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The role of paracetamol in the pathogenesis of asthma
Abstract
Paracetamol use represents a putative risk factor for the development of asthma. There is convincing epidemiological evidence that the risk of asthma may be increased with exposure to paracetamol in the intrauterine environment, infancy, later childhood and adult life. A dose-dependent association has also been observed in these different age groups in different populations world-wide. An association has also been shown between paracetamol use in both rhinoconjunctivitis and eczema. There is biological plausibility with paracetamol use leading to decreased glutathione levels resulting in increased oxidant-induced inflammation and potentially enhanced T-helper type 2 responses. At the population level, patterns of paracetamol use might explain, to some extent, the world-wide variation in the prevalence of asthma and related disorders, particularly the high rates in English-speaking countries, which have high per capita prescription and over-the-counter use of paracetamol. A temporal association also exists between the international trends of increasing paracetamol use and increasing prevalence of asthma over recent decades. Further research is urgently required, in particular randomized-controlled trials (RCTs) into the long-term effects of frequent paracetamol use in childhood, to determine the magnitude and characteristics of any such risk. Importantly, RCTs will also enable evidence-based guidelines for the recommended use of paracetamol to be developed.
Cite this as: H. Farquhar, A. Stewart, E. Mitchell, J. Crane, S. Eyers, M. Weatherall and R. Beasley, Clinical & Experimental Allergy, 2010 (40) 32–41.
... Over the past 20 years, growing human epidemiological data have also raised concern regarding early life exposure to paracetamol and an increased risk of neurodevelopmental, atopic and reproductive adverse outcomes [7]. Paracetamol's analgesic and antipyretic effects are mediated through activation of descending serotonergic pathways, inhibition of prostaglandin synthesis and effects on cannabinoids receptors through its active metabolites [8][9][10]. The non-selective inhibition of peripheral cyclooxygenase and the interference with the cannabinoid receptors are among paracetamol's mechanisms of action that could explain how such causal association could be biologically plausible [11]. ...
... The same reviewers then assessed all full-text articles for eligibility. After identifying the studies to be included in the final review, the same reviewers extracted the data independently, using a prespecified standardized data extraction form [10]. We resolved any discrepancies in the study selection and data extraction processes through discussion with a third reviewer (S.S.Z). ...
... Paracetamol use is also associated with decreased glutathione levels, resulting in increased oxidant-induced inflammation and enhancement of T-helper type-2 pathways. This could be the biological basis for a link between paracetamol and atopic adverse outcomes [10]. The available evidence also points toward paracetamol causing a perturbance in the hormonal process, such as steroidogenesis and depletion of sulfated sex hormones [60], providing the biological plausibility for the potential alteration in the development of the fetal reproductive system that is associated with paracetamol exposure. ...
Introduction:
Paracetamol is the most commonly used antipyretic and analgesic in pregnancy. It is also increasingly used off-label in the neonatal intensive care unit. Despite the frequent use of paracetamol, concerns have been raised regarding the high variability in neonatal dosing regimens and the long-term safety of early life exposure.
Objective:
To investigate the available evidence on the long-term safety of prenatal and neonatal paracetamol exposure.
Methods:
We conducted a systematic search of the electronic databases Ovid Medline, Ovid Embase and Web of Science from inception to August 2021 for original research studies of any design that described the use of paracetamol in the prenatal or neonatal (within the first four weeks of life) periods and examined the occurrence of neurodevelopmental, atopic or reproductive adverse outcomes at or beyond birth.
Results:
We identified 1313 unique articles and included 30 studies in the final review. Of all studies, 27 (90%), two (7%) and one (3%) were on the long-term safety of prenatal, neonatal and both prenatal and neonatal exposure, respectively. Thirteen (46%), 11 (39%) and four (15%) studies examined neurodevelopmental, atopic and reproductive outcomes. Eleven (100%), 11 (100%), and three (27%) studies on prenatal exposure reported adverse neurodevelopmental, atopic and reproductive outcomes. Only one study found a possible correlation between neonatal paracetamol exposure and long-term adverse outcomes.
Conclusions:
The available evidence, although limited, suggests a possible association between prenatal paracetamol exposure and an increased risk of neurodevelopmental, atopic and reproductive adverse outcomes. There is an immediate need for robust data on the long-term safety of paracetamol exposure in the prenatal and neonatal periods.
... Acetaminophen can cross the placenta, exposing the fetus during critical periods of development [5,6]. Acetaminophen was suggested to deplete glutathione (GSH) [7], a key antioxidant in the airways, and enhance immune responses that can predispose prenatally acetaminophen-exposed children to asthmatic phenotypes. ...
... Experimental studies suggested that acetaminophen can cause increased oxidative stress by depleting the anti-oxidant GSH, enhancing Th2 cytokine production linked to asthma, and by mediating non-eosinophilic inflammatory responses [7,26,27]. Unlike other antipyretics and analgesics, acetaminophen is not considered contra-indicated for use during pregnancy. In adults, acetaminophen is metabolized via glucuronidation, sulphation, and via the cytochrome P450 system. ...
... Interestingly, prenatal stress can also affect the glutathione system, leading to a decrease in the glutathione/glutathione disulfide (GSSG) ratio and an increase in oxidative stress [30,31]. The latter mechanism is similar to the biological pathways that acetaminophen targets [7,[32][33][34]. Thus, these two exposures could potentially interact to induce oxidative stress and enhance immune responses predisposing the children to the development of asthma. ...
Acetaminophen is the most common over-the-counter pain and fever medication used by pregnant women. While European studies suggest acetaminophen exposure in pregnancy could affect childhood asthma development, findings are less consistent in other populations. We evaluated whether maternal prenatal acetaminophen use is associated with childhood asthmatic symptoms (asthma diagnosis, wheeze, dry cough) in a Los Angeles cohort of 1201 singleton births. We estimated risk ratio (RR) and 95% confidence interval (CI) for childhood asthmatic outcomes according to prenatal acetaminophen exposure. Effect modification by maternal race/ethnicity and psychosocial stress during pregnancy was evaluated. The risks for asthma diagnosis (RR = 1.39, 95% CI 0.96, 2.00), wheezing (RR = 1.25, 95% CI 1.01, 1.54) and dry cough (RR =1.35, 95% CI 1.06, 1.73) were higher in children born to mothers who ever used acetaminophen during pregnancy compared with non-users. Black/African American and Asian/Pacific Islander children showed a greater than two-fold risk for asthma diagnosis and wheezing associated with the exposure. High maternal psychosocial stress also modified the exposure-outcome relationships. Acetaminophen exposure during pregnancy was associated with childhood asthmatic symptoms among vulnerable subgroups in this cohort. A larger study that assessed prenatal acetaminophen exposure with other social/environmental stressors and clinically confirmed outcomes is needed.
... Paracetamol use may also be a risk factor for developing rhinitis, conjunctivitis, and eczema [9,11]. The suspected mechanisms behind the observed correlations involve oxidative stress in the airways with its effect on inflammation, as well as a strong Th2-mediated response [15,16] or airway epithelial damage as the effect of inhibiting cyclooxygenase-2, which plays a role in the repair of damaged airway epithelium [17,18]. ...
... ECAP study results presented here are also consistent with the results of many other epidemiological studies conducted in various age groups and in various countries worldwide [12,13,14,15,16,19,20,21]. ECAP study results can be also compared to the results of the studies conducted in countries involved in the ISAAC Phase One study and ECRHS, which demonstrated that in countries with the highest per capita use of paracetamol, the prevalence of bronchial asthma is also high, which to some extent may indicates the existence of a correlation [22]. ...
... One of the postulated mechanisms of asthma development involves oxidative stress in the airways, which affects bronchial inflammation and promotes bronchial hyper-responsiveness via injury of the respiratory epithelium [25]. Paracetamol is a potential source of oxidative stress, as its use results in a dose-dependent decrease in the levels of the endogenous pulmonary anti-oxidant glutathione (GSH) [16,26,27,28]. Moreover, the Th2-mediated immunological response may become enhanced. ...
Introduction. A growing number of epidemiological studies suggest that paracetamol, which is commonly used in children,
may be a risk factor for asthma, allergic rhinitis, and atopic eczema.
Objective. The aim of this study was to determine and characterize the correlation between paracetamol use and asthma,
allergic rhinitis, and atopic eczema symptoms in the Polish population.
Materials and method. The study is part of the ECAP project involving the use of the ISAAC and ECRHS questionnaires.
Completed questionnaires of 18,617 subjects, including 10,011 (53.8%) females, were analyzed. Children aged 6–7 (n=4,510),
adolescents aged 13–14 (n=4,721), and adults aged 20–44 (n=9,386) constituted 24.2%, 25.4%, and 50.4% of respondents,
respectively. Study subjects lived in 8 major urban centres and one rural area. The frequency of paracetamol use during
the previous 12 months and symptoms of asthma, allergic rhinitis, and atopic eczema during that period were analyzed.
Results. The use of paracetamol was associated with a significant dose-dependent increase in the risk of asthma symptoms in
all evaluated age groups. This was demonstrated via odds ratios (OR) for developing asthma symptoms, including wheezing
or whistling in the chest in 6–7-year-olds and exercise-induced shortness of breath in 13–14-year-olds and adults, depending
on the frequency of paracetamol use in the previous 12 months, compared to no paracetamol intake during that period.
Conclusions. The use of paracetamol in the last 12 months was associated with a significant dose-dependent increase in
the risk of rhinitis and skin allergy symptoms, as demonstrated by the odds ratio. Therefore, frequent paracetamol use may
be a risk factor for symptoms of asthma, rhinitis, and skin allergy in the Polish population.
... Also attracting recent interest but lacking longitudinal support is the hypothesis that acetaminophen use might in-crease the risk of asthma and allergic disease, and that the shift from aspirin to acetaminophen use may have contributed to the rise in these conditions over recent decades (7). The evidence to date implicating acetaminophen in the etiology of asthma and other allergic diseases has been remarkably consistent (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), with adverse effects reported in relation to acetaminophen exposure in utero (8)(9)(10)(11), during infancy (11,12), in childhood (13,14), and during adult life (15)(16)(17)(18). The relation also extends to objective markers of allergy (14)(15)(16). ...
... The acetaminophen and asthma hypothesis has attracted interest for more than a decade (19) and many studies, although primarily cross-sectional, have independently demonstrated an increased prevalence of asthma and other allergic conditions among acetaminophen users (8,9,(11)(12)(13)(14)(15)(16)(17)(18)(19). Our current findings fit with our previous research in children and adults in the same Butajira study area, which reported a similar level of acetaminophen use (42% vs. 39% in the current study), and a significant dose-dependent association with wheeze (15). ...
... The acetaminophen and asthma hypothesis has attracted interest for more than a decade (19) and many studies, although primarily cross-sectional, have independently demonstrated an increased prevalence of asthma and other allergic conditions among acetaminophen users (8,9,(11)(12)(13)(14)(15)(16)(17)(18)(19). Our current findings fit with our previous research in children and adults in the same Butajira study area, which reported a similar level of acetaminophen use (42% vs. 39% in the current study), and a significant dose-dependent association with wheeze (15). ...
RATIONALE Acetaminophen has been hypothesized to increase the risk of asthma and allergic disease, and geohelminth infection to reduce the risk, but evidence from longitudinal cohort studies is lacking.
OBJECTIVES To investigate the independent effects of these exposures on the incidence of wheeze and eczema in a birth cohort.
METHODS In 2005-2006 a population-based cohort of 1,065 pregnant women from Butajira, Ethiopia, was established, to whom 1,006 live singleton babies were born. At ages 1 and 3, questionnaire data were collected on wheeze, eczema, child's use of acetaminophen, and various potential confounders, along with a stool sample for geohelminth analysis. Those without wheeze (n = 756) or eczema (n = 780) at age 1 were analyzed to determine the independent effects of geohelminth infection and acetaminophen use in the first year of life on the incidence of wheeze and eczema by age 3.
MEASUREMENTS AND MAIN RESULTS Wheeze and eczema incidence between the ages of 1 and 3 were reported in 7.7% (58 of 756) and 7.3% (57 of 780) of children, respectively. Acetaminophen use was significantly associated with a dose-dependent increased risk of incident wheeze (adjusted odds ratio = 1.88 and 95% confidence interval 1.03-3.44 for one to three tablets and 7.25 and 2.02-25.95 for ≥ 4 tablets in the past month at age 1 vs. never), but not eczema. Geohelminth infection was insufficiently prevalent (<4%) to compute estimates of effect.
CONCLUSIONS These findings suggest frequent acetaminophen use early in life increases the risk of new-onset wheeze, whereas the role of geohelminth infection on allergic disease incidence remains to be seen as the cohort matures.
... Epidemiologic studies have reported that APAP potentially may cause asthma in adult, children, and prenatal population. [47][48][49][50][51][52][53][54] An epidemiological study reported that increasing use of APAP, which has replaced aspirin as the analgesic/antipyretic choice for children, was consistent with an increase in the prevalence of asthma in U.S. children. 47) Farquhar et al. 52) suggested that patterns of APAP use, such as tendency of high per capita prescription and OTC use, might explain the increased prevalence of asthma and related disorders. ...
... [47][48][49][50][51][52][53][54] An epidemiological study reported that increasing use of APAP, which has replaced aspirin as the analgesic/antipyretic choice for children, was consistent with an increase in the prevalence of asthma in U.S. children. 47) Farquhar et al. 52) suggested that patterns of APAP use, such as tendency of high per capita prescription and OTC use, might explain the increased prevalence of asthma and related disorders. Etminan et al. 53) in a meta-analysis found a possibility of increased risk of asthma and wheezing in children and adults exposed to APAP. ...
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is the most popular analgesic/antipyretic agent in the world. APAP has been regarded as a safer drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in terms of lower risks of renal dysfunction, gastrointestinal injury, and asthma/bronchospasm induction, even in high-risk patients such as the elderly, children, and pregnant women. On the other hand, the recent increasing use of APAP has raised concerns about its toxicity. In this article, we review recent pharmacological and toxicological findings about APAP from basic, clinical, and epidemiological studies, including spontaneous drug adverse events reporting system, especially focusing on drug-induced asthma and pre-and post-natal closure of ductus arteriosus. Hepatotoxicity is the greatest fault of APAP and the most frequent cause of drug-induced acute liver failure in Western countries. However, its precise mechanism remains unclear and no effective cure beyond N-acetylcysteine has been developed. Recent animal and cellular studies have demonstrated that some cellular events, such as c-jun N-terminal kinase (JNK) pathway activation, endoplasmic reticulum (ER) stress, and mitochondrial oxidative stress may play important roles in the development of hepatitis. Herein, the molecular mechanisms of APAP hepatotoxicity are summarized. We also discuss the not-so-familiar “dark side” of APAP as an otherwise safe analgesic/antipyretic drug.
