Spectrum Of Adverse Drug Reactions Research Articles

Evaluating antiretroviral therapy–induced insulin resistance syndrome using the homeostasis model assessment method: an important global clarion call for concern among people living with HIV-disease

Abstract Background Antiretroviral treatment advances have been accompanied by a new spectrum of adverse drug reactions that affect metabolism and body composition. Purpose This review was principally designed to focus on how to comprehensively evaluate for the occurrence of antiretroviral therapy-induced insulin resistance syndrome with associated impaired glucose metabolism disorder(s) among people living with HIV disease. Data sources and materials During the course of this present study, original peer-reviewed articles reported in English language that investigated antiretroviral therapy-induced insulin resistance were identified by exploring the Medline-Entrez-PubMed search, Web of Science database, Google Scholar search, and Science Direct database online facilities. Also, information was sourced from printed textbooks and the reports documented by some recognized medically inclined and health professional bodies. These published materials containing documented reports relating to the subject matter of focus in this review were accessed and adequately referenced. This study spanned for 12-month duration from March 2023 to February 2024. Study selection and manuscript preparation with limitations A total number of 92 published articles were reviewed, out of which 55 referenced articles were found to contain information pertinent to this present study; while those parts of the referenced articles inapt to this study were neglected. Antiretroviral therapy-induced insulin resistance syndrome can be broadly classified into mild, moderate, and severe categories; based on the severity grading reviews of homeostasis model assessment-insulin resistance index values. Conclusion The clinical assessment of antiretroviral therapy-induced insulin resistance syndrome should be given utmost importance in HIV-disease individuals with considerably high-risk factor(s) for its occurrence.

Adverse Drug Reactions Monitoring in New Patients Admitted to the Cardiac Care Unit in a Tertiary Care Hospital

Background: Adverse Drug Reactions (ADRs) are amongst the commonly occurring event in the intensive care unit where patients are mostly on the polypharmacy. They affect the quality of life of patients and increase the burden on the health care system. Aim and Objectives: The study aimed to estimate the incidence of ADRs and to assess the causality and seriousness of such ADRs by using the Naranjo probability scale. A prospective, observational, longitudinal study was conducted on patients admitted to the cardiac care unit over a period of 10 months. ADRs profile was noted by spontaneous and intensive monitoring. For analysis, descriptive statistics with 95% CI were used. Results: A total of 77 ADRs were reported from the 173 patients, out of which 31 patients suffered from ADRs, with an incidence of 17.9%. The gastrointestinal system was the most common affected system followed by the cardiovascular and respiratory systems. When analyzed on the Naranjo ADR probability scale, the majority of the ADRs (67.5%) were rated as probable followed by possible (32.4%). It was observed that the number of drugs used as well as the duration of stay in the hospital, in patients with ADRs, was significantly higher than those who did not have any adverse effect. The pattern and spectrum of ADRs need to be studied further so that their occurrence can be prevented. Conclusion: The study can be useful in identifying and minimizing preventable ADRs and can be an effort to make the use of drugs more rational and safe

Hypersensitivity reactions to small molecule drugs.

Drug hypersensitivity reactions induced by small molecule drugs encompass a broad spectrum of adverse drug reactions with heterogeneous clinical presentations and mechanisms. These reactions are classified into allergic drug hypersensitivity reactions and non-allergic drug hypersensitivity reactions. At present, the hapten theory, pharmacological interaction with immune receptors (p-i) concept, altered peptide repertoire model, and altered T-cell receptor (TCR) repertoire model have been proposed to explain how small molecule drugs or their metabolites induce allergic drug hypersensitivity reactions. Meanwhile, direct activation of mast cells, provoking the complement system, stimulating or inhibiting inflammatory reaction-related enzymes, accumulating bradykinin, and/or triggering vascular hyperpermeability are considered as the main factors causing non-allergic drug hypersensitivity reactions. To date, many investigations have been performed to explore the underlying mechanisms involved in drug hypersensitivity reactions and to search for predictive and preventive methods in both clinical and non-clinical trials. However, validated methods for predicting and diagnosing hypersensitivity reactions to small molecule drugs and deeper insight into the relevant underlying mechanisms are still limited.

