are often used in the treatment of painful polyneuropathy. Venlafaxine is a serotonin and weak noradrenaline reuptake inhibitor antidepressant with a different profile of other pharmacologic actions from those of TCA.
To test if venlafaxine would relieve painful polyneuropathy and compare its possible efficacy with that of the TCA imipramine.
The study design was randomized, double blind, and placebo controlled, with a three-way crossover. Forty patients were assigned to one of the treatment sequences, and 29 completed all three study periods. The daily doses were venlafaxine 225 mg and imipramine 150 mg. During the three treatment periods, each of 4 weeks' duration, patients rated pain paroxysms, constant pain, and touch- and pressure-evoked pain by use of 0- to 10-point numeric rating scales.
The sum of the individual pain scores during treatment week 4 was lower on venlafaxine (80% of baseline score; p = 0.006) and imipramine (77%; p = 0.001) than on placebo (100%) and did not show any statistical difference between venlafaxine and imipramine (p = 0.44). The individual pain scores for pain paroxysms, constant pain, and pressure-evoked pain showed a similar pattern, whereas touch-evoked pain was uncommon and was not altered by any of the drugs. Numbers needed to treat to obtain one patient with moderate or better pain relief were 5.2 for venlafaxine and 2.7 for imipramine.
Venlafaxine relieves pain in polyneuropathy and may be as effective as imipramine.
Proinsulin C-peptide treatment can partially prevent nerve dysfunction in type 1 diabetic rats and patients. This could be due to a direct action on nerve fibers or via vascular mechanisms as C-peptide stimulates the nitric oxide (NO) system and NO-mediated vasodilation could potentially account for any beneficial C-peptide effects. To assess this further, we examined neurovascular function in streptozotocin-induced diabetic rats. After 6 weeks of diabetes, rats were treated for 2 weeks with C-peptide to restore circulating levels to those of nondiabetic controls. Additional diabetic groups were given C-peptide with NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) co-treatment or scrambled C-peptide. Diabetes caused 20 and 16% reductions in sciatic motor and saphenous sensory nerve conduction velocity, which were 62 and 78% corrected, respectively, by C-peptide. L-NNA abolished C-peptide effects on nerve conduction. Sciatic blood flow and vascular conductance were 52 and 41%, respectively, reduced by diabetes (P < 0.001). C-peptide partially (57-66%) corrected these defects, an effect markedly attenuated by L-NNA co-treatment. Scrambled C-peptide was without effect on nerve conduction or perfusion. Thus, C-peptide replacement improves nerve function in experimental diabetes, and the data are compatible with the notion that this is mediated by a NO-sensitive vascular mechanism.
Painful neuropathy is one of the most common long-term complications of diabetes mellitus and often proves difficult to relieve.
Patients with diabetic neuropathy with moderate or greater pain for at least 3 months, were evaluated for efficacy, safety and health-related quality of life (QOL) while receiving controlled-release (CR) oxycodone (OxyContin) or active placebo. Patients underwent washout from all opioids 2-7 days before randomization to 10 mg CR oxycodone or active placebo (0.25 mg benztropine) q12h. The dose was increased, approximately weekly, to a maximum of 40 mg q12h CR oxycodone or 1 mg q12h benztropine, with crossover to the alternate treatment after a maximum of 4 weeks. Acetaminophen, 325-650 mg q4-6h prn was provided as rescue.
Thirty-six patients were evaluable for efficacy (21 men, 15 women, mean age 63.0+/-9.4 years). CR oxycodone resulted in significantly lower (P=0.0001) mean daily pain (21.8+/-20.7 vs. 48.6+/-26.6 mm VAS), steady pain (23.5+/-23.0 vs. 47.6+/-30.7 mm VAS), brief pain (21.8+/-23.5 vs. 46.7+/-30.8 mm VAS), skin pain (14.3+/-20.4 vs. 43.2+/-31.3 mm VAS), and total pain and disability (16.8+/-15.6 vs. 25.2+/-16.7; P=0.004). Scores from 6 of the 8 SF-36 domains and both summary scales, Standardized Physical Component (P=0.0002) and Standardized Mental Component (P=0.0338) were significantly better during CR oxycodone treatment. The number needed to treat to obtain one patient with at least 50% pain relief is 2.6 and clinical effectiveness scores favoured treatment with CR oxycodone over placebo (P=0.0001).