Graphical Abstract Fullsize Image
... In diabetic women who is thinking to pregnant, an optimal metabolic control must been established, and the danger of paracetamol use must be informed [55][56][57][58][59][60]. Maternal hyperglycemia influence the development of the fetal heart, affecting both its structure and its function, and Paracetamol may be aggravated. ...
... Maternal hyperglycemia influence the development of the fetal heart, affecting both its structure and its function, and Paracetamol may be aggravated. Acetaminophen (Paracetamol) is one of the most common causes of poisoning worldwide, in particular in the patients with low amount of the hepatic glutathione, that is, insulin resistant and diabetic patients [60][61][62][63][64][65][66]. ...
Hyperglycemia can influence the development of the fetal heart, affecting both its structure and its function. Prospective and retrospective cohort studies have demonstrated an increased risk of congenital abnormalities with gestational diabetes. This observation is probably related to the inclusion of women with unrecognized type 2 diabetes [1, 2]. Substantial literature indicates that diabetes in pregnant rats and mice induces embryo lethality, growth retardation and a variable incidence of birth defects. Then, the maintenance of normal concentrations of metabolites from all nutrient classes may be important for prevention of adverse fetal outcome in diabetic pregnancy. Acetaminophen overdose is the most often cause of acute liver injury and obese women are in particular risk, because is able to induce mitochondrial oxidative stress [3]. Acetaminophen (Paracetamol) over doses decreased embryonic low-molecular-weight thiols (glutathione and cysteine), compounds that play a vital role in the detoxication of exogenous and endogenous chemicals [3-5]. The apparent safety of Paracetamol drug, a useful analgesic only (with no anti-inflammatory properties) is compromised by its widespread and extensive chronic use, particularly in Peruvian population, where its analgesic is doing without control [6-9]. In fact, paracetamol though considered safe at a considerable low dose, especially in women could cause kidney derangement and cardiac malformations during pregnant state if the drug is ingested in the first trimester [8]. Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers [10]. Thus, there is overcome potential maternal acetaminophen (paracetamol) toxicity [11].
... Depending on the dose, paracetamol decreases glutathione levels as such that it weakens the capacity of the body against the effects of oxidative stress [28]. This can lead to tissue damage, smooth muscle contraction, bronchial hyperreactivity, increase in vascular patency, release of inflammatory mediators, and interfere with the activity of beta-receptors [29]. ...
... Furthermore, glutathione exhaustion may lead to an exchange of T helper 1 (Th1) for Th2 that favours the appearance of allergic diseases [31]. Another possible mechanism could be the decrease in the release of Th1 cytokines that are normally produced during febrile episodes, which would then lead to a predominance of Th2 cytokines [29]. Baudouin et al. established that high doses of paracetamol are cytotoxic for pneumocytes, and can cause acute lung damage [32]. ...
Objective: To analyse the relationship between paracetamol and asthma.
Data sources: An English literature search using electronic search engines (PubMed and EMBASE) was conducted.
Study selections: Articles published in peer-review journals, from 1990 to December 2015 were included. In order to perform the search for the most suitable and representative articles, key words were selected (“asthma”, “paracetamol” and “acetaminophen”). The evidence level was rated according to the criteria of the Oxford Centre For Evidence-Based Medicine.
Results: The exposure to paracetamol during pregnancy was analysed in several cohort studies, showing an association between the prenatal exposure to paracetamol with suffering from asthma or presence of wheezing in childhood, especially for persistent wheezing. Nevertheless, a recent study concluded that the relationship between asthma and paracetamol is explained, at least in part, by confounding factors.
Several works have also associated the exposure to paracetamol in the first years of life or in adults with the development of childhood asthma.
Several pathophysiological mechanisms are known that could explain this relationship, such as the glutathione pathway, the decrease in the release of Th1 cytokines that are normally produced during febrile episodes, which would then lead to a predominance of Th2 cytokines, the cytotoxic effect of paracetamol for pneumocytes, a modulator effect on the activity of myeloperoxidase, as well as the possible antigenic effect of paracetamol, mediated by IgE.
Conclusions: There are many arguments that suggest a relationship between the use of paracetamol with the appearance of asthmatic symptoms, however the evidence is inconclusive.
... The temporal dynamics of the case also show that cumulative learning around the causal association between paracetamol and asthma emerges and grows through evidence of different types, which demand to be accounted for to provide guidance for action even before a definitive proof is available. The standard clinching way to assess causality Table 1 The consistency of interdisciplinary evidence makes the causal association between asthma and acetaminophen plausible enough to change prescription practice (in paediatrics): McBride (2011) 1. Strength of the association [57][58][59] 2. Robustness of association across geography, culture and age [51,[53][54][55][60][61][62][63] 3. Dose-response relationship between acetaminophen exposure and asthma [58,59] 4. Coincidence of time trends in acetaminophen use and asthma increase [64] 5. Lack of other equally strong causal explanations [65][66][67] 6. Relationship between asthma epidemic and per-capita sales of acetaminophen across countries [68] 7. Plausible mechanism [47,63,[69][70][71][72] 7 Contrary to commonsense intuition, ''safety signal'' does not refer to indicators of safety, but rather the contrary, i.e. signals suggesting possible risks associated with the drug. ...
... The temporal dynamics of the case also show that cumulative learning around the causal association between paracetamol and asthma emerges and grows through evidence of different types, which demand to be accounted for to provide guidance for action even before a definitive proof is available. The standard clinching way to assess causality Table 1 The consistency of interdisciplinary evidence makes the causal association between asthma and acetaminophen plausible enough to change prescription practice (in paediatrics): McBride (2011) 1. Strength of the association [57][58][59] 2. Robustness of association across geography, culture and age [51,[53][54][55][60][61][62][63] 3. Dose-response relationship between acetaminophen exposure and asthma [58,59] 4. Coincidence of time trends in acetaminophen use and asthma increase [64] 5. Lack of other equally strong causal explanations [65][66][67] 6. Relationship between asthma epidemic and per-capita sales of acetaminophen across countries [68] 7. Plausible mechanism [47,63,[69][70][71][72] 7 Contrary to commonsense intuition, ''safety signal'' does not refer to indicators of safety, but rather the contrary, i.e. signals suggesting possible risks associated with the drug. ...
It is increasingly acknowledged both among epidemiologists and regulators that the assessment of pharmaceutical harm requires specific methodological approaches that cannot simply duplicate those developed for testing efficacy. However, this intuition lacks sound epistemic bases and delivers ad hoc advice. This paper explains why the same methods of scientific inference do not fare equally well for efficacy and safety assessment by tracing them back to their epistemic foundations. To illustrate this, Cartwright’s distinction into clinching and vouching methods is adopted and a series of reasons is provided for preferring the latter to the former: (1) the need to take into account all available knowledge and integrate it with incoming data; (2) the awareness that a latent unknown risk may always change the safety profile of a given drug (precautionary principle); (3) cumulative learning over time; (4) requirement of probabilistic causal assessment to allow decision under uncertainty; (5) impartiality; and (6) limited and local information provided by randomised controlled trials. Subsequently, the clinchers/vouchers distinction is applied to a case study concerning the debated causal association between paracetamol and asthma. This study illustrates the tension between implicit epistemologies adopted in evaluating evidence and causality; furthermore, it also shows that discounting causal evidence may be a result of unacknowledged low priors or lack of valid alternative options. We conclude with a presentation of the changing landscape in pharmacology and the trend towards an increased use of Bayesian tools for assessment of harms.
... Esa asociación que parecía clara en la mayoría de los estudios realizados se debate ahora, ya que se piensa que hay factores como asma materna o infecciones respiratorias en la madre que actúan como factores de confusión y no se han tenido en cuenta apropiadamente (129)(130)(131). Aunque los mecanismos etiopatogénicos están siendo estudiados y reconocen posible causalidad, por ejemplo por acción de la reducción del glutatión en mecanismos oxidativos en el parénquima pulmonar y respuesta aumentada de los linfocitos Th2, más estudios son necesarios para clarificar esta asociación (132). Tampoco durante la infancia está del todo claro si el uso de paracetamol está asociado con el asma con estudios apuntando en esa dirección, pero sin respuesta concluyente. ...
Estudio Global Asthma Network en niños de 6-7 años de la provincia de Salamanca Salamanca, en el que se evalua la prevalencia de asma en 2388 niños, y los posibles factores de riesgo/proteccion, presentacion clínica, tratamientos...
Global Asthma Network study in Salamanca of 6-7 years old children from Salamanca province in Spain, with 2388 questionnaires collected where asthma prevalence, symptoms, treatments, and possible risk/protection factors are evaluated.
... Uma das duas vias secundárias é o citocromo P-450 (CYP P-450) mediado, formando um metabolito altamente reativo, n-acetil-p-benzoquinoneimina (NAPQI) que reage com a glutationa celular (GSH) para formar um conjugado não tóxico, que é posteriormente excretado. Uma vez que a GSH está esgotada, o NAPQI liga-se a proteínas celulares, incluindo proteínas mitocondriais, reduzindo a capacidade de desintoxicar, que pode levar ao estresse oxidativo, ativação do sistema imune, morte hepatocelular, nefropatia e asma (Jetten et al., 2012;Farquhar, et al., 2010). Os achados mostram a importância do papel de muitas das mesmas citocinas mediando os efeitos da ativação imune materna no neurodesenvolvimento de descendentes autistas (Deverman & Patterson, 2009;Abdallah et al., 2011). ...
Este estudo visa identificar os possíveis fatores de risco gestacional para o desenvolvimento do Transtorno do Espectro do Autismo (TEA). O estudo é do tipo quantitativo, descritivo, documental, com análise exploratória dos dados. Para sua realização foram utilizados dados secundários de 32 prontuários de crianças com diagnóstico de Autismo clássico. Em relação a idade dos genitores no momento da concepção, o maior percentual de mães encontrava-se entre 20 a 30 anos (56,25%) e de pais entre 32 a 45 anos (59,38%). As Infecções do Trato Urinário (ITU) foram as infecções mais comuns durante a gestação (43,80%). Em relação as demais intercorrências clínicas pré-natais, prevaleceram diferentes tipos (40,63%), seguidas por distúrbios metabólicos (25,00%). Para as intercorrências peri e pós-natais, a maioria foi definida como diferentes tipos (43,75%), seguidas de prematuridade (28,13%). No que diz respeito aos medicamentos utilizados na gravidez, a maioria das mães usou diferentes tipos de medicamentos (56,25%), seguidos de antibióticos (50,00%). Desse modo, procurar conhecer os prováveis fatores ambientais envolvidos na etiologia do TEA, possibilita que o profissional de saúde identifique as gestantes mais suscetíveis e busque estratégias oportunas de intervenção na assistência pré-natal.
... 48 As a result, reactive oxygen species in response to allergic, viral, or other non-allergic stimuli, may lead to enhanced inflammation and the development or worsening of pre-existing asthma, rhinoconjunctivitis, or eczema, depending on the organ system affected. [49][50][51] In addition, long-term use of broad-spectrum antibiotics has been shown to cause dysbiosis of the intestinal tract, which negatively impacts extraintestinal organs such as the lungs, the brain, and the skin, leading to chronic AD progression and asthma. 52,53 However, it is important to take into account the potential confounding effects of familial and genetic factors in this association. ...
Background:
In children, atopic dermatitis or eczema is the most common inflammatory disease of the skin. According to the International Study of Asthma and Allergies in Childhood (ISAAC) Phase IIIB in Mexico, 5.8% of children and 4.9% of adolescents had eczema symptoms. In 2012, Global Asthma Network (GAN) was established to update the prevalence of eczema and estimate potential factors contributing to its development.
Objective:
To estimate the prevalence and associated factors for atopic eczema symptoms and diagnosis in children and adolescents according to GAN Phase I and compare the results with ISAAC Phase IIIB in Mexico.
Methods:
A cross-sectional, multicenter survey was conducted in 15 Mexican centers during the period of 2015-2017 using the GAN Phase I questionnaires in children (6-7-year-olds) and adolescents (13-14-year-olds). The prevalences obtained from the GAN Phase I study, were compared with ISAAC Phase IIIB results; a Spearman's correlation analysis was conducted between temperature, relative humidity, and altitude and eczema symptoms, and a logistic regression was performed to predict current eczema symptoms by age group.
Results:
A total of 35 777 children and 41 399 adolescents were included. Since ISAAC Phase IIIB, the prevalence of itchy rash in the past 12 months significantly increased in the children's group [6.6% (95% CI 5.7-7.4) vs 7.8 (95% CI 7.5-8.1), p = 0.000] and adolescents' group [5.8% (95% CI 5.0-6.7) vs 6.7% (95% CI 6.5-7.0), p = 0.000].In the adolescents' group, the prevalence of nocturnal awakenings caused by rash symptoms on more than one night per week had a negative correlation between altitude (Spearman's Rho = -0.558, p value = 0.031), and a positive correlation with the average annual temperature (Spearman's Rho = 0.604, p value = 0.017) and annual relative humidity (Spearman's Rho = 0.742, p value = 0.002). The most significant associations in children were the presence of sneezing or runny or blocked nose in the past 12 months [(OR 3.13, 95% CI 2.60-3.77), p = 0.000], the use of paracetamol in the first year of life ([OR 1.52, 95% CI 1.15-2.01), p = 0.003] and the use of antibiotics in the first year of life [(OR 1.30, 95% CI 1.08-1.55) p = 0.004]. Moreover, altitude at 100-1000 m above sea level was associated with current eczema symptoms in adolescents (p = 0.001).
Conclusions:
There has been a significant increase in eczema symptoms in both age groups since ISAAC Phase IIIB study. Additionally, eczema symptoms were associated with temperature, relative humidity, asthma, hay fever symptoms, the use of paracetamol and antibiotics.
... Recent epidemiological studies reported that PAR might be a putative risk factor for asthma, based on the evidence that asthma risk may increase due to PAR exposure in intrauterine environment, infancy, late childhood, and adult life (Rebordosa et al., 2009). Besides, a review of case-control studies showed that prenatal PAR exposure might increase asthma incidence in the fetus (Fan et al., 2017;Farquhar et al., 2010). Rebordosa et al. (2008) reported that prenatal exposure to PAR, especially in the first trimester, increased the risk of asthma and wheezing in unborn babies. ...
The toxicological effects of paracetamol on lung
... Glucuronidation, the main pathway for acetaminophen metabolism in adults, is not active in the fetus until around the 18th gestational week [71]. Acetaminophen is instead metabolized in early fetal stages through sulfation or the cytochrome P450 system pathways, where the latter would generate toxic metabolite (Nacetyl-p-benzoquinone imine (NAPQI)) that can induce oxidative stress and inflammatory responses [11, [72][73][74]. These mechanisms are implicated in the etiology of childhood asthma and autism [13]. ...