Accelerating High-Dimensional Temporal Modelling Using Graphics Processing Units for Pharmacovigilance Signal Detection on Real-Life Data.

Adverse drug reaction is a major public health issue. The increasing availability of medico-administrative databases offers major opportunities to detect real-life pharmacovigilance signals. We have recently adapted a pharmacoepidemiological method to the large dimension, the WCE (Weigthed Cumulative Exposure) statistical model, which makes it possible to model the temporal relationship between the prescription of a drug and the appearance of a side effect without any a priori hypothesis. Unfortunately, this method faces a computational time problem. The objective of this paper is to describe the implementation of the WCE statistical model using Graphics Processing Unit (GPU) programming as a tool to obtain the spectrum of adverse drug reactions from medico-administrative databases. The process is divided into three steps: pre-processing of care pathways using the Python library Panda, calculation of temporal co-variables using the Python library "KeOps", estimation of the model parameters using the Python library "PyTorch" - standard in deep learning. Programming the WCE method by distributing the heaviest portions (notably spline calculation) on the GPU makes it possible to accelerate the time required for this method by 1000 times using a computer graphics card and up to 10,000 times with a GPU server. This implementation makes it possible to use WCE on all the drugs on the market to study their spectrum of adverse effects, to highlight new vigilance signals and thus to have a global vigilance tool on medico-administrative database. This is a proof of concept for the use of this technology in epidemiology.

Pattern of adverse drug reaction in geriatric inpatients of medicine in a tertiary care center: a prospective observational study

Background: Adverse drug reactions (ADRs) represent a major public health problem in older age. In order to better evaluate this problem, this study was designed to assess the prevalence and spectrum of ADRs in terms of frequency, type, severity and preventability in geriatric patients in medicine ward of Guru-Gobind Sing hospital, Jamnagar during 12 months study period.Methods: All ADR related patient’s necessary data was obtained and recorded on a pre- designed case record form (CRF). The data record includes general details e.g., name, age, sex, past and present history, general and systemic examination, laboratory investigation, diagnosis and treatment. Details regarding suspected medications, treatment given, and the outcome were documented with prior permission of institutional ethics committee.Results: Demographic analysis of prospective study revealed that out of 84 patients, 45 male and 39 were female. The patients had developed ADR within the age ranges of 31 (65-69) followed by 23 (75-79). The majority of ADR was vomiting and diarrhea 15 followed by chills 08 and cough 04. It is evident that antimicrobials 31 agents were mainly suspected followed by NSAIDs 18. In causality assessment, the possible cases had a higher incidence 63, followed by probable 19 and certain 2. After estimating the severity by Hartwigs scale 79.8% were mild to moderate while 20.23% were severe in nature.Conclusions: Age is not an independent risk factor of ADRs and suitable monitoring and regular medication review can reduce the incidence of ADRs in geriatric people.

A prospective observational study of ophthalmic adverse drug reactions in a tertiary care hospital

Background: According to an epidemiological study, 1.7–25.1% of eye disease was drug induced, but the evidence of adverse drug reactions (ADRs) in ophthalmology is found to be scarce, as it is difficult in correlation between symptoms and ocular signs, and their causality assessment. Hence, the present study of ADR in ophthalmology is taken up. Aim and Objectives: The aim of the study was to assess the pattern of reported ophthalmic ADR due to ophthalmic or systemic drugs and systemic ADRs due to ophthalmic drugs and to assess the causality, severity, and preventability factors of reported ADRs. Materials and Methods: A prospective observational study enrolling 100 subjects with ocular ADRs due to ocular or systemic drugs, and systemic ADRs due to ocular drugs visiting KIMS Hospital and Research Centre, Bengaluru. Following Institutional Ethics Committee approval and clearance, and written informed consent from study subjects, 100 consecutive subjects fulfilling inclusion and exclusion criteria will be included for the study. The causality of ADRs is assessed by WHO-UMC and Naranjo’s causality assessment scale. The severity of ADR assessed using Modified Hartwig scale. The preventability of ADR assessed by Modified Schumock and Thornton scale follow-up will be done for severe ADRs. Results: The clinical spectrum of ADRs ranged from mild redness of the eyes, itching, lacrimation, blurred vision, and purulent discharge from the eyes and to loss of vision. The most common causative drugs were antimicrobials, anti-inflammatory agents, antiepileptics, and mydriatics. Majority of ADRs were probable in WHO-UMC causality assessment, mild in severity, and definitely preventable. No fatal cases were reported. Conclusion: The clinical pattern of reported ocular ADRs due to topical and systemic drugs from the ophthalmology department and in wards ranged from mild severity to moderately severe reactions requiring patient hospitalization.

African Pharmacogenomics Consortium:Consolidating pharmacogenomics knowledge, capacity development and translation in Africa: Consolidating pharmacogenomics knowledge, capacity development and translation in Africa.

The African Pharmacogenomics Consortium (APC) was formally launched on the 6th September 2018. This white paper outlines its vision, and objectives towards addressing challenges of conducting and applying pharmacogenomics in Africa and identifies opportunities for advancement of individualized drugs use on the continent. Africa, especially south of the Sahara, is beset with a huge burden of infectious diseases with much co-morbidity whose multiplicity and intersection are major challenges in achieving the sustainable development goals (SDG), SDG3, on health and wellness. The profile of drugs commonly used in African populations lead to a different spectrum of adverse drug reactions (ADRs) when compared to other parts of the world. Coupled with the genetic diversity among Africans, the APC is established to promote pharmacogenomics research and its clinical implementation for safe and effective use of medicine in the continent. Variation in the way patients respond to treatment is mainly due to differences in activity of enzymes and transporters involved in pathways associated with each drug's disposition. Knowledge of pharmacogenomics, therefore, helps in identifying genetic variants in these proteins and their functional effects. Africa needs to consolidate its pharmacogenomics expertise and technological platforms to bring pharmacogenomics to use.

The spectrum of adverse drug reactions in a multidisciplinary kidney clinic

Introduction: Data on adverse drug-reactions (ADR) in the medical field are rare. Objective: To report on the pattern of such problem in a multidisciplinary kidney clinic Patients and Methods: Medical records of patients were reviewed retrospectively for such phenomenon in the past 6 years Results: A total of 4834 patients were included for analysis. The unit is responsible for a large proportion of patients with acute and chronic kidney diseases of diverse etiologies and multiple co-morbid conditions. Acute and maintenance dialysis as well as immunosuppressive treatment for idiopathic glomerulopathy and autoimmune systemic diseases were common practice. Results: A total of 70044 ADR were diagnosed in 4438 patients. Most patients were adults (39+14) and had median follow up of 38 months. Nearly half of the ADR were due to drug-side effects while idiosyncrasy accounted for 1.2%. The former is due to misuse/abuse of medications while the latter is due to genetic, co-morbid conditions or synergetic between 2 drugs or a drug and disease. Details of drugs ADR are outlined with their respective prevalence. Our study indicates the need for careful auditing of patient’s response during follow up to improve their drug-compliance.
 Keywords: adverse drug reaction, allergy, medical clinic, kidney disease.

An intensive monitoring of adverse drug reaction in indoor patients of medicine department at tertiary care teaching hospital: A single center, prospective, and multisource observational study

Background: Adverse drug reactions (ADRs) have been evolved as a serious and major health-care problem affecting the quality of life of patients and increasing burden over the health-care system. Studying the pattern and spectrum of ADRs can help to find measures to address the problem and possibly prevent it effectively. Aims and Objectives: The study aimed to intensively monitor ADRs in indoor patients of medicine wards and estimate the incidence rate with documentation of the spectrum of ADRs in studied patients in terms of causality, severity, and preventability. Materials and Methods: This was prospective, observational, and single-center study, conducted at internal medicine wards of Sir Sayajirao General Hospital, Vadodara, over a duration of 8 months, after taking prior permission from the Institutional Ethics Committee. The necessary data were obtained and recorded on a pre-designed “case record form” and “Indian Pharmacopoeia Commission-ADR reporting form” after taking written informed consent and analyzed with Microsoft Excel-2016. Results: A total 11,400 admissions recorded during the study period in all nine wards of medicine department, of which 66 patients developed 88 ADRs with the incidence of 0.5789%. They were classified into Group A (38, 57.58%), ADR developed after hospitalization and Group B (28, 42.42%), ADR is the reason for hospitalization. The most common category of causality assessment was “probable” according to both WHO-UMC criteria (53, 54.65%) and Naranjo scale (54, 55.68%). According to modified Hartwig-Siegel scale majority, ADRs (43, 48.32%) fall into “moderate” category, and according to modified Thornton and Schumock criteria, the “preventable” ADRs were (29, 30.85%). Conclusion: The drug safety seems to be well considered in this setup with lower incidence rate found in our study, but there is still a need for improvement to reduce the huge portion of preventable ADRs.

Spectrum of adverse drug reactions and implicated drugs in a tertiary care centre: a prospective study

Background: Adverse Drug Reaction(ADR) is the major limitation in providing health care to patients at a global level. It affects patient’s recovery and is an important cause of mortality and morbidity in both hospitalized and ambulatory patients. ADR can occur with any class of drugs. Early detection and evaluation of ADR is essential to reduce harm to the patients. Thus, the present study was aimed to estimate the number of ADR’s reported, analyze its spectrum and the drugs attributed to it.Methods: This was a prospective study conducted in a tertiary care teaching hospital for a period of 3 months from March 2016 to May 2016 in SRM Medical College and Hospital, Potheri. Adverse drug reactions were collected by spontaneous reporting by active and passive methods. The causality assessment of the reported ADR’s was done using Naranjo causality assessment scale.Results: A total of 38 ADR’s were reported during the study period with male predominance (58%). Most of the ADR’s (42%) were common in patients in the age group 19-39 years. More number of ADR’s were from Medicine (29%) followed by Surgery (16%) and OG (16%) departments. Most commonly affected organ systems were skin (45%) followed by GIT (24%). The drugs mostly accounted were antibiotics (55%) especially Cephalosporins (33%). Most of the reactions were type A (68%) rather than type B (32%) and thus predictable. According to Naranjo’s causality assessment, 63% of reactions were probable, 26% were possible and 11% were definite. No reactions were unlikely. Severity assessment by Modified Hartwig and Seigel scale revealed 45% ADRs to be moderate, 42% were mild and 13% were severe and life threatening.Conclusions: The study concluded that Adverse Drug Reactions are common and some of them resulted in increased healthcare cost due to need of some interventions and increased length of hospital stay. As majority of ADR is predictable (Type A), so preventable. The health system should promote the spontaneous reporting of Adverse Drug Reactions (May be done mandatory). The proper documentation and periodic reporting to regional pharmacovigilance centres to ensure drug safety.

Adverse drug reactions

Adverse drug reactions are a cause of significant morbidity and mortality to patients and a source of financial burden to the healthcare system. Of the wide spectrum of adverse drug reactions, the most concerning to the anaesthetist remain anaphylaxis and malignant hyperthermia. Although the incidence of anaphylaxis under anaesthesia is difficult to ascertain, it occurs commonly enough that most anaesthetists will manage at least one case in their career. The wide range of drugs given in the peri-operative period and the variable presentation in the anaesthetised patient can delay diagnosis and treatment, and adversely affect outcome. Furthermore, despite improvements in testing, causative drugs can still be difficult to identify, as adverse reactions may be mediated by mechanisms other than IgE activation. With an increase in the reporting of anaphylaxis to newer anaesthetic drugs such as sugammadex, combined with change over the recent decades in the most likely causative peri-operative agents, it is imperative anaesthetists remain up to date on recent developments. In addition, they should be vigilant to patient characteristics, including pharmacogenetic variations that may predispose to adverse drug reactions, in order to help minimise risks of a reaction. The severity of adverse drug reactions to peri-operative drugs means morbidity and mortality remain high.

Association of Human Leukocyte Antigen Class 1 genes with Stevens Johnson Syndrome with severe ocular complications in an Indian population

Stevens Johnson syndrome (SJS) is part of a spectrum of adverse drug reactions resulting in the destruction of skin, mucous membranes, and the ocular surface. A similar, more severe form of the disorder included in this spectrum is toxic epidermal necrolysis (TEN). Approximately 35% of patients suffer chronic sequelae such as vascularization, corneal scarring, conjunctival inversion to the cornea, keratinization, symblepharon, scarring of the palpebral conjunctiva, trichiasis, and severe dry eye. We focused on 80 Indian patients with SJS/TEN with severe ocular complications (SOC) and investigated the association of alleles at HLA -A, HLA-B and HLA-C loci; the controls were 50 healthy Indian volunteers. Genotyping at HLA-A, HLA-B, and HLA-C loci showed a significant positive association with HLA-A*33:03, HLA-B*44:03, and HLA-C*07:01 alleles, and a significant negative association with HLA-B*57:01 and HLA-C*06:02. This indicates that HLA-A*33:03, HLA-B*44:03 and HLA-C*07:01 are risk alleles, and HLA-B*57:01 and HLA-C*06:02 are protective alleles in this population. We also found that the haplotypes consisting of HLA-B*44:03 and HLA-C*07:01 were strongly associated with SJS/TEN with SOC in our Indian population (p = 1.1 × 10−7, odds ratio = 11.0). Describing the association of the haplotype could facilitate the understanding of increased risk factors for developing SJS/TEN with SOC.

Drug Utilization Study of Psychotropic Drugs among Psychiatric Outpatients in a Tertiary Care Hospital

Availability and utilization of a wide variety of psychotropic drugs is associated with a wide spectrum of adverse drug reactions. To ensure the rational use of psychotropic drugs, it is imperative to monitor their pattern of use. The present study mainly focuses on the pattern of utilization of psychotropic drugs among psychiatric outpatients in a tertiary care hospital. A hospital based cross sectional study was carried out in the psychiatry outpatient department from January to December 2012. A total of 600 cases were studied. Demographic and drug related information was collected. With respect to the psychotropic drug utilization, sedative-hypnotics (42.9 %) were the most commonly prescribed group of psychotropic drugs followed by antidepressants (31.8 %), antipsychotics (19.6 %) and mood stabilizers (5.6 %). Among the sedative hypnotics, clonazepam (51.1 %) and amongst antidepressants, sertraline (28.9 %) and fluoxetine (17.3 %) were the most frequently utilized. The prescription of atypical antipsychotics like risperidone (41 %) and olanzapine (39.8 %) was predominant (95.4 %) over the typical ones. Valproate (54.7 %) was observed to have surpassed the use of lithium (32 %) as a mood stabilizer in bipolar disorders. A substantial increase in the use of anticonvulsants as mood stabilizers was observed. The use of the psychotropic drugs for different indications was in accordance to the current recommendations and guidelines. Newer drugs were being prescribed more often as compared to the conventional medications owing to their better safety and tolerability profiles. The psychotropic drug use in the health facility was a combination of rational and effective practice.

EPs 7630 in Acute Respiratory Tract Infections – A systematic Review and Meta-Analysis of Randomized Clinical Trials

Objective: We review the efficacy and safety of Pelargonium sidoides preparation EPs 7630 in children, adolescents, and adult patients with acute bronchitis (AB), acute rhinosinusitis (ARS), and acute tonsillopharyngitis (ATP). Methods: Double-blind, randomized, placebo-controlled trials were eligible for inclusion. Suitable trials were entered into meta-analyses performed separately for each indication. Efficacy analyses were based on change of disease specific symptom scores and on complete remission. Safety was analyzed based on the pooled data from all eligible trials, by comparing the incidence of adverse events in a set of pre-defined system groups between EPs 7630 and placebo. Results: 13 trials with a total of 3,392 participants were included, 10 of which could be entered into meta-analyses of efficacy (AB: 6/8 trials; ARS: 2/2 trials; ATP: 2/3 trials). In ARS, all trials included adults only, whereas studies in ATP had been conducted with children only. Compared to placebo, the analysis of safety showed slightly higher rates of events belonging to the known spectrum of adverse drug reactions to the herbal product, but risk increases ?1% could be excluded for all investigated system groups except gastrointestinal disorders and epistaxis. No serious adverse drug reactions were reported in any trial. In the meta-analyses of efficacy, EPs 7630 was superior to placebo in reducing both symptom severity and time until complete recovery for all indications investigated. Significant advantages for the herbal drug were also observed for time until the onset of a meaningful treatment effect, global therapy outcome, and days off work, school, or kindergarten. In AB, efficacy could also be shown for both subsets defined by age. Conclusion: EPs 7630 is an efficacious, safe, and well-tolerated herbal medicine in the management of acute respiratory tract infections such as AB, ARS, and ATP in children, adolescents and adults.

Prevalence and Spectrum of Adverse Drug Reactions in a community Hospital of North India.

Prevalence and Spectrum of Adverse Drug Reactions in a community Hospital of North India.

Adverse Drug Reactions Reported With Cholinesterase Inhibitors: An Analysis of 16 Years of Individual Case Safety Reports From VigiBase.

No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market. To describe ChEI related ADRs in Alzheimer's disease (donepezil, rivastigmine, and galantamine) and characterize their seriousness as reported by national pharmacovigilance systems to VigiBase, a World Health Organization International Drug Monitoring Program database, between 1998 and 2013. All ChEI RELATED REPORTS: , submitted to VigiBase between 1998 and 2013 from THE FIVE CONTINENTS: were extracted. Analyses were carried out for general, serious, and nonserious ADRs. A total of 18 955 reports (43 753 ADRs) FROM 58 COUNTRIES: were reported: 60.1% in women; mean age 77.4 ± 9.1 years. Most reports originated from Europe (47.6%) and North America (40.4%). Rivastigmine and donepezil were involved in MOST: reports (41.4% each). The most frequently reported ADRs were neuropsychiatric (31.4%), gastrointestinal (15.9%), general (11.9%), and cardiovascular (11.7%) disorders. During the 2006-2013 period, serious ADRs remained more often reported than nonserious ones; the most serious were neuropsychiatric (34.0%), general (14.0%), cardiovascular (12.1%), and gastrointestinal (11.6%) disorders. Medication errors were reported in 2.0% of serious cases. Death occurred in 2.3% of the reports. This international pharmacovigilance study highlights the ADR pattern induced by ChEIs. Neuropsychiatric events were the most frequently reported ADRs. Serious cardiovascular events were frequently reported, suggesting that their significance has probably been previously underestimated. Given the frailty of the patients and the frequent comedications, caution is advised before introducing a ChEI.

Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review

The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB.

A role forITPAvariants in the clinical course of pulmonary Langerhans' cell histiocytosis?

To the Editors: Interstitial lung diseases (ILD) comprise a number of clinical conditions, including sarcoidosis, pulmonary fibrosis and pulmonary Langerhans' cell histiocytosis (PLCH; histiocytosis X). The diagnostic workup for the classification of ILD is often complicated and tedious. PLCH is characterised by the proliferation of Langerhans' cells and their infiltration into pulmonary tissues. In disseminated LCH, additional tissues are affected. PLCH is strongly associated with smoking and the clinical outcome depends upon cessation of smoking 1. Treatment of ILD often requires corticosteroids and immunosuppressant drugs, including thiopurines and biologicals. It is mandatory to exclude genetic polymorphisms in genes involved in metabolism of thiopurine metabolism, because of the pharmacogenetic consequences of the use of thiopurines. The prospective measuring of erythrocyte enzyme activity of thiopurine S -methyltransferase (TPMT) and inosine triphosphatase (ITPase) or molecular analyses of the genes encoding these enzymes is recommended in clinical practice 2. Aberrant enzyme activity of either TPMT or ITPase gives rise to a broad spectrum of adverse drug reactions (ADR) associated with thiopurines, ranging from therapeutic failure to life-threatening leukopenia 3, 4. In order to avoid these ADR, we have incorporated pre-treatment screening of TPMT and ITPase of patients with ILD who are candidates for treatment with thiopurines in our hospital. An unexpectedly high number of decreased ITPase activities in patients with PLCH was found, all of which had an unfavourable outcome. We hypothesised about the role of the ITPA gene in relation to immunity, which might …

Immune mediation of hypersensitivity adverse drug reactions: implications for therapy

Adverse drug reactions are among the top causes of death in the developed world, and among the spectrum of adverse drug reactions, drug hypersensitivity is a principal contributor to serious adverse drug events. The pathophysiology of drug hypersensitivity remains incompletely understood, but seems to involve the initial recognition of a drug or metabolite by the immune system followed by an immune response that determines the clinical manifestations. At present, there are two competing theories for how immune recognition occurs: the Hapten Hypothesis in which drug hapten–carrier association is the key driver for immune recognition and the Pharmacological Interference Concept that postulates direct recognition of drugs by low affinity association with the T cell receptor. The Danger Hypothesis provides a potentially important addition to the Hapten Hypothesis. Therapy for drug hypersensitivity has traditionally involved excellent supportive care. Although corticosteroids and intravenous immunoglobulin have both been used as immunomodulatory therapy, there is no robust evidence supporting the efficacy of their therapy for drug hypersensitivity. Recent advances in molecular biology and genomic pharmacology offer previously unappreciated opportunities to clarify the controversies surrounding drug hypersensitivity and to better diagnose, treat and, it is hoped, prevent drug hypersensitivity in the future.

Newer anticonvulsant drugs: role of pharmacology, drug interactions and adverse reactions in drug choice.

In the last few years a number of new anticonvulsants have been introduced into clinical practice mainly as add-on therapy in patients who do not become seizure-free while receiving established anticonvulsants. Up to now, no single drug has been shown to be more effective at controlling seizures of a particular type than another, so other factors such as mechanism of action, pharmacokinetics, dosage regimens or the spectrum of adverse drug reactions and interactions are used when making a choice between one agent and another. The mechanism of action of tiagabine and vigabatrin is very specific; both agents increase gamma-aminobutyric acid (GABA) levels through inhibition of reuptake and catabolism respectively. However, the mechanism of action of gabapentin is unknown and those of felbamate, lamotrigine and topiramate are not sufficiently clarified as yet, and may be multiple. Great advances have been made in improving the pharmacokinetic characteristics of these newer anticonvulsants. Gabapentin and vigabatrin exhibit relatively ideal pharmacokinetic properties as they are not bound to proteins, are excreted mostly unchanged in the urine and show linear pharmacokinetics. Lamotrigine possesses a highly variable elimination half-life depending on the co-medication. Tiagabine is highly protein bound and zonisamide shows nonlinear pharmacokinetics; both these drugs are extensively metabolised. Problematic drug interactions between newer anticonvulsants and other drugs in general occur rarely when these agents are given concomitantly. However, in common with most new drugs, there are very few data on the use of the newer anticonvulsants in women of childbearing age. Studies done so far on interactions with oral contraceptives used low anticonvulsant dosages for a very short time. The newer anticonvulsants elicit adverse reactions that, while not being unique, are particularly associated with that drug. For example, felbamate may cause aplastic anaemia and fulminant liver failure, lamotrigine is prone to cause skin rash, and oxcarbazepine may cause symptomatic hyponatraemia. Topiramate and zonisamide cause kidney stones, and vigabatrin may induce psychiatric syndromes. Although highly diverse in structure and activity, these newer drugs offer new possibilities for treating refractory epilepsy. However, since no single factor can dictate the choice of drug nor predict the success of treatment, prescribing of these rather expensive drugs has to depend upon careful consideration of the aims of treatment, the characteristics of the drug and the needs of the individual patient.