CR oxycodone is effective and safe for the management of painful diabetic neuropathy and improves QOL.
The epidemiology, classification, pathology, and treatment of diabetic neuropathy are reviewed.
Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality. Some 30% of hospitalized and 20% of community-dwelling diabetes patients have peripheral neuropathy; the annual incidence rate is approximately 2%. The primary risk factor is hyperglycemia. Sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss. Cardiac autonomic neuropathy (CAN) may contribute to myocardial infarction, malignant arrhythmia, and sudden death. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy. Genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder. The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunction. For symptom management current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications. Citalopram, nonsteroidal antiinflammatory drugs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxetine, levodopa, and alpha-lipoic acid are alternative considerations. Evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal. Complementary therapies have also shown efficacy. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, and beta-blockers. Gastroparesis may be treated with metoclopramide or erythromycin. The most promising disease-modifying therapy is ruboxistaurin, which is in Phase III trials. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment.
Diabetic neuropathy is a many-faceted complication of diabetes that can be managed symptomatically with an array of drugs.
The treatment of painful diabetic polyneuropathy (DPN) is often inadequate and frequently limited by the systemic adverse effects of medications, necessitating the evaluation of novel treatments.
To evaluate the effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in painful diabetic polyneuropathy.
Open-label, flexible-dosing, 3-week study with a 5-week extension.
Outpatient clinics and clinical research centers.Patients Volunteer sample of 56 patients with clinically defined painful diabetic polyneuropathy of longer than 3 months' duration. Intervention The 5% lidocaine patch, with a maximum of 4 patches daily for 18 hours.
Change in mean daily pain diary ratings from baseline to week 3. Secondary end points included assessments of safety, tolerability, and quality of life.
Patients with painful diabetic polyneuropathy showed significant improvements in pain and quality-of-life outcome measures during a 3-week treatment period. These benefits were maintained in a subgroup of patients treated for an additional 5 weeks, during which taper of concomitant analgesic therapy was permitted. Adverse events were minimal, and systemic accumulation of lidocaine did not occur.
Up to four 5% lidocaine patches for up to 18 h/d are well tolerated in patients with painful diabetic polyneuropathy, significantly improve pain and quality-of-life ratings, and may allow tapering of concomitant analgesic therapy. Given the open-label design of this trial, a randomized controlled trial is necessary to confirm these results.
To evaluate the efficacy and safety of 6 weeks of venlafaxine extended-release (ER) (75 mg and 150-225 mg) treatment in patients with painful diabetic neuropathy. This multicenter, double-blind, randomized, placebo-controlled study included 244 adult outpatients with metabolically stable type 1 or 2 diabetes with painful diabetic neuropathy. Primary efficacy measures were scores on the daily 100 mm Visual Analog Pain Intensity (VAS-PI) and Pain Relief (VAS-PR) scales. Secondary efficacy measures included the Clinical Global Impressions-Severity of Illness and the Clinical Global Impressions-Improvement, Patient Global Rating of Pain Relief, and percentage of patients achieving 50% reduction in pain intensity. Baseline pain intensity was 68.7 mm (moderately severe). At week 6, the percentage reduction from baseline in VAS-PI was 27% (placebo), 32% (75 mg), and 50% (150-225 mg; P < 0.001 vs placebo). Mean VAS-PR scores in the 150-225 mg group were significantly greater than placebo at week 6 (44 vs 60 mm; P < 0.001). The number needed to treat (NNT) for 50% pain intensity reduction with venlafaxine ER 150-225 mg was 4.5 at week 6. Nausea and somnolence were the most common treatment-emergent adverse events. Seven patients on venlafaxine had clinically important ECG changes during treatment. Venlafaxine ER appears effective and safe in relieving pain associated with diabetic neuropathy. NNT values for higher dose venlafaxine ER are comparable to those of tricyclic antidepressants and the anticonvulsant gabapentin.