Purpose of Review
Acetaminophen (or paracetamol) is one of the most commonly used medications during pregnancy. We reviewed recent epidemiological evidence regarding intrauterine exposure to acetaminophen and risk for asthma, neurodevelopment disorders, and reproductive health in childhood.
Recent Findings
An increasing number of cohort studies have suggested that maternal use of acetaminophen during pregnancy was associated with increased risk for asthma; neurodevelopmental disorders, especially ADHD and behavioral problems; and genital malformations in the offspring. Oxidative stress and inflammation or endocrine effects are plausible shared biological mechanisms for the exposure to influence multiple developmental outcomes. We discussed methodological challenges that can threaten the validity of these observational data, including confounding and measurement errors. Novel statistical methods and research designs that can be used to mitigate these issues were introduced.
Summary
Given the high prevalence of use, findings regarding intrauterine exposure to acetaminophen on multiple child health outcomes raise concerns. Research on causal and non-causal mechanisms that might explain these associations should be a priority.
... 12 Fever reduction associated with paracetamol may also reduce the cytokine production that is part of the febrile response, reducing interferon gamma and interleukin-2, which are key agents that usually induce type 1 T helper cell profiles. 13 However, association and a plausible biological mechanism does not mean that paracetamol exposure in infancy causes later asthma and related allergic disorders. In particular there could be confounding of this association because this agent is used for respiratory tract infections, which themselves may be causal. ...
Introduction
Asthma is one of the most common diseases in the world and is a global public health burden. There is an urgent need for research that leads to evidenced-based primary prevention strategies to reduce the prevalence of asthma. One novel risk factor that might have a role in the pathogenesis of asthma is the use of paracetamol in early life. This trial aims to determine if paracetamol, compared with ibuprofen use, as required for fever and pain in the first year of life, increases the risk of asthma at age 6 years.
Methods and analysis
The Paracetamol and Ibuprofen in Primary Prevention of Asthma in Tamariki trial is a multicentre, open-label, two-arm parallel randomised controlled trial. 3922 infants born at ≥32 weeks’ gestation will be randomly allocated to receive only paracetamol or only ibuprofen for treatment of fever and pain, if required in the first year of life. The primary outcome is asthma at 6 years of age, defined as the presence of wheeze in the preceding 12 months. Secondary outcomes include hospital admissions for bronchiolitis, wheeze or asthma in the first year of life, and within the first 6 years of life; wheeze at 3 years of age; eczema within the first year and at 3 and 6 years of age; atopy at 3 and 6 years of age.
Ethics and dissemination
The trial has been approved by the Northern A Health and Disability Ethics Committee of New Zealand (17/NTA/233). Dissemination plans include publication in international peer-reviewed journals, and presentation at national and international scientific meetings, assimilation into national and international guidelines, and presentation of findings to lay audiences through established media links.
Trial registration number
ACTRN12618000303246; Pre-results.
... We specified the causal variables and their conditional (in-)dependencies in Theoretical Entities. The report variables for statistical and difference-making evidence and their conditional (in-)dependencies are described in 23 An older reference which also gives an assessment of © along the Bradford Hill Criteria is (Farquhar et al., 2009, Page 39). Sub-mechanisms nodes (μ i,k ) without children are to be read as hypothesised sub-mechanisms for which no evidence is available. ...
Background: Evidence suggesting adverse drug reactions often emerges unsystematically and unpredictably in form of anecdotal reports, case series and survey data. Safety trials and observational studies also provide crucial information regarding the (un-)safety of drugs. Hence, integrating multiple types of pharmacovigilance evidence is key to minimising the risks of harm.
Methods: In previous work, we began the development of a Bayesian framework for aggregating multiple types of evidence to assess the probability of a putative causal link between drugs and side effects. This framework arose out of a philosophical analysis of the Bradford Hill Guidelines. In this article, we expand the Bayesian framework and add “evidential modulators,” which bear on the assessment of the reliability of incoming study results. The overall framework for evidence synthesis, “E-Synthesis”, is then applied to a case study.
Results: Theoretically and computationally, E-Synthesis exploits coherence of partly or fully independent evidence converging towards the hypothesis of interest (or of conflicting evidence with respect to it), in order to update its posterior probability. With respect to other frameworks for evidence synthesis, our Bayesian model has the unique feature of grounding its inferential machinery on a consolidated theory of hypothesis confirmation (Bayesian epistemology), and in allowing any data from heterogeneous sources (cell-data, clinical trials, epidemiological studies), and methods (e.g., frequentist hypothesis testing, Bayesian adaptive trials, etc.) to be quantitatively integrated into the same inferential framework.
Conclusions: E-Synthesis is highly flexible concerning the allowed input, while at the same time relying on a consistent computational system, that is philosophically and statistically grounded. Furthermore, by introducing evidential modulators, and thereby breaking up the different dimensions of evidence (strength, relevance, reliability), E-Synthesis allows them to be explicitly tracked in updating causal hypotheses.
... Conversely, such a mechanism suppresses the Th-1 related cytokine release that plays a role for the onset of allergic diseases. Due to increased Th2 response, paracetamol could be involved for the increased prevalence of allergic diseases [20,22] . Our results suggest that maternal paracetamol exposure during pregnancy may play a role in development of SAC. ...
Aim:
To analyze the possible risk factors in the development of seasonal allergic conjunctivitis (SAC) through an evaluation of skin allergy tests and data obtained from questionnaires.
Methods:
The study included a total of 75 SAC patients and 71 control subjects without SAC diagnosis who were admitted to the Abant Izzet Baysal University Medical Faculty Ophthalmology Clinic between March 2016 and December 2016. Skin prick tests were performed for all participants. Serum levels of total IgE and 25-OH vitamin D were also measured. In the tear, total IgE levels were measured. Moreover, possible risk factors for the onset of SAC (smoking, paracetamol exposure, vitamin D supplementation and environmental factors etc.) were examined for all patients by both prenatal and postnatal aspects.
Results:
The patients with SAC were found to have a history of maternal paracetamol exposure during the prenatal period. Likewise, in the same patient group, the duration of postnatal vitamin D supplementation was shorter (P<0.001). However, no significant correlation was found between SAC and maternal antibiotic exposure, maternal smoking, the mode of delivery and birth weight, as well as presence of pets. Moreover, patients with SAC were more likely to have asthma, allergic rhinitis and oral allergy syndrome. We have also found that SAC patients' mothers and siblings were more likely to have allergic conjunctivitis. Likewise, their fathers were more likely to have allergic rhinitis.
Conclusion:
Prenatal maternal paracetamol exposure and shorter duration of vitamin D supplementation in the postnatal period may play a role in development of SAC. Therefore prevention of unnecessary gestational paracetamol intake and vitamin D supplementation during infancy could potentially reduce the onset and development of SAC.
... Furthermore, people with compromised kidney function can develop NSAID toxicity even at normal NSAID dosages (Whelton and Hamilton 1991). Additionally, APAP use represents a putative risk factor for the development of asthma because there is convincing epidemiological evidence that the risk of asthma may be increased with exposure to APAP in the intrauterine environment, infancy, later childhood, and adult life (Farquhar et al. 2010). ...
Paracetamol (APAP) is one of the most widely used and popular over-the-counter analgesic and antipyretic drugs in the world when used at therapeutic doses. APAP overdose can cause severe liver injury, liver necrosis and kidney damage in human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with APAP, and various antioxidants were evaluated to investigate their protective roles against APAP-induced liver and kidney toxicities. To date, almost no review has addressed the APAP toxicity in relation to oxidative stress. This review updates the research conducted over the past decades into the production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and oxidative stress as a result of APAP treatments, and ultimately their correlation with the toxicity and metabolism of APAP. The metabolism of APAP involves various CYP450 enzymes, through which oxidative stress might occur, and such metabolic factors are reviewed within. The therapeutics of a variety of compounds against APAP-induced organ damage based on their anti-oxidative effects is also discussed, in order to further understand the role of oxidative stress in APAP-induced toxicity. This review will throw new light on the critical roles of oxidative stress in APAP-induced toxicity, as well as on the contradictions and blindspots that still exist in the understanding of APAP toxicity, the cellular effects in terms of organ injury and cell signaling pathways, and finally strategies to help remedy such against oxidative damage.
... Paracetamol use has also been implicated in asthma development and the increasing incidence of asthma in adults and children in epidemiological, observational and pathophysiological studies (reviewed in McBride 2011; Farquhar et al. 2010;Eneli et al. 2005;Beasley et al. 2008Beasley et al. , 2011. and more recently in a prospective birth cohort study (Kreiner-Moller et al. 2012). ...
The antipyretic analgesics, paracetamol, and non-steroidal anti-inflammatory agents NSAIDs are one of the most widely used classes of medications in children. The aim of this review is to determine if there are any clinically relevant differences in safety between ibuprofen and paracetamol that may recommend one agent over the other in the management of fever and discomfort in children older than 3 months of age.
... [21][22][23] Since that date, paracetamol consumption throughout the world has increased dramatically. 24 Paracetamol sales in the United States (US) have had a continual upward trend. ...
Autism Spectrum Disorder (ASD) represents a major public health concern as a prevalent neurodevelopmental disorder with pronounced risk for failure of adaptation across social, educational, and psychological outcomes. The exact etiology of autism is unclear. However there is a lot of research work giving some insights about the possible predisposing factors that enhance chance of autism. Several lines of evidence suggest that prenatal and/or early life acetaminophen exposure may adversely affect neurodevelopment increasing incidence of autism. Since 1980 acetaminophen greatly has replaced aspirin as an analgesic and anti-pyretic following reports indicating that aspirin use was associated with Reye‟s syndrome. Notably acetaminophen use has been associated with at least a 10-fold rise of autism epidemic since the early 1980s.Several mechanisms have been suggested to implicate the role of acetaminophen in pathogenesis of autism as altered immune function and impaired hepatic detoxification capacity resulting in
accumulation of potentially neurotoxic metabolites. In early life, maturational compromises to the glucuronidation pathway in combination with the compromises to the sulfation pathway that typify autistic children, may lead to utilization of the suboptimal secondary metabolic routes with the potential for adverse neurological effects in susceptible individuals. Acetaminophen use during pregnancy has also been associated with altered metabolism increasing autism rates in born infants. The use of acetaminophen may also trigger autism by activating the endocannabinoid system thereby interfering with normal development. Accumulating evidence linking significantly increased rates of autism with prenatal and early life acetaminophen exposure strongly suggests its cautious use during these critical times.
... An additional immunologic pathway has been hypothesized by Nassini et al. (2010), namely the production of neurogenic airway inflammation caused by the transient receptor potential ankyrin-1 (TRPA1). Farquhar et al. (2010) have proposed another possible acetaminophen-asthma mediating mechanism based on its antipyretic effect. ...
In their comparative analysis of Randomised Clinical Trials and observational studies, Papanikoloau et al. (2006) assert that “it may be unfair to invoke bias and confounding to discredit observational studies as a source of evidence on harms”. There are two kinds of answers to the question why this is so. One is based on metaphysical assumptions, such as the problem of causal sufficiency, modularity and other statistical assumptions. The other is epistemological and relates to foundational issues and how they determine the constraints we put on evidence. I will address here the latter dimension and present recent proposals to amend evidence hierarchies for the purpose of safety assessment of pharmaceuticals; I then relate these suggestions to a case study: the recent debate on the causal association between paracetamol and asthma. The upshot of this analysis is that different epistemologies impose different constraints on the methods we adopt to collect and evaluate evidence; thus they grant “lower level” evidence on distinct grounds and at different conditions. Appreciating this state of affairs illuminates the debate on the epistemic asymmetry concerning benefits and harms and sets the basis for a foundational, as opposed to heuristic, justification of safety assessment based on heterogeneous evidence.
... Antibiotic [17][18][19][20][21][22][23][24] and analgesic/antipyretic [38][39][40][41] use in early childhood are putative risk factors for allergic and autoimmune diseases. In well-controlled paediatric epidemiological studies, an anthroposophic life-style (including low use of antibiotics and antipyretics and a diet containing fermented vegetables) was associated with a reduced risk for atopic disease [94,95] and with differences in intestinal bacterial flora [96]. ...
Children with acute respiratory or ear infections (RTI/OM) are often unnecessarily prescribed antibiotics. Antibiotic resistance is a major public health problem and antibiotic prescription for RTI/OM should be reduced. Anthroposophic treatment of RTI/OM includes anthroposophic medications, nonmedication therapy and if necessary also antibiotics. This secondary analysis from an observational study comprised 529 children <18 years from Europe (AT, DE, NL, and UK) or USA, whose caregivers had chosen to consult physicians offering anthroposophic (A-) or conventional (C-) treatment for RTI/OM. During the 28-day follow-up antibiotics were prescribed to 5.5% of A-patients and 25.6% of C-patients (
P
<
0.001
); unadjusted odds ratio for nonprescription in A- versus C-patients 6.58 (95%-CI 3.45–12.56); after adjustment for demographics and morbidity 6.33 (3.17–12.64). Antibiotic prescription rates in recent observational studies with similar patients in similar settings, ranged from 31.0% to 84.1%. Compared to C-patients, A-patients also had much lower use of analgesics, somewhat quicker symptom resolution, and higher caregiver satisfaction. Adverse drug reactions were infrequent (2.3% in both groups) and not serious. Limitation was that results apply to children of caregivers who consult A-physicians. One cannot infer to what extent antibiotics might be avoided in children who usually receive C-treatment, if they were offered A-treatment.
... Whilst genetics are likely to play some part in explaining these differences [4], most of the differences are thought to be due to environmental exposures [5]. One hypothesis which has gained much recent support from epidemiological studies in both developed and developing countries, is that paracetamol (acetaminophen) intake increases the risk of asthma and allergic diseases [6][7][8][9][10][11][12][13]. with meta-analyses of the available observational studies estimating a 63% increased risk of asthma in relation to personal paracetamol use [6], and a 21-28% increased risk of wheezing in relation to in utero exposure [6,7]. ...
... Un polimorfismo funcional genético en el gen de la glutatión S transferasa P1 es más común en hispanos y afroamericanos, y se asocia a una mayor susceptibilidad de desarrollar asma, y a la aparición de la misma con el uso del acetaminofén. 61,62 Este analgésico se utiliza con frecuencia en los episodios de dolor en los pacientes con drepanocitosis a lo largo de su vida, incluso desde edades tempranas. Sería importante investigar si su empleo se relaciona con el aumento de la prevalencia del asma o la hiperreactividad bronquial en estos pacientes. ...
