Drug-induced Adverse Reactions Research Articles

Dress Syndrome - A Case Report

Abstract The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse drug-induced reaction that occurs most commonly after exposure to drugs, most frequently anticonvulsants, sulfa derivates, antidepressants, nonsteroidal anti-inflammatory drugs, and antimicrobials. We present a 61-year-old male, with a generalized maculopapular exanthema on the trunk, face, extremities, palms, soles, palate, and fever (38°C). His medical history was notable for generalized epilepsy, treated with carbamazepine during 1 month. The diagnosis of DRESS syndrome was confirmed by specific RegiSCAR criteria. In our case, skin eruptions were successfully treated with oral methylprednisolone, cephalexin, and topical corticosteroid ointment. In conclusion, although the mechanisms of this syndrome are not completely understood, numerous cases were reported in children and adults. This syndrome should be considered in every patient with skin eruption, fever, eosinophilia, liver and hematological abnormalities. Prompt recognition, supportive therapy and initiation of corticosteroids may prevent systemic manifestations.

Ginger for Prevention of Antituberculosis-induced Gastrointestinal Adverse Reactions Including Hepatotoxicity: A Randomized Pilot Clinical Trial.

In this study, the potential benefits of ginger in preventing antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity have been evaluated in patients with tuberculosis. Patients in the ginger and placebo groups (30 patients in each group) received either 500 mg ginger (Zintoma)(®) or placebo one-half hour before each daily dose of antituberculosis drugs for 4 weeks. Patients' gastrointestinal complaints (nausea, vomiting, dyspepsia, and abdominal pain) and antituberculosis drug-induced hepatotoxicity were recorded during the study period. In this cohort, nausea was the most common antituberculosis drug-induced gastrointestinal adverse reactions. Forty eight (80%) patients experienced nausea. Nausea was more common in the placebo than the ginger group [27 (90%) vs 21 (70%), respectively, p = 0.05]. During the study period, 16 (26.7%) patients experienced antituberculosis drug-induced hepatotoxicity. Patients in the ginger group experienced less, but not statistically significant, antituberculosis drug-induced hepatotoxicity than the placebo group (16.7% vs 36.7%, respectively, p = 0.07). In conclusion, ginger may be a potential option for prevention of antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity. Copyright © 2016 John Wiley & Sons, Ltd.

Role of endoplasmic reticulum stress in drug-induced toxicity.

Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

Use of Diuretics is not associated with mortality in patients admitted to the emergency department: results from a cross-sectional study.

BackgroundPatients with diuretic therapy are at risk for drug-induced adverse reactions. It is unknown if presence of diuretic therapy at hospital emergency room admission is associated with mortality.MethodsIn this cross sectional analysis, all emergency room patients 2010 and 2011 at the Inselspital Bern, Switzerland were included. A multivariable logistic regression model was performed to assess the association between pre-existing diuretic medication and 28 day mortality.ResultsTwenty-two thousand two hundred thirty-nine subjects were included in the analysis. A total of 8.5 %, 2.5 %, and 0.4 % of patients used one, two, or three or more diuretics. In univariate analysis spironolactone, torasemide and chlortalidone use were associated with 28 day mortality (all p < 0.05). In a multivariate cox regression model no association with mortality was detectable (p > 0.05). No difference existed between patients with or without diuretic therapy (P > 0.05). Age and creatinine were independent risk factors for mortaliy (both p < 0.05).ConclusionUse of diuretics is not associated with mortality in an unselected cohort of patients presenting in an emergency room.

Diagnosis of Human Axillary Osmidrosis by Genotyping of the Human ABCC11 Gene: Clinical Practice and Basic Scientific Evidence.

The importance of personalized medicine and healthcare is becoming increasingly recognized. Genetic polymorphisms associated with potential risks of various human genetic diseases as well as drug-induced adverse reactions have recently been well studied, and their underlying molecular mechanisms are being uncovered by functional genomics as well as genome-wide association studies. Knowledge of certain genetic polymorphisms is clinically important for our understanding of interindividual differences in drug response and/or disease risk. As such evidence accumulates, new clinical applications and practices are needed. In this context, the development of new technologies for simple, fast, accurate, and cost-effective genotyping is imperative. Here, we describe a simple isothermal genotyping method capable of detecting single nucleotide polymorphisms (SNPs) in the human ATP-binding cassette (ABC) transporter ABCC11 gene and its application to the clinical diagnosis of axillary osmidrosis. We have recently reported that axillary osmidrosis is linked with one SNP 538G>A in the ABCC11 gene. Our molecular biological and biochemical studies have revealed that this SNP greatly affects the protein expression level and the function of ABCC11. In this review, we highlight the clinical relevance and importance of this diagnostic strategy in axillary osmidrosis therapy.

Levofloxacin-induced bullous fixed drug eruption: A rare case report

Drug-induced cutaneous adverse drug reactions are very much common, especially with antibiotics. Fluoroquinolones are widely used antibiotics for different types of infective conditions. However, dermatological adverse drug reactions to this category of antibiotics are very rare but many times fatal. Bullous fixed drug eruption (FDE), being one of them, is very important to watch for. Here, we are reporting levofloxacin-induced bullous FDE in elderly hypertensive patient.

Drug reaction with eosinophilia and systemic symptom induced in a 9-year-old boy

The drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction. Acetaminophen is extensively used as an over-the-counter drug as well as a medical therapeutic. In spite of its frequent use, drug eruptions related to DRESS caused by acetaminophen are rare. This case report describes a 9-year-old boy who experienced fever and maculopapular skin rashes after taking acetaminophen. Leukocytosis with marked eosinophilia and slightly elevated levels of liver enzymes were observed. Symptoms resolved after withdrawal of acetaminophen, followed by intravenous methylprednisolone administration. The diagnosis of DRESS induced by acetaminophen was confirmed by an oral challenge test after 2 months. No allergic reactions to ibuprofen were observed. (Allergy Asthma Respir Dis 2016:4:296-300)

Structural modeling of HLA-B*1502/peptide/carbamazepine/T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis

Drug-induced adverse reactions are a significant problem in healthcare worldwide and are estimated to cost billions of dollars annually in the United States. A portion of such reactions is observed to strongly associate with certain human leukocyte antigen (HLA) alleles; one of the strongest associations is the HLA-B*1502 protein with carbamazepine (CBZ)-induced Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – the odds ratio value can even be higher than one thousand. The particularly strong association in CBZ-induced SJS/TEN suggests that the HLA-B*1502 is not only a genetic marker but also a participant in the pathogenesis of the disease. In the current study, we attempt to computationally model the atomic-level structure of the complete HLA-B*1502/peptide/CBZ/T-cell receptor (TCR) complex architecture based on prior knowledge obtained from epidemiological investigations as well as in vitro and in vivo assays. The model tells a different story about the molecular mechanism of CBZ-induced SJS/TEN from that previously reported for abacavir (ABC)-induced hypersensitivity (HSR); the CBZ molecule is located at the interface between HLA-B*1502/peptide and TCR, directly contacts the P3–P6 residues of antigen peptide, and bound within a pocket region encompassed by two TCR CDR3 fingers. Molecular dynamics simulation and binding energy analysis further reveal that the CBZ shows considerably high affinity to TCR over HLA-B*1502/peptide, which can tightly interact with the former rather than the latter. From the model, two hypotheses are proposed that can well explain most previous observations and are expected to guide next wet-lab experiments. This study could help to promote our understanding of the molecular mechanism and pathological implication underlying CBZ-induced SJS/TEN.

HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs.

PurposeStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea.Materials and MethodsWe enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01.ResultsHLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03.ConclusionHLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.

Evidence for neurotoxicity associated with amoxicillin in juvenile rats.

Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity.

Hypersensitivity to Aspirin and other NSAIDs: Diagnostic Approach in Patients with Chronic Rhinosinusitis.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) associated with chronic rhinosinusitis (CRS) and/or asthma comprises a distinct clinical syndrome referred to as NSAIDs exacerbated respiratory disease (NERD). Patients with NERD tend to have more severe course of both upper (CRS and nasal polyps) and lower airway (asthma) diseases and are usually recalcitrant to conventional treatment modalities. Diagnosing and phenotyping of patients with NERD are critical for prevention of drug-induced adverse reactions and open novel options for management of underlying chronic airway inflammatory diseases. Diagnosis of NERD is based on detailed clinical history confirmed by challenge with aspirin, but new diagnostic approaches are currently being developed. This review article focuses on the diagnostic approach to a patient with CRS and hypersensitivity to NSAIDs, emphasizing the importance of diagnosis for proper patient’s management.

Drug-induced ocular adverse reactions: review of the safety alerts issued during the last decade.

The purpose of this study was to evaluate ocular-related adverse events associated with the use of drugs by analyzing the content of safety alerts issued by major regulatory authorities during the last decade. The websites of 4 health regulatory authorities were reviewed to identify safety alerts issued on ocular adverse events. Safety alerts were included if they have been issued between January 2005 and December 2014. Only safety alerts on drugs with market authorization were considered for inclusion. Thirty-eight safety alerts were included in the study. Urologicals (n = 11; 29%), followed by drugs used in diabetes, antibacterials for systemic use, antineoplastic agents, and ophthalmologicals were the most frequently suspected drugs evaluated in the safety alerts (n = 4; 10%, each). The most frequently evaluated adverse events were visual disorders NEC (n = 12; 32%), including visual impairment, diplopia, and blurred vision. The majority (n = 25; 66%) of the safety alerts were supported by postmarketing spontaneous reports. The most commonly updated drug label section was the Warnings and Precautions section (n = 33; 87%), followed by the Adverse Reactions section (n = 26; 68%). Ocular adverse events, newly identified during this decade, come mostly from systemic drugs, some of them marketed for several years. Physicians should be aware of drug-induced adverse events in the eye to avoid, as soon as possible, their progression, which can lead to visual impairment.

A Case of the Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) Following Isoniazid Treatment.

The drug reaction with eosinophilia and systemic symptom (DRESS) syndrome is a severe adverse drug-induced reaction which includes a severe skin eruption, fever, hematologic abnormalities (eosinophilia or atypical lymphocytes) and internal organ involvement. The most frequently reported drug was anticonvulsants. The diagnosis of DRESS syndrome is challenging because the pattern of cutaneous eruption and the types of organs involved are various. The treatments for DRESS syndrome are culprit drug withdrawal and corticosteroids. Here we report a 71-year-old man with skin eruption with eosinophilia and hepatic and renal involvement that appeared 4 weeks after he had taken anti-tuberculosis drugs (isoniazid, ethambutol, rifampicin, and pyrazinamide), and resolved after stopping anti-tuberculosis drugs and the administration of systemic corticosteroids. DRESS recurred after re-challenging isoniazid, we identified isoniazid was causative drug.

A study on anti-tubercular drug-induced adverse reactions in South Indian district tuberculosis center

Background: An adverse drug reaction (ADR) is any response to a drug which is noxious and unintended occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease or the modification of physiological function, anti-tubercular drugs can cause ADR and involving almost all systems in the body including the gastrointestinal (GI) tract, liver, skin, nervous system, and eyes. Methods: A prospective observational study was conducted on tuberculosis (TB) patient. The suspected drug identified for ADRs and the type, nature, severity of reaction were recorded. A total of 239 patients were enrolled in the study. The patient was monitored the suspected ADRs were recorded and assessed for causality and severity. Results: Out of 239 patients, 60 (25.11%) developed one and more than one ADR. A maximum number of tubercular patients were in age group of 21-40 years (44.4%). The majority of patients were males (69%). Incidence of ADRs based on affected organ was GI system disorders (30.33%), skin and appendages disorders (23.62%), central and peripheral nervous system disorders (15.28%), musculo-skeletal system disorders and liver and biliary disorder (9.72% each), hearing disorder (5.55%), and visual disorder accounts of (2.78%). Conclusion: TB still becomes worldwide health problem not only on developing country but also in the developed country even the number of TB patients most large in the developing country. The importance of developing strategies to ameliorate ADRs both to improve the quality of patient care and to control TB safely.

Drug-induced adverse reactions via breastfeeding: a descriptive study in the French Pharmacovigilance Database.

Most drugs are excreted in maternal milk and may therefore be ingested by children during breastfeeding. Data concerning the safety of the use of drugs by breastfeeding women are patchy, and almost nothing is known about this issue for many drugs. The aim of this study was to describe the adverse drug reactions of drugs transmitted in breast milk on the basis of the data collected in the French Pharmacovigilance Database. All spontaneous reports of adverse drug reactions (ADRs) in breastfed infants recorded in the National Pharmacovigilance Database by the 31 French regional pharmacovigilance centres between 1984 and June 2011 were investigated. Between January 1985 and June 2011, 276 adverse drug reactions in 174 breastfed children were notified to the French Pharmacovigilance Network. The most frequently reported adverse drug reactions were neurological (28.6 %) and gastrointestinal (20.3 %). Sixty-five of the adverse drug reactions recorded were considered to be serious (37.4 %). The results of our study confirm that certain drugs were frequently implicated in serious adverse drug reactions. Two cases of ADRs (1.1 %) had a 'certain' causality score (I4) and 13 (7.5 %) a 'likely' score (I3). The suspected drugs include antiepileptic drugs, opiate analgesics and benzodiazepines. These results also demonstrate that some drugs that were thought to be anodyne or for which no data were available, such as ketoprofen and hydroxyzine, may be implicated in adverse effects. Finally, these data show that certain drugs, like pseudoephedrine, which should not be used during breastfeeding, were nevertheless implicated in several of the adverse drug reactions recorded. This study shows that ADR via breastfeeding are rarely reported due to low awareness or low occurrence of ADR via breast milk. These results highlight the need for additional pharmacokinetic, clinical and epidemiological studies, given the paucity of published data. They also demonstrate the need to improve information for the general public about drugs and self-medication during breastfeeding.

PS-080 Multiple antituberculosis drug-induced adverse reactions occurring in the same patient: How to treat?

BackgroundThe first-line treatment of tuberculosis relies on four essential drugs (isoniazid, rifampicin, pyrazinamide, ethambutol). This association increases the frequency of side effects of each anti-tuberculosis drug.PurposeTo report a clinical case...

Pharmacoepidemiological characterization of drug-induced adverse reaction clusters towards understanding of their mechanisms

A big challenge in pharmacology is the understanding of the underlying mechanisms that cause drug-induced adverse reactions (ADRs), which are in some cases similar to each other regardless of different drug indications, and are in other cases different regardless of same drug indications. The FDA Adverse Event Reporting System (FAERS) provides a valuable resource for pharmacoepidemiology, the study of the uses and the effects of drugs in large human population. However, FAERS is a spontaneous reporting system that inevitably contains noise that deviates the application of conventional clustering approaches. By performing a biclustering analysis on the FAERS data we identified 163 biclusters of drug-induced adverse reactions, counting for 691ADRs and 240 drugs in total, where the number of ADR occurrences are consistently high across the associated drugs. Medically similar ADRs are derived from several distinct indications for use in the majority (145/163=88%) of the biclusters, which enabled us to interpret the underlying mechanisms that lead to similar ADRs. Furthermore, we compared the biclusters that contain same drugs but different ADRs, finding the cases where the populations of the patients were different in terms of age, sex, and body weight. We applied a biclustering approach to catalogue the relationship between drugs and adverse reactions from a large FAERS data set, and demonstrated a systematic way to uncover the cases different drug administrations resulted in similar adverse reactions, and the same drug can cause different reactions dependent on the patients’ conditions.

A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

N-Acetyltransferase 2 (NAT2) is an important enzyme involved in the metabolism of a wide spectrum of naturally occurring xenobiotics, including therapeutic drugs and common environmental carcinogens. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in acetylation capacity, which influences individual susceptibility to various drug-induced adverse reactions and cancers. Striking patterns of geographic differentiation have been described for the main slow acetylation variants of the NAT2 gene, suggesting the action of natural selection at this locus. In the present study, we took advantage of whole-genome sequence data available from the 1000 Genomes project to investigate the global patterns of population genetic differentiation at NAT2 and determine whether they are atypical compared with the remaining variation of the genome. The nonsynonymous substitution c.590G>A (rs1799930) defining the slow NAT2*6 haplotype cluster exhibited an unusually low FST value compared with the genome average (FST = 0.006, P = 0.016). It was indicated as the most likely target of a homogenizing process of selection promoting the same allelic variant in globally distributed populations. The rs1799930 A allele has been associated with the slowest acetylation capacity in vivo, and its substantial correlation with the subsistence strategy adopted by past human populations suggests that it may have conferred a selective advantage in populations shifting from foraging to agricultural and pastoral activities in the Neolithic period. Results of neutrality tests further supported an adaptive evolution of the NAT2 gene through either balancing selection or directional selection acting on multiple standing slow acetylation variants.

Drug-induced cutaneous adverse drug reactions in dermatology in Dr. B.R. Ambedkar Medical College

Background: Cutaneous adverse drug reactions (ADRs) affect 2-3% of hospitalized patients. The severity varies from mild itching to life-threatening Stevens-Johnson syndrome (SJS). Hence, this study was undertaken to emphasize the need to report ADRs. Methods: The study was carried out in the Department of Dermatology in Dr. B.R Ambedkar Medical College Hospital from June to December 2012. Naranjo’s algorithm was used to determine the causality of an ADR. Informed consent was obtained from each patient, and thorough clinical examination was conducted. All the information was carefully recorded in a pre-designed proforma. To establish the etiologic agent for a particular type of reaction, attention was paid to the drug history, temporal correlation with the drug, duration of the reaction, morphology of the reaction, associated mucosal or systemic involvement, improvement of lesions on withdrawal of the drug. Results: In the present study, all the age groups were affected with cutaneous ADRs, with a higher incidence in age group between 31 and 40 years, non-steroidal anti-inflammatory drugs (NSAIDs) (41.66%) were most commonly observed drug, followed by anti-microbials (25%) and anti-convulsants (21.66%). Fixed drug eruptions (FDE) (46.66%) most commonly observed cutaneous reaction, followed by SJS (16.66%), erythema multiformae (16.66%) most commonly observed ADRs. Conclusions: ADRs are potentially avoidable causes for seeking medical care. FDE was most common ADR and NSAIDs were most common causative agents in our study. ADRs can be prevented by avoiding polypharmacy, obtaining history of any previous skin reaction and the causative agent.

Chronic Hepatitis C Therapy in Liver Cirrhosis Complicated by Telaprevir-Induced DRESS.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare yet severe adverse drug-induced reaction with up to 10% mortality rate. Recent clinical trials reported an association between DRESS and telaprevir (TVR), an NS3/4A protease inhibitor of chronic hepatitis C (CHC) virus genotype 1. Its diagnosis is challenging given the variable pattern of cutaneous eruption and the myriad internal organ involvement. We present two patients who are middle-aged, obese, and white with CHC cirrhosis. They both developed a progressive diffuse, painful pruritic maculopapular rash at weeks 8 and 10 of CHC therapy with TVR, Peg-Interferon alfa-2a, and Ribavirin. They had no exposures to other medications that can cause this syndrome. Physical exam and labs and skin biopsy supported a “Definite” clinical diagnosis of DRESS, per RegiSCAR criteria. Thus Telaprevir-based triple therapy was discontinued and both patients experienced rapid resolution of the systemic symptoms with gradual improvement of eosinophilia and the skin eruption. These two cases illustrate the paramount importance of having a high index of suspicion for TVR-induced DRESS, critical for early diagnosis. Immediate discontinuation of TVR is essential in prevention of a potentially life-threatening complication. Risk factors for development of DRESS in patients receiving TVR remain to be elucidated.