A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy (DPN). For enrollment, patients must have had at baseline: 1- to 5-year history of DPN pain; pain score > or =40 mm (Short-Form McGill Pain Questionnaire [SF-MPQ] visual analogue scale); average daily pain score of > or =4 (11-point numerical pain rating scale [0 = no pain, 10 = worst possible pain]). One hundred forty-six (146) patients were randomized to receive placebo (n = 70) or pregabalin 300 mg/day (n = 76). Primary efficacy measure was endpoint mean pain score from daily patient diaries (11-point numerical pain rating scale). Secondary measures included SF-MPQ scores; sleep interference scores; Patient and Clinical Global Impression of Change (PGIC and CGIC); Short Form-36 (SF-36) Health Survey scores; and Profile of Mood States (POMS) scores. Safety assessment included incidence and intensity of adverse events, physical and neurological examinations, and laboratory evaluations. Pregabalin produced significant improvements versus placebo for mean pain scores (P < 0.0001); mean sleep interference scores SF-36 Bodily Pain subscale (P < 0.0001); total SF-MPQ score (P < 0.01); SF-36 Bodily Pain subscale (P < 0.03); PGIC (P = 0.001); and Total Mood Disturbance and Tension-Anxiety components of POMS (P < 0.03). Pain relief and improved sleep began during week 1 and remained significant throughout the study (P < 0.01). Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.
Using identical methods, three simultaneous placebo-controlled trials of topiramate for painful diabetic neuropathy (PDN) did not reach significance. This independent yet concurrent placebo-controlled trial used different methods to assess topiramate efficacy and tolerability in PDN.
This 12-week, multicenter, randomized, double-blind trial included 323 subjects with PDN and pain visual analog (PVA) score of at least 40 on a scale from 0 (no pain) to 100 (worst possible pain). Topiramate (n = 214) or placebo (n = 109) was titrated to 400 mg daily or maximum tolerated dose. Short-acting rescue analgesics were permitted only during the first 6 weeks.
Baseline characteristics were comparable between groups except for mean body weight (topiramate, 101.4 kg; placebo, 95.7 kg; p = 0.028). Twelve weeks of topiramate treatment reduced PVA scale score (from 68.0 to 46.2 mm) more effectively than placebo (from 69.1 to 54.0 mm; p = 0.038). Fifty percent of topiramate-treated subjects and 34% of placebo-treated subjects responded to treatment, defined as >30% reduction in PVA scale score (p = 0.004). Topiramate monotherapy also reduced worst pain intensity (p = 0.003 vs placebo) and sleep disruption (p = 0.020 vs placebo). Diarrhea, loss of appetite, and somnolence were the most commonly reported adverse events in the topiramate group. Topiramate reduced body weight (-2.6 vs +0.2 kg for placebo; p < 0.001) without disrupting glycemic control.
Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy.
Erythropoietin (EPO)-deficient anaemia has been described in Type 1 diabetic patients with both severe autonomic neuropathy (AN) and proteinuria. This study was aimed at distinguishing between the effects of AN and nephropathy on haemoglobin and EPO levels in Type 2 diabetic patients at an early stage of diabetic nephropathy.
In 64 Type 2 diabetic patients (age 52 +/- 10 years, duration 10 +/- 9 years) without overt nephropathy and other causes of anaemia or EPO deficit, we assessed cardiovascular tests of AN, 24-h blood pressure (BP) monitoring, urinary albumin excretion rate (UAE), a full blood count, and serum EPO.
Although the Type 2 diabetic patients with AN did not show differences in haemoglobin and EPO when compared with patients without AN, the presence of haemoglobin < 13 g/dl was associated with the presence of AN (chi(2)= 3.9, P < 0.05) and of postural hypotension (chi(2)= 7.8, P < 0.05). In a multiple regression analysis including as independent variables gender, body mass index, duration of diabetes, smoking, creatinine, 24-h UAE, 24-h diastolic BP, ferritin, erythrocyte sedimentation rate, and autonomic score, we found that the only variables independently related to haematocrit were autonomic score, ferritin and erythrocyte sedimentation rate. Finally, the physiological inverse relationship between EPO and haemoglobin present in a control group of 42 non-diabetic non-anaemic subjects was completely lost in Type 2 diabetic patients. The slopes of the regression lines between EPO and haemoglobin of the control subjects and the Type 2 diabetic patients were significantly different (t = 14.4, P < 0.0001).
This study documents an early abnormality of EPO regulation in Type 2 diabetes before clinical nephropathy and points to a contributory role of AN in EPO dysregulation.