The diagnosis of asthma in children and adults with sickle cell disease has been associated with increased painful crises and acute chest syndrome, as well as an increased risk of death and a lower life expectancy. The mechanism by which asthma affects patients with sickle cell disease is not well defined and its prevalence in this condition is highly variable. Both are inflammatory diseases and their mediators and alterations in the nitric oxide pathway contribute to its pathophysiology. Hypovitaminosis D occurs in sickle cell disease and is related to the severity of asthma with a diminished response to steroids and may contribute to the high morbidity in these patients. The airway hyperresponsiveness and the abnormalities of lung function tests are common in sickle cell disease. The pulmonary obstructive pattern is associated to an increased risk of death and hospitalizations for acute chest syndrome and painful vaso-occlusive crises. On the other hand, acetaminophen is associated to an increased risk of asthma and is frequently used in painful episodes in sickle cell disease; therefore, it should be investigated whether there is any relationship between its use in sickle cell disease and asthma prevalence. An adequate diagnosis and treatment of asthma can reduce its impact on sickle cell disease.
... A recent worldwide study showed that exposure to acetaminophen in the intrauterine environment, infancy, childhood, and adult life as significantly increasing the risk of asthma that being so acetaminophen usage is one of the most convincing candidates for influencing asthma development in children (4)(5)(6)(7). ...
The risk of asthma has been increasing in parallel with use of acetaminophen, which is a potential source of oxidative stress. Toll-like receptor 4 (TLR4) plays a critical role not only in innate immunity, but also in mediating reactive oxygen species induced inflammation. Therefore, we investigated associations between acetaminophen usage and TLR4 polymorphism on asthma and bronchial hyperresponsiveness (BHR). The number of 2,428 elementary school children in Seoul and Jeongeup cities was recruited. Subjects who used acetaminophen with a family history of asthma had an increased risk of both asthma diagnosis ever and current asthma. Individuals with CT+TT genotypes at the TLR4 polymorphism, in combination with acetaminophen usage, also demonstrated an increased risk of asthma diagnosis ever (aOR, 2.08; 95% confidence interval [CI], 1.10-3.92). Family history of asthma and acetaminophen usage were risk factors for BHR. Although TLR4 was not an independent risk factor for BHR, individuals with CT+TT genotypes at the TLR4 polymorphism had an increased risk of BHR when combined with acetaminophen usage (aOR, 1.74; 95% CI, 1.03-2.94). In conclusion, acetaminophen usage may be associated with asthma and BHR in genetically susceptible subjects. This effect may be modified by polymorphism at TLR4.
Graphical Abstract
Il paracetamolo è uno dei farmaci analgesici e antipiretici più popolari e più comunemente usati in tutto il mondo. È commercializzato senza richiesta di prescrizione medica, sia come unica molecola, sia in associazione con altre molecole nella stessa specialità commerciale. È il farmaco di scelta nei malati che non possono essere trattati con farmaci antinfiammatori non steroidei (FANS), come le persone con asma bronchiale, ulcera peptica, emofilia, persone sensibili ai salicilati, bambini sotto i 7 anni di età, donne in gravidanza o che allattano. Il paracetamolo è anche consigliato come trattamento di prima linea per molte condizioni dolorose. Il suo meccanismo d'azione è complesso e include gli effetti dei processi di analgesia sia periferica (inibizione della cicloossigenasi: COX), sia centrale (con la mediazione di varie azioni). Il paracetamolo è un farmaco abbastanza ben tollerato (a basse dosi) e produce pochi effetti indesiderati (a livello del tratto gastrointestinale), tuttavia, nonostante ciò, in tutto il mondo ogni anno viene registrato un numero costantemente crescente di casi di intossicazione epatica. Questo lavoro vuole ricordare che il paracetamolo non è una panacea priva di reazioni avverse. Anzi, soprattutto quando viene assunto regolarmente e in dosi elevate (> 4 g/giorno nell'adulto), esiste il rischio di gravi effetti indesiderati che in alcuni casi possono anche portare a morte o aggravare danni epatici preesistenti o condizioni di stress ossidativo che a loro volta possono aprire la porta a innumerevoli patologie.
Hepatic fat and abdominal adiposity in early pregnancy promotes impaired glucose homeostasis in mid-pregnancy (De Souza, 2016) and paracetamol overuse predisposes to liver fat. Hyperglycemia induces apoptosis in myocardium, and an amount evidence have demonstrated an increased risk of congenital abnormalities with gestational diabetes. Acetaminophen overdose is the most often cause of acute liver injury and obese women are in particular risk, because is able to induce mitochondrial oxidative stress (Rousar, 2012). Acetaminophen (Paracetamol) usual high doses decreased embryonic hepatic antioxidant systems as glutathione, that play a vital role in the detoxification of exogenous and endogenous chemicals (Mitchell, 1973, Ishibashi, 1997, Beck, 2001, Rousar, 2012, rev). The apparent safety of Paracetamol drug, a useful analgesic only (with no anti-inflammatory properties) (Neto, 2004; Hamlyn, 1978, Ucheya, 2006, Bessems, 2001) is compromized by its widespread and extensive chronic use, particularly in Peruvian population. Paracetamol though considered safe at a considerable low dose, especially in women, could cause kidney derangement and cardiac malformations during pregnant state (Ucheya, 2006), if the drug is ingested in the first trimester. Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers (Pinter, 2001). Thus, there is an overcome potential maternal acetaminophen (paracetamol) toxicity (Horowitz, 1997). Abstract-Hepatic fat and abdominal adiposity in early pregnancy promotes impaired glucose homeostasis in mid-pregnancy (De Souza, 2016) and paracetamol overuse predisposes to liver fat. Hyperglycemia induces apoptosis in myocardium, and an amount evidence have demonstrated an increased risk of congenital abnormalities with gestational diabetes. Acetaminophen overdose is the most often cause of acute liver injury and obese women are in particular risk, because is able to induce mitochondrial oxidative stress (Rousar, 2012). Acetaminophen (Paracetamol) usual high doses decreased embryonic hepatic antioxidant systems as glutathione, that play a vital role in the detoxification of exogenous and endogenous chemicals
Over the past decade, clinicians have increasingly prescribed acetaminophen (APAP) for patients in the neonatal intensive care unit (NICU). Acetaminophen has been shown to reduce post-operative opiate burden, and may provide similar efficacy for closure of the patent ductus arteriosus (PDA) as nonsteroidal anti-inflammatory drugs (NSAIDs). Despite these potential benefits, APAP exposures have spread to increasingly less mature infants, a highly vulnerable population for whom robust pharmacokinetic and pharmacodynamic data for APAP are lacking. Concerningly, preclinical studies suggest that perinatal APAP exposures may result in unanticipated adverse effects that are unique to the developing lung. In this review, we discuss the clinical observations linking APAP exposures to adverse respiratory outcomes and the preclinical data demonstrating a developmental susceptibility to APAP-induced lung injury. We show how clinical observations linking perinatal APAP exposures to pulmonary injury have been taken to the bench to produce important insights into the potential mechanisms underlying these findings. We argue that the available data support a more cautious approach to APAP use in the NICU until large randomized controlled trials provide appropriate safety and efficacy data.
Both pre-clinical and clinical studies have demonstrated that exposures to acetaminophen (APAP) at levels that cause hepatic injury cause pulmonary injury as well. However, whether exposures that do not result in hepatic injury have acute pulmonary implications is unknown. Thus, we sought to determine the how APAP exposures at levels that do not result in significant hepatic injury impact the mature lung. Adult male ICR mice (8-12 weeks) were exposed to a dose of APAP known to cause hepatotoxicity in adult mice (280 mg/kg, IP), as well as a lower dose previously reported to not cause hepatic injury (140 mg/kg, IP). We confirm that the lower dose exposures did not result in significant hepatic injury. However, like high dose, lower exposure resulted in increased cellular content of the bronchoalveolar lavage fluid, and induced a pro-inflammatory pulmonary transcriptome. Both the lower and higher dose exposures resulted in measurable changes in lung morphometrics, with the lower dose exposure causing alveolar wall thinning. Using RNAScope, we were able to detect dose-dependent, APAP-induced pulmonary Cyp2e1expression. Finally, using FLIM we determined that both APAP exposures resulted in acute pulmonary metabolic changes consistent with mitochondrial overload in lower dose and a shift to glycolysis at a high dose. Our findings demonstrate that APAP exposures that do not cause significant hepatic injury result in acute inflammatory, morphometric and metabolic changes in the mature lung. These previously unreported findings may help explain the potential relationship between APAP exposures and pulmonary-related morbidity.
Work-related asthma (WRA) is a condition of asthma symptoms that has a connection with a workplace. Based on the different types of exposure at the workplace and onset of asthma symptoms, WRA is broadly divided into two categories: occupational asthma (OA) and work-exacerbated asthma (WEA). OA and WEA can be further categorized based on various clinical and immunological definitions, and their clinical course and etiology are different. In this chapter, we discuss the clinical features, diagnostic approaches, and prevention and management of the WRA.
Hyperglycemia can influence the development of the fetal heart, affecting both its structure and its function. Prospective and retrospective cohort studies have demonstrated an increased risk of congenital abnormalities with gestational diabetes. This observation is probably related to the inclusion of women with unrecognized type 2 diabetes (Allen, 2007, Pasarella, 2013).
Substantial literature indicates that diabetes in pregnant rats and mice induces embryo lethality, growth retardation, and a variable incidence of birth defects. Then, the maintenance of normal concentrations of metabolites from all nutrient classes may be important for prevention of adverse fetal outcome in diabetic pregnancy.
Acetaminophen overdose is the most often cause of acute liver injury and obese women are in particular risk, because is able to induce mitochondrial oxidative stress (Rousar, 2012). Acetaminophen (Paracetamol) over doses decreased embryonic low-molecular-weight thiols (glutathione and cysteine), compounds that play a vital role in the detoxication of exogenous and endogenous chemicals (Mitchell, 1973, Beck, 2001, Rousar, 2012, rev).
The apparent safety of Paracetamol drug, a useful analgesic only (with no anti-inflammatory properties) (Neto, 2004; Hamlyn, 1978, Ucheya, 2006, Bessems, 2001) is compromized by its widespread and extensive chronic use, particularly in Peruvian population- Paracetamol though considered safe at a considerable low dose, especially in women, could cause kidney derangement and cardiac malformations during pregnant state (Ucheya, 2006), if the drug is ingested in the first trimester. Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers (Pinter, 2001). Thus, there is an overcome potential maternal acetaminophen (paracetamol) toxicity (Horowitz, 1997).
Background:
Due to the high prevalence of recurrent wheezing in the pediatric population, it is important to be able to identify environmental risk factors that may affect the etiology of asthma in several regions.
Objective:
to identify possible risk factors associated with asthma in children (9-12 years old) in Passo Fundo, Rio Grande do Sul, Brazil.
Material and methods:
A total of 1003 school-age children were selected for the cross-sectional study by applying a standardized written questionnaire from the International Study of Asthma and Allergy, and a supplementary questionnaire (ISAAC phase II) was added to address personal, family and environmental factors. Of these, 125 children were excluded because they did not accept to do the skin prick test, resulting in a sample of 878.
Results:
Independent risk factors associated with asthma were bronchiolitis before two years old [OR]=3.11; 2.23-4.33, current rhinitis [0R]=2.07; 1.43-3.0; sharing bedroom during the first year of life [OR]=2.03; 1.36-3.04; atopy [OR]=1,82; 1.26-2.50; use of paracetamol more than 12 times a year [OR]=1.68; 1.20-2.31; use of antibiotics in the first six months of life [OR]=1,57 1;13-2.17; maternal asthma [OR]=1.75; 1.05-2.78, having an indoor cat during the first year of life [OR]=1.73, 1.07-2.78; premature birth [OR]=1.60,1.02-2.50.
Conclusion:
our results show that genetic backgrounds, environmental factors, premature birth, use of antibiotics before six months of life, using paracetamol once per month and the presence of co-morbidities such as rhinitis are the risk factors associated with asthma in Brazilian children.
Kinder, die mit starken Schmerzen zum Arzt kommen, sollten nach sorgfältiger initialer klinischer Beurteilung unverzüglich eine adäquate Schmerztherapie erhalten. Analgetika beeinflussen weder die weiteren klinischen Untersuchungen oder das diagnostische Procedere noch verzögern sie den chirurgischen Eingriff. In weiterer Folge verbessert eine effektive intraoperative Schmerztherapie das operative Outcome. Wann immer möglich, sollte dabei eine Regionalanästhesie eingesetzt werden, um Opiate einzusparen. Ziel der postoperativen Schmerztherapie ist eine an individuell akzeptable Schmerzen angepasste Schmerztherapie mit möglichst wenigen Nebenwirkungen bei optimaler Mobilisierung. Neben Analgetika und Fortführung regionalanästhesiologischer Katheter-Verfahren sind unterstützende nichtpharmakologische Maßnahmen im Kindesalter eine weitere unverzichtbare Therapiesäule der Schmerztherapie.
Paracetamol (Acetaminophen) is the most commonly used drug in the world, with a long record of use in acute and chronic pain. In recent years the benefits of paracetamol use in chronic conditions has been questioned, notably in the areas of osteoarthritis and lower back pain. Over the same period, concerns over the long‐term adverse effects of paracetamol use have increased, initially in the field of hypertension, but more recently in other areas also. The evidence base for adverse effects of chronic paracetamol use consists of many cohort and observational studies, with few randomised controlled trials that in many cases contradict each other, so these studies must be interpreted with caution. Nevertheless, there are some areas where the evidence for harm is more robust, and if a clinician is starting paracetamol with the expectation of chronic use it might be advisable to discuss these side effects with patients first. In particular, an increased risk of GI bleeding and a small (~4mmHg) increase in systolic BP are adverse effects for which the evidence is particularly strong, and which show a degree of dose dependence. As our estimation of the benefits decreases, an accurate assessment of the harms is ever more important. This review summarises the current evidence on the harms associated with chronic paracetamol use, focusing on cardiovascular disease, asthma and renal injury, and the effects of in utero exposure.
Background:
An association of acetaminophen use and asthma was observed in the International Study of Asthma and Allergies in Childhood study. However there are no clear mechanisms to explain an association between acetaminophen use and immunologic pathology. In acidic conditions like those in the stomach and inflamed airway, tyrosine residues are nitrated by nitrous and peroxynitrous acids. The resulting nitrotyrosine is structurally similar to 2,4-dinitrophenol and 2,4-dinitrochlorobenzene, known haptens that enhance immune responses by covalently binding proteins. Nitrated acetaminophen shares similar molecular structure.
Objective:
We hypothesized the acetaminophen phenol ring undergoes nitration under acidic conditions, producing 3-nitro-acetaminophen which augments allergic responses by acting as a hapten for environmental allergens.
Methods:
3-nitro-acetaminophen was formed from acetaminophen in the presence of acidified nitrite, purified by high performance liquid chromatography, and assayed by gas-chromatography mass spectrometry. Purified 3-nitro-acetaminophen was reacted with Dermatophagoides pteronyssinus (Der p1) and analyzed by mass spectrometry to identify the modification site. Human peripheral blood mononuclear cells proliferation response was measured in response to 3-nitro-acetaminophen and to 3-nitro-acetaminophen-modified Der p1.
Results:
Acetaminophen was modified by nitrous acid forming 3-nitro-acetaminophen over a range of different acidic conditions consistent with airway inflammation and stomach acidity. The Der p1 protein-hapten adduct creation was confirmed by liquid chromatography-mass spectrometry proteomics modifying cysteine 132. Peripheral blood mononuclear cells exposed to 3-nitro-acetaminophen-modified Der p1 had increased proliferation and cytokine production compared to acetaminophen and Der p1 alone (n = 7; p < 0.05).
Conclusion:
These data suggests 3-nitro-acetaminophen formation and reaction with Der p1 provides a mechanism by which stomach acid or infection-induced low airway pH in patients could enhance the allergic response to proteins such as Der p1.
Herbs have long been a part of the human diet. Today herbs are used primarily for seasoning and flavor; but historically herbs had a much broader use. Herbs were the medicines of the day and were often added to the diet to enhance overall health, improve endurance, and increase resistance to infection. In Asian culture ginger was taken with seafood as it was believed to mitigate the ill effects of eating bad fish. Today sushi is still accompanied by (pickled) ginger. Aside from simple folk medicine, herbs and herb combinations were developed and used medicinally in the context of the cultural understanding of health and disease such as Chinese medicine, Ayurvedic medicine, and even early Western herbal traditions. Herbal medicine continues to be practiced this way by many traditional practitioners.
Use of antibiotics to treat acute respiratory tract or ear infections in children – prospective observational study to compare anthroposophic and conventional treatment in routine home care medical practice
Children with acute respiratory or ear infections (RTI/OM) are often unnecessarily prescribed antibiotics. Antibiotic resistance is a major public health problem and antibiotic prescription for RTI/OM should be reduced. Anthroposophic treatment of RTI/OM includes anthroposophic medications, nonmedication therapy, and if necessary also antibiotics. This secondary analysis from an observational primary care study comprised 529 children < 18 years from Europe (AT, DE, NL and UK) or USA, whose caregivers had chosen to consult physicians offering anthroposophic (A-) or conventional (C-) treatment for RTI/OM. During the 28-day follow-up antibiotics were prescribed to 5.5 % of A-patients and 25.6 % of C-patients (p < 0.001); unadjusted odds ratio for nonprescription in A- versus C-patients 6.58 (95 %-CI 3.45–12.56); after adjustment for demographics and morbidity 6.33 (3.17–12.64). Antibiotic prescription rates in recent observational studies with similar patients in similar settings ranged from 31.0 % to 84.1 %. Compared to C-patients, A-patients also had much lower use of analgesics, somewhat quicker symptom resolution, and higher caregiver satisfaction. Adverse drug reactions were infrequent (2.3 % in both groups) and not serious. Limitation was that results apply to children of caregivers consulting A-physicians. One cannot infer to what extent antibiotics might be avoided, if children who usually receive C-treatment were offered A-treatment.
Various drug and chemical exposures are associated with adverse effects on airways. These effects may induce or worsen the symptoms of asthma. The mechanisms of these airway changes vary from direct effects on receptors to immunologically mediated alterations.
Purpose:
Some studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma, and whether such a potential association could be modified by maternal coffee consumption.
Methods:
We included 63 652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards regression model.
Results:
After adjusting for potential confounders, acetaminophen use during pregnancy was associated with an increased risk of offspring asthma (HR = 1.16, 95% confidence interval (CI): 1.11-1.22). Coffee drinking during pregnancy was associated with a slightly decreased risk (HR = 0.94, 95%CI: 0.90-0.99). But there was no strong evidence of effect measure modification of acetaminophen use on offspring asthma by coffee consumption.
Conclusions:
Acetaminophen use during pregnancy was associated with a modest increased risk for offspring asthma, which was not modified by coffee consumption. Copyright © 2015 John Wiley & Sons, Ltd.
An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre-mutations" to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects).
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
The incidence and prevalence of asthma are increasing. One reason for this trend is the rise in adult-onset asthma, especially occupational asthma, which is 1 of the 2 forms of work-related asthma. Occupational asthma is defined as asthma caused by agents that are present exclusively in the workplace. The presence of pre-existing asthma does not rule out the possibility of developing occupational asthma. A distinction has traditionally been made between immunological occupational asthma (whether IgE-mediated or not) and nonimmunological occupational asthma caused by irritants, the most characteristic example of which is reactive airway dysfunction syndrome. The other form of work-related asthma is known as work-exacerbated asthma, which affects persons with pre-existing or concurrent asthma that is worsened by work-related factors. It is important to differentiate between the 2 entities because their treatment, prognosis, and medical and social repercussions can differ widely. In this review, we discuss diagnostic methods, treatment, and avoidance/nonavoidance of the antigen in immunological occupational asthma and work-exacerbated asthma. Key words: Specific inhalation challenge. Peak expiratory flow. Workplace. Irritants.
Asthma is difficult to diagnose in the child with sickle cell disease because symptoms and pulmonary function abnormalities are similar to the spectrum of pulmonary manifestations in sickle cell disease. There are no published reports of controlled trials of asthma medications in children with sickle cell disease. Thus, treatment decisions should be guided by the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf). However, issues specific to children with sickle cell disease should be considered. Initial strategies should focus on control of environmental triggers, as effectiveness on asthma outcomes is proven and the cost for implementation can be low. Use of short- and long-acting beta(2)-agonists may prolong QTc, particularly in this population of children who already have a higher prevalence of prolonged QTc than the general population. Long-acting beta(2)-agonist use has been associated with life-threatening asthma exacerbations with potentially higher risks in African Americans. Montelukast has been reported to increase suicidal thinking and behavior, and persons with asthma and sickle cell disease are already at risk for these events. Oral corticosteroids in the treatment of acute chest syndrome may increase risk of readmission even in children with asthma. The lack of prospective controlled trials of asthma drug treatment in children with asthma and sickle cell disease compels us to move this issue forward.
The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD–ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.
A better understanding of the causation of asthma and allergic disorders could potentially lead to intervention strategies that reduce their prevalence and severity. One potential causative factor is the use of paracetamol. Most of the evidence for the link with asthma is from non-experimental studies of paracetamol exposure in utero, infancy, childhood and adult life, however it has been difficult to rule out confounding and bias in the associations observed. The two randomised clinical trials of the effect of paracetamol in patients with asthma have been difficult to interpret, due to methodological issues. There have been no randomised controlled trials of paracetamol use and the development of asthma. Both asthma and paracetamol use are common, and so even if there is a relatively small effect of paracetamol exposure on the development of asthma or its severity, then such an effect would be of major public health significance. It is proposed that randomised controlled trials of the effect of paracetamol on the development of asthma and its severity are a high research priority. This article is protected by copyright. All rights reserved.
Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This Review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic. ANN NEUROL 2014. © 2014 American Neurological Association
Background: There is a paucity of detailed longitudinal data on wheeze in early childhood. Not all children who wheeze in early infancy will continue to wheeze into childhood and beyond. This study aims to investigate possible risk factors for different patterns of wheeze in the pre-school years.
Subjects and Methods: Study participants were part of the Avon Longitudinal Study of Parents and Children (ALSPAC). Maternal reports of child wheeze between birth and 6 months and again between 30 and 42 months were gathered prospectively. Children were categorized into early wheeze, persistent wheeze or late onset wheeze. A large number of risk factors were assessed for each wheezing phenotype using multivariable logistic regression models.
Results: Over 70% of children who wheezed in the first 6 months did not wheeze 3 years later. Wheezing between 0–6 months was independently associated with the presence of older siblings, male sex, delivery between April and December, bottle feeding, young maternal age, prenatal tobacco smoke exposure, atopy and parental history of asthma. From within this group of early wheezers, risk factors for wheeze that persisted beyond 6 months included pre-term delivery, young maternal age, living in rented local authority housing, atopy and a maternal (not paternal) history of asthma. Atopy and a family history of asthma emerged as the main predictors of wheeze that developed after 6 months of age.
Conclusion: It is clear that a number of wheezing syndromes exist by 3½ years, albeit with some degree of overlap. Detailed follow-up of this cohort is underway to determine whether risk factor associations determined in the first 3½ years have long-term significance for the clinical entity termed ‘asthma’.
Current thinking attributes the balance between T helper 1 (Th1) and Th2 cytokine response patterns in immune responses to the nature of the antigen, the genetic composition of the host, and the cytokines involved in the early interaction between T cells and antigen-presenting cells. Here we introduce glutathione, a tripeptide that regulates intracellular redox and other aspects of cell physiology, as a key regulatory element in this process. By using three different methods to deplete glutathione from T cell receptor transgenic and conventional mice and studying in vivo and/or in vitro responses to three distinct antigens, we show that glutathione levels in antigen-presenting cells determine whether Th1 or Th2 response patterns predominate. These findings present new insights into immune response alterations in HIV and other diseases. Further, they potentially offer an explanation for the well known differences in immune responses in "Th1" and "Th2" mouse strains.
There seems to be an association between paracetamol consumption during late pregnancy and the prevalence of wheezing in infancy and childhood. The aim of the present study is to determine whether the aforementioned association is modified by the presence of asthma in the mother.
A total of 1,741 children aged 3-5 years from an epidemiological survey performed in the province of Murcia (Spain) were included in the analysis. Data on paracetamol consumption (never, at least once during pregnancy or at least once per month during pregnancy), wheezing symptoms in the offspring (according to the International Study of Asthma and Allergies in Childhood protocol) and the presence of asthma in the mother, together with other known risk factors for asthma, were obtained by means of a questionnaire.
The mean age of the children was 4.08 +/- 0.8 years and 51.1% were males. The overall prevalence of current wheezing was 20.2%. The frequency of paracetamol usage was similar among asthmatic and non-asthmatic mothers, and only a small proportion of them took this drug at least once a month (13.8% of asthmatics and 11.0% of non-asthmatics). Compared to the mothers who never took paracetamol, there was a significant association between the mother having taken paracetamol at least once per month during pregnancy and the offspring suffering from wheezing at preschool age, but only among non-asthmatic mothers (odds ratio 1.94, 95% confidence interval 1.34-2.79 vs. odds ratio 1.05, 95% confidence interval 0.21-5.08). This association was maintained after controlling for potential confounders (odds ratio 1.74, 95% confidence interval 1.15-2.61).
The frequent usage of paracetamol during pregnancy is associated with the prevalence of wheezing in offspring during preschool years. Asthma in the mother might modify this association.
A free radical is any molecule that has an odd number of electrons. Free radicals, which can occur in both organic (i.e., quinones) and inorganic molecules (i.e., O(2)), are highly reactive and, therefore, transient. Free radicals are generated in vivo as by products of normal metabolism. They are also produced when an organism is exposed to ionizing radiation, to drugs capable of redox cycling, or to xenobiotics that can form free radical metabolites in situ. Cellular targets at risk from free radical damage depend on the nature of the radical and its site of generation. In this review we survey cellular sources of free radicals and the reactions they can undergo and discuss cellular defenses and adaptive mechanisms.
Glutathione (GSH) levels in rat testis and lung after oral administration (3 g/kg) of acetaminophen (APAP) were studied. At the administered dose APAP is present in each organ and influences the GSH levels. APAP value of 114 micrograms/g was obtained in testis at 6 hr (peak time); in the lung the Cmax was 92 mu/g at 8 hr and this value lasted several hours longer than that in testis. GSH levels are also affected differently in the organs studied after APAP administration; the lungs seem to be the primary organ undergoing the depleting action of APAP. This process could not only cause toxicity, but also predispose those organs to the action of toxic compounds responsible for specific pathologies.
To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response.
A randomized, double-blind, placebo-controlled trial was conducted in parallel groups. Subjects received an intravenous endotoxin bolus of 4 ng/kg after premedication with either placebo, 1000 mg aspirin, or 1000 mg acetaminophen by mouth.
Peak body temperatures were 38.5 degrees C +/- 0.2 degrees C in the placebo group, 37.6 degrees C +/- 0.2 degrees C in the acetaminophen group (P = .001 versus placebo), and 38.6 degrees C +/- 0.2 degrees C in the subjects treated with aspirin (P = .001 versus acetaminophen; P = .570 versus placebo) at 4 hours after lipopolysaccharide infusion. Subjective symptom scores for chills and perception of fever were higher in the placebo group than in the acetaminophen group (chills, 2.5 +/- 0.3 versus 1.0 +/- 0.2, P = .009 and fever, 2.5 +/- 0.2 versus 2.0 +/- 0.2, P = .021). Tumor necrosis factor-alpha, interleukin-6, and interleukin-8 levels rose by several orders of magnitude (P < .001 versus baseline in all groups), without significant intergroup differences.
Acetaminophen was the superior antipyretic drug in endotoxemia compared with aspirin. Treatment with acetaminophen ameliorates subjective symptoms induced by endotoxemia without compromising the humoral response of a subject to endotoxin. This observation has clinical interest and may also help to improve the lipopolysaccharide model, which can be used to test anti-inflammatory and anticoagulatory drugs.
The authors recently observed that frequent paracetamol use was positively associated with asthma and rhinitis in young adults. Therefore, an ecological analysis was performed to measure international associations between paracetamol sales and atopic disease prevalences in children and adults. Published data from the International Study of Asthma and Allergies in Childhood (ISAAC) on the prevalence of four atopic symptoms in 13-14-yr-olds (112 centres) and 67-yr-olds (66 centres) in 1994/1995, and European Community Respiratory Health Survey (ECRHS) data on the prevalence of asthma symptoms, diagnosed asthma and rhinitis (44 centres), prevalence of atopy, mean bronchial responsiveness and mean total immunoglobulin E levels (34 centres) in young adults in 1991/1992, were used. Their associations with national 1994/1995 per capita paracetamol sales were measured using linear regression. Paracetamol sales were high in English-speaking countries, and were positively associated with asthma symptoms, eczema and allergic rhinoconjunctivitis in 13-14-yr-olds, and with wheeze, diagnosed asthma, rhinitis and bronchial responsiveness in adults. The prevalence of wheeze increased by 0.52% in 13-14-yr-olds and by 0.26% in adults (p<0.0005) for each gram increase in per capita paracetamol sales. These ecological findings require cautious interpretation, but raise the possibility that variation in paracetamol usage may explain some of the variation in atopic disease prevalence between countries.
There is a paucity of detailed longitudinal data on wheeze in early childhood. Not all children who wheeze in early infancy will continue to wheeze into childhood and beyond. This study aims to investigate possible risk factors for different patterns of wheeze in the pre-school years.
Study participants were part of the Avon Longitudinal Study of Parents and Children (ALSPAC). Maternal reports of child wheeze between birth and 6 months and again between 30 and 42 months were gathered prospectively. Children were categorized into early wheeze, persistent wheeze or late onset wheeze. A large number of risk factors were assessed for each wheezing phenotype using multivariable logistic regression models.
Over 70% of children who wheezed in the first 6 months did not wheeze 3 years later. Wheezing between 0-6 months was independently associated with the presence of older siblings, male sex, delivery between April and December, bottle feeding, young maternal age, prenatal tobacco smoke exposure, atopy and parental history of asthma. From within this group of early wheezers, risk factors for wheeze that persisted beyond 6 months included pre-term delivery, young maternal age, living in rented local authority housing, atopy and a maternal (not paternal) history of asthma. Atopy and a family history of asthma emerged as the main predictors of wheeze that developed after 6 months of age.
It is clear that a number of wheezing syndromes exist by 3(1/2) years, albeit with some degree of overlap. Detailed follow-up of this cohort is underway to determine whether risk factor associations determined in the first 3(1/2) years have long-term significance for the clinical entity termed 'asthma'.
Earlier studies have suggested a link between asthma and severe headache, and also between migraine and wheezing illness. Recent analysis have also shown an increase of asthma among cases with a prior history of migraine but without a history of hay fever, allergic rhinitis or eczema.
To examine whether there is an association between migraine and asthma in the United Kingdom.
Matched case-control study using the General Practice Research Database (GPRD).
Practices in the United Kingdom providing data on 5,110,619 patients to the GPRD.
The subjects were the patients with one or more diagnoses of migraine plus treatment for migraine. Each case was matched by general practice, sex, and age, with one control who had never been given a diagnosis of migraine. Case and control groups were compared for prevalence of asthma, chronic obstructive pulmonary disease, respiratory symptoms treated with inhalers or hay fever. Investigations were carried out to determine whether the association between migraine and asthma was stronger among patients with hayfever or those without hayfever, and whether patients with migraine had an increased prescription of other (non-migraine and non-asthma) medications.
Among 64 678 case-control pairs, the relative risk of asthma in patients with migraine was 1.59 (95% CI = 1.54 to 1.65) among definite cases, and 0.75 (95% CI = 0.67 to 0.83) among those whose selection as case included beta-blocker prophylaxis. Among definite migraine cases, relative risks of chronic obstructive pulmonary disease, respiratory symptoms, eczema, and hay fever (pollinosis), were all raised (at 1.22, 1.85, 1.55, and 1.67, respectively). The association between migraine and asthma was stronger in patients without a diagnosis of hay fever, than in those with hayfever (relative risk = 1.32 and 1.19, respectively). The relative risk of prescription for a range of non-migraine, non-asthma medications was raised, the exception being anti-diabetic medication.
This large case-control study provides evidence for an association between migraine and asthma. Frequent attendance at a general practice surgery may confound this association. However, if the association is real, its elucidation may help the understanding of disease mechanisms shared by migraine and asthma.
We recently reported links between frequent paracetamol (acetaminophen) use and wheezing and asthma in adults and children, but data are lacking on possible effects of prenatal exposure on wheezing in early childhood.
In the population based Avon Longitudinal Study of Parents and Children (ALSPAC) women were asked twice during pregnancy (at 18-20 weeks and 32 weeks) about their usage of paracetamol and aspirin. Six months after birth, and at yearly intervals thereafter, mothers were asked about wheezing and eczema symptoms in their child. The effects of paracetamol and aspirin use in pregnancy on the risk in the offspring of wheezing at 30-42 months (n=9,400) and eczema at 18-30 months (n=10,216) and on their risk of different wheezing patterns (defined by presence or absence of wheezing at <6 months and at 30-42 months) were examined.
Paracetamol was taken frequently (most days/daily) by only 1% of women. After controlling for potential confounders, frequent paracetamol use in late pregnancy (20-32 weeks), but not in early pregnancy (<18-20 weeks), was associated with an increased risk of wheezing in the offspring at 30-42 months (adjusted odds ratio (OR) compared with no use 2.10 (95% CI 1.30 to 3.41); p=0.003), particularly if wheezing started before 6 months (OR 2.34 (95% CI 1.24 to 4.40); p=0.008). Assuming a causal relation, only about 1% of wheezing at 30-42 months was attributable to this exposure. Frequent paracetamol use in pregnancy was not associated with an increased risk of eczema. Frequent aspirin use in pregnancy was associated with an increased risk of wheezing only at <6 months.
Frequent use of paracetamol in late pregnancy may increase the risk of wheezing in the offspring, although such an effect could explain only about 1% of the population prevalence of wheezing in early childhood.
Oxidative stress is implicated in the pathogenesis of asthma, and clinical studies show an imbalance in the level of oxidants to the level of antioxidants in subjects with asthma. Aldehydes and glutathione are examples of biomarkers of oxidant-induced damage and antioxidant status in asthma, respectively. In the study, we applied analytical techniques based on liquid chromatography for the assessment of aldehydes and glutathione in the exhaled breath condensate of children with asthma and in control subjects without asthma. Twelve subjects with asthma were evaluated at exacerbation and after 5 days of therapy with prednisone. At exacerbation, malondialdehyde levels were higher in patients with asthma (30.2 +/- 2.4 nM) than in control subjects (19.4 +/- 1.9 nM, p = 0.002) and were reduced after steroid therapy (18.5 +/- 1.6 nM, p = 0.001). At exacerbation, glutathione levels were lower in subjects with asthma (5.96 +/- 0.6 nM) than in control subjects (14.1 +/- 0.8 nM, p < 0.0001) and were increased after the therapy (8.44 +/- 1.2 nM, p = 0.04). Malondialdehyde and glutathione both in subjects with asthma and control subjects were negatively correlated (r = -0.5, p = 0.001). The study shows that aldehydes and glutathione are detectable in the exhaled breath condensate of children with asthma and healthy children and that their levels are modified during asthma exacerbation and after a 5-day course of therapy with oral prednisone.
Background
We recently reported links between frequent paracetamol (acetaminophen) use and wheezing and asthma in adults and children, but data are lacking on possible effects of prenatal exposure on wheezing in early childhood.
Methods
In the population based Avon Longitudinal Study of Parents and Children (ALSPAC) women were asked twice during pregnancy (at 18–20 weeks and 32 weeks) about their usage of paracetamol and aspirin. Six months after birth, and at yearly intervals thereafter, mothers were asked about wheezing and eczema symptoms in their child. The effects of paracetamol and aspirin use in pregnancy on the risk in the offspring of wheezing at 30–42 months (n=9400) and eczema at 18–30 months (n=10 216) and on their risk of different wheezing patterns (defined by presence or absence of wheezing at <6 months and at 30–42 months) were examined.
Results
Paracetamol was taken frequently (most days/daily) by only 1% of women. After controlling for potential confounders, frequent paracetamol use in late pregnancy (20–32 weeks), but not in early pregnancy (<18–20 weeks), was associated with an increased risk of wheezing in the offspring at 30–42 months (adjusted odds ratio (OR) compared with no use 2.10 (95% CI 1.30 to 3.41); p=0.003), particularly if wheezing started before 6 months (OR 2.34 (95% CI 1.24 to 4.40); p=0.008). Assuming a causal relation, only about 1% of wheezing at 30–42 months was attributable to this exposure. Frequent paracetamol use in pregnancy was not associated with an increased risk of eczema. Frequent aspirin use in pregnancy was associated with an increased risk of wheezing only at <6 months.
Conclusions
Frequent use of paracetamol in late pregnancy may increase the risk of wheezing in the offspring, although such an effect could explain only about 1% of the population prevalence of wheezing in early childhood.
BACKGROUND The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma. METHODS Information was collected on the use of analgesics as part of a population based case-control study of dietary antioxidants and asthma in adults aged 16–49 years registered with 40 general practices in Greenwich, South London. The frequency of use of paracetamol and aspirin was compared in 664 individuals with asthma and in 910 without asthma. Asthma was defined by positive responses to questions about asthma attacks, asthma medication, or waking at night with shortness of breath. The association between analgesic use and severity of disease amongst asthma cases, as measured by a quality of life score, was also examined. RESULTS Paracetamol use was positively associated with asthma. After controlling for potential confounding factors the odds ratio for asthma, compared with never users, was 1.06 (95% CI 0.77 to 1.45) in infrequent users (<monthly), 1.22 (0.87 to 1.72) in monthly users, 1.79 (1.21 to 2.65) in weekly users, and 2.38 (1.22 to 4.64) in daily users (p (trend) = 0.0002). This association was present in users and non-users of aspirin and was stronger when cases with more severe disease were compared with controls; amongst cases increasing paracetamol use was associated with more severe disease. Frequency of aspirin use was not associated with asthma when cases as a whole were compared with controls, nor with severity of asthma amongst cases. Frequent paracetamol use was positively associated with rhinitis, but aspirin use was not. CONCLUSIONS Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults.
Infants hospitalized for bronchiolitis have a high rate of early childhood asthma. It is not known whether bronchiolitis severity correlates with the risk of early childhood asthma or with asthma-specific morbidity.
We sought to determine whether a dose-response relationship exists between severity of infant bronchiolitis and both the odds of early childhood asthma and asthma-specific morbidity.
We conducted a population-based retrospective birth cohort study of term healthy infants born from 1995-2000 and enrolled in a statewide Medicaid program. We defined bronchiolitis severity by categorizing infants into mutually exclusive groups based on the most advanced level of health care for bronchiolitis. Health care visits, asthma-specific medications, and demographics were identified entirely from Medicaid and linked vital records files. Asthma was ascertained at between 4 and 5.5 years of age, and 1-year asthma morbidity (hospitalization, emergency department visit, or oral corticosteroid course) was determined between 4.5 and 5.5 years among children with prevalent asthma.
Among 90,341 children, 18% had an infant bronchiolitis visit, and these infants contributed to 31% of early childhood asthma diagnoses. Relative to children with no infant bronchiolitis visit, the adjusted odds ratios for asthma were 1.86 (95% CI, 1.74-1.99), 2.41 (95% CI, 2.21-2.62), and 2.82 (95% CI, 2.61-3.03) in the outpatient, emergency department, and hospitalization groups, respectively. Children hospitalized with bronchiolitis during infancy had increased early childhood asthma morbidity compared with that seen in children with no bronchiolitis visit.
To our knowledge, this is the first study to demonstrate the dose-response relationship between the severity of infant bronchiolitis and the increased odds of both early childhood asthma and asthma-specific morbidity.
Intake of paracetamol has been associated with development of asthma. The aim of this study was to address a possible association between intake of paracetamol and risk of adult-onset asthma. Using a multidisciplinary postal questionnaire survey concerning health and lifestyle we prospectively studied 19,349 adult twins enrolled in the nationwide Danish Twin Registry. There was a higher prevalence of new-onset asthma in subjects who reported frequent intake of paracetamol at baseline compared with subjects without this determinant (12.0% vs. 4.3%), OR = 3.03 (1.51-6.11), p = 0.005. The result remained significant after adjusting for sex, age, smoking, BMI, hay fever, eczema, and intake of medications other than paracetamol, OR = 2.16 (1.03-4.53), p = 0.041. Frequent intake of paracetamol is an independent risk factor for adult-onset asthma.
Prevalence of asthma in developed countries increased between the 1970s and the 1990s. One factor that might contribute to the trends in asthma is the increased use of acetaminophen vs aspirin in children and pregnant women.
To examine relationships between in utero exposure to acetaminophen and incidence of respiratory symptoms in the first year of life.
A total of 345 women were recruited in the first trimester of pregnancy and followed up with their children through the first year of life. Use of acetaminophen in pregnancy was determined by questionnaire and related to incidence of respiratory symptoms.
Use of acetaminophen in middle to late but not early pregnancy was significantly related to wheezing (odd ratio, 1.8; 95% confidence interval, 1.1-3.0) and to wheezing that disturbed sleep (odds ratio, 2.1; 95% confidence interval, 1.1-3.8) in the first year of life after control for potential confounders.
This study suggests that use of acetaminophen in middle to late but not early pregnancy may be related to respiratory symptoms in the first year of life. Additional follow-up will examine relationships of maternal and early childhood use of acetaminophen with incidence of asthma at ages 3 to 5 years, when asthma diagnosis is more firmly established.
Exposure to paracetamol during intrauterine life, childhood, and adult life may increase the risk of developing asthma. We studied 6-7-year-old children from Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) programme to investigate the association between paracetamol consumption and asthma.
As part of Phase Three of ISAAC, parents or guardians of children aged 6-7 years completed written questionnaires about symptoms of asthma, rhinoconjunctivitis, and eczema, and several risk factors, including the use of paracetamol for fever in the child's first year of life and the frequency of paracetamol use in the past 12 months. The primary outcome variable was the odds ratio (OR) of asthma symptoms in these children associated with the use of paracetamol for fever in the first year of life, as calculated by logistic regression.
205 487 children aged 6-7 years from 73 centres in 31 countries were included in the analysis. In the multivariate analyses, use of paracetamol for fever in the first year of life was associated with an increased risk of asthma symptoms when aged 6-7 years (OR 1.46 [95% CI 1.36-1.56]). Current use of paracetamol was associated with a dose-dependent increased risk of asthma symptoms (1.61 [1.46-1.77] and 3.23 [2.91-3.60] for medium and high use vs no use, respectively). Use of paracetamol was similarly associated with the risk of severe asthma symptoms, with population-attributable risks between 22% and 38%. Paracetamol use, both in the first year of life and in children aged 6-7 years, was also associated with an increased risk of symptoms of rhinoconjunctivitis and eczema.
Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhinoconjunctivitis, and eczema at age 6 to 7 years. We suggest that exposure to paracetamol might be a risk factor for the development of asthma in childhood.
To examine whether antipyretic therapy in young children is associated with potential risks (interference with enhanced host defences at febrile temperatures) or benefits (improved comfort and behaviour), a randomised, double-blind, placebo-controlled trial of paracetamol was conducted among 225 children 6 months to 6 years of age who presented with acute (less than or equal to 4 days) fever (greater than or equal to 38 degrees C per rectum) without evident bacterial focus of infection. Parents were asked to give paracetamol liquid 10-15 mg/kg or placebo every 4 h as needed for fever and to avoid bathing, sponging, or other pharmacological agents. Parents kept temperature and symptom diaries and recorded changes in child comfort and behaviour according to a pretested, 5-category Likert-type questionnaire 1-2 h after every dose. There were no significant differences between treated and placebo groups in mean duration of subsequent fever (34.7 vs 36.1 h) or other symptoms (72.9 vs 71.7 h). Paracetamol-treated children were more likely to be rated by their parents as having at least a 1-category improvement in activity (38 vs 11%; p = 0.005) and alertness (33 vs 12%; p = 0.036) but no significant differences were noted in mood, comfort, appetite, or fluid intake. That overall improvement in behaviour and comfort with paracetamol was not impressive is underscored by the inaccuracy of parents' "guess" at the end of the trial as to which agent their child had received-45% correct guesses for paracetamol and 52% for placebo. The data suggest that the clinically relevant hazards and benefits of paracetamol antipyresis have been exaggerated.
Our previous finding of a glutathione (GSH) deficiency in aging or senescent mice suggested that a concomitant decrease in detoxification capacity also may occur. To test this, mice at different biological stages of the life span (growth, maturity, aging or senescence) were injected with various doses of acetaminophen (APAP), and GSH depletion and recovery rates were determined. At intervals for 24 hr, samples of blood and other tissues were obtained, processed, and analyzed for reduced GSH, glutathione disulfide (GSSG), cysteine, and cystine using HPLC with dual electrochemical detection. In the uninjected controls, the GSH concentration decreased about 30% in all tissues of the aging mouse, but the GSSG cysteine, and cystine levels were unchanged during the life span. APAP administration depleted liver and lung GSH contents in a dose- and time-dependent manner. Four hr after APAP administration, hepatic GSH levels of all ages had decreased 70-80%. After 24 hr, the GSH levels of the young, growing (3-6 months), and mature (12 months) mice recovered to 94 and 66%, respectively, of the controls. In contrast, the level in aging (31 months) mice rose only 41%, a lower recovery that was correlated with their decreased GSH content. The lungs of old mice also were GSH-deficient but differed from liver, for there was less GSH depletion by APAP and no decrease in GSH recovery. Thus, these findings demonstrate clearly the occurrence of decreased detoxification capacity in the GSH-deficient, aging mouse.
Using 30 anesthetized cats, we examined whether oxygen radicals produce airway constriction or hyperresponsiveness. In one group, we administered aerosolized xanthine (0.1%) for 3 min followed by aerosolized xanthine oxidase (XO) (1 U/ml) for 5 min in order to generate oxygen radicals enzymatically in the airways. Pulmonary resistance (RL) instantaneously increased from 14.8 +/- 0.9 to 30.8 +/- 1.4 cm H2O/L/s (p less than 0.01). The increase in RL was significantly depressed by prior administration of polyethylene glycol-superoxide dismutase (PEG-SOD) or polyethylene glycolcatalase (PEG-CAT). In a second group, in order to examine changes in airway responsiveness, we studied acetylcholine (ACh) challenge before and 30, 60, and 120 min after inhalations of xanthine and XO. After xanthine-XO, the airways were hyperresponsive to ACh at 30 and at 60 min (p less than 0.05) but not at 120 min. The geometric means of ACh provocative concentrations that caused an increase in RL of 10 cm H2O/L/s above the baseline value before and 30, 60, and 120 min after xanthine-XO were 0.25, 0.045, 0.073, and 0.15%, respectively. The increase in responsiveness to ACh was significantly correlated with the increase in RL after xanthine-XO inhalation (r = 0.88, p less than 0.05). These data support the concept that oxygen radicals generated by xanthine-XO inhalation may induce bronchoconstriction and airway hyperresponsiveness.
Reactive oxygen species may be generated by several inflammatory cells which participate in airway inflammation and their production may be increased in asthma. Oxygen metabolites may contribute to the epithelial damage which is characteristic of asthmatic airways and may activate cells such as mast cells in the airway mucosa. Reactive oxygen species may cause bronchoconstriction, mucus secretion, have effects on airway vasculature, and may increase airway responsiveness. The role of reactive oxygen species in airway disease has been largely neglected, but appears to be an important area for future study. It is also possible that antioxidant defenses may be defective in asthma. If reactive oxygen species participate in the inflammatory response in airway disease, then radical scavengers or antioxidants could play a useful role in therapy.
Mounting evidence suggests that reactive oxygen metabolites can initiate the release and metabolism of arachidonic acid (AA). We therefore examined the effects of hydrogen peroxide (H2O2), a biologically relevant oxygen metabolite, on AA release and cyclooxygenase metabolism by the rat alveolar macrophage (AM). At concentrations between 10(-4) and 10(-3) M, which were largely noncytotoxic as assessed by chromium release, H2O2 exposure for 30 min caused a steep dose-dependent increase in AA release that peaked at approximately 5-fold stimulation at 10(-3) M H2O2. AA release induced by H2O2 was inhibited by the H2O2 scavenger catalase, but not by inactivated catalase or by scavengers of superoxide anion, hydroxyl radical, or ferric iron. An evaluation of cyclooxygenase metabolite formation by specific radioimmunoassays and high performance liquid chromatography demonstrated a greater than 2-fold increment in thromboxane (Tx)A2 (measured as TxB2) synthesis at 10(-4) M H2O2, but no increment in prostaglandin (PG) E2 synthesis. H2O2-induced TxB2 synthesis was cyclooxygenase-dependent, since it was inhibited by indomethacin (1 microM). There was no significant degradation of either PGE2 or TxB2 in AM cultures by H2O2 at concentrations to 10(-2) M. The effect of H2O2 on agonist-induced cyclooxygenase metabolism was also examined. H2O2 at 10(-4) M inhibited PGE2 synthesis induced by zymosan and A23187, whereas agonist-induced TxB2 synthesis was either unaffected (zymosan) or augmented (A23187) by H2O2. These findings suggest inhibition by H2O2 of PGE2 synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
The number of cases of Reye syndrome reported annually to the Centers for Disease Control declined markedly between 1980 and 1985. In this article, we present pharmaceutical marketing research data that suggest sharp decreases in the use and purchase of children's aspirin between 1980 and 1985. These trends appear to correspond to the decrease in reporting of Reye syndrome cases. Additionally, analysis of physician mentions of aspiring and acetaminophen for treating flu and chickenpox showed statistically significant trends toward decreasing recommendations for the use of aspirin and significant trends toward increasing recommendations for use of acetaminophen. Trends in wholesale purchases of aspirin and acetaminophen by drug stores from 1979 through 1985 demonstrated a significant decline for the 81-mg children's aspirin tablet and an increase in purchases of children's acetaminophen products. Many factors may influence physician and parents' choice of analgesic/antipyretic medication, including information about Reye syndrome. Data suggest that a continuing decline in the use of aspirin for children may be accompanied by a continuing decline in the reported number of Reye syndrome cases.
We have examined the effect of activated neutrophils on the release of prostacyclin (PGI2) from cultured endothelial cells by radioimmunoassay and thin layer chromatography of its stable metabolite, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Phorbol myristate acetate-activated neutrophils induced a time- and dose-dependent release of 6-keto-PGF1 alpha from human and bovine endothelial cell monolayers, whereas phorbol myristate acetate alone and neutrophils alone did not. Pretreatment of the endothelial cells with aspirin prevented neutrophil-mediated 6-keto-PGF1 alpha release, indicating that it did not depend upon neutrophil-generated endoperoxides. Phorbol myristate acetate-activated neutrophils from a patient with chronic granulomatous disease failed to induce endothelial 6-keto-PGF1 alpha release. Addition of catalase but not of superoxide dismutase significantly reduced human and bovine endothelial 6-keto-PGF1 alpha release by phorbol myristate acetate-activated neutrophils. Catalase-inhibitable endothelial 6-keto-PGF1 alpha release was also observed after the addition of the hydrogen peroxide-generating system, glucose-glucose oxidase, to bovine and human endothelial cell monolayers. Bovine endothelial 6-keto-PGF1 alpha release induced by exogenously generated hydrogen peroxide was attenuated by the phospholipase inhibitor mepacrine, suggesting that hydrogen peroxide may act by triggering endothelial membrane phospholipase activation. The release of 6-keto-PGF1 alpha by enzymatically or neutrophil-generated hydrogen peroxide was not associated with endothelial cell lysis as assessed by 51Cr release. We conclude that exogenously generated hydrogen peroxide or a hydrogen peroxide-derived product mediates rapid nonlytic release of PGI2 from cultured endothelial cells.
The inflammatory process is associated with the activation of phagocytic cells such as polymorphonuclear leukocytes with the subsequent release and generation into the extracellular space of a group of active compounds, some of which are free radicals. The relationship of these radical species to the other features of inflammation is unknown. The aim of this study was to assess the influence of free radicals generated by the aerobic oxidation of hypoxanthine by xanthine oxidase on the in vivo microvascular preparation of the hamster cheek pouch. Fluorescein-labeled Dextran, 150,000, was used to assess microvascular permeability. The application of xanthine oxidase alone or hypoxanthine and xanthine oxidase resulted in a significant increase in macromolecular extravasation which was not seen after addition of hypoxanthine, uric acid, or denatured enzyme. Increased leukocyte rolling and arteriolar vasoconstriction were also observed. The addition of xanthine oxidase to cheek pouch homogenates, in vitro, demonstrated that intrinsic cheek pouch substrates were available for enzyme-induced generation of superoxide anion radical. These results suggest that xanthine oxidase acting on exogenous and/or endogenous substrates generates a flux of free radicals which may further interact to result in the increased macromolecular permeability seen. It is suggested that the permeability changes seen during the inflammatory process may be in part related to the release of free radicals from inflammatory cells.
Acetaminophen and low doses of diazepam were evaluated for the prevention of recurrences of febrile seizures in a placebo-controlled, double-blind trial. Children after their first febrile seizure were assigned to receive either one dose of rectally administered diazepam, and then, after 6 hours, oral doses of 0.2 mg/kg three times a day for the first 2 days if the fever stayed greater than 38.5 degrees C, or a placebo similarly during forthcoming febrile episodes. In addition, each febrile episode was randomly assigned to be treated with acetaminophen or the placebo. Thus four groups were examined for 2 years: patients receiving two kinds of placebo, patients receiving diazepam and a placebo, patients receiving acetaminophen and a placebo, and patients receiving both diazepam and acetaminophen. Of a total of 180 patients (102 boys), 161 were followed for the 2-year period and 157 were seen at the last outpatient examination: 80 in the diazepam group and 77 in the placebo group. The final analysis of the efficacy of the drugs was made on the basis of the data from 153 patients who had had at least one febrile episode during follow-up. There were 641 fever events during this period, and 38 children (21.1%) had 55 recurrences of febrile seizures. Acetaminophen had no effect on the recurrence rate. Seizures recurred at least once in 21 patients (28.4%) receiving diazepam and 17 (21.5%) receiving a placebo (p = 0.4138, log-rank test). The combination of antipyretic agents with anticonvulsant medication did not reduce the recurrence of febrile seizures. Our results show that low doses of acetaminophen or diazepam or both are ineffective for preventing febrile seizures.
Many young children wheeze during viral respiratory infections, but the pathogenesis of these episodes and their relation to the development of asthma later in life are not well understood.
In a prospective study, we investigated the factors affecting wheezing before the age of three years and their relation to wheezing at six years of age. Of 1246 newborns in the Tucson, Arizona, area enrolled between May 1980 and October 1984, follow-up data at both three and six years of age was available for 826. For these children, assessments in infancy included measurement of cord-serum IgE levels (measured in 750 children), pulmonary-function testing before any lower respiratory illness had occurred (125), measurement of serum IgE levels at nine months of age (672), and questionnaires completed by the children's parents when the children were one year old (800). Assessments at six years of age included measurement of serum IgE levels (in 460), pulmonary-function testing (526), and skin allergy testing (629).
At the age of six years, 425 children (51.5 percent) had never wheezed, 164 (19.9 percent) had had at least one lower respiratory illness with wheezing during the first three years of life but had no wheezing at six years of age, 124 (15.0 percent) had no wheezing before the age of three years but had wheezing at the age of six years, and 113 (13.7 percent) had wheezing both before three years of age and at six years of age. The children who had wheezing before three years of age but not at the age of six had diminished airway function (length-adjusted maximal expiratory flow at functional residual capacity [Vmax FRC]) both before the age of one year and at the age of six years, were more likely than the other children to have mothers who smoked but not mothers with asthma, and did not have elevated serum IgE levels or skin-test reactivity. Children who started wheezing in early life and continued to wheeze at the age of six were more likely than the children who never wheezed to have mothers with a history of asthma (P < 0.001), to have elevated serum IgE levels (P < 0.01), to have normal lung function in the first year of life, and to have elevated serum IgE levels (P < 0.001) and diminished values for VmaxFRC (P < 0.01) at six years of age.
The majority of infants with wheezing have transient conditions associated with diminished airway function at birth and do not have increased risks of asthma or allergies later in life. In a substantial minority of infants, however, wheezing episodes are probably related to a predisposition to asthma.
A controlled clinical study compared the antipyretic effectiveness of acetaminophen administered at regular 4h intervals (group 1, n = 53) versus sporadic usage contingent upon a body temperature above 37.9 degrees C (group 2, n = 51) in 104 children presenting with simple febrile convulsions. The incidence of febrile episodes or temperature values were similar in spite of significantly larger amounts of acetaminophen administered to patients in group 1. Four and 4 children in groups 1 and 2, respectively, had a second episode of febrile seizures, in all of them within the first 24h of admission. We conclude that the prophylactic administration of acetaminophen in children with febrile seizures is not effective in the prevention of fever, the reduction of its degree, or in preventing the early recurrence of febrile seizures.
Oxygen radicals have been implicated in a variety of disease processes including asthma. In this study we investigated the production of superoxide by airspace cells in 56 patients with asthma as compared with 49 normal controls. We found that with patients with asthma with a forced expiratory vital capacity in the 1st second (FEV1) of less than 80% (n = 13) had higher spontaneous superoxide (SO) production when compared with normal subjects (3.6 +/- 1.0 versus 1.9 +/- 0.2 nmol/5 x 10(5) cells/hour, p < 0.01), whereas those with FEV1 > 80% (n = 40) were similar to normal subjects in superoxide generation (2.1 +/- 0.3 nmol/5 x 10(5) cells/hour). Airspace cells from patients with mild asthma and those with moderate asthma had higher phorbol myristate acetate (PMA)-stimulated SO production when compared with those from normal subjects (8.9 +/- 0.7, 11.1 +/- 2.4, and 6.5 +/- 0.4 nmol/5 x 10(5) cells/hour respectively, p < 0.005, r = -0.35, both comparisons). However, PMA-stimulated SO production was similar in both asthmatic subgroups. Finally, spontaneous generation of SO inversely correlated with FEV1% prediction (r = 0.35, p < 0.01) in the asthma group. We conclude that worsening of airway obstruction in asthma is associated with increased spontaneous generation of SO by airspace leukocytes.
Patients with asthma generate increased amounts of reactive oxygen species (ROS) from peripheral blood cells and cells recovered by bronchoalveolar lavage (BAL). ROS produce many of the pathophysiologic changes associated with asthma and may contribute to its pathogenesis. Although antioxidant defenses inhibit the changes produced by ROS, no data are available on local antioxidant defenses in asthma. The present study was designed to begin to explore these defenses by measuring superoxide dismutase (SOD) and catalase activities and total glutathione (GSH) levels in BAL fluid from normal subjects and patients with mild asthma. Baseline pulmonary function and methacholine bronchoprovocation tests were performed on all subjects. BAL was achieved by instilling five 20-ml aliquots of phosphate-buffered saline in each of three lung segments. The fluids recovered from the first 20-ml aliquot and that from the next four aliquots were labeled bronchial and alveolar fluid, respectively. Patients with asthma had a lower FEV1 (p < 0.005), less BAL fluid recovered (p < 0.05), and an increased percentage of bronchial eosinophils (p < 0.05). There were no differences in BAL total cell count or protein concentration. Catalase activity was not consistently detected in the unconcentrated BAL fluid from either group. SOD activity was found in both bronchial and alveolar samples, but it was similar in the two groups of subjects. The GSH concentration in bronchial fluid was higher in the patients with asthma (23.9 +/- 6.2 vs 13.0 +/- 1.8 microM/mg protein; p < 0.05); a similar trend was seen in the alveolar fluid (36.5 +/- 9.4 vs 23.3 +/- 3.0 microM/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)
To describe the incidence and prognosis of wheezing illness from birth to age 33 and the relation of incidence to perinatal, medical, social, environmental, and lifestyle factors.
Prospective longitudinal study.
England, Scotland and Wales.
18,559 people born on 3-9 March 1958. 5801 (31%) contributed information at ages 7, 11, 16, 23, and 33 years. Attrition bias was evaluated using information on 14, 571 (79%) subjects.
History of asthma, wheezy bronchitis, or wheezing obtained from interview with subjects' parents at ages 7, 11, and 16 and reported at interview by subjects at ages 23 and 33.
The cumulative incidence of wheezing illness was 18% by age 7, 24% by age 16, and 43% by age 33. Incidence during childhood was strongly and independently associated with pneumonia, hay fever, and eczema. There were weaker independent associations with male sex, third trimester antepartum haemorrhage, whooping cough, recurrent abdominal pain, and migraine. Incidence from age 17 to 33 was associated strongly with active cigarette smoking and a history of hay fever. There were weaker independent associations with female sex, maternal albuminuria during pregnancy, and histories of eczema and migraine. Maternal smoking during pregnancy was weakly and inconsistently related to childhood wheezing but was a stronger and significant independent predictor of incidence after age 16. Among 880 subjects who developed asthma or wheezy bronchitis from birth to age 7, 50% had attacks in the previous year at age 7; 18% at 11, 10% at 16, 10% at 23, and 27% at 33. Relapse at 33 after prolonged remission of childhood wheezing was more common among current smokers and atopic subjects.
Atopy and active cigarette smoking are major influences on the incidence and recurrence of wheezing during adulthood.
Respiratory symptoms are frequent in very young children, and the relation of these symptoms to later asthma in some of these children is unknown.
The aim of the study was to describe the natural history of respiratory symptoms in a community-based sample of young children who were prospectively observed for as long as 11 years.
Subjects were participants in the Tucson Epidemiologic Study of Airways Obstructive Disease. They were under 5 years of age at enrollment and were studied by means of a parent-administered mail survey instrument every 1 to 2 years for 3 to 11 years.
Among subjects younger than 1 year of age, no single respiratory symptom, such as cough or wheeze only with colds, significantly increased the risk of a subsequent diagnosis of asthma. Among 1- and 2-year-olds, however, those with wheeze only with colds and those with attacks of shortness of breath with wheeze were more likely to be diagnosed with asthma later when compared with children without those symptoms (odds ration = 2.1; p < 0.05 for wheeze only with colds). At ages 3 to 4 years, symptoms were even more strongly associated with subsequent asthma (odds ratio = 7.2; p < 0.0001 for attacks of shortness of breath with wheeze).
Although respiratory symptoms reported by parents very early in life are not significantly associated with future asthma, those symptoms that begin at or persist through ages 3 to 4 years are.
Routine antipyretic therapy in children with infectious diseases has long been the source of controversy. Each year, in addition to antimalarial medication, millions of children with Plasmodium falciparum malaria receive paracetamol to reduce fever. However, the usefulness of this practice has not been proven.
In a randomised trial in Lambaréné, Gabon, 50 children with P falciparum malaria were treated with intravenous quinine, and received either mechanical antipyresis alone, or in combination with paracetamol. Rectal body temperature and parasitaemia were recorded every 6 h for 4 days. Plasma concentrations and inducible concentrations of tumour necrosis factor (TNF) and interleukin-6 were measured every 24 h. In addition, production of oxygen radicals was measured in both groups.
The mean fever clearance time was 32 h for children treated with paracetamol and 43 h for those who received mechanical antipyresis alone; however, this 11 h difference was not significant (95% CI -2 to 24 h; p = 0.176). Parasite clearance time was significantly prolonged in patients who received paracetamol with a difference of 16 h (8-24 h; p = 0.004). Plasma concentrations of TNF and interleukin-6 were similar in both groups during the study. However, the induced concentrations of TNF, and the production of oxygen radicals, were significantly lower in children treated with paracetamol than those who received mechanical antipyresis alone.
These data suggest that paracetamol has no antipyretic benefits over mechanical antipyresis alone in P falciparum malaria. Moreover, paracetamol prolongs parasite clearance time, possibly by decreased production of TNF and oxygen radicals.
The prevalence of asthma, atopic eczema, and allergic rhinitis has increased over the last three decades in Western countries. Speculation on the causes of this trend have focused on changes in environmental factors. We hypothesize that the decreased use of aspirin in favor of acetaminophen, due to the association of aspirin with Reye's syndrome during febrile respiratory infections, may be contributing to these trends in the United States.
A detailed literature search was conducted utilizing Medline. Studies considered relevant and important involving both humans and animals in English language were used.
In the United States, the documented prevalence of childhood asthma has increased since 1970, but the rate of this increase accelerated upward beginning in the early 1980s when the use of pediatric aspirin decreased. During the resolution of common respiratory viral infections, prostaglandin E2 (PGE2) is produced through the actions of cyclooxygenase-2 (COX-2). Aspirin, but not acetaminophen, inhibits COX-2 activity. As PGE2 promotes TH2 and inhibits THI type cytokine generation, we hypothesize that the decreased use of aspirin may be a factor in facilitating allergic sensitization and asthma by augmenting the relative TH1/TH2 cytokine imbalance in genetically predisposed children.
We have presented an hypothesis based upon epidemiologic trends, known biologic effects of cytokines and PGE2 on allergic sensitization, and a potentially relevant pharmacologic effect of aspirin to explain a component of the increasing prevalence of childhood asthma in the United States. We suggest this theory be examined further in animal models as well as in other countries where the prevalence of childhood asthma is increasing.
The relation between lower respiratory tract illnesses in early life caused by the respiratory syncytial virus (RSV) and the subsequent development of wheezing and atopy in childhood is not well understood. We studied this relation in children who had lower respiratory tract illnesses that occurred before 3 years of age.
Children were enrolled at birth and cases of lower respiratory tract illness were ascertained by a physician. Viral tests were done for specimens collected at the time of the illness. Children were classified into five groups according to type and cause of lower respiratory tract illness. Children were then followed prospectively up to age 13, and we measured frequency of wheezing, pulmonary function, and atopic status (allergy skin-prick tests, serum IgE concentrations).
RSV lower respiratory tract illnesses were associated with an increased risk of infrequent wheeze (odds ratio 3.2 [95% CI 2.0-5.0], p < 0.001), and an increased risk of frequent wheeze (4.3 [2.2-8.7], p < or = 0.001) by age 6. Risk decreased markedly with age and was not significant by age 13. There was no association between RSV lower respiratory tract illnesses and subsequent atopic status. RSV lower respiratory tract illnesses were associated with significantly lower measurements of forced expiratory volume (2.11 [2.05-2.15], p < or = 0.001) when compared with those of children with no lower respiratory tract illnesses, but there was no difference in forced expiratory volume after inhalation of salbutamol.
RSV lower respiratory tract illnesses in early childhood are an independent risk factor for the subsequent development of wheezing up to age 11 years but not at age 13. This association is not caused by an increased risk of allergic sensitisation.
Reports have suggested that certain infants are predisposed to wheezing in the first 2 yrs of life due to abnormal lung function, prior to the first wheezing illness. The authors investigated the association between infant lung function and wheeze during the first 2 yrs of life. A cohort of 253 infants was evaluated. Respiratory function assessment was performed at 1, 6, and 12 months of age. Parental history of asthma, atopy, and maternal antenatal smoking habits were recorded. An infant was identified as having wheezed on the basis of parental report and, where possible, physician diagnosis. One hundred and sixty infants (63%) had complete diary and questionnaire information on wheeze available for analysis. Of these: 79 infants (50%) had never wheezed (NW) during the first 2 yrs of life and 81 had reported wheeze (W) (50%). Of those with a report of wheeze, the distribution through the first 2 yrs of life was; 28 during the first year of life only (Y1), 21 in the second year of life only (Y2), and 32 wheezed in both the first and second years of life (Y1&2). At the age of 1 month, prior to any lower respiratory illness, the W group had impaired lung function in comparison to the NW group. In Y1 infants, the neonatal lung function differences resolved by 12 months of age. In Y2 and Y1&2 infants lung function differences persisted throughout the first year of life. Prevalence of parental asthma and maternal antenatal smoking was increased in the W group p=0.001, p=0.008, respectively), in comparison to the NW infants. Maternal antenatal smoking prevalence was increased in the Y2 and Y1&2 infants in comparison to the NW group (p=0.04), (p=0.01), respectively. Wheezing during the first year of life is often a transient condition which improves with time. It appears to be related to early life reduced small airway calibre. Wheezing that begins or persists into the second year of life is usually associated with a different abnormality of the airways. Commencement or persistence of wheeze into the second year of life may be part of the clinical entity recognized as asthma.
The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma.
Information was collected on the use of analgesics as part of a population based case-control study of dietary antioxidants and asthma in adults aged 16-49 years registered with 40 general practices in Greenwich, South London. The frequency of use of paracetamol and aspirin was compared in 664 individuals with asthma and in 910 without asthma. Asthma was defined by positive responses to questions about asthma attacks, asthma medication, or waking at night with shortness of breath. The association between analgesic use and severity of disease amongst asthma cases, as measured by a quality of life score, was also examined.
Paracetamol use was positively associated with asthma. After controlling for potential confounding factors the odds ratio for asthma, compared with never users, was 1.06 (95% CI 0.77 to 1.45) in infrequent users (<monthly), 1.22 (0.87 to 1.72) in monthly users, 1. 79 (1.21 to 2.65) in weekly users, and 2.38 (1.22 to 4.64) in daily users (p (trend) = 0.0002). This association was present in users and non-users of aspirin and was stronger when cases with more severe disease were compared with controls; amongst cases increasing paracetamol use was associated with more severe disease. Frequency of aspirin use was not associated with asthma when cases as a whole were compared with controls, nor with severity of asthma amongst cases. Frequent paracetamol use was positively associated with rhinitis, but aspirin use was not.
Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults.
One of the major questions regarding long-term side effects of bronchiolitis by respiratory syncytial virus (RSV) is whether or not it induces asthma in later life. In this quantitative review, the data of 10 controlled studies are analysed.
Follow-up studies of RSV bronchiolitis published between January 1978 and December 1998 were identified through a MEDLINE search. Studies were selected if (i) postnatal age at the time of the initial illness was below 12 mo, (ii) all children were hospitalized for RSV bronchiolitis, (iii) the diagnosis RSV was virologically confirmed in all cases, and (iv) a control group was used.
Six studies met all selection criteria. Up to 5 y of follow-up after RSV bronchiolitis in infancy, 40% of children reported wheezing as compared to only 11% in the control group (p <0.001). Between 5 and 10 y of follow-up 22% of the bronchiolitis group reported wheezing against 10% of the control group (p = 0.19). The incidence of recurrent wheezing as defined by three or more wheezing episodes also decreased with increasing years of follow-up: at 5 or more years of follow-up the difference between the RSV group and the control group was no longer significant. Furthermore, the presence of either a personal and/or a family history of either atopy and/or asthma did not differ between the two groups.
Wheezing is common after RSV bronchiolitis in infancy. It may persist for > or = 5 y of follow-up. However, no significant difference between the RSV bronchiolitis and the control group was observed regarding recurrent wheezing by 5 y of follow-up. No significant difference between the RSV bronchiolitis and the control group were found regarding a personal history of atopy, a family history of atopy and/or asthma. Therefore it seems unlikely that RSV bronchiolitis is a cause of atopic asthma in later life.
To test the hypothesis that short-term use of ibuprofen increases asthma morbidity in children.
A randomized, double-blind, acetaminophen-controlled clinical trial was conducted. Children who had asthma and a febrile illness were randomly assigned to receive either acetaminophen suspension or ibuprofen suspension for fever control. Rates of hospitalization and outpatient visits for asthma during follow-up were compared by randomization group.
A total of 1879 children receiving asthma medications were studied. Rates of hospitalization for asthma did not vary significantly by antipyretic assignment; compared with children who were randomized to acetaminophen, the relative risk for children who were assigned to ibuprofen was 0.63 (95% confidence interval: 0.25-1.6). However, the risk of an outpatient visit for asthma was significantly lower in the ibuprofen group; compared with children who were randomized to acetaminophen, the relative risk for children who were assigned to ibuprofen was 0.56 (95% confidence interval: 0.34-0.95).
Rather than supporting the hypothesis that ibuprofen increases asthma morbidity among children who are not known to be sensitive to aspirin or other nonsteroidal antiinflammatory drugs, these data suggest that compared with acetaminophen, ibuprofen may reduce such risks. Whether the observed difference in morbidity according to treatment group is attributable to increased risk after acetaminophen use or a decrease after ibuprofen cannot be determined. These data provide evidence of the relative safety of ibuprofen use in children with asthma.