Pregabalin, an alpha2-delta ligand with analgesic, anxiolytic, and anticonvulsant activity, has been evaluated for treatment of neuropathic pain. The authors assessed the efficacy and tolerability of pregabalin (75, 300, 600 mg/day) vs placebo in patients with diabetic peripheral neuropathy (DPN).
Patients with a 1- to 5-year history of DPN and average weekly pain score of > or =4 on an 11-point numeric pain-rating scale were enrolled in a 5-week, double-blind, multicenter, placebo-controlled study. Patients (n = 338) were randomized to receive one of three doses of pregabalin or placebo TID. Pregabalin 600 mg/day was titrated over 6 days; lower doses were initiated on day 1.
Patients in the 300- and 600-mg/day pregabalin groups showed improvements in endpoint mean pain score (primary efficacy measure) vs placebo (p = 0.0001). Improvements were also seen in weekly pain score, sleep interference score, patient global impression of change, clinical global impression of change, SF-McGill Pain Questionnaire, and multiple domains of the SF-36 Health Survey. Improvements in pain and sleep were seen as early as week 1 and were sustained throughout the 5 weeks. Responders (patients with > or =50% reduction in pain compared to baseline) were 46% (300 mg/day), 48% (600 mg/day), and 18% (placebo). Pregabalin was well tolerated with a low discontinuation rate. The most common adverse events were dizziness and somnolence.
In patients with diabetic peripheral neuropathy, pregabalin demonstrated early and sustained improvement in pain and a beneficial effect on sleep, which were confirmed by positive patient global impression. Pregabalin was well tolerated at all doses.
Diabetic peripheral neuropathy (DPN) is a frequent and potentially traumatic complication in diabetic individuals. The chronic nature of diabetes and its associated hyperglycemic episodes initiate a complex and inter-related series of metabolic and vascular insults that contribute to the polygenic etiology of DPN. One contributing factor in DPN is an altered neurotrophism that results from changes in the synthesis and expression of neurotrophins, insulin-like growth factor, and various cytokine-like growth factors that can directly act upon distinct subpopulations of sensory and motor neurons. Although considerable effort has focused upon examining growth factor signaling in hyperglycemically stressed neurons, myelin-forming Schwann cells also undergo substantial degenerative changes in DPN. However, scant attention has been devoted to understanding the effect of hyperglycemia on the response of Schwann cells to growth factors critical to their function. Neuregulins are gliotrophic growth factors that signal through members of the Erb B receptor-tyrosine kinase family. The neuregulin/Erb B ligand-receptor cassette can differentially influence the response of Schwann cells throughout their development by regulating cell survival, mitogenesis, and differentiation. The activity of Erb B receptors may also be affected by their interaction with caveolin-1, a protein marker of caveolae ("little caves"). However, whether neuregulin signaling may be directly or indirectly altered under conditions of hyperglycemic stress and contribute to the physiological progression of DPN is unknown. This brief review will provide a perspective on a putative role of changes in the caveolar proteome of Schwann cells in contributing to an "altered neuregulinism" in DPN.
The aim of the study was to evaluate the efficacy of benfotiamine administered over three weeks (allithiamine; a lipid-soluble vitamin B1 prodrug with high bioavailability) to patients with diabetic polyneuropathy in a randomized, placebo-controlled, double-blind, two-center pilot study.
Forty inpatients (23 male, 18 female, age range 18 - 70 years) with a history of type 1 or 2 diabetes and polyneuropathy of not longer than two years, were included in the study. Twenty Patients received two 50 mg benfotiamine tablets four times daily and 20 patients received placebo over the three-week study period. Two clinical units were involved with 10 patients receiving placebo and 10 patients benfotiamine in each. The neuropathy score according to Katzenwadel et al. [1987] was used to evaluate symptoms of polyneuropathy, vibration perception threshold and both the physician's and the patient's own assessment were documented.
A statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). More patients in the benfotiamine-treated group than in the placebo group considered their clinical condition to have improved (p = 0.052). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in the HbA1 levels and blood sugar profiles. The body mass index of the two groups did not differ.
This pilot investigation (BEDIP Study) has confirmed the results of two earlier randomized controlled trials and has provided further evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy.