The use of herbal supplements in the US has increased dramatically in recent years. These products are not regulated by the Food and Drug Administration (FDA) with the same scrutiny as conventional drugs. Patients who use herbal supplements often do so in conjunction with conventional drugs. This article is a review of potential adverse interactions between some of the commonly used herbal supplements and analgesic drugs. Non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, have the potential to interact with herbal supplements that are known to possess antiplatelet activity (ginkgo, garlic, ginger, bilberry, dong quai, feverfew, ginseng, turmeric, meadowsweet and willow), with those containing coumarin (chamomile, motherworth, horse chestnut, fenugreek and red clover) and with tamarind, enhancing the risk of bleeding. Acetaminophen may also interact with ginkgo and possibly with at least some of the above herbs to increase the risk of bleeding. Further, the incidences of hepatotoxicity and nephrotoxicity may be augmented by acetaminophen when concomitantly used with the potentially hepatotoxic herbs Echinacea and kava, and with herbs containing salicylate (willow, meadowsweet), respectively. The concomitant use of opioid analgesics with the sedative herbal supplements, valerian, kava and chamomile, may lead to increased central nervous system (CNS) depression. The analgesic effect of opioids may also be inhibited by ginseng. It is suggested that health-care professionals should be more aware of the potential adverse interactions between herbal supplements and analgesic drugs, and take appropriate precautionary measures to avoid their possible occurrences. However, as most of the interaction information available is based on individual case reports, animal studies and in vitro data, further research is needed to confirm and assess the clinical significance of these potential interactions.
Wang, Kejian; Wan, Mei; Wang, Rui-Sheng
Background Drug repositioning refers to the process of developing new indications for existing drugs. As a phenotypic indicator of drug response in humans, clinical side effects may provide straightforward signals and unique opportunities for drug repositioning. Objective We aimed to identify drugs frequently associated with hypotension adverse reactions (ie, the opposite condition of hypertension), which could be potential candidates as antihypertensive agents. Methods We systematically searched the electronic records of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) through the openFDA platform to assess the association between hypotension incidence and antihypertensive therapeutic effect regarding a list of 683 drugs. Results Statistical analysis of FAERS data demonstrated that those drugs frequently co-occurring with hypotension events were more likely to have antihypertensive activity. Ranked by the statistical significance of frequent hypotension reporting, the well-known antihypertensive drugs were effectively distinguished from others (with an area under the receiver operating characteristic curve > 0.80 and a normalized discounted cumulative gain of 0.77). In addition, we found a series of antihypertensive agents (particularly drugs originally developed for treating nervous system diseases) among the drugs with top significant reporting, suggesting the good potential of Web-based and data-driven drug repositioning. Conclusions We found several candidate agents among the hypotension-related drugs on our list that may be redirected for lowering blood pressure. More important, we showed that a pharmacovigilance system could alternatively be used to identify antihypertensive agents and sustainably create opportunities for drug repositioning. PMID:27036325
Galli, Thamires B.; Reis, Wálleri C.; Andrzejevski, Vânia M.
Background: Potentially inappropriate medication (PIM) use in the elderly is associated with increased risk of adverse drug reactions (ADRs), but there is limited information regarding PIM use in the intensive care unit (ICU) setting. Objective: The aim of the study is to describe the prevalence and factors associated with the use of PIM and the occurrence of PIM-related adverse reactions in the critically ill elderly. Methods: This study enrolled all critically ill older adults (60 years or more) admitted to medical or cardiovascular ICUs between January and December 2013, in a large tertiary teaching hospital. For all patients, clinical pharmacists listed the medications given during the ICU stay and data on drugs were analyzed using 2012 Beers Criteria, to identify the prevalence of PIM. For each identified PIM the medical records were analyzed to evaluate factors associated with its use. The frequency of ADRs and, the causal relationship between PIM and the ADRs identified were also evaluated through review of medical records. Results: According to 2012 Beers Criteria, 98.2% of elderly patients used at least one PIM (n=599), of which 24.8% were newly started in the ICUs. In 29.6% of PIMs, there was a clinical circumstance that justified their prescription. The number of PIMs was associated with ICU length of stay and total number of medications. There was at least one ADR identified in 17.8% of patients; more than 40% were attributed to PIM, but there was no statistical association. Conclusions: There is a high prevalence of PIM used in acutely ill older people, but they do not seem to be the major cause of adverse drug reactions in this population. Although many PIMs had a clinical circumstance that led to their prescription during the course of ICU hospitalization, many were still present upon hospital discharge. Therefore, prescription of PIMs should be minimized to improve the safety of elderly patients. PMID:28042352
Böhmdorfer, Birgit; Schaffarzick, Daniel; Nagano, Marietta; Janowitz, Susanne Melitta; Schweitzer, Ekkehard
We present a multidisciplinary (anaesthesiology--clinical pharmacy--bioinformatics) analysis of pain as possible adverse drug reaction taking different manifestations of pain, indication groups, relevance to the Austrian drug market and possible mechanistic influence of drugs on development and apprehension of pain into consideration.We designed an overview that shows how transmitters that play a part in nociception and antinociception can be influenced by drugs. This allows conclusions to the dolorigene potential of therapeutics.
Novak, Philipp H; Ekins-Daukes, Suzie; Simpson, Colin R; Milne, Robert M; Helms, Peter; McLay, James S
Aims To investigate the extent of acute coprescribing in primary care to children on chronic antiepileptic therapy, which could give rise to potentially harmful drug–drug interactions. Design Acute coprescribing to children on chronic antiepileptic drug therapy in primary care was assessed in 178 324 children aged 0–17 years for the year 1 November 1999 to 31 October 2000. Computerized prescribing data were retrieved from 161 representative general practices in Scotland. Setting One hundred and sixty-one general practices throughout Scotland. Results During the study year 723 (0.41%) children chronically prescribed antiepileptic therapy were identified. Fourteen antiepileptic agents were prescribed, with carbamazepine, sodium valproate and lamotrigine accounting for 80% of the total. During the year children on chronic antiepileptic therapy were prescribed 4895 acute coprescriptions for 269 different medicines. The average number of acute coprescriptions for non-epileptic drug therapy were eight, 11, six, and six for the 0–1, 2–4, 5–11, and 12–17-year-olds, respectively. Of these acute coprescriptions 72 (1.5%) prescribed to 22 (3.0%) children were identified as a potential source of clinically serious interactions. The age-adjusted prevalence rates for potentially serious coprescribing were 86, 26, 22, and 33/1000 children chronically prescribed antiepileptic therapy in the 0–1, 2–4, 5–11, and 12–17-year-old age groups, respectively. The drugs most commonly coprescribed which could give rise to such interactions were antacids, erythromycin, ciprofloxacin, theophylline and the low-dose oral contraceptive. For 10 (45.5%0 of the 20 children identified at risk of a potentially clinically serious adverse drug interaction, the acute coprescription was prescribed off label because of age or specific contraindication/warning. Conclusions In primary care, 3.0% of children on chronic antiepileptic therapy are coprescribed therapeutic agents, which could
Lebrun-Vignes, B; Valeyrie-Allanore, L
Cutaneous adverse drug reactions (CADR) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Exanthematous eruptions, urticaria and vasculitis are the most common forms of CADR. Fixed eruption is uncommon in western countries. Serious reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly diagnosed to guide their management. The main risk factors are immunosuppression, autoimmunity and some HLA alleles in bullous reactions and DRESS. Most systemic drugs may induce cutaneous adverse reactions, especially antibiotics, anticonvulsivants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Pathogenesis includes immediate or delayed immunologic mechanism, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent. In case of immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test and intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case if the involved drug is a newly marketed one or unusually related to cutaneous reactions.
What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article defined the different types of adverse drug reactions (ADRs) and explored when they can occur. It emphasised the importance of being knowledgeable about medications, considering patient safety when patients are taking medications, being alert to the possibility of ADRs, and recognising and responding to suspected ADRs.
Harpaz, Rave; Haerian, Krystl; Chase, Herbert S; Friedman, Carol
Many adverse drug effects (ADEs) can be attributed to drug interactions. Spontaneous reporting systems (SRS) provide a rich opportunity to detect novel post-marketed drug interaction adverse effects (DIAEs), as they include populations not well represented in clinical trials. However, their identification in SRS is nontrivial. Most existing research have addressed the statistical issues used to test or verify DIAEs, but not their identification as part of a systematic large scale database-wide mining process as discussed in this work. This paper examines the application of a highly optimized and tailored implementation of the Apriori algorithm, as well as methods addressing data quality issues, to the identification of DIAEs in FDAs SRS.
Nayak, Surajit; Acharjya, Basanti
In everyday clinical practice, almost all physicians come across many instances of suspected adverse cutaneous drug reactions (ACDR) in different forms. Although such cutaneous reactions are common, comprehensive information regarding their incidence, severity and ultimate health effects are often not available as many cases go unreported. It is also a fact that in the present world, almost everyday a new drug enters market; therefore, a chance of a new drug reaction manifesting somewhere in some form in any corner of world is unknown or unreported. Although many a times, presentation is too trivial and benign, the early identification of the condition and identifying the culprit drug and omit it at earliest holds the keystone in management and prevention of a more severe drug rash. Therefore, not only the dermatologists, but all practicing physicians should be familiar with these conditions to diagnose them early and to be prepared to handle them adequately. However, we all know it is most challenging and practically difficult when patient is on multiple medicines because of myriad clinical symptoms, poorly understood multiple mechanisms of drug-host interaction, relative paucity of laboratory testing that is available for any definitive and confirmatory drug-specific testing. Therefore, in practice, the diagnosis of ACDR is purely based on clinical judgment. In this discussion, we will be primarily focusing on pathomechanism and approach to reach a diagnosis, which is the vital pillar to manage any case of ACDR.
de Boer, Alie; van Hunsel, Florence; Bast, Aalt
Food supplements and herbal products are increasingly popular amongst consumers. This leads to increased risks of interactions between prescribed drugs and these products containing bioactive ingredients. From 1991 up to 2014, 55 cases of suspected adverse drug reactions due to concomitant intake of health-enhancing products and drugs were reported to Lareb, the Netherlands Pharmacovigilance Centre. An overview of these suspected interactions is presented and their potential mechanisms of action are described. Mainly during the metabolism of xenobiotics and due to the pharmacodynamics effects interactions seem to occur, which may result in adverse drug reactions. Where legislation is seen to distinct food and medicine, legislation concerning these different bioactive products is less clear-cut. This can only be resolved by increasing the molecular knowledge on bioactive substances and their potential interactions. Thereby potential interactions can be better understood and prevented on an individual level. By considering the dietary pattern and use of bioactive substances with prescribed medication, both health professionals and consumers will be increasingly aware of interactions and these interactive adverse effects can be prevented.
Alvim, Mariana Macedo; da Silva, Lidiane Ayres; Leite, Isabel Cristina Gonçalves; Silvério, Marcelo Silva
Objective To evaluate the incidence of potential drug-drug interactions in an intensive care unit of a hospital, focusing on antimicrobial drugs. Methods This cross-sectional study analyzed electronic prescriptions of patients admitted to the intensive care unit of a teaching hospital between January 1 and March 31, 2014 and assessed potential drug-drug interactions associated with antimicrobial drugs. Antimicrobial drug consumption levels were expressed in daily doses per 100 patient-days. The search and classification of the interactions were based on the Micromedex® system. Results The daily prescriptions of 82 patients were analyzed, totaling 656 prescriptions. Antimicrobial drugs represented 25% of all prescription drugs, with meropenem, vancomycin and ceftriaxone being the most prescribed medications. According to the approach of daily dose per 100 patient-days, the most commonly used antimicrobial drugs were cefepime, meropenem, sulfamethoxazole + trimethoprim and ciprofloxacin. The mean number of interactions per patient was 2.6. Among the interactions, 51% were classified as contraindicated or significantly severe. Highly significant interactions (clinical value 1 and 2) were observed with a prevalence of 98%. Conclusion The current study demonstrated that antimicrobial drugs are frequently prescribed in intensive care units and present a very high number of potential drug-drug interactions, with most of them being considered highly significant. PMID:26761473
Meyer, Roger E. , Ed.
This reports a conference of psychologists, psychiatrists, geneticists and others concerned with the biological and psychological effects of lysergic acid diethylamide and other hallucinogenic drugs. Clinical data are presented on adverse drug reactions. The difficulty of determining the causes of adverse reactions is discussed, as are different…
Spiteri, M. A.; James, D. G.
Drugs acting on various parts of the body may also affect the eye insidiously. Increased awareness of such drug toxicity by the prescribing doctor should encourage him to consider effects on the cornea, lens, retina, optic nerve and elsewhere when checking the patient's progress. The following review concerns adverse ocular effects of systemic drug administration. PMID:6356101
Husserl, F E; Messerli, F H
Early essential hypertension is asymptomatic and should remain so throughout treatment. In view of the increasing number of available antihypertensive agents, clinicians need to become familiar with the potential side effects of these drugs. By placing more emphasis on non-pharmacological treatment (sodium restriction, weight loss, exercise) and thoroughly evaluating each case in particular, the pharmacological regimen can be optimally tailored to the patient's needs. Potential side effects should be predicted and can often be avoided; if they become clinically significant they should be rapidly recognised and corrected. These side effects can be easily remembered in most instances, as they fall into 3 broad categories: (a) those caused by an exaggerated therapeutic effect; (b) those due to a non-therapeutic pharmacological effect; and (c) those caused by a non-therapeutic, non-pharmacological effect probably representing idiosyncratic reactions. This review focuses mainly on adverse effects of the second and third kind. Each group of drugs in general shares the common side effects of the first two categories, while each individual drug has its own idiosyncratic side effects.
Hauben, Manfred; Reich, Lester
The objective of this study was to apply 2 data-mining algorithms to a drug safety database to determine if these methods would have flagged potentially fatal/disabling adverse drug reactions that triggered black box warnings/drug withdrawals in advance of initial identification via "traditional" methods. Relevant drug-event combinations were identified from a journal publication. Data-mining algorithms using commonly cited disproportionality thresholds were then applied to the US Food and Drug Administration database. Seventy drug-event combinations were considered sufficiently specific for retrospective data mining. In a minority of instances, potential signals of disproportionate reporting were provided clearly in advance of initial identification via traditional pharmacovigilance methods. Data-mining algorithms have the potential to improve pharmacovigilance screening; however, for the majority of drug-event combinations, there was no substantial benefit of either over traditional methods. They should be considered as potential supplements to, and not substitutes for, traditional pharmacovigilance strategies. More research and experience will be needed to optimize deployment of data-mining algorithms in pharmacovigilance.
Wooten, James M
Pharmacovigilance is the process of identifying, monitoring, and effectively reducing adverse drug reactions. Adverse drug reactions (ADRs) are an important consideration when assessing a patient's health. The proliferation of new pharmaceuticals means that the incidence of ADRs is increasing. The goal for all health care providers must be to minimize the risk of ADRs as much as possible. Steps to achieve this include understanding the pharmacology for all drugs prescribed and proactively assessing and monitoring those patients at greatest risk for developing an ADR. Groups at greatest risk for developing ADRs include the elderly, children, and pregnant patients, as well as others. Pharmacovigilance must be effectively practiced by all health care providers in order to avoid ADRs.
Wooten, James M
Pharmacovigilance is the process of identifying, monitoring, and effectively reducing adverse drug reactions. Adverse drug reactions (ADRs) are an important consideration when assessing a patient's health. The proliferation of new pharmaceuticals means that the incidence of ADRs is increasing. The goal for all health care providers must be to minimize the risk of ADRs as much as possible. Steps to achieve this include understanding the pharmacology for all drugs prescribed and proactively assessing and monitoring those patients at greatest risk for developing an ADR. Groups at greatest risk for developing ADRs include the elderly, children, and pregnant patients, as well as others. Pharmacovigilance must effectively be practiced by all health providers in order to avoid ADRs.
Wiciński, Michał; Węclewicz, Mateusz M; Miętkiewicz, Mateusz; Malinowski, Bartosz; Grześk, Elżbieta; Klonowska, Joanna
Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis. The mechanism in idiosyncratic agranulocytosis is not dose related and involves either a direct toxic or an immune-allergic effect. It is suspected that the clozapine metabolites nitrenium ion and N-desmethylclozapine may cause apoptosis or impair growth of granulocytes. Formation of N-desmethylclozapine is correlated with activity of the cytochrome P450 enzymes 1A2 and 3A4 (CYP1A2 and CYP3A4). Nitrenium ion is produced by the flavin-containing monooxygenase system of leukocytes. A drug interaction between clozapine and a PPI is a consequence of the induction of common metabolic pathways either by the PPI or clozapine. Findings to date suggest that indirect induction of flavin-containing monooxygenase by omeprazole through the aryl hydrocarbon receptor increases the expression of the enzyme mRNA and in the long term may cause the increase in activity. Moreover, induction of CYP1A2, especially by omeprazole and lansoprazole, may increase the serum concentration of N-desmethylclozapine, which can accumulate in lymphocytes and may achieve toxic levels. Another hypothesis that may explain hematological adverse drug reactions is competitive inhibition of CYP2C19, which may contribute to increased serum concentrations of toxic metabolites.
Poluzzi, Elisabetta; Raschi, Emanuel; Godman, Brian; Koci, Ariola; Moretti, Ugo; Kalaba, Marija; Wettermark, Bjorn; Sturkenboom, Miriam; De Ponti, Fabrizio
Background There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in ’90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines. Aim To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries. Methods We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance. Results Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible. Conclusions Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by
Arnet, Isabelle; Seidling, Hanna M; Hersberger, Kurt E
Community pharmacists represent an important pillar for the identification and the reporting of adverse drug effects (ADE}. Thanks to their broad view on the pharmacotherapy, over-the-counter medication included, they contribute greatly to the improvement of drug safety. In principle, the community pharmacy will face three groups of ADE which require specific attention. This article deals with these specific ADE groups and presents some illustrative examples from daily practice. Furthermore, we suggest some solutions to identify potential relevant interactions - including herbal-drug interactions - and give tips for daily practice, along with some often overseen cutaneous ADE.
Langendam, Miranda W.; Tiemersma, Edine W.; van der Werf, Marieke J.; Sandgren, Andreas
A recent systematic review concluded that there is insufficient evidence on the effectiveness to support or reject preventive therapy for treatment of contacts of patients with multidrug resistant tuberculosis (MDR-TB). Whether preventive therapy is favorable depends both on the effectiveness and the adverse events of the drugs used. We performed a systematic review to assess adverse events in healthy individuals and MDR-TB contacts treated with anti-tuberculosis drugs potentially effective for preventing development of MDR-TB. We searched MEDLINE, EMBASE, and other databases (August 2011). Record selection, data extraction, and study quality assessment were done in duplicate. The quality of evidence was assessed using the GRADE approach. Of 6,901 identified references, 20 studies were eligible. Among the 16 studies in healthy volunteers (a total of 87 persons on either levofloxacin, moxifloxacin, ofloxacin, or rifabutin, mostly for 1 week), serious adverse events and treatment discontinuation due to adverse events were rare (<1 and <5%, respectively), but mild adverse events frequently occurred. Due to small sample sizes of the levofloxacin and ofloxacin studies an increased frequency of mild adverse events compared to placebo could not be demonstrated or excluded. For moxifloxacin the comparative results were inconsistent. In four studies describing preventive therapy of MDR-TB contacts, therapy was stopped for 58–100% of the included persons because of the occurrence of adverse events ranging from mild adverse events such as nausea and dizziness to serious events requiring treatment. The quality of the evidence was very low. Although the number of publications and quality of evidence are low, the available evidence suggests that shortly after starting treatment the occurrence of serious adverse events is rare. Mild adverse events occur more frequently and may be of importance because these may provoke treatment interruption. PMID:23326464
Langendam, Miranda W; Tiemersma, Edine W; van der Werf, Marieke J; Sandgren, Andreas
A recent systematic review concluded that there is insufficient evidence on the effectiveness to support or reject preventive therapy for treatment of contacts of patients with multidrug resistant tuberculosis (MDR-TB). Whether preventive therapy is favorable depends both on the effectiveness and the adverse events of the drugs used. We performed a systematic review to assess adverse events in healthy individuals and MDR-TB contacts treated with anti-tuberculosis drugs potentially effective for preventing development of MDR-TB. We searched MEDLINE, EMBASE, and other databases (August 2011). Record selection, data extraction, and study quality assessment were done in duplicate. The quality of evidence was assessed using the GRADE approach. Of 6,901 identified references, 20 studies were eligible. Among the 16 studies in healthy volunteers (a total of 87 persons on either levofloxacin, moxifloxacin, ofloxacin, or rifabutin, mostly for 1 week), serious adverse events and treatment discontinuation due to adverse events were rare (<1 and <5%, respectively), but mild adverse events frequently occurred. Due to small sample sizes of the levofloxacin and ofloxacin studies an increased frequency of mild adverse events compared to placebo could not be demonstrated or excluded. For moxifloxacin the comparative results were inconsistent. In four studies describing preventive therapy of MDR-TB contacts, therapy was stopped for 58-100% of the included persons because of the occurrence of adverse events ranging from mild adverse events such as nausea and dizziness to serious events requiring treatment. The quality of the evidence was very low. Although the number of publications and quality of evidence are low, the available evidence suggests that shortly after starting treatment the occurrence of serious adverse events is rare. Mild adverse events occur more frequently and may be of importance because these may provoke treatment interruption.
Onat, Filiz; Ozkara, Cigdem
Starting with phenobarbital in the 1900s, it took almost 70-80 years to introduce old-generation agents for the treatment of epilepsy. Then, in eleven years, nine more new antiepileptic drugs were added to the armamentarium. These drugs produce a nearly 40-50% decrease in seizure incidence in refractory patients, but few patients have been able to achieve complete freedom from seizures. So the search for more effective drugs with minimal adverse effect profiles will continue. Although the new antiepileptic drugs do not demonstrate a superior efficacy compared to the older ones, they do offer some advantages in terms of tolerability, fewer drug interactions and simpler pharmacokinetics. However, our knowledge concerning their safety profiles can not yet be considered adequate due to the relatively short time these drugs have been on the market and to the limited number of patients exposed to them. The fact that the serious side effects of felbamate and vigabatrine appeared late after marketing should be taken as an important lesson because it implies the potential for unknown side effects at any time during treatment. Antiepileptic drug treatment should begin with diagnosis of the seizure and epileptic syndrome, followed by selection of the drug most appropriate for treatment of the individual patient, and continued with monitoring of not only the seizures but the adverse effect profile as well.
Mattila, Riikka; Gomez-Font, Rafael; Meurman, Jukka H.
Objectives: The main objectives are to present the different adverses effects of the immunomodulatory drugs that can impair the quality of life of the immunosupressed patients and study the impact of immunomodualtion on oral diseases. Immunomodulatory drugs have changed the treatment protocols of many diseases where immune functions play a central role, such as rheumatic diseases. Their effect on oral health has not been systematically investigated, however. Study Design: We review current data on the new immunomodulatory drugs from the oral health perspective based on open literature search of the topic. Results: These target specific drugs appear to have less drug interactions than earlier immunomodulating medicines but have nevertheless potential side effects such as activating latent infections. There are some data showing that the new immunomodulatory drugs may also have a role in the treatment of certain oral diseases such as lichen planus or ameliorating symptoms in Sjögren´s syndrome, but the results have not been overly promising. Conclusions: In general, data are sparse of the effect of these new drugs vs. oral diseases and there are no properly powered randomized controlled trials published on this topic. Key words:Immunomodulatory drugs, oral diseases, adverse effects, therapeutic action. PMID:23986016
Simon, R A
There is a long list of additives used by the pharmaceutical industry. Most of the agents used have not been implicated in hypersensitivity reactions. Among those that have, only reactions to parabens and sulfites have been well established. Parabens have been shown to be responsible for rare immunoglobulin E-mediated reactions that occur after the use of local anesthetics. Sulfites, which are present in many drugs, including agents commonly used to treat asthma, have been shown to provoke severe asthmatic attacks in sensitive individuals. Recent studies indicate that additives do not play a significant role in "hyperactivity." The role of additives in urticaria is not well established and therefore the incidence of adverse reactions in this patient population is simply not known. In double-blind, placebo-controlled studies, reactions to tartrazine or additives other than sulfites, if they occur at all, are indeed quite rare for the asthmatic population, even for the aspirin-sensitive subpopulation.
Lucas, L. M.; Colley, C. A.
Although physicians in practice are most likely to see patients with adverse drug reactions, they may fail to recognize an adverse effect or to attribute it to a drug effect and, when recognized, they may fail to report serious reactions to the US Food and Drug Administration (FDA). To recognize and attribute an adverse event to a drug effect, physicians should review the patient's clinical course, looking at patient risk factors, the known adverse reactions to the suspected drug, and the likelihood of a causal relationship between the drug and the adverse event-based on the temporal relationship, response to stopping or restarting the drug, and whether other factors could explain the reaction. Once an adverse drug reaction has been identified, the patient should be informed and appropriate documentation made in the patient's medical record. Serious known reactions and all reactions to newly released drugs or those not previously known to occur (even if the certainty is low) should be reported to the FDA. PMID:1536067
Wang, Liwei; Jiang, Guoqian; Li, Dingcheng; Liu, Hongfang
Normalizing data in the Adverse Event Reporting System (AERS), an FDA database, would improve the mining capacity of AERS for drug safety signal detection. In this study, we aim to normalize AERS and build a publicly available normalized Adverse drug events (ADE) data source.he drug information in AERS is normalized to RxNorm, a standard terminology source for medication. Drug class information is then obtained from the National Drug File - Reference Terminology (NDF-RT). Adverse drug events (ADE) are aggregated through mapping with the PT (Preferred Term) and SOC (System Organ Class) codes of MedDRA. Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). The AERS-DM could provide more perspectives to mine AERS database for drug safety signal detection and could be used by research community in the data mining field.
Hristovski, Dimitar; Kastrin, Andrej; Dinevski, Dejan; Burgun, Anita; Žiberna, Lovro; Rindflesch, Thomas C
We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects.
Díaz-Agudelo, Daniela; Burgos-Flórez, Francisco Javier; Vaca, Claudia; Serrano-Meriño, Dolores Vanessa
Introduction: The occurrence of adverse drug reactions is an important issue due to the lack of drug safety data in children. Objective: To describe the Adverse Drug Reactions in inpatient children under 6 years of age in two general pediatrics wards located in Barranquilla, Colombia. Methods: A prospective cohort study based on intensive pharmacovigilance was conducted during six months in order to monitor the emergence of Adverse Drug Reactions in inpatients children under 6 years of age with at least one medication prescribed. The study was conducted in two pediatric wards of two hospitals located in Barranquilla, Colombia. Naranjo´s Algorithm was used to evaluate imputability, the modified Hartwig and Siegel assessment scale to establish severity and the Schumock and Thornton criteria to determine preventability. Results: Of a total of 772 monitored patients, 156 Adverse Drug Reactions were detected on 147 children. The cumulative incidence of Adverse Drug Reactions was 19.0% (147/772); the incidence density was 37.6 Adverse Drug Reactions per 1,000 patients-days (147/3,913). The frequency was higher in children under 2 years of age (12.7%). Emergence of Adverse Drug Reactions was higher in male patients (RR= 1.66; 95% CI= 1.22-2.22, p= 0.001) and in those who used systemic antibiotics (RR= 1.82; 95% CI= 1.17-2.82, p= 0.005). Conclusions: Adverse Drug Reactions are common among hospitalized children and represent an additional burden of morbidity and risk, particularly in those who used several medicines, including antibiotics. PMID:27821893
Marcilly, Romaric; Chazard, Emmanuel; Beuscart-Zéphir, Marie-Catherine; Hackl, Werner; Băceanu, Adrian; Kushniruk, Andre; Borycki, Elizabeth M
This paper presents the design of Adverse Drug Event-Scorecards. The scorecards described are innovative and novel, not having previously been reported in the literature. The Scorecards provide organizations (e.g. hospitals) with summary information about Adverse Drug Events (ADEs) using a Web-based platform. The data used in the Scorecards are routinely updated and report on ADEs detected through data mining processes. The development of the ADE Scorecards is ongoing and they are currently undergoing clinical testing.
Aronson, Jeffrey K
The terms 'adverse drug effects' and 'adverse drug reactions' are commonly used interchangeably, but they have different implications. Adverse drug reactions arise when a compound (e.g. a drug or metabolite, a contaminant or adulterant) is distributed in the same place as a body tissue (e.g. a receptor, enzyme, or ion channel), and the encounter results in an adverse effect (a physiological or pathological change), which results in a clinically appreciable adverse reaction. Both the adverse effect and the adverse reaction have manifestations by which they can be recognized: adverse effects are usually detected by laboratory tests (e.g. biochemical, haematological, immunological, radiological, pathological) or by clinical investigations (e.g. endoscopy, cardiac catheterization), and adverse reactions by their clinical manifestations (symptoms and/or signs). This distinction suggests five scenarios: (i) adverse reactions can result directly from adverse effects; (ii) adverse effects may not lead to appreciable adverse reactions; (iii) adverse reactions can occur without preceding adverse effects; (iv) adverse effects and reactions may be dissociated; and (v) adverse effects and reactions can together constitute syndromes. Defining an adverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product" suggests a definition of an adverse drug effect: "a potentially harmful effect resulting from an intervention related to the use of a medicinal product, which constitutes a hazard and may or may not be associated with a clinically appreciable adverse reaction and/or an abnormal laboratory test or clinical investigation, as a marker of an adverse reaction."
Pushkin, Richard; Frassetto, Lynda; Tsourounis, Candy; Segal, Eleanor S; Kim, Stephanie
The US Food and Drug Administration (FDA) is perceived by the public as having a substantial responsibility to ensure drug safety; however, the FDA has limited resources for active surveillance and relies on voluntary reporting of adverse events and potential adverse drug reactions. Studies have shown that underreporting of adverse events and adverse drug reactions is widespread. Furthermore, a review of several studies demonstrates that most adverse drug reactions are reported by pharmacists and nurses, with physicians reporting the fewest. The hospital setting, with its clearly defined patient population observed around the clock, is an ideal setting in which to identify potential adverse drug reaction signals and to report them to either the drug manufacturer or the FDA. In this article we describe the present system for addressing adverse events, obstacles to reporting them, and the important role any hospital physician could play in reporting adverse events and potential adverse drug reactions.
Onda, Mitsuko; Imai, Hirohisa; Takada, Yurina; Fujii, Shingo; Shono, Takako; Nanaumi, Yoko
Objectives A nationwide large-scale survey was conducted to identify the prevalence and causal medications of adverse drug events (ADEs) that are caused by potentially inappropriate medications (PIMs) given to homebound elderly patients, factors associated with ADEs, and measures taken by pharmacists to manage ADEs and their effects on ADEs. Settings A questionnaire was mailed to 3321 pharmacies nationwide. It asked about the details of PIMs and ADEs of up to 5 patients for whom home visits were provided by a pharmacist. Questionnaire forms were filled in by pharmacists who visited the patients. Design and participants Between 23 January and 13 February 2013, comprehensive assessment forms were sent to 3321 pharmacies. Data collected from 1890 pharmacies including data of 4815 patients were analysed and 28 patients of unknown sex were excluded. Their average age was 82.7 years. PIMs were identified based on the 2003 Beers Criteria Japan. Results There were 600 patients who did not provide valid answers regarding the medications. In the remaining 4243 patients, one or more medications that were considered to be PIMs had been prescribed to 48.4% of patients. PIM-induced ADEs were found in 8% of these patients by pharmacists during home visits. The top ADE-inducing medications were strong anticholinergic antihistamines, benzodiazepines, sulpiride and digoxin. The most common ADEs associated with benzodiazepines were frequent lightheadedness, somnolence and sleepiness, which increase the risk of falls and subsequent fractures in elderly patients. The following factors associated with ADEs were identified: sex, pharmacist awareness of prescription issues, frequency of visits and time spent at patients’ homes, and the frequency of detailed checks for patient adverse reactions by pharmacists. Conclusions The PIM prevalence associated with home healthcare in Japan was relatively high, as reported in previous studies. The present study suggests that pharmacists could
Day, R O; Quinn, D I; Conaghan, P G; Tett, S E
Drugs administered as therapy for rheumatological disorders are a relatively common cause of adverse events. Important data regarding the effects of drugs on patients with rheumatological conditions is being lost or rendered inaccessible because of deficiencies in classification, measurement, and collection methods for adverse drug reactions. A significant number of adverse reactions to drugs will not be known before marketing, and hence vigilance on the part of clinicians and patients in observing and documenting these reactions is paramount in building our knowledge and modifying our practice accordingly. A variety of systems and methods for detecting adverse drug reactions are described, critically evaluated, and compared for cost, potential bias, ethical concerns, and subject recruitment required for necessary statistical power. Systems need to be developed to give access to the wealth of clinical experimental data available in the individual practices of a broad spectrum of clinicians. To facilitate this, representative organizations need to make adverse drug reactions a high priority as well as contributing expertise and finance to database formulation and accessibility.
Whitten, P L; Lewis, C; Russell, E; Naftolin, F
Evaluation of the potential benefits and risks offered by naturally occurring plant estrogens requires investigation of their potency and sites of action when consumed at natural dietary concentrations. Our investigations have examined the effects of a range of natural dietary concentrations of the most potent plant isoflavonoid, coumestrol, using a rat model and a variety of estrogen-dependent tissues and endpoints. Treatments of immature females demonstrated agonistic action in the reproductive tract, brain, and pituitary at natural dietary concentrations. Experiments designed to test for estrogen antagonism demonstrated that coumestrol did not conform to the picture of a classic antiestrogen. However, coumestrol did suppress estrous cycles in adult females. Developmental actions were examined by neonatal exposure of pups through milk of rat dams fed a coumestrol, control, or commercial soy-based diet during the critical period of the first 10 postnatal days or throughout the 21 days of lactation. The 10-day treatment did not significantly alter adult estrous cyclicity, but the 21-day treatment produced in a persistent estrus state in coumestrol-treated females by 132 days of age. In contrast, the 10-day coumestrol treatments produced significant deficits in the sexual behavior of male offspring. These findings illustrate the broad range of actions of these natural estrogens and the variability in potency across endpoints. This variability argues for the importance of fully characterizing each phytoestrogen in terms of its sites of action, balance of agonistic and antagonistic properties, natural potency, and short-term and long-term effects.
Naisbitt, Dean J.
Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs. PMID:23476052
Koch, Tina; Mueller, Ralf S.; Dobenecker, Britta; Fischer, Andrea
Epilepsy is one of the most common neurologic disorders in dogs and life-long treatment with antiepileptic drugs (AED) is frequently required. Adverse events of AED targeting the skin are only rarely reported in veterinary medicine and the true incidence and spectrum of cutaneous reactions in epileptic dogs remains unknown. In this study, we hypothesized that cutaneous reactions commonly occur in epileptic dogs and are related to AED treatment. A retrospective case review of 185 dogs treated for epilepsy identified 20.0% with simultaneous appearance of dermatologic signs. In a subsequent prospective case investigation (n = 137), we identified newly appearing or distinct worsening of skin lesions following initiation of AED therapy in 10.9% of dogs treated for epilepsy (95% CI 6.8–17.7%). Cutaneous lesions were classified as probably drug-induced in 40.0% of these cases. Patch testing and intradermal testing were further investigated as potential diagnostic methods to confirm AED hypersensitivity. They were of high specificity but sensitivity and positive predictive value appeared inappropriate to recommend their routine use in clinical practice. PMID:27148543
Cheng, Feixiong; Li, Weihua; Wang, Xichuan; Zhou, Yadi; Wu, Zengrui; Shen, Jie; Tang, Yun
Adverse drug events (ADEs) are the harms associated with uses of given medications at normal dosages, which are crucial for a drug to be approved in clinical use or continue to stay on the market. Many ADEs are not identified in trials until the drug is approved for clinical use, which results in adverse morbidity and mortality. To date, millions of ADEs have been reported around the world. Methods to avoid or reduce ADEs are an important issue for drug discovery and development. Here, we reported a comprehensive database of adverse drug events (namely MetaADEDB), which included more than 520,000 drug-ADE associations among 3059 unique compounds (including 1330 drugs) and 13,200 ADE items by data integration and text mining. All compounds and ADEs were annotated with the most commonly used concepts defined in Medical Subject Headings (MeSH). Meanwhile, a computational method, namely the phenotypic network inference model (PNIM), was developed for prediction of potential ADEs based on the database. The area under the receive operating characteristic curve (AUC) is more than 0.9 by 10-fold cross validation, while the AUC value was 0.912 for an external validation set extracted from the US-FDA Adverse Events Reporting System, which indicated that the prediction capability of the method was reliable. MetaADEDB is accessible free of charge at http://www.lmmd.org/online_services/metaadedb/. The database and the method provide us a useful tool to search for known side effects or predict potential side effects for a given drug or compound.
Roitmann, Eva; Eriksson, Robert; Brunak, Søren
Purpose: New pharmacovigilance methods are needed as a consequence of the morbidity caused by drugs. We exploit fine-grained drug related adverse event information extracted by text mining from electronic medical records (EMRs) to stratify patients based on their adverse events and to determine adverse event co-occurrences. Methods: We analyzed the similarity of adverse event profiles of 2347 patients extracted from EMRs from a mental health center in Denmark. The patients were clustered based on their adverse event profiles and the similarities were presented as a network. The set of adverse events in each main patient cluster was evaluated. Co-occurrences of adverse events in patients (p-value < 0.01) were identified and presented as well. Results: We found that each cluster of patients typically had a most distinguishing adverse event. Examination of the co-occurrences of adverse events in patients led to the identification of potentially interesting adverse event correlations that may be further investigated as well as provide further patient stratification opportunities. Conclusions: We have demonstrated the feasibility of a novel approach in pharmacovigilance to stratify patients based on fine-grained adverse event profiles, which also makes it possible to identify adverse event correlations. Used on larger data sets, this data-driven method has the potential to reveal unknown patterns concerning adverse event occurrences. PMID:25249979
Wing, S S; Fantus, I G
Propylthiouracil and methimazole are frequently used in the management of hyperthyroidism. Two patients in whom adverse immunologic effects other than isolated agranulocytosis developed during treatment with propylthiouracil are described. A review of the literature revealed 53 similar cases over a 35-year period. Rash, fever, arthralgias and granulocytopenia were the most common manifestations. Vasculitis, particularly with cutaneous manifestations, occurs and may be fatal. The clinical evidence suggests that an immunologic mechanism is involved. A number of different autoantibodies were reported, but antinuclear antibodies were infrequent, and none of the cases met the criteria for a diagnosis of systemic lupus erythematosus. Thus, the reactions do not represent a true drug-induced lupus syndrome. Current hypotheses and experimental data regarding the cause of the reactions are reviewed. No specific clinical subgroup at high risk can be identified, and manifestations may occur at any dosage and at any time during therapy. Cross-reactivity between the two antithyroid drugs can be expected. Except for minor symptoms (e.g., mild arthralgias or transient rash), such reactions are an indication for withdrawal of the drug and the use of alternative methods to control the hyperthyroidism. In rare cases of severe vasculitis a short course of high-dose glucocorticoid therapy may be helpful. PMID:3539299
Mull, Hillary J.; Rosen, Amy K.; Shimada, Stephanie L.; Rivard, Peter E.; Nordberg, Brian; Long, Brenna; Hoffman, Jennifer M.; Leecaster, Molly; Savitz, Lucy A.; Shanahan, Christopher W.; Helwig, Amy; Nebeker, Jonathan R.
Background: Adverse drug event (ADE) detection is an important priority for patient safety research. Trigger tools have been developed to help identify ADEs. In previous work we developed seven concurrent, action-oriented, electronic trigger algorithms designed to prompt clinicians to address ADEs in outpatient care. Objectives: We assessed the potential adoption and usefulness of the seven triggers by testing the positive predictive validity and obtaining stakeholder input. Methods: We adapted ADE triggers, “bone marrow toxin—white blood cell count (BMT-WBC),” “bone marrow toxin - platelet (BMT-platelet),” “potassium raisers,” “potassium reducers,” “creatinine,” “warfarin,” and “sedative hypnotics,” with logic to suppress flagging events with evidence of clinical intervention and applied the triggers to 50,145 patients from three large health care systems. Four pharmacists assessed trigger positive predictive value (PPV) with respect to ADE detection (conservatively excluding ADEs occurring during clinically appropriate care) and clinical usefulness (i.e., whether the trigger alert could change care to prevent harm). We measured agreement between raters using the free kappa and assessed positive PPV for the trigger’s detection of harm, clinical usefulness, and both. Stakeholders from the participating health care systems rated the likelihood of trigger adoption and the perceived ease of implementation. Findings: Agreement between pharmacist raters was moderately high for each ADE trigger (kappa free > 0.60). Trigger PPVs for harm ranged from 0 (Creatinine, BMT-WBC) to 17 percent (potassium raisers), while PPV for care change ranged from 0 (WBC) to 60 percent (Creatinine). Fifteen stakeholders rated the triggers. Our assessment identified five of the seven triggers as good candidates for implementation: Creatinine, BMT-Platelet, Potassium Raisers, Potassium Reducers, and Warfarin. Conclusions: At least five outpatient ADE triggers
Horen, Benjamin; Montastruc, Jean-Louis; Lapeyre-mestre, Maryse
Aims To investigate the potential relationship between off-label drug use and increased risk of adverse drug reactions in paediatric outpatients. Methods A prospective pharmacovigilance survey of drug prescribing in office based paediatricians was carried out in Haute-Garonne County (south west of France). Results The study involved a sample of 1419 children under 16 years old. Forty-two percent of patients were exposed to at least one off-label prescription. The incidence of adverse drug reactions was 1.41% (95% CI 0.79, 2.11). Off-label drug use was significantly associated with adverse drug reactions (relative risk 3.44; 95% CI 1.26, 9.38), particularly when it was due to an indication different than that defined in the Summary Product Characteristics (relative risk 4.42; 95% CI 1.60, 12.25). Conclusions Our data suggest an increasing risk of adverse drug reactions related to off-label drug use. This risk would be acceptable if further studies prove the potential benefit of such a drug use. PMID:12492616
Sammons, Helen M.; Choonara, Imti
Drug toxicity is, unfortunately, a significant problem in children both in the hospital and in the community. Drug toxicity in children is different to that seen in adults. At least one in 500 children will experience an adverse drug reaction each year. For children in hospital, the risk is far greater (one in ten). Additionally, different and sometimes unique adverse drug reactions are seen in the paediatric age groups. Some of the major cases of drug toxicity historically have occurred in neonates. It is important that we understand the mechanism of action of adverse drug reactions. Greater understanding alongside rational prescribing should hopefully reduce drug toxicity in children in the future. PMID:27417239
Leung, Angela M.; Pearce, Elizabeth N.; Braverman, Lewis E.
Purpose of review This review will present a general overview of the sources, human studies, and proposed regulatory action regarding environmental perchlorate exposure. Recent findings Some recent studies have reported significant associations between urinary perchlorate concentrations, thyroid dysfunction, and decreased infant IQ in groups who would be particularly susceptible to perchlorate effects. An update regarding the recent proposed regulatory actions and potential costs surrounding amelioration of perchlorate contamination is provided. Summary The potential adverse thyroidal effects of environmental perchlorate exposure remain controversial, and further research is needed to further define its relationship to human health among pregnant and lactating women and their infants. PMID:25106002
Issa, Amalia M
The problem of adverse drug reactions is a well-documented global public health problem. Recent withdrawals of several widely used prescription medications in the USA and other countries have raised concerns among patients, clinicians, scientists and policy makers. The increasing interest and concern regarding withdrawal of previously approved prescription medications and drug safety has prompted renewed research efforts aimed at improving surveillance of approved drugs and reducing adverse drug reactions. Pharmacogenomics research is increasingly directed at developing genomic diagnostics and tests with predictive ability for adverse drug reactions. This paper focuses on the problem of adverse drug reactions and reviews the evidence and the state of the science for the application of pharmacogenomics to adverse drug reactions.
Clarke, Janet B
Biologics encompass a broad range of therapeutics that include proteins and other products derived from living systems. Although the multiplicity of target organs often seen with new chemical entities is generally not seen with biologics, they can produce significant adverse reactions. Examples include IL-12 and an anti-CD28 antibody that resulted in patient deaths and/or long stays in intensive care units. Mechanisms of toxicities can be categorized as pharmacological or nonpharmacological, with most, excepting hypersensitivity reactions, associated with the interaction of the agent with its planned target. Unexpected toxicities generally arise as a result of previously unknown biology. Manufacturing quality is a significant issue relative to the toxicity of biologics. The development of recombinant technology represented the single biggest advance leading to humanized products with minimal or no contaminants in comparison to products purified from animal tissues. Nevertheless, the type of manufacturing process including choice of cell type, culture medium, and purification method can result in changes to the protein. For example, a change to the closure system for erythropoietin led to an increase in aplastic anemia as a result of changing the immunogenicity characteristics of the protein. Monoclonal antibodies represent a major class of successful biologics. Toxicities associated with these agents include those associated with the binding of the complementary determining region (CDR) with the target. First dose reactions or infusion reactions are generally thought to be mediated via the Fc region of the antibody activating cytokine release, and have been observed with several antibodies. Usually, these effects (flu-like symptoms, etc.) are transient with subsequent dosing. Although biologics can have nonpharmacologic toxicities, these are less common than with small molecule drugs.
Chee, Brant W; Berlin, Richard; Schatz, Bruce
Adverse drug events (ADEs) remain a large problem in the United States, being the fourth leading cause of death, despite post market drug surveillance. Much post consumer drug surveillance relies on self-reported "spontaneous" patient data. Previous work has performed datamining over the FDA's Adverse Event Reporting System (AERS) and other spontaneous reporting systems to identify drug interactions and drugs correlated with high rates of serious adverse events. However, safety problems have resulted from the lack of post marketing surveillance information about drugs, with underreporting rates of up to 98% within such systems. We explore the use of online health forums as a source of data to identify drugs for further FDA scrutiny. In this work we aggregate individuals' opinions and review of drugs similar to crowd intelligence3. We use natural language processing to group drugs discussed in similar ways and are able to successfully identify drugs withdrawn from the market based on messages discussing them before their removal.
Greenwich Bay is an urbanized embayment of Narragansett Bay potentially impacted by multiple stressors. The present study identified the important stressors affecting Greenwich Bay benthic fauna. First, existing data and information were used to confirm that the waterbody was impaired. Second, the presence of source, stressor, and effect were established. Then linkages between source, stressor, and effect were developed. This allows identification of probable stressors adversely affecting the waterbody. Three pollutant categories were assessed: chemicals, nutrients, and suspended sediments. This weight of evidence approach indicated that Greenwich Bay was primarily impacted by eutrophication-related stressors. The sediments of Greenwich Bay were carbon enriched and low dissolved oxygen concentrations were commonly seen, especially in the western portions of Greenwich Bay. The benthic community was depauperate, as would be expected under oxygen stress. Although our analysis indicated that contaminant loads in Greenwich Bay were at concentrations where adverse effects might be expected, no toxicity was observed, as a result of high levels of organic carbon in these sediments reducing contaminant bioavailability. Our analysis also indicated that suspended sediment impacts were likely nonexistent for much of the Bay. This analysis demonstrates that the diagnostic procedure was useful to organize and assess the potential stressors impacting the ecological well-being
Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung
Objective We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Methods Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary’s teaching hospital, Daejeon, Korea) from 2010–2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton’s preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Results Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization–Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001). Conclusions We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse
Sawarkar, Abhivyakti; Keohane, Carol A.; Maviglia, Saverio; Gandhi, Tejal K; Poon, Eric G
OBJECTIVE To determine how often serious or life-threatening medication administration errors with the potential to cause patient harm (or potential adverse drug events) result in actual patient harm (or adverse drug events (ADEs)) in the hospital setting. DESIGN Retrospective chart review of clinical events that transpired following observed medication administration errors. BACKGROUND Medication errors are common at the medication administration stage for hospitalized patients. While many of these errors are considered capable of causing patient harm, it is not clear how often patients are actually harmed by these errors. METHODS In a previous study where 14,041 medication administrations in an acute-care hospital were directly observed, investigators discovered 1271 medication administration errors, of which 133 had the potential to cause serious or life-threatening harm to patients and were considered serious or life-threatening potential ADEs. In the current study, clinical reviewers conducted detailed chart reviews of cases where a serious or life-threatening potential ADE occurred to determine if an actual ADE developed following the potential ADE. Reviewers further assessed the severity of the ADE and attribution to the administration error. RESULTS Ten (7.5% [95% C.I. 6.98, 8.01]) actual adverse drug events or ADEs resulted from the 133 serious and life-threatening potential ADEs, of which 6 resulted in significant, three in serious, and one life threatening injury. Therefore 4 (3% [95% C.I. 2.12, 3.6]) serious and life threatening potential ADEs led to serious or life threatening ADEs. Half of the ten actual ADEs were caused by dosage or monitoring errors for anti-hypertensives. The life threatening ADE was caused by an error that was both a transcription and a timing error. CONCLUSION Potential ADEs at the medication administration stage can cause serious patient harm. Given previous estimates of serious or life-threatening potential ADE of 1.33 per 100
Ribeiro-Vaz, Inês; Santos, Cristina Costa; Cruz-Correia, Ricardo
ABSTRACT OBJECTIVE To describe different approaches to promote adverse drug reaction reporting among health care professionals, determining their cost-effectiveness. METHODS We analyzed and compared several approaches taken by the Northern Pharmacovigilance Centre (Portugal) to promote adverse drug reaction reporting. Approaches were compared regarding the number and relevance of adverse drug reaction reports obtained and costs involved. Costs by report were estimated by adding the initial costs and the running costs of each intervention. These costs were divided by the number of reports obtained with each intervention, to assess its cost-effectiveness. RESULTS All the approaches seem to have increased the number of adverse drug reaction reports. We noted the biggest increase with protocols (321 reports, costing 1.96 € each), followed by first educational approach (265 reports, 20.31 €/report) and by the hyperlink approach (136 reports, 15.59 €/report). Regarding the severity of adverse drug reactions, protocols were the most efficient approach, costing 2.29 €/report, followed by hyperlinks (30.28 €/report, having no running costs). Concerning unexpected adverse drug reactions, the best result was obtained with protocols (5.12 €/report), followed by first educational approach (38.79 €/report). CONCLUSIONS We recommend implementing protocols in other pharmacovigilance centers. They seem to be the most efficient intervention, allowing receiving adverse drug reactions reports at lower costs. The increase applied not only to the total number of reports, but also to the severity, unexpectedness and high degree of causality attributed to the adverse drug reactions. Still, hyperlinks have the advantage of not involving running costs, showing the second best performance in cost per adverse drug reactions report. PMID:27143614
Dawson, Dominic R
This article provides an overview of the more common toxins and adverse drug reactions, along with more rare toxins and reactions (Table 1), that result in neurologic dysfunction in horses. A wide variety of symptoms, treatments, and outcomes are seen with toxic neurologic disease in horses. An in-depth history and thorough physical examination are needed to determine if a toxin or adverse drug reaction is responsible for the clinical signs. Once a toxin or adverse drug reaction is identified, the specific antidote, if available, and supportive care should be administered promptly.
Yasnoff, William A.; Tomkins, Edward L.; Dunn, Louise M.
Adverse drug reactions (ADRs) are a major source of preventable morbidity and mortality, especially among the elderly, who use more drugs and are more sensitive to them. The insurance industry has recently addressed this problem through the implementation of drug interaction alerts to pharmacists in conjunction with immediate online claims adjudication for almost 60% of prescriptions (expected to reach 90% within 5 years). These alerts are based on stored patient drug profiles maintained by pharmacy benefit managers (PBMs) which are updated whenever prescriptions are filled. While these alerts are very helpful, the pharmacist does not prescribe, resulting in time-consuming and costly delays to contact the physician and remedy potential interactions. We have developed and demonstrated the feasibility of the PINPOINT (Pharmaceutical Information Network for prevention of interactions) system for making the drug profile and interaction information easily available to the physician before the prescription is written. We plan to test the cost-effectiveness of the system in a prospective controlled clinical trial.
Karimi, Sarvnaz; Metke-Jimenez, Alejandro; Kemp, Madonna; Wang, Chen
CSIRO Adverse Drug Event Corpus (Cadec) is a new rich annotated corpus of medical forum posts on patient-reported Adverse Drug Events (ADEs). The corpus is sourced from posts on social media, and contains text that is largely written in colloquial language and often deviates from formal English grammar and punctuation rules. Annotations contain mentions of concepts such as drugs, adverse effects, symptoms, and diseases linked to their corresponding concepts in controlled vocabularies, i.e., SNOMED Clinical Terms and MedDRA. The quality of the annotations is ensured by annotation guidelines, multi-stage annotations, measuring inter-annotator agreement, and final review of the annotations by a clinical terminologist. This corpus is useful for studies in the area of information extraction, or more generally text mining, from social media to detect possible adverse drug reactions from direct patient reports. The corpus is publicly available at https://data.csiro.au.(1).
Davies, E A; O’Mahony, M S
The International Conference on Harmonization considers older people a ‘special population’, as they differ from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions (ADRs). Medical practice is often based on single disease guidelines derived from clinical trials that have not included frail older people or those with multiple morbidities. This presents a challenge caring for older people, as drug doses in trials may not be achievable in real world patients and risks of ADRs are underestimated in clinical trial populations. The majority of ADRs in older people are Type A, potentially avoidable and associated with commonly prescribed medications. Several ADRs are particularly associated with major adverse consequences in the elderly and their reduction is therefore a clinical priority. Falls are strongly associated with benzodiazepines, neuroleptics, antidepressants and antihypertensives. There is good evidence for medication review as part of a multifactorial intervention to reduce falls risk in community dwelling elderly. Multiple medications also contribute to delirium, another multifactorial syndrome resulting in excess mortality particularly in frail older people. Clostridium difficile associated with use of broad spectrum antibiotics mainly affects frail older people and results in prolonged hospital stay with substantial morbidity and mortality. Antipsychotics increase the risk of stroke by more than three-fold in patients with dementia. Inappropriate prescribing can be reduced by adherence to prescribing guidelines, suitable monitoring and regular medication review. Given the heterogeneity within the older population, providing individualized care is pivotal to preventing ADRs. PMID:25619317
Reynolds, J. L.
In this study, 232 Canadian family physicians recorded suspected adverse drug reactions (SADRs) in their practices for five months. Patients' age and sex, the drug(s) implicated, type of reaction and any disability were recorded on a card and sent to a central coordinating office each week. The number of SADRs in clinical practice seems to be small. An estimated 300,000 patients were involved in the study, and a total of 314 suspected adverse drug reactions in 314 patients were reported. A proposal is made for a surveillance system for new drugs. Family physicians would monitor all patients taking a drug or group of drugs and matched controls. The status of patients and controls would be recorded regularly and any SADRs reported to a central coordinating centre. PMID:21283495
Amalyste is a French patient-advocacy group for victims of two very serious adverse drug reactions: Lyell and Stevens-Johnson syndromes. The aims of this organisation are to represent the interests of patients who have experienced these syndromes; to better inform the public about these syndromes; to provide analyses of drug-related risks; and to demand collective compensation for victims of serious adverse drug reactions. The following text is our translation of an Amalyste position statement on drug-related risks. It provides valuable food for thought, both for healthcare professionals and for drug regulatory agencies, and has the potential to improve practice (a).
Lin, Wen-Yang; Li, He-Yi; Du, Jhih-Wei; Feng, Wen-Yu; Lo, Chiao-Feng; Soo, Von-Wun
Adverse Drug Reaction (ADR) is one of the most important issues in the assessment of drug safety. In fact, many adverse drug reactions are not discovered during limited pre-marketing clinical trials; instead, they are only observed after long term post-marketing surveillance of drug usage. In light of this, the detection of adverse drug reactions, as early as possible, is an important topic of research for the pharmaceutical industry. Recently, large numbers of adverse events and the development of data mining technology have motivated the development of statistical and data mining methods for the detection of ADRs. These stand-alone methods, with no integration into knowledge discovery systems, are tedious and inconvenient for users and the processes for exploration are time-consuming. This paper proposes an interactive system platform for the detection of ADRs. By integrating an ADR data warehouse and innovative data mining techniques, the proposed system not only supports OLAP style multidimensional analysis of ADRs, but also allows the interactive discovery of associations between drugs and symptoms, called a drug-ADR association rule, which can be further developed using other factors of interest to the user, such as demographic information. The experiments indicate that interesting and valuable drug-ADR association rules can be efficiently mined.
Yu, Yue; Chen, Jun; Li, Dingcheng; Wang, Liwei; Wang, Wei; Liu, Hongfang
Increasing evidence has shown that sex differences exist in Adverse Drug Events (ADEs). Identifying those sex differences in ADEs could reduce the experience of ADEs for patients and could be conducive to the development of personalized medicine. In this study, we analyzed a normalized US Food and Drug Administration Adverse Event Reporting System (FAERS). Chi-squared test was conducted to discover which treatment regimens or drugs had sex differences in adverse events. Moreover, reporting odds ratio (ROR) and P value were calculated to quantify the signals of sex differences for specific drug-event combinations. Logistic regression was applied to remove the confounding effect from the baseline sex difference of the events. We detected among 668 drugs of the most frequent 20 treatment regimens in the United States, 307 drugs have sex differences in ADEs. In addition, we identified 736 unique drug-event combinations with significant sex differences. After removing the confounding effect from the baseline sex difference of the events, there are 266 combinations remained. Drug labels or previous studies verified some of them while others warrant further investigation. PMID:27102014
Petrovic, Mirko; van der Cammen, Tischa; Onder, Graziano
Adverse drug reactions (ADRs) in older adults are an important healthcare problem since they are frequently a cause of hospitalization, occur commonly during admission, and are an important cause of morbidity and mortality. Older adults are particularly susceptible to ADRs because they are usually on multiple drug regimens and because age is associated with changes in pharmacokinetics and pharmacodynamics. The presentation of an ADR in older adults is often atypical, which further complicates its recognition. One potential strategy for improving recognition of ADRs is to identify those patients who are at risk of an ADR. The recently developed GerontoNet ADR Risk Score is a practical tool for identification of older patients who are at increased risk for an ADR and who may represent a target for interventions aimed at reducing ADRs. Provision of adequate education in the domain of clinical geriatric pharmacology can improve recognition of ADRs. Besides formal surveillance systems, built-in computer programs with electronic prescribing databases and clinical pharmacist involvement in patient care within multidisciplinary geriatric teams might help to minimize the occurrence of ADRs. In addition, a number of actions can be taken in hospitals to stimulate appropriate prescribing and to assure adequate communication between primary and hospital care. In older adults with complex medical problems and needs, a global evaluation obtained through a comprehensive geriatric assessment may be helpful in simplifying drug prescription and prioritizing pharmacological and healthcare needs, resulting in an improvement in quality of prescribing.
Jin, Huidong Warren; Chen, Jie; He, Hongxing; Williams, Graham J; Kelman, Chris; O'Keefe, Christine M
In various real-world applications, it is very useful mining unanticipated episodes where certain event patterns unexpectedly lead to outcomes, e.g., taking two medicines together sometimes causing an adverse reaction. These unanticipated episodes are usually unexpected and infrequent, which makes existing data mining techniques, mainly designed to find frequent patterns, ineffective. In this paper, we propose unexpected temporal association rules (UTARs) to describe them. To handle the unexpectedness, we introduce a new interestingness measure, residual-leverage, and develop a novel case-based exclusion technique for its calculation. Combining it with an event-oriented data preparation technique to handle the infrequency, we develop a new algorithm MUTARC to find pairwise UTARs. The MUTARC is applied to generate adverse drug reaction (ADR) signals from real-world healthcare administrative databases. It reliably shortlists not only six known ADRs, but also another ADR, flucloxacillin possibly causing hepatitis, which our algorithm designers and experiment runners have not known before the experiments. The MUTARC performs much more effectively than existing techniques. This paper clearly illustrates the great potential along the new direction of ADR signal generation from healthcare administrative databases.
Rozenfeld, Suely; Giordani, Fabiola; Coelho, Sonia
OBJECTIVE To estimate the frequency of and to characterize the adverse drug events at a terciary care hospital. METHODS A retrospective review was carried out of 128 medical records from a hospital in Rio de Janeiro in 2007, representing 2,092 patients. The instrument used was a list of triggers, such as antidotes, abnormal laboratory analysis results and sudden suspension of treatment, among others. A simple random sample of patients aged 15 and over was extracted. Oncologic and obstetric patients were excluded as were those hospitalized for less than 48 hours or in the emergency room. Social and demographic characteristics and those of the disease of patients who underwent adverse events were compared with those of patients who did not in order to test for differences between the groups. RESULTS Around 70.0% of the medical records assessed showed at least one trigger. Adverse drug events triggers had an overall positive predictive value of 14.4%. The incidence of adverse drug events was 26.6 per 100 patients and 15.6% patients suffered one or more event. The median length of stay for patients suffering an adverse drug event was 35.2 days as against 10.7 days for those who did not (p < 0.01). The pharmacological classes most commonly associated with an adverse drug event were related to the cardiovascular system, nervous system and alimentary tract and metabolism. The most common active substances associated with an adverse drug event were tramadol, dypirone, glibenclamide and furosemide. Over 80.0% of events provoked or contributed to temporary harm to the patient and required intervention and 6.0% may have contributed to the death of the patient. It was estimated that in the hospital, 131 events involving drowsiness or fainting 33 involving falls, and 33 episodes of hemorrhage related to adverse drug effects occur annually. CONCLUSIONS Almost one-sixth of in-patients (16,0%) suffered an adverse drug event. The instrument used may prove useful as a technique for
Lortie, F M
The surveillance of adverse drug reactions (ADRs) is an unqualified must. However, the optimal means of surveillance is still unclear. Although anecdotal reports are the backbone of an ADR surveillance system, they are not enough. The pharmaceutical industry, academics and regulatory agencies need to expand their efforts in monitoring ADRs. The author discusses the various techniques for counting and evaluating adverse reactions and suggests ways in which the system could be improved. PMID:3719483
Müntener, C R; Bruckner, L; Gassner, B; Demuth, D C; Althaus, F R; Zwahlen, R
We received 105 reports of suspected adverse events (SARs) following the use of veterinary drugs for the year 2005. This corresponds to a 35% increase compared to 2004. Practicing veterinarians sent most of these declarations. 73% of these concerned drugs used on companion animals. Antiparasitic drugs approved for topical use were the most frequently represented group with 48%, followed by drugs used to treat gastrointestinal disorders (11%) and drugs used off-label (14%; other target species or other indication). For the first time 2 declarations concerning the application of permethrin containing spot-on preparations used by mistake on cats were received. An overview of 20 declarations about adverse reactions following application of different vaccines is also presented with emphasis on the problem of fibrosarcoma in cats. We are pleased by the growing interest shown by practicing veterinarians for the vigilance system and hope to further develop this collaboration in the future.
Background Pharmacovigilance aims to uncover and understand harmful side-effects of drugs, termed adverse events (AEs). Although the current process of pharmacovigilance is very systematic, the increasing amount of information available in specialized health-related websites as well as the exponential growth in medical literature presents a unique opportunity to supplement traditional adverse event gathering mechanisms with new-age ones. Method We present a semi-automated pipeline to extract associations between drugs and side effects from traditional structured adverse event databases, enhanced by potential drug-adverse event pairs mined from user-comments from health-related websites and MEDLINE abstracts. The pipeline was tested using a set of 12 drugs representative of two previous studies of adverse event extraction from health-related websites and MEDLINE abstracts. Results Testing the pipeline shows that mining non-traditional sources helps substantiate the adverse event databases. The non-traditional sources not only contain the known AEs, but also suggest some unreported AEs for drugs which can then be analyzed further. Conclusion A semi-automated pipeline to extract the AE pairs from adverse event databases as well as potential AE pairs from non-traditional sources such as text from MEDLINE abstracts and user-comments from health-related websites is presented. PMID:24559132
Hawcutt, Daniel B; O'Connor, Olya; Turner, Mark A
Neonates are vulnerable to adverse drug reactions but reports of these events are relatively infrequent. Reporting can be increased by adapting a number of standard techniques to the unique features of neonatal care and pathology. However, clinicians and parents will be reluctant to report information about harms in the absence of mechanisms to ensure that reports affect clinical practice. Improved reporting will depend on education and cultural change that are informed by research about pharmacovigilance in neonatal settings. The efficient use of neonatal adverse drug reaction reports will require harmonization of terminology and interoperable databases.
Pulford, Andrew; Malcolm, William
The reporting of adverse drug reactions (ADRs) by health professionals forms an important component of ongoing surveillance of post-marketing drug safety. The extension of responsibility for all health professionals to report ADRs has coincided with national immunization programmes, such as the national childhood immunization, human papillomavirus (HPV), and seasonal and H1N1 influenza programmes. The study objective was to evaluate knowledge of, and attitudes to, reporting ADRs among the professional groups most likely to see suspected reactions to vaccines. This included nursing professionals, whose views have not been included in previous studies. A survey of 91 practice nurses, health visitors, school nurses and GPs working in Ayrshire and Arran during June, July and August 2007 was undertaken. The respondents' knowledge of ADR reporting varied considerably. Although the majority of respondents recognized that it is the responsibility of health professionals to report suspected ADRs, there were lower levels of knowledge about the purpose of the Yellow Card system specifically; less than 50% of the respondents reported good knowledge about the system. The study suggests implications for practice with regard to the implementation of large-scale immunization programmes and potential solutions to under-reporting among these professional groups.
O’Connor, Karen; Pimpalkhute, Pranoti; Nikfarjam, Azadeh; Ginn, Rachel; Smith, Karen L; Gonzalez, Graciela
Recent research has shown that Twitter data analytics can have broad implications on public health research. However, its value for pharmacovigilance has been scantly studied – with health related forums and community support groups preferred for the task. We present a systematic study of tweets collected for 74 drugs to assess their value as sources of potential signals for adverse drug reactions (ADRs). We created an annotated corpus of 10,822 tweets. Each tweet was annotated for the presence or absence of ADR mentions, with the span and Unified Medical Language System (UMLS) concept ID noted for each ADR present. Using Cohen’s kappa1, we calculated the inter-annotator agreement (IAA) for the binary annotations to be 0.69. To demonstrate the utility of the corpus, we attempted a lexicon-based approach for concept extraction, with promising success (54.1% precision, 62.1% recall, and 57.8% F-measure). A subset of the corpus is freely available at: http://diego.asu.edu/downloads. PMID:25954400
Soukavong, Mick; Kim, Jungmee; Park, Kyounghoon; Yang, Bo Ram; Lee, Joongyub; Jin, Xue Mei; Park, Byung Joo
We conducted pharmacovigilance data mining for a β-lactam antibiotics, amoxicillin, and compare the adverse events (AEs) with the drug labels of 9 countries including Korea, USA, UK, Japan, Germany, Swiss, Italy, France, and Laos. We used the Korea Adverse Event Reporting System (KAERS) database, a nationwide database of AE reports, between December 1988 and June 2014. Frequentist and Bayesian methods were used to calculate disproportionality distribution of drug-AE pairs. The AE which was detected by all the three indices of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) was defined as a signal. The KAERS database contained a total of 807,582 AE reports, among which 1,722 reports were attributed to amoxicillin. Among the 192,510 antibiotics-AE pairs, the number of amoxicillin-AE pairs was 2,913. Among 241 AEs, 52 adverse events were detected as amoxicillin signals. Comparing the drug labels of 9 countries, 12 adverse events including ineffective medicine, bronchitis, rhinitis, sinusitis, dry mouth, gastroesophageal reflux, hypercholesterolemia, gastric carcinoma, abnormal crying, induration, pulmonary carcinoma, and influenza-like symptoms were not listed on any of the labels of nine countries. In conclusion, we detected 12 new signals of amoxicillin which were not listed on the labels of 9 countries. Therefore, it should be followed by signal evaluation including causal association, clinical significance, and preventability.
We conducted pharmacovigilance data mining for a β-lactam antibiotics, amoxicillin, and compare the adverse events (AEs) with the drug labels of 9 countries including Korea, USA, UK, Japan, Germany, Swiss, Italy, France, and Laos. We used the Korea Adverse Event Reporting System (KAERS) database, a nationwide database of AE reports, between December 1988 and June 2014. Frequentist and Bayesian methods were used to calculate disproportionality distribution of drug-AE pairs. The AE which was detected by all the three indices of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) was defined as a signal. The KAERS database contained a total of 807,582 AE reports, among which 1,722 reports were attributed to amoxicillin. Among the 192,510 antibiotics-AE pairs, the number of amoxicillin-AE pairs was 2,913. Among 241 AEs, 52 adverse events were detected as amoxicillin signals. Comparing the drug labels of 9 countries, 12 adverse events including ineffective medicine, bronchitis, rhinitis, sinusitis, dry mouth, gastroesophageal reflux, hypercholesterolemia, gastric carcinoma, abnormal crying, induration, pulmonary carcinoma, and influenza-like symptoms were not listed on any of the labels of nine countries. In conclusion, we detected 12 new signals of amoxicillin which were not listed on the labels of 9 countries. Therefore, it should be followed by signal evaluation including causal association, clinical significance, and preventability. PMID:27510377
Sasidharanpillai, Sarita; Riyaz, Najeeba; Khader, Anza; Rajan, Uma; Binitha, Manikoth P; Sureshan, Deepthi N
Background: Drug eruptions range from transient erythema to the life threatening severe cutaneous adverse reactions (SCAR) that encompass Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms complex (DRESS). Aims and Objectives: To study the clinical and epidemiological aspects of cutaneous adverse drug reactions (CADR). Materials and Methods: Ethical clearance was obtained from the institutional ethics committee. All patients admitted in the Dermatology ward of our tertiary care hospital with CADR (those who fit in the category of probable or possible drug reaction as per WHO casuality assessment) from first September 2011 to 31st August 2012 were included in this cross sectional study after obtaining written informed consent. The drug reaction patterns observed in the study population were determined and the common offending drugs were identified. Results: In the study, population of males outnumbered females and the majority were between 46 and 60 years of age. The commonest reaction pattern observed was SJS- TEN spectrum of illness and aromatic anticonvulsants were the common offending drugs. Prompt withdrawal of the culprit drug and administration of systemic steroids with or without I/V Ig reverted the adverse reaction in all except one. Conclusion: Severe drug reactions predominated as the study population was comprised of inpatients of a tertiary referral centre. Though; previous authors had reported a mortality rate of up to 20% in DRESS, all our patients with this reaction pattern, responded well to treatment. The mortality rate among TEN cases was much lower than the previous reports. Early diagnosis, prompt withdrawal of the suspected drug, careful monitoring for development of complications and immediate intervention can improve the prognosis of CADR. PMID:25657416
Chabi, Yossounon; Brahim, Kheira; Da Costa, Maryline; Caffin, Anne-Gaëlle; Camus, Gisèle; Paillet, Michel; Bohand, Xavier
The photodegradation of an active substance during treatment is a rare drug-related adverse event which can sometimes have serious consequences. Health professionals must be aware of the specific storage and administration instructions with regard to chlorpromazine and ensure that they are respected.
Resende, Laíse Soares Oliveira; Santos-Neto, Edson Theodoro Dos
This review sought to identify the available scientific evidence on risk factors associated with adverse reactions to antituberculosis drugs. We performed a systematic review of studies published in the 1965-2012 period and indexed in the MEDLINE and LILACS databases. A total of 1,389 articles were initially selected. After reading their abstracts, we selected 85 studies. Of those 85 studies, 16 were included in the review. Risk factors for adverse reactions to antituberculosis drugs included age > 60 years, treatment regimens, alcoholism, anemia, and HIV co-infection, as well as sodium, iron, and albumin deficiency. Protective factors against hepatic adverse effects of antituberculosis drugs included being male (combined OR = 0.38; 95% CI: 0.20-0.72) and showing a rapid/intermediate N-acetyltransferase 2 acetylator phenotype (combined OR = 0.41; 95% CI: 0.18-0.90). There is evidence to support the need for management of adverse reactions to antituberculosis drugs at public health care facilities.
Resende, Laíse Soares Oliveira; dos Santos-Neto, Edson Theodoro
This review sought to identify the available scientific evidence on risk factors associated with adverse reactions to antituberculosis drugs. We performed a systematic review of studies published in the 1965-2012 period and indexed in the MEDLINE and LILACS databases. A total of 1,389 articles were initially selected. After reading their abstracts, we selected 85 studies. Of those 85 studies, 16 were included in the review. Risk factors for adverse reactions to antituberculosis drugs included age > 60 years, treatment regimens, alcoholism, anemia, and HIV co-infection, as well as sodium, iron, and albumin deficiency. Protective factors against hepatic adverse effects of antituberculosis drugs included being male (combined OR = 0.38; 95% CI: 0.20-0.72) and showing a rapid/intermediate N-acetyltransferase 2 acetylator phenotype (combined OR = 0.41; 95% CI: 0.18-0.90). There is evidence to support the need for management of adverse reactions to antituberculosis drugs at public health care facilities. PMID:25750677
Jacquot, Julien; Bagheri, Haleh; Montastruc, Jean-Louis
In August 2012, general practitioners of Haute- Garonne received a letter from Health insurance system, informing that prescriptions could be endorsed by "not substituable" after reporting an adverse drug reactions (ADR). Compared to an equivalent period before this letter, we observed an increase of ADRs reports for generics, mainly concerning gastrointestinal ADR and lack of efficacy.
Morimoto, T; Gandhi, T K; Seger, A C; Hsieh, T C; Bates, D W
Investigating the incidence, type, and preventability of adverse drug events (ADEs) and medication errors is crucial to improving the quality of health care delivery. ADEs, potential ADEs, and medication errors can be collected by extraction from practice data, solicitation of incidents from health professionals, and patient surveys. Practice data include charts, laboratory, prescription data, and administrative databases, and can be reviewed manually or screened by computer systems to identify signals. Research nurses, pharmacists, or research assistants review these signals, and those that are likely to represent an ADE or medication error are presented to reviewers who independently categorize them into ADEs, potential ADEs, medication errors, or exclusions. These incidents are also classified according to preventability, ameliorability, disability, severity, stage, and responsible person. These classifications, as well as the initial selection of incidents, have been evaluated for agreement between reviewers and the level of agreement found ranged from satisfactory to excellent (kappa = 0.32-0.98). The method of ADE and medication error detection and classification described is feasible and has good reliability. It can be used in various clinical settings to measure and improve medication safety.
Lucca, Jisha M; Ramesh, Madhan; Parthasarathi, Gurumurthy; Raman, Rajesh
Drug interactions are known to play a significant role in the incidence of adverse drug reactions (ADRs) both in the community and in hospitals. Both the newer atypical antipsychotics and their more traditional counterparts are subject to drug - drug interactions amongst themselves, with other psychotropics, and with the agents used in the treatment of various physical ailments. The most common interactions encountered in clinical practice are pharmacodynamic in nature. It is well established that antipsychotic drugs reduce the efficacy of levodopa in parkinson's disease by blockade of dopamine receptors in the corpus striatum. The case reported here illustrates a common pharmacodynamic drug interaction of haloperidol with levodopa in a 60-year-old female patient.
Harpaz, Rave; Odgers, David; Gaskin, Greg; DuMouchel, William; Winnenburg, Rainer; Bodenreider, Olivier; Ripple, Anna; Szarfman, Ana; Sorbello, Alfred; Horvitz, Eric; White, Ryen W; Shah, Nigam H
Undetected adverse drug reactions (ADRs) pose a major burden on the health system. Data mining methodologies designed to identify signals of novel ADRs are of deep importance for drug safety surveillance. The development and evaluation of these methodologies requires proper reference benchmarks. While progress has recently been made in developing such benchmarks, our understanding of the performance characteristics of the data mining methodologies is limited because existing benchmarks do not support prospective performance evaluations. We address this shortcoming by providing a reference standard to support prospective performance evaluations. The reference standard was systematically curated from drug labeling revisions, such as new warnings, which were issued and communicated by the US Food and Drug Administration in 2013. The reference standard includes 62 positive test cases and 75 negative controls, and covers 44 drugs and 38 events. We provide usage guidance and empirical support for the reference standard by applying it to analyze two data sources commonly mined for drug safety surveillance.
Muñoz, Emir; Nováček, Vít; Vandenbussche, Pierre-Yves
We propose a new computational method for discovery of possible adverse drug reactions. The method consists of two key steps. First we use openly available resources to semi-automatically compile a consolidated data set describing drugs and their features (e.g., chemical structure, related targets, indications or known adverse reaction). The data set is represented as a graph, which allows for definition of graph-based similarity metrics. The metrics can then be used for propagating known adverse reactions between similar drugs, which leads to weighted (i.e., ranked) predictions of previously unknown links between drugs and their possible side effects. We implemented the proposed method in the form of a software prototype and evaluated our approach by discarding known drug-side effect links from our data and checking whether our prototype is able to re-discover them. As this is an evaluation methodology used by several recent state of the art approaches, we could compare our results with them. Our approach scored best in all widely used metrics like precision, recall or the ratio of relevant predictions present among the top ranked results. The improvement was as much as 125.79% over the next best approach. For instance, the F1 score was 0.5606 (66.35% better than the next best method). Most importantly, in 95.32% of cases, the top five results contain at least one, but typically three correctly predicted side effect (36.05% better than the second best approach). PMID:28269889
Nanji, Karen C.; Patel, Amit; Shaikh, Sofia; Seger, Diane L.; Bates, David W.
Background The purpose of this study is to assess the rates of perioperative medication errors (MEs) and adverse drug events (ADEs) as percentages of medication administrations, evaluate their root causes, and formulate targeted solutions to prevent them. Methods In this prospective observational study, anesthesia-trained study staff (anesthesiologists/nurse anesthetists) observed randomly selected operations at a 1,046 bed tertiary care academic medical center to identify MEs and ADEs over eight months. Retrospective chart abstraction was performed to flag events that were missed by observation. All events subsequently underwent review by two independent reviewers. Primary outcomes were the incidence of MEs and ADEs. Results A total of 277 operations were observed with 3,671 medication administrations of which 193 (5.3%, 95% CI 4.5 to 6.0) involved a ME and/or ADE. Of these, 153 (79.3%) were preventable and 40 (20.7%) were non-preventable. The events included 153 (79.3%) errors and 91 (47.2%) ADEs. While 32 (20.9%) of the errors had little potential for harm, 51 (33.3%) led to an observed ADE and an additional 70 (45.8%) had the potential for patient harm. Of the 153 errors, 99 (64.7%) were serious, 51 (33.3%) were significant and 3 (2.0%) were life-threatening. Conclusions One in twenty perioperative medication administrations included an ME and/or ADE. More than one third of the MEs led to observed ADEs, and the remaining two thirds had the potential for harm. These rates are markedly higher than those reported by retrospective surveys. Specific solutions exist which have the potential to decrease the incidence of perioperative MEs. PMID:26501385
Umetsu, Ryogo; Abe, Junko; Ueda, Natsumi; Kato, Yamato; Nakayama, Yoko; Kinosada, Yasutomi; Nakamura, Mitsuhiro
Over-the-counter (OTC) drugs play an important role in self-medication. To ensure patient safety, pharmacists should ask patients to pay attention to possible adverse events (AE) associated with OTC drugs and educate patients about the symptoms related to those AEs. The aims of the present study were as follows: (1) to assess the tendency of AEs to occur with OTC drug use in Japan; (2) to detect a safety signal for OTC drugs using the reporting odds ratio (ROR); and (3) to evaluate clustery features, which include suspected drugs and therapeutic classifications, and safety signal indices (number of reports and the ROR), using cluster analysis. The number of reports of AEs following use of combination cold remedy, antipyretic and analgesic remedy, and herbal medicine was 1007, 566, and 221, respectively. We set the cluster number at five; clustery features obtained were as follows: (1) high reporting rate for skin and subcutaneous tissue disorder AEs was the largest group related to combination cold remedy; (2) high reporting rate for nervous system disorder AEs including dizziness was the second largest group. The same medicinal ingredient may demonstrate similar tendencies of the occurrence of AEs and similar clustery features in the Japanese Adverse Drug Event Report database. Our analysis of AEs associated with OTC drugs may be useful for pharmacists and patients alike. Further studies are required to draw better-informed conclusions.
Pierson, W.E.; Koenig, J.Q.; Bardana, E.J. Jr.
The use of wood stoves has increased greatly in the past decade, causing concern in many communities about the health effects of wood smoke. Wood smoke is known to contain such compounds as carbon monoxide, nitrogen oxides, sulfur oxides, aldehydes, polycyclic aromatic hydrocarbons, and fine respirable particulate matter. All of these have been shown to cause deleterious physiologic responses in laboratory studies in humans. Some compounds found in wood smoke--benzo(a)pyrene and formaldehyde--are possible human carcinogens. Fine particulate matter has been associated with decreased pulmonary function in children and with increased chronic lung disease in Nepal, where exposure to very high amounts of wood smoke occurs in residences. Wood smoke fumes, taken from both outdoor and indoor samples, have shown mutagenic activity in short-term bioassay tests. Because of the potential health effects of wood smoke, exposure to this source of air pollution should be minimal.29 references.
Sanger, Todd M.
Drug repositioning (i.e., drug repurposing) is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics) and PolyAnalyst (Megaputer) were utilized. An I2E query extracts “Serious Adverse Events” (SAE) data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer). PMID:28348935
Bartalena, L; Bogazzi, F; Martino, E
Thyroid hormone preparations, especially thyroxine, are widely used either at replacement doses to correct hypothyroidism or at suppressive doses to abolish thyrotropin (thyroid-stimulating hormone) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse/ nodular nontoxic goitre. In order to suppress thyrotropin secretion, it is necessary to administer slightly supraphysiological doses of thyroxine. Possible adverse effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats and, possibly, left ventricular hypertrophy) and bone changes (reduced bone density and bone mass), but the risk of these adverse effects can be minimised by carefully monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and adjusting the dosage accordingly. Thionamides [thiamazole (methimazole), carbimazole, propylthiouracil] are the most widely used antithyroid drugs. They are given for long periods of time and cause adverse effects in 3 to 5% of patients. In most cases, adverse effects are minor and transient (e.g. skin rash, itching, mild leucopenia). The most dangerous effect is agranulocytosis, which occurs in 0.1 to 0.5% of patients. This life-threatening condition can now be effectively treated by granulocyte colony-stimulating factor administration. Other major adverse effects (aplastic anaemia, thrombocytopenia, lupus erythematosus-like syndrome, vasculitis) are exceedingly rare.
Staniszewska, Anna; Dąbrowska-Bender, Marta; Olejniczak, Dominik; Duda-Zalewska, Aneta; Bujalska-Zadrożny, Magdalena
Aim The aim of the study was to assess patient knowledge on reporting of adverse drug reactions. Materials and methods A prospective study was conducted among 200 patients. The study was based on an original survey composed of 15 single- and multiple-choice questions. The study involved individuals who have experienced adverse reactions as well as individuals who have never experienced any adverse reactions; people over the age of 18; literate; residing in Mazowieckie Voivodeship, who have not been diagnosed with any disease that could compromise their logical thinking skills. Results The respondents who lived in the city had a greater knowledge compared to the respondents who lived in the countryside (Pearson’s χ2=47.70, P=0.0013). The respondents who lived in the city were also more statistically likely to provide a correct answer to the question about the type of adverse reactions to be reported (Pearson’s χ2=50.66, P=0.012). Statistically significant associations were found between the place of residence of the respondents and the correct answer to the question about the data that must be included in the report on adverse reactions (Pearson’s χ2=11.7, P<0.0001). PMID:28096661
Benichou, C; Castle, W
Global management of drug safety data is the best way to make the detection and validation of adverse drug reactions (ADRs) earlier. Centralization needs a previous standardization, of which terminology is a crucial component. ADR terminology must be designed so as to enable users to know exactly what is covered by each term regarding the nature of the reaction and its significance for public health. A worldwide standardized terminology for all drug reporting purposes is currently being developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. However, practical definitions of medical terms will be necessary and could be developed by specialists on drug safety in collaboration with specialists of different system organs, as has already been achieved for some of them.
Moore, Nicholas; Pollack, Charles; Butkerait, Paul
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug–drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254
Witt, Juri-Alexander; Elger, Christian E; Helmstaedter, Christoph
The study was set up to evaluate the impact of the total drug load of antiepileptic pharmacotherapy on cognition. Retrospective analyses were based on 834 patients with epilepsy who underwent a brief routine assessment of executive function and verbal memory (EpiTrack Plus) at our department. The total drug load was quantified in two ways: (1) number of concurrent antiepileptic drugs (AEDs) and (2) total drug load according to the defined daily dose (DDD) provided by the World Health Organization. The cognitive measures showed higher inverse correlations with the number of AEDs (executive function: r=-0.35, p<0.001; memory: r=-0.22, p<0.001) than with the total DDD (executive function: r=-0.27, p<0.001; memory: r=-0.17, p<0.001). Reanalysis with statistical control for disease severity hardly changed the aforementioned results. With each additional drug in polytherapy, we observed a significantly lower performance in executive function. In this regard an additional explorative approach revealed that regimens combining AEDs with favorable cognitive profiles were associated with higher cognitive performance. Correlations between indicators of disease severity and drug load indices were low: altogether explaining only up to 9% of the observed variance in drug load. The findings demonstrate a considerable adverse effect of a higher drug load on cognition, especially on executive functions. Simply counting the number of drugs may be sufficient as a rough estimate of the risk of side effects. However, the combination of AEDs with favorable cognitive profiles may attenuate the negative effect of the total drug load.
Yadav, Sankalp; Kumar, Raj; Wani, Umar Rasool
The Adverse Drug Reaction (ADR) to a commonly prescribed anti-microbial can pose a major public health problem. The authors report a rare case of 24-year-old young lady who presented with angioedema of lips after ingestion of Ofloxacin, prescribed to her for treatment of loose motions. Fluoroquinolones are widely prescribed antibiotics for various disease conditions. The history, clinical examination and normal laboratory parameters led to the diagnosis of ofloxacin induced hypersensitivity reaction and the patient was successfully treated with corticosteroids and antihistamines. The hypersensitivity reactions to fluoroquinolones are rare with an incidence of 0.4% to 2%. The pharmacovigilance program and self-reporting of all the ADR’s by the health care workers can help in ensuring the judicious use of the drug, drug safety and thus decrease the associated morbidity and mortality. PMID:28050397
Witcher, Robert; Dzierba, Amy L.; Kim, Catherine; Smithburger, Pamela L.; Kane-Gill, Sandra L.
Background: Therapeutic hypothermia (TH) improves survival and neurologic function in comatose survivors of cardiac arrest. Many medications used to support TH have altered pharmacokinetics and pharmacodynamics during this treatment. It is unknown if or at what frequency the medications used during TH cause adverse drug reactions (ADRs). Methods: A retrospective chart review was conducted for patients admitted to an intensive care unit (ICU) after cardiac arrest and treated with TH from January 2009 to June 2012 at two urban, university-affiliated, tertiary-care medical centres. Medications commonly used during TH were screened for association with significant ADRs (grade 3 or greater per Common Terminology Criteria for Adverse Events) using three published ADR detection instruments. Results: A total of 229 patients were included, the majority being males with median age of 62 presenting with an out-of-hospital cardiac arrest in pulseless electrical activity or asystole. The most common comorbidities were hypertension, coronary artery disease, and diabetes mellitus. There were 670 possible ADRs and 69 probable ADRs identified. Of the 670 possible ADRs, propofol, fentanyl, and acetaminophen were the most common drugs associated with ADRs. Whereas fentanyl, insulin, and propofol were the most common drugs associated with a probable ADR. Patients were managed with TH for a median of 22 hours, with 38% of patients surviving to hospital discharge. Conclusions: Patients undergoing TH after cardiac arrest frequently experience possible adverse reactions associated with medications and the corresponding laboratory abnormalities are significant. There is a need for judicious use and close monitoring of drugs in the setting of TH until recommendations for dose adjustments are available to help prevent ADRs.
Alomar, Muaed Jamal
Objectives To discuss the effect of certain factors on the occurrence of Adverse Drug Reactions (ADRs). Data Sources A systematic review of the literature in the period between 1991 and 2012 was made based on PubMed, the Cochrane database of systematic reviews, EMBASE and IDIS. Key words used were: medication error, adverse drug reaction, iatrogenic disease factors, ambulatory care, primary health care, side effects and treatment hazards. Summary Many factors play a crucial role in the occurrence of ADRs, some of these are patient related, drug related or socially related factors. Age for instance has a very critical impact on the occurrence of ADRs, both very young and very old patients are more vulnerable to these reactions than other age groups. Alcohol intake also has a crucial impact on ADRs. Other factors are gender, race, pregnancy, breast feeding, kidney problems, liver function, drug dose and frequency and many other factors. The effect of these factors on ADRs is well documented in the medical literature. Taking these factors into consideration during medical evaluation enables medical practitioners to choose the best drug regimen. Conclusion Many factors affect the occurrence of ADRs. Some of these factors can be changed like smoking or alcohol intake others cannot be changed like age, presence of other diseases or genetic factors. Understanding the different effects of these factors on ADRs enables healthcare professionals to choose the most appropriate medication for that particular patient. It also helps the healthcare professionals to give the best advice to patients. Pharmacogenomics is the most recent science which emphasizes the genetic predisposition of ADRs. This innovative science provides a new perspective in dealing with the decision making process of drug selection. PMID:24648818
Takarabe, Masataka; Kotera, Masaaki; Nishimura, Yosuke; Goto, Susumu; Yamanishi, Yoshihiro
Motivation: Unexpected drug activities derived from off-targets are usually undesired and harmful; however, they can occasionally be beneficial for different therapeutic indications. There are many uncharacterized drugs whose target proteins (including the primary target and off-targets) remain unknown. The identification of all potential drug targets has become an important issue in drug repositioning to reuse known drugs for new therapeutic indications. Results: We defined pharmacological similarity for all possible drugs using the US Food and Drug Administration's (FDA's) adverse event reporting system (AERS) and developed a new method to predict unknown drug–target interactions on a large scale from the integration of pharmacological similarity of drugs and genomic sequence similarity of target proteins in the framework of a pharmacogenomic approach. The proposed method was applicable to a large number of drugs and it was useful especially for predicting unknown drug–target interactions that could not be expected from drug chemical structures. We made a comprehensive prediction for potential off-targets of 1874 drugs with known targets and potential target profiles of 2519 drugs without known targets, which suggests many potential drug–target interactions that were not predicted by previous chemogenomic or pharmacogenomic approaches. Availability: Softwares are available upon request. Contact: firstname.lastname@example.org Supplementary Information: Datasets and all results are available at http://cbio.ensmp.fr/~yyamanishi/aers/. PMID:22962489
Błaszczyk, Barbara; Lasoń, Władysław; Czuczwar, Stanisław Jerzy
This paper summarizes current views on clinical manifestation, pathogenesis, prognosis and management of antiepileptic drug (AED)-induced adverse skin reactions. Cochrane Central Register of Controlled Trials, MEDLINE (PubMed) and ISI Web of Knowledge were searched. The recent classification, among drug-induced skin injuries, points to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis and hypersensitivity syndrome (HSS), which may be also recognized as a drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). The use of aromatic AEDs, e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone, zonisamide, and lamotrigine is more frequently associated with cutaneous eruption and other signs or symptoms of drug hypersensitivity. There is a high degree of cross-reactivity (40-80%) in patients with hypersensitivity or allergic reactions to AEDs. Pharmacogenetic variations in drug biotransformation may also play a role in inducing these undesired effects. It is suggested that avoidance of specific AEDs in populations at special risk, cautious dose titration and careful monitoring of clinical response and, if applicable, laboratory parameters can minimize the serious consequences of idiosyncratic reactions.
Vilar, Santiago; Tatonetti, Nicholas P.; Hripcsak, George
Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining.
Vilar, Santiago; Tatonetti, Nicholas P; Hripcsak, George
Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining.
(1) When oral morphine does not relieve severe pain and when there is no specific treatment for the underlying cause, the first option is to try subcutaneous or intravenous administration. If this standard treatment fails or is poorly tolerated, intrathecal injection is usually preferred as the direct route to the central nervous system. However, one-quarter to one-half of patients still do not achieve adequate pain relief, and adverse effects are relatively frequent; (2) Ziconotide is not an opiate and is not related to the usual classes of drugs that interfere with nervous transmission in the posterior horn of the spinal cord. Marketing authorization has been granted for "severe, chronic pain in patients who require intrathecal analgesia". The Summary of Product Characteristics (SPC) recommends continuous infusion via an intrathecal catheter connected to a pump; (3) Clinical evaluation of ziconotide does not include any trials versus morphine in patients with nociceptive pain, or any trials versus tricyclic or antiepileptic drugs in patients with neurogenic pain; (4) In a trial in 220 patients in whom systemic morphine had failed, the mean pain score on a 100-mm visual analogue scale was 69.8 mm after three weeks on ziconotide, compared to 75.8 mm with placebo. This difference, although statistically significant, is clinically irrelevant. The proportion of "responders" (reduction of at least 30% in the initial pain score) was respectively 16.1% and 12.0% (no statistically significant difference); (5) The two other placebo-controlled trials included 112 patients with pain linked to cancer or HIV infection, and 257 patients with non-cancer pain. After a titration phase lasting 5 to 6 days, a combined analysis of the two trials showed that the mean pain score was 48.8 mm with ziconotide and 68.4 mm with placebo (statistically significant difference). However, many patients did not complete the titration phase. Efficacy also appeared to differ according to the type
Martínez-Mir, Inocencia; García-López, Mercedes; Palop, Vicente; Ferrer, José M; Rubio, Elena; Morales-Olivas, Francisco J
Aims There are few publications of adverse drug reactions (ADRs) among paediatric patients, though ADR incidence is usually stated to be higher during the first year of life and in male patients. We have carried out a prospective study to assess the extent, pattern and profile risk for ADRs in hospitalized patients between 1 and 24 months of age. Methods An intensive events monitoring scheme was used. A total of 512 successive admissions to two medical paediatric wards (47 beds) were analysed. The hospital records were screened daily during two periods (summer, 105 days and winter, 99 days), and adverse clinical events observed were recorded. Results A total of 282 events were detected; of these, 112 were considered to be manifestations of ADRs. The cumulative incidence was 16.6%, no differences being observed between periods. Although there were no differences between patients under and over 12 months of age, risk was found to be significantly higher among girls compared with boys (RR = 1.66, 95% CI 1.03–2.52). The gastro-intestinal system was most frequently affected. The therapeutic group most commonly implicated was anti-infective drugs and vaccines (41.5%). The ADRs were mild or moderate in over 90% of cases. A consistent relationship was noted between the number of drugs administered and the incidence of ADRs. Conclusions Hospitalized patients exhibited an ADR risk profile that included female sex and the number of drugs administered. No particular age predisposition was observed. The most commonly prescribed drugs are those most often implicated in ADRs in paediatric patients. PMID:10383547
Helfenstein, M; Zweifel, S; Barthelmes, D; Meier, F; Fehr, J; Böni, C
Background There are different treatment options for ocular toxoplasmosis (OT). "Classic" therapy consists of pyrimethamine, sulfadiazine and folinic acid combined with systemic steroids and is still widely used. However, potentially severe side effects of this therapy have been reported. The aim of this retrospective study was to evaluate the incidence and types of adverse drug reactions in patients treated for OT. Clinical management of each adverse drug reaction was assessed. Patients and Methods In this retrospective analysis, we reviewed data of patients with OT, who were consecutively examined between December 2011 and December 2015 at the Department of Ophthalmology, University Hospital Zurich. Results In total, 49 patients had at least one episode of active OT. In 54 (83.0 %) of 65 treated episodes, the classic regimen was used. Of the 37 patients who received classic treatment, 9 (24.3 %) developed at least one adverse drug reaction which led to drug discontinuation, including elevated creatinine (5.4 %), elevated liver enzymes (5.4 %), vomiting (5.4 %), rash (5.4 %) and facial swelling (2.7 %). In 5 patients, treatment was switched to another drug, while in the other 4 patients, therapy was stopped. In these 9 patients, inflammation was well controlled 8 weeks after onset of therapy. No patient suffered from severe side effects, such as potentially life-threatening allergic reactions or pancytopenia. Conclusions In OT patients who were treated with classic therapy, adverse drug reactions are common. Therefore, clinical and laboratory monitoring is mandatory. Adverse drug reactions may require interdisciplinary management.
Chazard, Emmanuel; Preda, Cristian; Merlin, Béatrice; Ficheur, Grégoire; Beuscart, Régis
Every year adverse drug events (ADEs) are known to be responsible for 98,000 deaths in the USA. Classical methods rely on report statements, expert knowledge, and staff operated record review. One of our objectives, in the PSIP project framework, is to use data mining (e.g., decision trees) to electronically identify situations leading to risk of ADEs. 10,500 hospitalization records from Denmark and France were used. 500 rules were automatically obtained, which are currently being validated by experts. A decision support system to prevent ADEs is then to be developed. The article examines a decision tree and the rules in the field of vitamin K antagonists.
Jadav, Hasmukh R.; Ghetiya, Hitesh; Prashanth, B.; Galib; Patgiri, B. J.; Prajapati, P. K.
Adverse drug reactions (ADR) are an expression that describes harm associated with the use of medications at therapeutic dose. Traditional medicines also can develop ADRs due to their improper use. Shvitrahara Varti, one of such medicines holds Bakuchi as a component and is to be used judiciously. Furanocoumarins like psoralen present in Bakuchi makes skin hypersensitive and causes phytophotodermatitis in few cases. Hence, one should be careful while using medicines that contain Bakuchi. One such case is observed, where extensive reactions with application of Shvitrahara Varti were noticed and managed with Ayurvedic treatment. PMID:24250129
Palaniappan, Muthiah; George, Melvin; Subramaniyan, Ganesan; Dkhar, Steven Aibor; Pillai, Ajith Ananthakrishna; Jayaraman, Balachander; Chandrasekaran, Adithan
Background Cardiovascular diseases (CVD) are one of the leading causes of non-communicable disease related deaths globally. Patients with cardiovascular diseases are often prescribed multiple drugs and have higher risk for developing more adverse drug reactions due to polypharmacy. Aim To evaluate the pattern of adverse drug reactions reported with cardiovascular drugs in an adverse drug reaction monitoring centre (AMC) of a tertiary care hospital. Settings and Design Adverse drug reactions related to cardiovascular drugs reported to an AMC of a tertiary care hospital were included in this prospective observational study. Materials and Methods All cardiovascular drugs related adverse drug reactions (ADRs) received in AMC through spontaneous reporting system and active surveillance method from January 2011 to March 2013 were analysed for demographic profile, ADR pattern, severity and causality assessment. Statistical Analysis used The study used descriptive statistics and the values were expressed in numbers and percentages. Results During the study period, a total of 463 ADRs were reported from 397 patients which included 319 males (80.4%) and 78 females (19.6%). The cardiovascular drug related reports constituted 18.1% of the total 2188 ADR reports. In this study, the most common ADRs observed were cough (17.3%), gastritis (7.5%) and fatigue (6.5%). Assessment of ADRs using WHO-causality scale revealed that 62% of ADRs were possible, 28.2% certain and 6.8% probable. As per Naranjo’s scale most of the reports were possible (68.8%) followed by probable (29.7%). According to Hartwig severity scale majority of the reports were mild (95%) followed by moderate (4.5%). A system wise classification of ADRs showed that gastrointestinal system (20.7%) related reactions were the most frequently observed adverse reactions followed by respiratory system (18.4%) related adverse effects. From the reported ADRs, the drugs most commonly associated with ADRs were found to be
Yang, Chao; Srinivasan, Padmini; Polgreen, Philip M
We present and test the intuition that letters to the editor in journals carry early signals of adverse drug events (ADEs). Surprisingly these letters have not yet been exploited for automatic ADE detection unlike for example, clinical records and PubMed. Part of the challenge is that it is not easy to access the full-text of letters (for the most part these do not appear in PubMed). Also letters are likely underrated in comparison with full articles. Besides demonstrating that this intuition holds we contribute techniques for post market drug surveillance. Specifically, we test an automatic approach for ADE detection from letters using off-the-shelf machine learning tools. We also involve natural language processing for feature definitions. Overall we achieve high accuracy in our experiments and our method also works well on a second new test set. Our results encourage us to further pursue this line of research.
Winstanley, P A; Irvin, L E; Smith, J C; Orme, M L; Breckenridge, A M
A pharmacy-based adverse drug reaction (ADR) reporting scheme, using pharmacists, nurses and medical practitioners as initiators of reports, was set up at the end of 1984 in the Royal Liverpool Hospital in order to encourage reporting. New reports were inspected at weekly intervals by a staff pharmacist, and a clinical pharmacologist. Reports were forwarded to the Committee on Safety of Medicines if the reaction was considered to be serious by the clinicians, or the ADR team or involved 'black triangle' drugs. The total number of ADR reports was increased eightfold by the introduction of the scheme (from 14 in 1984 to 76, 102 and 94 in 1985, 1986 and 1987 respectively), and this rate of reporting has been sustained. PMID:2775609
Lavan, Amanda Hanora; Gallagher, Paul
Adverse drug reactions (ADRs) are common in older adults, with falls, orthostatic hypotension, delirium, renal failure, gastrointestinal and intracranial bleeding being amongst the most common clinical manifestations. ADR risk increases with age-related changes in pharmacokinetics and pharmacodynamics, increasing burden of comorbidity, polypharmacy, inappropriate prescribing and suboptimal monitoring of drugs. ADRs are a preventable cause of harm to patients and an unnecessary waste of healthcare resources. Several ADR risk tools exist but none has sufficient predictive value for clinical practice. Good clinical practice for detecting and predicting ADRs in vulnerable patients includes detailed documentation and regular review of prescribed and over-the-counter medications through standardized medication reconciliation. New medications should be prescribed cautiously with clear therapeutic goals and recognition of the impact a drug can have on multiple organ systems. Prescribers should regularly review medication efficacy and be vigilant for ADRs and their contributory risk factors. Deprescribing should occur at an individual level when drugs are no longer efficacious or beneficial or when safer alternatives exist. Inappropriate prescribing and unnecessary polypharmacy should be minimized. Comprehensive geriatric assessment and the use of explicit prescribing criteria can be useful in this regard. PMID:26834959
Krasowski, Matthew D.; McGehee, Daniel S.
Purpose Acetylcholinesterase and butyrylcholinesterase are two closely related enzymes important in the metabolism of acetylcholine and anaesthetic drugs, including succinylcholine, mivacurium, and cocaine. The solanaceous glycoalkaloids (SGAs) are naturally occurring steroids in potatoes and related plants that inhibit both acetylcholinesterase and butyrylcholinesterase. There are many clinical examples of direct SGA toxicity due to cholinesterase inhibition. The aim of this study was to review the hypotheses that (1) SGAs may be the evolutionary driving force for atypical butyrylcholinesterase alleles and that (2) SGAs may adversely influence the actions of anaesthetic drugs that metabolized by acetylcholinesterase and butyrylcholinesterase. Source The information was obtained by Medline search and consultation with experts in the study of SGAs and cholinesterases. Principal findings The SGAs inhibit both acetylcholinesterase and butyrylcholinesterase in numerous in vitro and in vivo experiments. Although accurate assays of SGA levels are difficult, published data indicate human serum SGA concentrations at least ten-fold lower than required to inhibit acetylcholinesterase and butyrylcholinesterase in vitro. However, we review evidence that suggests the dietary ingestion of SGAs can initiate a cholinergic syndrome in humans. This syndrome occurs at SGA levels lower than those which interfere with anaesthetic drug catabolism. The world distribution of solanaceous plants parallels the distribution of atypical alleles of butyrylcholinesterase and may explain the genetic diversity of the butyrylcholinesterase gene. Conclusion Correlative evidence suggests that dietary SGAs may be the driving force for atypical butyrylcholinesterase alleles. In addition, SGAs may influence the metabolism of anaesthetic drugs and this hypothesis warrants experimental investigation. PMID:9161749
Chazard, Emmanuel; Ficheur, Grégoire; Bernonville, Stéphanie; Luyckx, Michel; Beuscart, Régis
Adverse drug events (ADEs) are a public health issue. Their detection usually relies on voluntary reporting or medical chart reviews. The objective of this paper is to automatically detect cases of ADEs by data mining. 115,447 complete past hospital stays are extracted from six French, Danish, and Bulgarian hospitals using a common data model including diagnoses, drug administrations, laboratory results, and free-text records. Different kinds of outcomes are traced, and supervised rule induction methods (decision trees and association rules) are used to discover ADE detection rules, with respect to time constraints. The rules are then filtered, validated, and reorganized by a committee of experts. The rules are described in a rule repository, and several statistics are automatically computed in every medical department, such as the confidence, relative risk, and median delay of outcome appearance. 236 validated ADE-detection rules are discovered; they enable to detect 27 different kinds of outcomes. The rules use a various number of conditions related to laboratory results, diseases, drug administration, and demographics. Some rules involve innovative conditions, such as drug discontinuations.
Tan, Yuxiang; Hu, Yong; Liu, Xiaoxiao; Yin, Zhinan; Chen, Xue-Wen; Liu, Mei
Adverse drug reactions (ADRs) are a major public health concern, causing over 100,000 fatalities in the United States every year with an annual cost of $136 billion. Early detection and accurate prediction of ADRs is thus vital for drug development and patient safety. Multiple scientific disciplines, namely pharmacology, pharmacovigilance, and pharmacoinformatics, have been addressing the ADR problem from different perspectives. With the same goal of improving drug safety, this article summarizes and links the research efforts in the multiple disciplines into a single framework from comprehensive understanding of the interactions between drugs and biological system and the identification of genetic and phenotypic predispositions of patients susceptible to higher ADR risks and finally to the current state of implementation of medication-related decision support systems. We start by describing available computational resources for building drug-target interaction networks with biological annotations, which provides a fundamental knowledge for ADR prediction. Databases are classified by functions to help users in selection. Post-marketing surveillance is then introduced where data-driven approach can not only enhance the prediction accuracy of ADRs but also enables the discovery of genetic and phenotypic risk factors of ADRs. Understanding genetic risk factors for ADR requires well organized patient genetics information and analysis by pharmacogenomic approaches. Finally, current state of clinical decision support systems is presented and described how clinicians can be assisted with the integrated knowledgebase to minimize the risk of ADR. This review ends with a discussion of existing challenges in each of disciplines with potential solutions and future directions.
Cao, D-S; Xiao, N; Li, Y-J; Zeng, W-B; Liang, Y-Z; Lu, A-P; Xu, Q-S; Chen, AF
Identifying potential adverse drug reactions (ADRs) is critically important for drug discovery and public health. Here we developed a multiple evidence fusion (MEF) method for the large-scale prediction of drug ADRs that can handle both approved drugs and novel molecules. MEF is based on the similarity reference by collaborative filtering, and integrates multiple similarity measures from various data types, taking advantage of the complementarity in the data. We used MEF to integrate drug-related and ADR-related data from multiple levels, including the network structural data formed by known drug–ADR relationships for predicting likely unknown ADRs. On cross-validation, it obtains high sensitivity and specificity, substantially outperforming existing methods that utilize single or a few data types. We validated our prediction by their overlap with drug–ADR associations that are known in databases. The proposed computational method could be used for complementary hypothesis generation and rapid analysis of potential drug–ADR interactions. PMID:26451329
Background Multi-item adverse drug event (ADE) associations are associations relating multiple drugs to possibly multiple adverse events. The current standard in pharmacovigilance is bivariate association analysis, where each single drug-adverse effect combination is studied separately. The importance and difficulty in the detection of multi-item ADE associations was noted in several prominent pharmacovigilance studies. In this paper we examine the application of a well established data mining method known as association rule mining, which we tailored to the above problem, and demonstrate its value. The method was applied to the FDAs spontaneous adverse event reporting system (AERS) with minimal restrictions and expectations on its output, an experiment that has not been previously done on the scale and generality proposed in this work. Results Based on a set of 162,744 reports of suspected ADEs reported to AERS and published in the year 2008, our method identified 1167 multi-item ADE associations. A taxonomy that characterizes the associations was developed based on a representative sample. A significant number (67% of the total) of potential multi-item ADE associations identified were characterized and clinically validated by a domain expert as previously recognized ADE associations. Several potentially novel ADEs were also identified. A smaller proportion (4%) of associations were characterized and validated as known drug-drug interactions. Conclusions Our findings demonstrate that multi-item ADEs are present and can be extracted from the FDA’s adverse effect reporting system using our methodology, suggesting that our method is a valid approach for the initial identification of multi-item ADEs. The study also revealed several limitations and challenges that can be attributed to both the method and quality of data. PMID:21044365
Bahna, Sami L; Khalili, Barzin
Our understanding of drug reactions and their management has changed markedly in recent years with the development of several new concepts. Epidermal cell death seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may result from Fas-Fas ligand-mediated apoptosis. Intravenous immunoglobulin (IVIG) contains anti-Fas antibodies that can abrogate apoptosis. Most studies on IVIG in SJS and TEN reported improvement in arresting disease progression and reduction in time to healing. Furthermore, several studies have dispelled the myth of sulfonamide cross-reactivity. Immune-mediated reactions against antibacterial sulfonamides are directed against two unique side chains that non-antibacterial sulfonamides do not contain. Certain patients seem to have a genetic predisposition for "multiple drug sensitivities." Hence, they may react to several drugs that are not necessarily cross-reacting. Also, multiple studies have shown that IgE-mediated nonsteroidal anti-inflammatory drugs (NSAIDs) cross-reactivity is uncommon. Rather, it is cyclooxygenase (COX) 1 inhibition that results in pseudoallergic reactions to multiple NSAIDs. Several studies have indicated that selective COX-2 inhibitors can be safely administered in patients with aspirin-exacerbated respiratory disease and NSAID-induced cutaneous reactions, although their use has been curtailed by their cardiovascular side effects. Biological agents, such as infliximab, are being increasingly used for a variety of diseases and have caused adverse reactions in some patients. Studies differ as to whether concomitant immunosuppressive use with infliximab affects the development of drug-specific antibodies and infusion reactions. Successful desensitization protocols have been developed for reactions to some of these agents.
Visacri, Marília Berlofa; de Souza, Cinthia Madeira; Sato, Catarina Miyako Shibata; Granja, Silvia; de Marialva, Mécia; Mazzola, Priscila Gava; Moriel, Patricia
Objectives The aim of this study was to determine the frequency and profile of spontaneous reports of Adverse Drug Reactions (ADRs) and quality deviations in a Brazilian teaching hospital and propose a consistent classification to study quality deviations. Methods This is a descriptive and retrospective study involving the analysis of spontaneous reports of ADRs and quality deviations in 2010. ADRs were classified according to the reaction mechanism, severity, and causality. The drugs were classified according to their therapeutic classes and symptoms according to the affected organ. The quality deviations were classified according to the type of deviation and type of medicine available in the Brazilian market. Results A total of 68 forms were examined; ADRs accounted for 39.7% of the notifications, while quality deviations accounted for 60.3%. ADRs occurred more frequently in men (51.9%) and adults (63.0%). The skin (28.0%) was the most affected organ, while anti-infectives (40.7%) were the therapeutic class that caused the most ADRs. The most common ADRs were type B (74.0%), moderates (37.0%), and probables (55.6%). In relation to quality deviations, the most frequent notifications were breaks, splits and leaks (20.9%) and related to generic drugs (43.9%). Conclusion The classification system to study quality deviations was clear and consistent. This study demonstrated that practices and public policies related to more effective pharmacovigilance need to be implemented so that the number of spontaneous reports increases. PMID:25972731
Chan, Kelvin; Zhang, Hongwei; Lin, Zhi-Xiu
The safe use of Chinese materia medica (CMM) and products in traditional Chinese medicine (TCM) practice conventionally relies on correct pharmacognostic identification, good agricultural and manufacturing practices based on pharmacopoeia standards and rational/correct CMM combinations with TCM-guided clinical prescribing. These experience-based principles may not absolutely ensure safety without careful toxicological investigations when compared with development of new pharmaceutical drugs. Clinically observed toxicity reports remain as guidance for gathering toxicological evidence, though essential as pharmacovigilance, but are considered as late events for ensuring safety. The overview focuses on the following factors: global development of TCM that has affected conventional healthcare; examples of key toxic substances in CMM; reported adverse drug reactions (ADRs) consequential to taking CMM and TCM products; and proposals on rational approaches to integrate the knowledge of biomedical science and the principles of TCM practice for detecting early ADRs if both TCM products and orthodox drugs are involved. It is envisaged that good control of the quality and standards of CMM and proprietary Chinese medicines can certainly reduce the incidence of ADRs in TCM practice when these medications are used. PMID:25619530
Ernst, E; Sieder, C; März, R
Our knowledge relating to adverse drug reactions (ADRs) of phytomedicines is highly fragmentary. The aim of this study was to define the prevalence of ADRs following medication with herbal or synthetic expectorants. In a multicentre, comparative post-marketing surveillance study of more than 3000 patients with acute bronchitis, about half were treated with a herbal remedy (SinupretR) and the other half with various other expectorants. In ascending order of incidence, ADRs were noted during mono-medication of SinupretR (0.8%), Ambroxol (1.0%) and acetylcysteine (4.3%). When concomitant drugs were used, this rank order was unchanged but incidence rates were markedly increased (3.4, 6.5 and 8.2%, respectively). The most frequent ADRs were gastrointestinal symptoms. It is concluded that expectorants are associated with ADRs in roughly 1-5% of cases undergoing single drug treatment and in 3-10% when more than one medication is being used. Amongst the expectorants used in this study, the herbal preparation SinupretR is associated with the lowest incidence of ADRs.
Visweswaran, Shyam; Hanbury, Paul; Saul, Melissa; Cooper, Gregory F
Detection and prevention of adverse events and, in particular, adverse drug events (ADEs), is an important problem in health care today. We describe the implementation and evaluation of four variations on the simple Bayes model for identifying ADE-related discharge summaries. Our results show that these probabilistic techniques achieve an ROC curve area of up to 0.77 in correctly determining which patient cases should be assigned an ADE-related ICD-9-CM code. These results suggest a potential for these techniques to contribute to the development of an automated system that helps identify ADEs, as a step toward further understanding and preventing them.
de Rouw, Hendrika J. A.; Jessurun, Naomi T.; Masen-Poos, Lucie J. P.; Derijks, Hieronymus J.
In this report we describe a 53-year-old woman with advanced non-small cell lung cancer, treated with pemetrexed and cisplatin combination therapy, followed by pemetrexed monotherapy. The patient developed severe muscle spasms at least twice, shortly after administration of pemetrexed monotherapy. A possible explanation for this observation is that in combination with cisplatin therapy, the patient was hyperhydrated before administration to promote renal excretion and reduce toxicity. Pemetrexed is also renally excreted, which supports the finding that toxicity did not occur when the patient was hyperhydrated. After discontinuation of pemetrexed the symptoms did not reoccur. All aspects of this case point to a possible relationship between pemetrexed and an adverse drug reaction (ADR). We conclude that muscle spasms are a rare, but possibly dose-related ADR of pemetrexed-based therapy. PMID:28203304
Takeuchi, T; Takenoshita, S; Taka, F; Nakao, M; Nomura, K
Introduction: Very few studies have explored the adverse effect of psychotropic drugs worldwide. Methods: This study analyzed 1 813 suicide-related drug reports involving 553 patients collected from the Japanese National Adverse Drug Report Database between October 2001 and January 2012 to investigate psychotropic drugs associated with completed suicide vs. other suicide-related behaviors, including ideation and self-injury. The drugs investigated included antidepressants, antipsychotics, benzodiazepines, non-benzodiazepine hypnotic agents, noradrenergic and specific serotonergic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and other drugs. Results: These reports referenced 300 (54.2%) individuals who completed suicide. Adjusting for age, sex, and drugs used, the multivariate model revealed that participants who took antipsychotics were 1.70 times (95% CI, 1.11-2.61) more likely to complete suicide compared with those who did not. All other drugs became non-significant. Compared with those who took only one medication, those prescribed more than 4 drugs were more likely to complete suicide (OR 4.44, 95% CI, 2.40-8.20). Discussion: Antipsychotic drugs and polypharmacy may be regarded as predictors of completed suicide.
Naples, Jennifer G.; Hanlon, Joseph T.; Schmader, Kenneth E.; Semla, Todd P.
Medication errors and adverse drug events are common in older adults, but locating literature addressing these issues is often challenging. The objective of this article was to summarize recent studies addressing medication errors and adverse drug events in a single location to improve accessibility for individuals working with older adults. The authors conducted a comprehensive literature search for studies published in 2014 and identified 51 potential articles. After critical review, 17 studies were selected for inclusion based on innovation, rigorous observational or experimental study designs, and use of reliable, valid measures. Four articles characterizing potentially inappropriate prescribing and interventions to optimize medication regimens were annotated and critiqued in detail. We hope that health policy makers and clinicians find this information helpful in improving the quality of care for older adults. PMID:26804210
[Evaluation of the Association of Hand-Foot Syndrome with Anticancer Drugs Using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) Databases].
Sasaoka, Sayaka; Matsui, Toshinobu; Abe, Junko; Umetsu, Ryogo; Kato, Yamato; Ueda, Natsumi; Hane, Yuuki; Motooka, Yumi; Hatahira, Haruna; Kinosada, Yasutomi; Nakamura, Mitsuhiro
The Japanese Ministry of Health, Labor, and Welfare lists hand-foot syndrome as a serious adverse drug event. Therefore, we evaluated its association with anticancer drug therapy using case reports in the Japanese Adverse Drug Event Report (JADER) and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). In addition, we calculated the reporting odds ratio (ROR) of anticancer drugs potentially associated with hand-foot syndrome, and applied the Weibull shape parameter to time-to-event data from JADER. We found that JADER contained 338224 reports from April 2004 to November 2014, while FAERS contained 5821354 reports from January 2004 to June 2014. In JADER, the RORs [95% confidence interval (CI)] of hand-foot syndrome for capecitabine, tegafur-gimeracil-oteracil, fluorouracil, sorafenib, and regorafenib were 63.60 (95%CI, 56.19-71.99), 1.30 (95%CI, 0.89-1.89), 0.48 (95%CI, 0.30-0.77), 26.10 (95%CI, 22.86-29.80), and 133.27 (95%CI, 112.85-157.39), respectively. Adverse event symptoms of hand-foot syndrome were observed with most anticancer drugs, which carry warnings of the propensity to cause these effects in their drug information literature. The time-to-event analysis using the Weibull shape parameter revealed differences in the time-dependency of the adverse events of each drug. Therefore, anticancer drugs should be used carefully in clinical practice, and patients may require careful monitoring for symptoms of hand-foot syndrome.
White, Ryen W; Wang, Sheng; Pant, Apurv; Harpaz, Rave; Shukla, Pushpraj; Sun, Walter; DuMouchel, William; Horvitz, Eric
The timely and accurate identification of adverse drug reactions (ADRs) following drug approval is a persistent and serious public health challenge. Aggregated data drawn from anonymized logs of Web searchers has been shown to be a useful source of evidence for detecting ADRs. However, prior studies have been based on the analysis of established ADRs, the existence of which may already be known publically. Awareness of these ADRs can inject existing knowledge about the known ADRs into online content and online behavior, and thus raise questions about the ability of the behavioral log-based methods to detect new ADRs. In contrast to previous studies, we investigate the use of search logs for the early detection of known ADRs. We use a large set of recently labeled ADRs and negative controls to evaluate the ability of search logs to accurately detect ADRs in advance of their publication. We leverage the Internet Archive to estimate when evidence of an ADR first appeared in the public domain and adjust the index date in a backdated analysis. Our results demonstrate how search logs can be used to detect new ADRs, the central challenge in pharmacovigilance.
Kuroda, Junji; Plassmann, Stephanie; Hayashi, Makoto; Prentice, David E.
To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions. PMID:22272032
Rackham, Daniel M; C Herink, Megan; Stevens, Ian G; Cardoza, Natalie M; Singh, Harleen
The U.S. Food and Drug Administration (FDA) periodically publishes Drug Safety Communications and Drug Alerts notifying health care practitioners and the general public of important information regarding drug therapies following FDA approval. These alerts can result in both positive and negative effects on patient care. Most clinical trials are not designed to detect long-term safety end points, and postmarketing surveillance along with patient reported events are often instrumental in signaling the potential harmful effect of a drug. Recently, many cardiovascular (CV) safety announcements have been released for FDA-approved drugs. Because a premature warning could discourage a much needed treatment or prompt a sudden discontinuation, it is essential to evaluate the evidence supporting these FDA alerts to provide effective patient care and to avoid unwarranted changes in therapy. Conversely, paying attention to these warnings in cases involving high-risk patients can prevent adverse effects and litigation. This article reviews the evidence behind recent FDA alerts for drugs with adverse CV effects and discusses the clinical practice implications.
Genco, Emma K.; Forster, Jeri E.; Flaten, Hanna; Goss, Foster; Heard, Kennon J.; Hoppe, Jason; Monte, Andrew A.
Study objective We examine the characteristics of clinical decision support alerts triggered when opioids are prescribed, including alert type, override rates, adverse drug events associated with opioids, and preventable adverse drug events. Methods This was a retrospective chart review study assessing adverse drug event occurrences for emergency department (ED) visits in a large urban academic medical center using a commercial electronic health record system with clinical decision support. Participants include those aged 18 to 89 years who arrived to the ED every fifth day between September 2012 and January 2013. The main outcome was characteristics of opioid drug alerts, including alert type, override rates, opioid-related adverse drug events, and adverse drug event preventability by clinical decision support. Results Opioid drug alerts were more likely to be overridden than nonopioid alerts (relative risk 1.35; 95% confidence interval [CI] 1.21 to 1.50). Opioid drug-allergy alerts were twice as likely to be overridden (relative risk 2.24; 95% CI 1.74 to 2.89). Opioid duplicate therapy alerts were 1.57 times as likely to be overridden (95% CI 1.30 to 1.89). Fourteen of 4,581 patients experienced an adverse drug event (0.31%; 95% CI 0.15% to 0.47%), and 8 were due to opioids (57.1%). None of the adverse drug events were preventable by clinical decision support. However, 46 alerts were accepted for 38 patients that averted a potential adverse drug event. Overall, 98.9% of opioid alerts did not result in an actual or averted adverse drug event, and 96.3% of opioid alerts were overridden. Conclusion Overridden opioid alerts did not result in adverse drug events. Clinical decision support successfully prevented adverse drug events at the expense of generating a large volume of inconsequential alerts. To prevent 1 adverse drug event, providers dealt with more than 123 unnecessary alerts. It is essential to refine clinical decision support alerting systems to eliminate
Vural, Fisun; Ciftci, Seval; Vural, Birol
OBJECTIVE: With the use of any drug comes the possibility of unintended consequences which when harmful are referred to as adverse drug reactions (ADRs). The development of national pharmacovigilance systems is the responsibility of all health workers. The aim of this study was to investigate the knowledge of nurses about pharmacovigilance and attitudes about ADR and adverse event reporting. METHODS: This descriptive-cross sectional study was performed in 112 nurses working in a public hospital. The questionnaire was applied about pharmacovigilance and adverse drug reactions. The knowledge, attitudes and practices about adverse drug reactions were asked. RESULTS: The 74.1% of the nurses definition of “severe adverse effect” of drug therapy. The ratio of participants who knew that ADRs are reported to contact person responsible from pharmacovigilance was 34.9%. Although 70.5% of nurses knew the necessity of ADR reporting, the 8% of the nurses knew Turkish Pharmacovigilance Center (TÜFAM). Only 8% of nurses reported ADRs in their professionality. CONCLUSION: Although most of the participants knew the importance of ADR event reporting, event reporting was low. Thiese results showed that there is a lack of knowledge about pharmacovigilance. Futher studies with different settings and healthcare staff are needed to improve awareness about pharmacovigilance. PMID:28058321
Bracken, Louise E.; Nunn, Anthony J.; Kirkham, Jamie J.; Peak, Matthew; Arnott, Janine; Smyth, Rosalind L.; Pirmohamed, Munir; Turner, Mark A.
Aim To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings. Methods The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the ‘gold standard’ (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist). Main Outcome Measures Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories. Results Preliminary work—Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52–90%. Phase 3: Percentage exact agreement ranged from 35–70%. Overall, individuals had better agreement with the ‘gold standard’. Conclusion Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than
Seger, Donna; BARKER, Kimberly; McNAUGHTON, Candace D.
Context When an adverse event occurs in an overdose patient, it may be difficult to determine whether the event was caused by the ingested drug or by medical therapy. Naranjo and colleagues developed a probability scale, the Naranjo Adverse Drug Reaction Probability Scale (Naranjo Scale), to assess the probability that a drug administered in therapeutic doses caused an adverse event thereby classifying the event as an adverse drug reaction (ADR). Although Naranjo et al. specifically excluded the application of this scale to adverse events in overdose patients, case reports demonstrate that authors continue to apply the Naranjo Scale to events in these patients. Objective The World Health Organization defines an ADR as occurring only when drugs are administered in therapeutic doses. Yet ADRs continue to be reported in overdose patients. We sought to examine the use of the Naranjo scale in case reports of overdose patients to assess the potential consequences of that application. Methods A Medline search via PubMed without language limits, through September 2012, using the search terms “Naranjo” and “overdose” or “poisoning” yielded 146 publications. Additional searches were performed to find articles with keywords of the Naranjo Scale development, current applications and validity of application in specific populations such as critically ill and overdose patients. Results From the 146 publications, we identified 17 case reports or series of overdose patients in which the Naranjo Scale was applied to a clinical complication to support a causal relationship between an administered drug and the clinical complication and thereby classify the clinical complication as an ADR. We also identified a recent publication in which the Naranjo Scale was applied to a new treatment modality (lipid emulsion) that is currently administered to overdose patients. Conclusion Adverse events that occur in overdose patients are excluded from the definition of ADR. Yet in case
Banda, Juan M.; Evans, Lee; Vanguri, Rami S.; Tatonetti, Nicholas P.; Ryan, Patrick B.; Shah, Nigam H.
Identification of adverse drug reactions (ADRs) during the post-marketing phase is one of the most important goals of drug safety surveillance. Spontaneous reporting systems (SRS) data, which are the mainstay of traditional drug safety surveillance, are used for hypothesis generation and to validate the newer approaches. The publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data requires substantial curation before they can be used appropriately, and applying different strategies for data cleaning and normalization can have material impact on analysis results. We provide a curated and standardized version of FAERS removing duplicate case records, applying standardized vocabularies with drug names mapped to RxNorm concepts and outcomes mapped to SNOMED-CT concepts, and pre-computed summary statistics about drug-outcome relationships for general consumption. This publicly available resource, along with the source code, will accelerate drug safety research by reducing the amount of time spent performing data management on the source FAERS reports, improving the quality of the underlying data, and enabling standardized analyses using common vocabularies. PMID:27193236
Banda, Juan M; Evans, Lee; Vanguri, Rami S; Tatonetti, Nicholas P; Ryan, Patrick B; Shah, Nigam H
Identification of adverse drug reactions (ADRs) during the post-marketing phase is one of the most important goals of drug safety surveillance. Spontaneous reporting systems (SRS) data, which are the mainstay of traditional drug safety surveillance, are used for hypothesis generation and to validate the newer approaches. The publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data requires substantial curation before they can be used appropriately, and applying different strategies for data cleaning and normalization can have material impact on analysis results. We provide a curated and standardized version of FAERS removing duplicate case records, applying standardized vocabularies with drug names mapped to RxNorm concepts and outcomes mapped to SNOMED-CT concepts, and pre-computed summary statistics about drug-outcome relationships for general consumption. This publicly available resource, along with the source code, will accelerate drug safety research by reducing the amount of time spent performing data management on the source FAERS reports, improving the quality of the underlying data, and enabling standardized analyses using common vocabularies.
Mastroianni, Patricia de Carvalho
Background & objectives Different algorithms have been developed to standardize the causality assessment of adverse drug reactions (ADR). Although most share common characteristics, the results of the causality assessment are variable depending on the algorithm used. Therefore, using 10 different algorithms, the study aimed to compare inter-rater and multi-rater agreement for ADR causality assessment and identify the most consistent to hospitals. Methods Using ten causality algorithms, four judges independently assessed the first 44 cases of ADRs reported during the first year of implementation of a risk management service in a medium complexity hospital in the state of Sao Paulo (Brazil). Owing to variations in the terminology used for causality, the equivalent imputation terms were grouped into four categories: definite, probable, possible and unlikely. Inter-rater and multi-rater agreement analysis was performed by calculating the Cohen´s and Light´s kappa coefficients, respectively. Results None of the algorithms showed 100% reproducibility in the causal imputation. Fair inter-rater and multi-rater agreement was found. Emanuele (1984) and WHO-UMC (2010) algorithms showed a fair rate of agreement between the judges (k = 0.36). Interpretation & conclusions Although the ADR causality assessment algorithms were poorly reproducible, our data suggest that WHO-UMC algorithm is the most consistent for imputation in hospitals, since it allows evaluating the quality of the report. However, to improve the ability of assessing the causality using algorithms, it is necessary to include criteria for the evaluation of drug-related problems, which may be related to confounding variables that underestimate the causal association. PMID:28166274
Gattuso, J M; Kamm, M A
Most laxatives, if used intermittently in the absence of contraindications, are relatively safe. Bulking agents may diminish absorption of some minerals and drugs, but this is not usually clinically significant. Ispaghula can cause serious allergic reactions. The chronic ingestion of stimulant laxatives has been blamed for the development of the 'cathartic colon', but there are no definitive studies which have demonstrated this. Dantron (danthron) preparations should only be used in older patients and the terminally ill because of the risk of hepatotoxicity with this drug. Oral oxyphenisatine should no longer be used. Senna would appear to be the stimulant laxative of choice during pregnancy and lactation. Bisacodyl is the polyphenolic derivative of choice. Lactulose, sorbitol and lactilol rarely cause significant adverse effects. Magnesium salt laxatives and phosphate enemas can cause serious metabolic disturbances in babies and young children. Liquid paraffin is contraindicated if there is any risk of aspiration. Interference with the absorption of fat soluble vitamins would not appear to be clinically significant. Docusate sodium may potentiate the hepatotoxicity of other drugs, but reports of this are rare. The role of cisapride in constipation has not been established. Antidiarrhoeal drugs are second line drugs whose use is aimed at minimising inconvenience and discomfort. No antidiarrhoeals can be recommended for children under 4 years of age. Loperamide is the drug of choice in older children and adults. The atropine component of diphenoxylate/atropine combinations can cause significant adverse effects. Bismuth salicylate is an inconvenient treatment for travellers' diarrhoea as large frequent doses of the liquid formulation are needed. Some bismuth can be absorbed and there is the potential to cause encephalopathy. Octreotide, methysergide and cholestyramine have a role for specific causes of diarrhoea only. Octreotide is effective in high output states
Hoigné, R; Lawson, D H; Weber, E
Age by itself is not an important risk factor for ADRs. Age-related changes are the consequence of a number of individual factors, for example morbidity associated with polypharmacy, decline in renal or liver function in the elderly, hypoalbuminaemia, reduced body weight, etc. The relationship between gastrointestinal bleeding and non-steroidal anti-inflammatory drugs can be assessed globally in large cohort studies with access to computerized data, but complete accuracy requires access to the original patient records. The increase in the risk of GI bleeding in users of NSAIDs and aspirin was 50% above that in non-users. About a quarter of ADRs in hospitalized patients seem not to arise from purely pharmacological mechanisms. They are mainly due to allergic, anaphylactoid, or idiosyncratic reactions and to intolerance. In such non-pharmacological reactions, the time of exposure, reaction time, and even dosage may be important factors in identification of the causal drug. The use of benzodiazepines can be optimized by taking into account potency, time of action and the different syndromes encountered after withdrawal. Following long-term use problems of relapse and rebound are being increasingly recognized, in addition to organic withdrawal symptoms. In psychiatric patients extrapyramidal disorders due to neuroleptics are common. The rates of these ADRs differ markedly between various drugs, even after dosages and co-medications are taken into account. Epidemiological screening for potentially carcinogenic drugs can only be done in large cohorts of patients with pre-recorded full information sets as may be found in an HMO (Health Maintenance Organization). The findings of several such studies have been published in specialist cancer journals.(ABSTRACT TRUNCATED AT 250 WORDS)
Ahn, Hee-Jung; Park, Hyeoun-Ae
The purpose of this study was to determine whether the frequency of adverse drug events can be extracted by analyzing narrative nursing statements documented in standardized terminology-based electronic nursing records. For this study, we reviewed the narrative nursing documentations of 487 admissions of 355 cancer patients who were treated with cisplatin at a tertiary-care hospital in Korea. Narrative nursing statements with the terms "adverse drug reaction," "allergy," "hypersensitivity," and other adverse drug events listed in the safety information were analyzed. In addition, nausea, one of the most frequent adverse drug events, was further examined. Narrative statements documenting the presence or absence of an "adverse drug reaction," "allergy," and "hypersensitivity" were found in 162 admissions (33.3%). The presence or absence of adverse drug events due to cisplatin was documented in 476 admissions (97.7%). At least one adverse drug event was noted in 258 admissions (53.0%). The presence of nausea was documented in 214 admissions (43.9%), and the mean duration of nausea was 5.2 days. The results of this study suggest that adverse drug events can be monitored using narrative nursing statements documented in standardized terminology-based electronic nursing records.
Paul, Lindsay; Robinson, Kerin M
Allergic responses to prescription drugs are largely preventable, and incur significant cost to the community both financially and in terms of healthcare outcomes. The capacity to minimise the effects of repeated events rests predominantly with the reliability of allergy documentation in medical records and computerised physician order entry systems (CPOES) with decision support such as allergy alerts. This paper presents an overview of the nature and extent of adverse drug reactions (ADRs) in Australia and other developed countries, a discussion and evaluation of strategies which have been devised to address this issue, and a commentary on the role of coded data in informing this patient safety issue. It is not concerned with pharmacovigilance systems that monitor ADRs on a global scale. There are conflicting reports regarding the efficacy of these strategies. Although in many cases allergy alerts are effective, lack of sensitivity and contextual relevance can often induce doctors to override alerts. Human factors such as user fatigue and inadequate adverse drug event reporting, including ADRs, are commonplace. The quality of and response to allergy documentation can be enhanced by the participation of nurses and pharmacists, particularly in medication reconciliation. The International Classification of Diseases (ICD) coding of drug allergies potentially yields valuable evidence, but the quality of local and national level coded data is hampered by under-documenting and under-coding.
Piparva, Kiran G.; Buch, J. G.; Chandrani, Kalpesh V.
Background: Novel atypical antipsychotics are superior to conventional antipsychotics as they significantly reduce both positive and negative symptoms of schizophrenia and have lower risk of extrapyramidal symptoms (EPS). However, these drugs have separate set of adverse drug reactions (ADRs). Therefore, this study was carried out to assess these ADRs, which can have impact on long-term compliance and achieving successful treatment. Materials and Methods: A prospective study of analysis of ADR of atypical antipsychotic drugs was carried out in the psychiatry outpatient department. Patients of psychotic disorder (any age, either sex), who were prescribed atypical antipsychotic drugs, were included. Those who were prescribed conventional antipsychotics or combinations of antipsychotics were excluded from the study. Apart from spontaneously reported ADRs, a questionnaire related to the likely ADR was used and patients’ responses were recorded in the case record form. Results: Totally 93 ADRs were recorded from 84 prescriptions. Majority of the ADRs (82 out of 93) were seen with risperidone and olanzepine, as they were the commonly prescribed drugs. Weight gain, dizziness, sleep disturbance and appetite disturbance accounted for nearly 78% of the total events. With risperidone (at 4–6 mg/day) and olanzepine (at 10–15 mg/day), gastrointestinal and sleep disturbance were observed in the initial (within 7 days to 2–3 months after treatment) course of treatment, while EPS, fatigue, seizure, increased frequency of micturition and dizziness were observed after long-term (3–9 months) use. Conclusion: The present study adds to the existing information on the prevalence of adverse effects of atypical antipsychotic drugs. Role of active surveillance in post-marketing phase is also emphasized. PMID:22345840
Fattinger, Karin; Roos, Malgorzata; Vergères, Patrice; Holenstein, Clemens; Kind, Brigitt; Masche, Urspeter; Stocker, David N; Braunschweig, Suzanne; Kullak-Ublick, Gerd A; Galeazzi, Renato L; Follath, Ferenc; Gasser, Theo; Meier, Peter J
Aims To explore drug exposure, frequency of adverse drug reactions (ADRs), types of ADRs, predisposing risk factors and ADR-related excess hospital stay in medical inpatients. Methods Structured data regarding patient characteristics, ‘events’ (symptoms, laboratory results), diagnoses (ICD10) and drug therapy were collected using a computer-supported data entry system and an interface for data retrieval from electronic patient records. ADR data were collected by ‘event monitoring’ to minimize possible bias by the drug monitor. The causality of each event was assessed in relation to disease(s) and drug therapy. Results The analysis included 4331 (100%) hospitalizations. The median observation period was 8 days. The median number of different drugs administered per patient and day was 6 and varied between 4 (Q1) and 9 (Q3) different drugs in 50% of all hospital days. In 41% of all hospitalizations at least one disease-unrelated event could be possibly attributed to drug therapy. Clinically relevant ADRs occurred in 11% of all hospitalizations. In 3.3% of all hospitalizations ADRs were the cause of hospital admission. The incidence of possibly ADR-related deaths was 1.4. Factors predisposing for clinically relevant ADRs were female gender and polypharmacy. ADR-related excess hospital stay accounted for 8.6% of hospital days. Conclusions These data demonstrate the feasibility of the developed ‘event monitoring’ system for quantitative analysis of ADRs in medical inpatients. With increasing numbers of recorded patients the pharmacoepidemiological database provides a valuable tool to study specific questions regarding drug efficacy and safety in hospitalized patients. PMID:10671911
Marangu, Diana; Kovacs, Stephanie; Walson, Judd; Bonhoeffer, Jan; Ortiz, Justin R.; John-Stewart, Grace; Horne, David J.
Introduction Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs). Objective To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement. Methods We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥ 1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement. Results Of 1,205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity. Conclusion Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as
Palleria, Caterina; Leporini, Christian; Chimirri, Serafina; Marrazzo, Giuseppina; Sacchetta, Sabrina; Bruno, Lucrezia; Lista, Rosaria M.; Staltari, Orietta; Scuteri, Antonio; Scicchitano, Francesca; Russo, Emilio
Introduction: Nowadays, based on several epidemiological data, iatrogenic disease is an emerging public health problem, especially in industrialized countries. Adverse drugs reactions (ADRs) are extremely common and, therefore, clinically, socially, and economically worthy of attention. Spontaneous reporting system for suspected ADRs represents the cornerstone of the pharmacovigilance, because it allows rapid detection of potential alarm signals related to drugs use. However, spontaneous reporting system shows several limitations, which are mainly related to under-reporting. In this paper, we describe two particular case reports, which emphasize some reasons of under-reporting and other common criticisms of spontaneous reporting systems. Materials and Methods: We performed a computer-aided search of Medline, PubMed, Embase, Cochrane library databases, national and international databases of suspected ADRs reports in order to identify previous published case reports and spontaneous reports about the ADRs reviewed in this paper, and to examine the role of suspected drugs in the pathogenesis of the described adverse reactions. Results: First, we reported a case of tizanidine-induced hemorrhagic cystitis. In the second case report, we presented an episode of asthma exacerbation after taking bimatoprost. Through the review of these two cases, we highlighted some common criticisms of spontaneous reporting systems: under-reporting and false causality attribution. Discussion and Conclusion: Healthcare workers sometimes do not report ADRs because it is challenging to establish with certainty the causal relationship between drug and adverse reaction; however, according to a key principle of pharmacovigilance, it is always better to report even a suspicion to generate an alarm in the interest of protecting public health. PMID:24347986
Wright, Jackie; Kenneally, Michaela E; Edwards, John W; Walker, G Stewart
The manufacture of methamphetamine in clandestine drug laboratories occurs in various locations, including residential houses and apartments. Unlike the controlled manufacture of chemicals and drugs, clandestine manufacture results in the uncontrolled storage, use, generation, and disposal of a wide range of chemicals and the deposit of methamphetamine drug residues on indoor surfaces (1). These residues have been found at high levels on porous and nonporous surfaces and have been shown to persist for months to years (1). Persons exposed to these environments often have poorly defined exposures and health effects. It is commonly assumed that these levels of exposure are low compared with those related to illicit drug use or therapeutic use of amphetamine-based drugs for managing behavioral issues such as attention deficit hyperactivity disorder (2). In 2015, a family that was unknowingly exposed to methamphetamine residues in a house in Australia was found to have adverse health effects and elevated methamphetamine levels in hair samples, highlighting the potential for public health risks for persons who might live in methamphetamine-contaminated dwellings. This case study highlights the importance of the identification and effective decontamination of former clandestine drug laboratories.
Uthayathas, Subramaniam; Shaffer, Christopher L; Menniti, Frank S; Schmidt, Christopher J; Papa, Stella M
Research into therapeutics for neuropsychiatric disorders is increasingly focusing on drugs with new mechanisms of action, and such agents are often assessed in preclinical studies using nonhuman primates. However, researchers lack a standardised method to compare different drugs for common adverse effects on the nervous system. We have developed a new scale for this purpose, named "Drug Effects on the Nervous System" (DENS), and tested its utility in an analysis of the second-generation antipsychotic risperidone in monkeys. The behavioural effects of risperidone over a ten-fold clinically relevant exposure range were rated with the DENS scale and compared with a standard motor disability scale for primates. The ratings were correlated with projected D2 and 5-HT2A receptor occupancies over time. The DENS scale detected dose-dependent side effects of risperidone in addition to the motor effects detected with the motor disability scale, including cognitive, sensorimotor and autonomic functions. A consistent temporal association between the DENS scale changes and the projected D2 receptor occupancy was observed, and the DENS scale ratings demonstrated high inter-rater reliability. These results demonstrate the usefulness of the DENS scale as a highly sensitive, reliable and accurate method to identify common adverse effects of risperidone and potentially other neurotropics for translational studies in primates.
Hirsch, Michael J.; Meneses, Claudio N.; Pardalos, Panos M.; Ragle, Michelle; Resende, Mauricio G. C.
Adverse drag reactions (ADRs) are estimated to be one of the leading causes of death. Many national and international agencies have set up databases of ADR reports for the express purpose of determining the relationship between drugs and adverse reactions that they cause. We formulate the drug-reaction relationship problem as a continuous optimization problem and utilize C-GRASP, a new continuous global optimization heuristic, to approximately determine the relationship between drugs and adverse reactions. Our approach is compared against others in the literature and is shown to find better solutions.
Hirsch, Michael J.; Meneses, Claudio N.; Pardalos, Panos M.; Ragle, Michelle; Resende, Mauricio G. C.
Adverse drag reactions (ADRs) are estimated to be one of the leading causes of death. Many national and international agencies have set up databases of ADR reports for the express purpose of determining the relationship between drugs and adverse reactions that they cause. We formulate the drug-reaction relationship problem as a continuous optimization problem and utilize C-GRASP, a new continuous global optimization heuristic, to approximately determine the relationship between drugs and adverse reactions. Our approach is compared against others in the literature and is shown to find better solutions.
Woosley, Raymond L; Romero, Klaus; Heise, Craig W; Gallo, Tyler; Tate, Jared; Woosley, Raymond David; Ward, Sophie
Growing evidence indicates that many drugs have the ability to cause a potentially lethal cardiac arrhythmia, torsades de pointes (TdP). This necessitates the development of a compilation of drugs that have this potential toxicity. Such a list is helpful in identifying the etiology of TdP in patients taking multiple drugs and assists decision making by those caring for patients at high risk of TdP. The Arizona Center for Education and Research on Therapeutics (AZCERT) has developed a process to standardize the identification of drugs and place them in risk categories for their clinical ability to cause TdP and QT prolongation. AZCERT's Adverse Drug Event Causality Analysis (ADECA) utilizes 16 types of data drawn from four sources to compile an open-source knowledge base, QTdrugs, which is maintained on the CredibleMeds.org website. Because the evidence for most drugs is incomplete, the ADECA process is used to place drugs into one of three categories that represent different levels of certainty: known TdP risk, possible TdP risk, and conditional TdP risk. Each category has strict evidentiary requirements for clinical evidence of TdP and/or QT prolongation. These are described in this paper. Because evidence can evolve over time, the ADECA process includes the continuous gathering and analysis of newly emerging evidence to revise the lists. The QTdrugs lists have proven to be a valued, readily available, commercial influence-free resource for healthcare providers, patients, researchers, and authors of consensus guidelines for the safe use of medicines.
Clarke, John D; Cherrington, Nathan J
Introduction Organic anion transporting polypeptide (OATP) uptake transporters are important for the disposition of many drugs and perturbed OATP activity can contribute to adverse drug reactions (ADRs). It is well documented that both genetic and environmental factors can alter OATP expression and activity. Genetic factors include single nucleotide polymorphisms (SNPs) that change OATP activity and epigenetic regulation that modify OATP expression levels. SNPs in OATPs contribute to ADRs. Environmental factors include the pharmacological context of drug--drug interactions and the physiological context of liver diseases. Liver diseases such as non-alcoholic fatty liver disease, cholestasis and hepatocellular carcinoma change the expression of multiple OATP isoforms. The role of liver diseases in the occurrence of ADRs is unknown. Areas covered This article covers the roles OATPs play in ADRs when considered in the context of genetic or environmental factors. The reader will gain a greater appreciation for the current evidence regarding the salience and importance of each factor in OATP-mediated ADRs. Expert opinion A SNP in a single OATP transporter can cause changes in drug pharmacokinetics and contribute to ADRs but, because of overlap in substrate specificities, there is potential for compensatory transport by other OATP isoforms. By contrast, the expression of multiple OATP isoforms is decreased in liver diseases, reducing compensatory transport and thereby increasing the probability of ADRs. To date, most research has focused on the genetic factors in OATP-mediated ADRs while the impact of environmental factors has largely been ignored. PMID:22280100
Liu, Xiao; Chen, Hsinchun
Social media offer insights of patients' medical problems such as drug side effects and treatment failures. Patient reports of adverse drug events from social media have great potential to improve current practice of pharmacovigilance. However, extracting patient adverse drug event reports from social media continues to be an important challenge for health informatics research. In this study, we develop a research framework with advanced natural language processing techniques for integrated and high-performance patient reported adverse drug event extraction. The framework consists of medical entity extraction for recognizing patient discussions of drug and events, adverse drug event extraction with shortest dependency path kernel based statistical learning method and semantic filtering with information from medical knowledge bases, and report source classification to tease out noise. To evaluate the proposed framework, a series of experiments were conducted on a test bed encompassing about postings from major diabetes and heart disease forums in the United States. The results reveal that each component of the framework significantly contributes to its overall effectiveness. Our framework significantly outperforms prior work.
Chen, Xiaowen; Shi, Hongbo; Yang, Feng; Yang, Lei; Lv, Yingli; Wang, Shuyuan; Dai, Enyu; Sun, Dianjun; Jiang, Wei
Adverse drug reactions (ADRs) are responsible for drug failure in clinical trials and affect life quality of patients. The identification of ADRs during the early phases of drug development is an important task. Therefore, predicting potential protein targets eliciting ADRs is essential for understanding the pathogenesis of ADRs. In this study, we proposed a computational algorithm,Integrated Network for Protein-ADR relations (INPADR), to infer potential protein-ADR relations based on an integrated network. First, the integrated network was constructed by connecting the protein-protein interaction network and the ADR similarity network using known protein-ADR relations. Then, candidate protein-ADR relations were further prioritized by performing a random walk with restart on this integrated network. Leave-one-out cross validation was used to evaluate the ability of the INPADR. An AUC of 0.8486 was obtained, which was a significant improvement compared to previous methods. We also applied the INPADR to two ADRs to evaluate its accuracy. The results suggested that the INPADR is capable of finding novel protein-ADR relations. This study provides new insight to our understanding of ADRs. The predicted ADR-related proteins will provide a reference for preclinical safety pharmacology studies and facilitate the identification of ADRs during the early phases of drug development. PMID:27805066
Rodgers, Amie D.; Zhu, Hao; Fourches, Dennis; Rusyn, Ivan; Tropsha, Alexander
Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals both in development and post-marketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the Quantitative Structure Activity Relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs. inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity and balanced (40/60) active/inactive ratio were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external datasets. Models with high sensitivity (>73%) and specificity (>94%) for prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in pre-clinical screening of drug candidates for potential hepatotoxicity in humans. PMID:20192250
Saini, V K; Sewal, R K; Ahmad, Yusra; Medhi, B
Adverse drug reactions associated with the use of anticancer drugs are a worldwide problem and cannot be ignored. Adverse drug reactions can range from nausea, vomiting or any other mild reaction to severe myelosuppression. The study was planned to observe the suspected adverse drug reactions of cancer chemotherapy in patients aged >18 years having cancer attending Postgraduate Institute of Medical Education and Research, Chandigarh. During the study period, 101 patients of breast cancer and 73 patients of lung cancer were screened for occurrence of adverse drug reactions during their treatment with chemotherapy. About 87.36% patients experienced adverse drug reactions, 90.09% and 83.56% of breast and lung cancer patients experienced at least one adverse drug reaction respectively. In breast cancer patients, 41.58% patients were prescribed fluorouracil+doxorubicin+cyclophosphamide while paclitaxel was prescribed to 22.77% patients. Alopecia (54.94%), nail discolouration (43.96%), dysgeusia (38.46%), anorexia (30.77%), nausea (29.67%), and neuropathy (29.67%) were found to be very common in breast cancer patients treated with single/combined regimen. In lung cancer group of patients, cisplatin with docetaxel, cisplatin with pemetrexed and cisplatin with irinotecan were prescribed to 30.14, 24.65 and 17.81% patients, respectively. Dysgeusia (40.98%), diarrhoea (39.34%), anorexia (32.77%) and constipation (31.15%) and alopecia (31.15%) were commonly observed adverse drug reactions having lung cancer patients. Causality assessments using World Health Organization causality assessment scale showed that observed adverse drug reactions were of probable (64.67%) and possible (35.33%) categories. Alopecia, dysgeusia, anorexia, constipation diarrhoea, nausea, nail discoloration were more prevalent amongst the cancer patients undergoing chemotherapy.
Berlin, Jesse A; Glasser, Susan C; Ellenberg, Susan S
Premarketing studies of drugs, although large enough to demonstrate efficacy and detect common adverse events, cannot reliably detect an increased incidence of rare adverse events or events with significant latency. For most drugs, only about 500 to 3000 participants are studied, for relatively short durations, before a drug is marketed. Systems for assessment of postmarketing adverse events include spontaneous reports, computerized claims or medical record databases, and formal postmarketing studies. We briefly review the strengths and limitations of each. Postmarketing surveillance is essential for developing a full understanding of the balance between benefits and adverse effects. More work is needed in analysis of data from spontaneous reports of adverse effects and automated databases, design of ad hoc studies, and design of economically feasible large randomized studies.
Damasceno, Glauciene Santana; Guaraldo, Lusiele; Engstrom, Elyne Montenegro; Filha, Mariza Miranda Theme; Santos, Reinaldo Souza-; Vasconcelos, Ana Gloria Godoi; Rozenfeld, Suely
OBJECTIVES: This study aimed to characterize and estimate the frequency of adverse reactions to antituberculosis drugs in the population treated at the Centro de Saúde Escola Germano Sinval Faria, a primary health care clinic in Manguinhos, Rio de Janeiro City, and to explore the relationship between adverse drug reactions and some of the patients' demographic and health characteristics. METHODS: This descriptive study was conducted via patient record review of incident cases between 2004 and 2008. RESULTS: Of the 176 patients studied, 41.5% developed one or more adverse reactions to antituberculosis drugs, totaling 126 occurrences. The rate of adverse reactions to antituberculosis drugs was higher among women, patients aged 50 years or older, those with four or more comorbidities, and those who used five or more drugs. Of the total reactions, 71.4% were mild. The organ systems most affected were as follows: the gastrointestinal tract (29.4%), the skin and appendages (21.4%), and the central and peripheral nervous systems (14.3%). Of the patients who experienced adverse reactions to antituberculosis drugs, 65.8% received no drug treatment for their adverse reactions, and 4.1% had one of the antituberculosis drugs suspended because of adverse reactions. “Probable reactions” (75%) predominated over “possible reactions” (24%). In the study sample, 64.3% of the reactions occurred during the first two months of treatment, and most (92.6%) of the reactions were ascribed to the combination of rifampicin + isoniazid + pyrazinamide (Regimen I). A high dropout rate from tuberculosis treatment (24.4%) was also observed. CONCLUSION: This study suggests a high rate of adverse reactions to antituberculosis drugs. PMID:23644852
Khan, Moin; Cheung, Angela M; Khan, Aliya A
Postmenopausal osteoporosis is associated with microarchitectural deterioration and increased risk of fracture. Osteoporosis therapy effectively reduces the risk of vertebral, nonvertebral, and hip fracture and has been associated with increased survival. Currently approved treatments for osteoporosis include bisphosphonates, denosumab, selective estrogen receptor modulators, and teriparatide. This article reviews the adverse events of therapy associated with these medical interventions. Hormone replacement therapy is not included, because it is no longer indicated for the treatment of osteoporosis in all countries. Calcitonin and strontium ranelate are also not included, because their indication for osteoporosis has recently been limited or withdrawn.
Hernández-Hernández, Dulce María; Vargas-Rivera, María Josefa E; Nava-Ocampo, Alejandro A; Palma-Aguirre, José Antonio; Sumano-López, Héctor
Background Adverse drug reactions (ADR's) could be expected more frequently in pregnant women. This study was performed in order to identify ADR's to tocolytic drugs in hospitalised pregnant women. Methods A prospective cohort study was performed in two General Hospitals of the Instituto Mexicano del Seguro Social (IMSS) in Mexico City. Two hundred and seven women undergoing labor, premature labor, threatened abortion or suffering any obstetric related disease were included. Drug prescription and signs and symptoms of any potential ADR were registered daily during the hospital stay. Any potential ADR to tocolytic drugs was evaluated and classified by three of the authors using the Kramer's algorithm. Results Of the 207 patients, an ADR was positively classified in 25 cases (12.1%, CI95% 8.1 to 17.5%). All ADR's were classified as minor reactions. Grouping patients with diagnosis of threatened abortion, premature labor or under labor (n= 114), 24 ADR's were related to terbutaline, accounting for a rate of 21.1 ADR's per 100 obstetric patients. Obstetric patients suffering an ADR were older than obstetric patients without any ADR. However, the former received less drugs/day × patient-1 and had a shorter hospital stay (p < 0.05) whereas the dose of terbutaline was similar between the two groups. Terbutaline inhibited uterine motility in women with and without any ADR at a similar rate, 70 and 76% respectively (x2 = 0.07; p = 0.8). Conclusion Terbutaline, used as a tocolytic drug, was related to a high frequency of minor ADRs and to a high rate of effcicacy. PMID:11934352
Manohar, Hasitha Diana; Adiga, Shalini; Thomas, Joseph; Sharma, Ajitha
Objectives: The aim of the study was to analyze the adverse drug reaction (ADR) profile of microtubule-damaging antineoplastic drugs (taxanes and vinca alkaloids) and to look for unexpected ADRs among the local population. Focused study on these drugs, rampantly used in oncology department for a wide variety of tumors including early and advanced malignancies, would enable better treatment care by physicians. Materials and Methods: Data on ADRs were collected from the cancer patients belonging to both gender and of all ages, on taxanes- or vinca-based cancer chemotherapy and reported in the Indian Pharmacopoeia Commission form. Causality was assessed using the WHO criteria and Naranjo's Algorithm. Preventability and severity of ADRs were also assessed. Results: A total of 97 ADRs were reported among 488 patients on microtubule-damaging anticancer drugs admitted over a period of 1 year. The incidence rate was 19.87%. Gastrointestinal system (40.2%) was the most affected followed by bone marrow (33%) and skin (8.2%). The highest incidence of ADRs was reported among paclitaxel (54.6%), and vincristine (39.2%). Most of the reported ADRs were of milder nature and preventable. The WHO causality assessment scale indicated 71.1% possible reactions. Conclusions: This study showed that most ADRs are preventable with effective ADR monitoring. There is a great need to create awareness among healthcare professionals regarding the importance of the pharmacovigilance system. Judicious use of the preventive measures will lead to a reduction in the incidence of ADRs due to the drug armamentarium, thereby enabling additional economic benefit to the patient and society. PMID:27721535
El-Sayed, Wael M; Al-Kahtani, Mohamed Ali
Oseltamivir is the most widely used antiviral drug for the treatment and prophylaxis of influenza. However, not much is known about its adverse effects. The potential side effects were investigated in male and female rats (140-170 g). Oseltamivir was administered at 2.2 mg·kg(-1)·day(-1) for 5 days. For both genders, treatment with oseltamivir resulted in significant reductions in the hepatic activities of glutathione reductase, glutathione peroxidase, and glutathione S-transferase. Also for both genders, oseltamivir produced modest reductions in the hepatic activities of UDP-glucuronosyltransferase, quinone oxidoreductase, thioredoxin reductase, CYP1A1/2, and CYP3A, as well as hepatic glutathione content. For both genders, neither the kidney functions nor protein profile was affected by oseltamivir. Oseltamivir also caused significant elevation in serum levels of both triacylglycerols and LDL-cholesterol and in the activity of γ-glutamyl transpeptidase, in both genders. For male animals only, oseltamivir treatment elevated the serum level of total cholesterol as well as the activity of serum alanine aminotransferase, and reduced the hepatic activities of superoxide dismutase and catalase. Oseltamivir caused oxidative stress and acute toxicity in the liver, and disrupted the cholesterol and lipid metabolism but was less likely to cause serious drug interactions. There was a sexual differentiation in these adverse effects, with adverse effects being more evident in male rats.
Wang, Kejian; Weng, Zuquan; Sun, Liya; Sun, Jiazhi; Zhou, Shu-Feng; He, Lin
Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.
Lake, C R; Gallant, S; Masson, E; Miller, P
Phenylpropanolamine (PPA) is contained in about 106 products, over half of which are available over-the-counter (OTC). Most are cough/cold remedies; nine are OTC diet aids. More than nine million Americans were using OTC diet aids in 1981, making PPA the fifth most used drug in the United States, responsible for over $200 million in revenues. The safety of PPA remains controversial. Although most controlled studies indicate minimal pressor effects with recommended doses, adverse drug reactions (ADRs) continue to be documented. Since 1965, 142 ADRs have been reported in 85 studies, 69% of these in North America. Many such cases may go unrecognized. About two thirds of all ADRs occurred in females and in patients under 30. Of ADRs attributed to legitimately sold PPA products, 85% occurred after consumption of OTC products versus only 15% after prescription drugs. The PPA product often contained combination ingredients, or PPA was consumed along with additional drugs. An overdose of PPA was taken in about a third of the cases. After ingestion of non-overdose amounts, 82% of the ADRs were severe. The most frequent side effects involved symptoms compatible with acute hypertension, with severe headache the most common complaint. Twenty-four intracranial hemorrhages, eight seizures, and eight deaths (most due to stroke) were associated with PPA ingestion. We have summarized these data in an effort to alert clinicians to the prevalence of usage of PPA products and the potential for adverse effects. In patients who present with elevated blood pressure or signs of acute hypertension, especially hypertensive encephalopathy of undetermined origin, we recommend inquiry about recent ingestion of PPA-containing diet aids and cough/cold products and suggest having such patients remain upright rather than supine.
Laatikainen, Outi; Sneck, Sami; Bloigu, Risto; Lahtinen, Minna; Lauri, Timo; Turpeinen, Miia
Adverse drug events (ADEs) are more likely to affect geriatric patients due to physiological changes occurring with aging. Even though this is an internationally recognized problem, similar research data in Finland is still lacking. The aim of this study was to determine the number of geriatric medication-related hospitalizations in the Finnish patient population and to discover the potential means of recognizing patients particularly at risk of ADEs. The study was conducted retrospectively from the 2014 emergency department patient records in Oulu University Hospital. A total number of 290 admissions were screened for ADEs, adverse drug reactions (ADRs) and drug-drug interactions (DDIs) by a multi-disciplinary research team. Customized Naranjo scale was used as a control method. All admissions were categorized into “probable,” “possible,” or “doubtful” by both assessment methods. In total, 23.1% of admissions were categorized as “probably” or “possibly” medication-related. Vertigo, falling, and fractures formed the largest group of ADEs. The most common ADEs were related to medicines from N class of the ATC-code system. Age, sex, residence, or specialty did not increase the risk for medication-related admission significantly (min p = 0.077). Polypharmacy was, however, found to increase the risk (OR 3.3; 95% CI, 1.5–6.9; p = 0.01). In conclusion, screening patients for specific demographics or symptoms would not significantly improve the recognition of ADEs. In addition, as ADE detection today is largely based on voluntary reporting systems and retrospective manual tracking of errors, it is evident that more effective methods for ADE detection are needed in the future. PMID:27761112
Background Our objective was to develop a model for measuring re-identification risk that more closely mimics the behaviour of an adversary by accounting for repeated attempts at matching and verification of matches, and apply it to evaluate the risk of re-identification for Canada’s post-marketing adverse drug event database (ADE).Re-identification is only demonstrably plausible for deaths in ADE. A matching experiment between ADE records and virtual obituaries constructed from Statistics Canada vital statistics was simulated. A new re-identification risk is considered, it assumes that after gathering all the potential matches for a patient record (all records in the obituaries that are potential matches for an ADE record), an adversary tries to verify these potential matches. Two adversary scenarios were considered: (a) a mildly motivated adversary who will stop after one verification attempt, and (b) a highly motivated adversary who will attempt to verify all the potential matches and is only limited by practical or financial considerations. Methods The mean percentage of records in ADE that had a high probability of being re-identified was computed. Results Under scenario (a), the risk of re-identification from disclosing the province, age at death, gender, and exact date of the report is quite high, but the removal of province brings down the risk significantly. By only generalizing the date of reporting to month and year and including all other variables, the risk is always low. All ADE records have a high risk of re-identification under scenario (b), but the plausibility of that scenario is limited because of the financial and practical deterrent even for highly motivated adversaries. Conclusions It is possible to disclose Canada’s adverse drug event database while ensuring that plausible re-identification risks are acceptably low. Our new re-identification risk model is suitable for such risk assessments. PMID:24094134
Empey, Philip E
Adverse drug reactions are a significant public health problem that leads to mortality, hospital admissions, an increased length of stay, increasing healthcare costs, and withdrawal of drugs from market. Intensive care unit patients are particularly vulnerable and are at an elevated risk. Critical care practitioners, regulatory agencies, and the pharmaceutical industry aggressively seek biomarkers to mitigate patient risk. The rapidly expanding field of pharmacogenomics focuses on the genetic contributions to the variability in drug response. Polymorphisms may explain why some groups of patients have the expected response to pharmacotherapy whereas others experience adverse drug reactions. Historically, genetic association studies have focused on characterizing the effects of variation in drug metabolizing enzymes on pharmacokinetics. Recent work has investigated drug transporters and the variants of genes encoding drug targets, both intended and unintended, that comprise pharmacodynamics. This has led to an appreciation of the role that genetics plays in adverse drug reactions that are either predictable extensions of a drug's known therapeutic effect or idiosyncratic.This review presents the evidence for a genetic predisposition to adverse drug reactions, focusing on gene variants producing alterations in drug pharmacokinetics and pharmacodynamics in intensive care unit patients. Genetic biomarkers with the strongest associations to adverse drug reaction risk in the intensive care unit are presented along with the medications involved. Variant genotypes and phenotypes, allelic frequencies in different populations, and clinical studies are discussed. The article also presents the current recommendations for pharmacogenetic testing in clinical practice and explores the drug, patient, research study design, regulatory, and practical issues that presently limit more widespread implementation.
Hashiguchi, Masayuki; Imai, Shungo; Uehara, Keiko; Maruyama, Junya; Shimizu, Mikiko; Mochizuki, Mayumi
We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.
Sakai, Takamasa; Ohtsu, Fumiko; Sekiya, Yasuaki; Mori, Chiyo; Sakata, Hiroshi; Goto, Nobuyuki
Safety information regarding drug use during pregnancy is insufficient. The present study aimed to establish an optimal signal detection method to identify adverse drug reactions in pregnant women and to evaluate information in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and November 2014. We identified reports on pregnant women using the Standardised MedDRA Queries. We calculated the proportional reporting ratio (PRR) and reporting odds ratio (ROR) of the risk factors for the two known risks of antithyroid drugs and methimazole (MMI) embryopathy, and ritodrine and fetal/infant cardiovascular events. The PRR and ROR values differed between all reports in the JADER database and those on pregnant women, affecting whether signal detection criteria were met. Therefore we considered that reports on pregnant women should be used when risks associated with pregnancy were determined using signal detection. Analyses of MMI embryopathy revealed MMI signals [PRR, 159.7; ROR, 669.9; 95% confidence interval (CI), 282.4-1588.7] but no propylthiouracil signals (PRR, 1.98; ROR, 2.0; 95%CI, 0.3-15.4). These findings were consistent with those of reported risks. Analyses of fetal/infant cardiovascular events revealed ritodrine signals (PRR, 2.1; ROR, 2.1; 95%CI, 1.4-3.3). These findings were also consistent with reported risks. Mining the JADER database was helpful for analyzing adverse drug reactions in pregnant women.
Anderson, Judy K; Fox, Jodie R
Medication administration at mealtimes may result in food-drug interactions. Older adults are especially at risk of food-drug interactions leading to adverse drug effects and subtherapeutic responses. Research on potential food-drug interactions is limited and dated. This study examined the frequency of potential food-drug interactions in long-term care. Forty-nine percent of drugs administered at mealtimes had potential for interaction, with cardiovascular medications given most frequently. The frequency of potential interactions makes this phenomenon critically important to review. Collaboration between nurses and pharmacists may identify optimal medication scheduling. Nurses can enhance care by identifying strategies to limit interactions through knowledge and creative, collaborative administration schedules.
Becker, Mara L; Leeder, J Steven
Adverse drug reactions are a concern for all clinicians who utilize medications to treat adults and children; however, the frequency of adult and pediatric adverse drug reactions is likely to be under-reported. In this age of genomics and personalized medicine, identifying genetic variation that results in differences in drug biotransformation and response has contributed to significant advances in the utilization of several commonly used medications in adults. In order to better understand the variability of drug response in children however, we must not only consider differences in genotype, but also variation in gene expression during growth and development, namely ontogeny. In this article, recommendations for systematically approaching pharmacogenomic studies in children are discussed, and several examples of studies that investigate the genomic and developmental contribution to adverse drug reactions in children are reviewed. PMID:21121777
Apte, Aditi Anand
Pharmacovigilance is an evolving discipline in the Indian context. However, there is limited regulatory guidance for adverse event reporting outside the purview of clinical trials. There are number of deficiencies in the framework for adverse event reporting from the perspective of pharma industry, health-care professional and general public due to which adverse events for marketed drugs are highly underreported. This article discusses the need to strengthen national safety database by promoting and mandating reporting of adverse events by all the stakeholders. PMID:27453826
Brown, S Lori; Reid, Marie H; Duggirala, Hesha Jani
A silicone adjustable gastric banding system was approved by the Food and Drug Administration (FDA) in June, 2001. The purpose of this report is to review and characterize the reports on silicone adjustable gastric banding systems received by the FDA through August 8, 2002. We also review medical literature on adverse events with silicone adjustable gastric banding systems. Manufacturers of regulated medical devices, such as adjustable silicone gastric bands, are required to report adverse events, including deaths and serious injuries, to the FDA. We reviewed all such reports received by the FDA through August 8, 2002, for adjustable silicone gastric bands and summarize the data by type of adverse event, reported device problems, and reported patient problems. The FDA received 556 reports of adverse events related to the use of adjustable silicone gastric bands. Two of these reports were for deaths, one during surgery and the other as a result of an erosion of the gastric band into the stomach 9 weeks after implantation. Forty-four reports were for injuries including band erosions, slippage, and infection. The most common type of report (499) was for device malfunction, and of these, 485 (97.2%) described a leak at or near the port. Of the 485 leaks reported as malfunctions, 99.4% were treated surgically. The majority of reports were related to disconnection, breakage, and leakage at or near the access port. Physicians and potential patients should be aware of these problems and recognize the possibility that additional surgery(ies) may be required for leaking access port/connections. The loose connection may cause pain and the device no longer performs as intended when there is a leak.
Timbo, Babgaleh; Koehler, Kathleen M; Wolyniak, Cecilia; Klontz, Karl C
Sulfite-sensitive individuals can experience adverse reactions after consuming foods containing sulfiting agents (sulfites), and some of these reactions may be severe. In the 1980s and 1990s, the U.S. Food and Drug Administration (FDA) acted to reduce the likelihood that sulfite-sensitive individuals would unknowingly consume foods containing sulfites. The FDA prohibited the use of sulfites on fruits and vegetables (except potatoes) to be served or presented fresh to the public and required that the presence of detectable levels of sulfites be declared on food labels, even when these sulfites are used as a processing aid or are a component of another ingredient in the food. In the present study, data from FDA recall records and adverse event reports were used to examine the current status of problems of sensitivity to sulfites in foods. From 1996 through 1999, the FDA processed a total of 59 recalls of foods containing undeclared sulfites; these 59 recalls involved 93 different food products. Fifty (55%) of the recalled products were classified as class I, a designation indicating that a consumer reasonably could have ingested > or = 10 mg of undeclared sulfites on a single occasion, a level that could potentially cause a serious adverse reaction in a susceptible person. From 1996 through mid-1999, the FDA received a total of 34 reports of adverse reactions allegedly due to eating foods containing undeclared sulfites. The average of 10 reports per year, although derived from a passive surveillance system, was lower than the average of 111 reports per year that the FDA received from 1980 to 1987, a decrease that may have resulted in part from FDA regulatory action.
Dr. Ansell has produced a scholarly review of the radiology of drug reactions and toxic hazards in his latest book, which is based on over 1,200 articles in the world literature. About 800 of these articles are taken from outside the radiology literature, which indicates the need for this subject to be brought to the attention of the radiologist, particularly as concern about drug reactions and toxic hazards is always increasing. The book includes sections covering the chest, gastrointestinal tract, renal tract, skeletal system and soft tissues, and skull and central nervous system. Each section treats specific substances, such as steroids and heavy metals; specific radiologic signs, such as ureteric dilation; specific symptoms, such as dysphagia; industrial toxins; radiographic abnormalities are discussed; and numerous high-quality radiographs.
..., and reporting of postmarketing adverse drug experiences to FDA. (b) Definitions. The following... severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral... and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. (1) Postmarketing...
Skin-lightening cosmetics are used by many women and men around the world. The products contain a variety of substances, which are often unknown to the users. Most of these products include topical corticosteroids, hydroquinone and mercury salts. Many other substances may be added. Several surveys and cohort studies, including several thousand individuals, have shown that regular application of skin-lightening cosmetics to large surface areas can have irreversible cutaneous adverse effects, such as patchy hyper- or hypopigmentation, skin atrophy, stretch marks and delayed wound healing, and can also mask or, on the contrary, promote or reactivate skin infections. Cases of skin cancer have been attributed to skin-lightening cosmetics. A Senegalese cohort study of 147 women showed a statistically significant increase in the risk of hypertension and diabetes linked to the use of skin-lightening agents. Other systemic adverse effects attributed to skin-lightening cosmetics include Cushing's syndrome, adrenal insufficiency, nephrotic syndrome, neurological disorders, and ocular disorders. Hypersensitivity reactions, including anaphylaxis, have also been attributed to these products. Many skin-lightening cosmetics contain substances that can harm the unborn child. For example, tretinoin is teratogenic while salicylic acid is feto-toxic. In practice, users are often unaware of the risk of severe adverse effects associated with skin-lightening cosmetics. Users should be informed of these adverse effects and encouraged to stop using these products, especially when skin disorders appear.
Zhang, Hui; Yu, Peng; Xiang, Ming-Li; Li, Xi-Bo; Kong, Wei-Bao; Ma, Jun-Yi; Wang, Jun-Long; Zhang, Jin-Ping; Zhang, Ji
Drug-induced eosinophilia is a potentially life-threatening adverse effect; clinical manifestations, eosinophilia-myalgia syndrome, mainly include severe skin eruption, fever, hematologic abnormalities, and organ system dysfunction. Using experimental methods to evaluate drug-induced eosinophilia is very complicated, time-consuming, and costly in the early stage of drug development. Thus, in this investigation, we established computational prediction models of drug-induced eosinophilia using SVM and naïve Bayesian approaches. For the SVM modeling, the overall prediction accuracy for the training set by means of fivefold cross-validation is 91.6 and for the external test set is 82.9 %. For the naïve Bayesian modeling, the overall prediction accuracy for the training set is 92.5 and for the external test set is 85.4 %. Moreover, some molecular descriptors and substructures considered as important for drug-induced eosinophilia were identified. Thus, we hope the prediction models of drug-induced eosinophilia built in this work should be applied to filter early-stage molecules for potential eosinophilia adverse effect, and the selected molecular descriptors and substructures of toxic compounds should be taken into consideration in the design of new candidate drugs to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.
Caplan, Arthur; Zink, Amanda
The ethical challenges of reporting and managing adverse events (AEs) and serious AEs (SAEs) in the context of mass drug administration (MDA) for the treatment of neglected tropical diseases (NTDs) require reassessment of domestic and international policies on a global scale. Although the World Health Organization has set forth AE/SAE guidelines specifically for NTD MDA that incorporate suspected causality, and recommends that only SAEs get reported in this setting, most regulatory agencies continue to require the reporting of all SAEs exhibiting even a merely temporal relationship to activities associated with an MDA program. This greatly increases the potential for excess "noise" and undue risk aversion and is not only impractical but arguably unethical where huge proportions of populations are being treated for devastating diseases, and no good baseline exists against which to compare possible AE/SAE reports. Other population-specific variables that might change the way drug safety ought to be assessed include differing efficacy rates of a drug, background morbidity/mortality rates of the target disease in question, the growth rate of the incidence of disease, the availability of rescue or salvage therapies, and the willingness of local populations to take risks that other populations might not. The fact that NTDs are controllable and potentially eradicable with well-tolerated, effective, existing drugs might further alter our assessment of MDA safety and AE/SAE tolerability. At the same time, diffuseness of population, communication barriers, lack of resources, and other difficult surveillance challenges may present in NTD-affected settings. These limitations could impair the ability to monitor an MDA program's success, as well as hinder efforts to obtain informed consent or provide rescue therapy. Denying beneficial research interventions and MDA programs intended to benefit millions requires sound ethical justification based on more than the identification of
Gotta, Verena; van den Anker, Johannes; Pfister, Marc
Developmental pharmacology influences the safety profile of drugs in pediatrics. Altered pharmacokinetics and/ or pharmacodynamics of drugs make pediatric patients susceptible to adverse drug reactions (ADRs), especially infants and newborns. Since the efficacy/ safety balance of most available drugs has not been formally evaluated in pediatric clinical trials, optimal dosing is rarely known in pediatrics. Suboptimal pediatric drug formulations make dose optimization even more difficult exposing pediatric patients to medication errors like overdosing and associated ADRs. We provide an overview of pediatric ADRs and discuss recent regulatory and pharmacological measures to understand and reduce risk of ADRs in pediatric patients.
Liu, Yi; LePendu, Paea; Iyer, Srinivasan; Shah, Nigam H.
Researchers estimate that electronic health record systems record roughly 2-million ambulatory adverse drug events and that patients suffer from adverse drug events in roughly 30% of hospital stays. Some have used structured databases of patient medical records and health insurance claims recently—going beyond the current paradigm of using spontaneous reporting systems like AERS—to detect drug-safety signals. However, most efforts do not use the free-text from clinical notes in monitoring for drug-safety signals. We hypothesize that drug–disease co-occurrences, extracted from ontology-based annotations of the clinical notes, can be examined for statistical enrichment and used for drug safety surveillance. When analyzing such co-occurrences of drugs and diseases, one major challenge is to differentiate whether the disease in a drug–disease pair represents an indication or an adverse event. We demonstrate that it is possible to make this distinction by combining the frequency distribution of the drug, the disease, and the drug-disease pair as well as the temporal ordering of the drugs and diseases in each pair across more than one million patients. PMID:22779050
Cantor, Michael N; Feldman, Henry J; Triola, Marc M
Background As medical care moves towards an outpatient focus, monitoring systems for ambulatory patients are increasingly important. Because adverse outcomes due to medications are an important problem in outpatients, the authors developed an automated monitoring system for detecting adverse drug reactions (ADRs) in ambulatory patients. Methods The authors obtained a set of approximately 110 000 ambulatory care notes from the medicine clinic at Bellevue Hospital Centre for 2003–4, and manually analysed a representative sample of 1250 notes to obtain a gold standard. To detect ADRs in the text of electronic ambulatory notes, the authors used a “trigger phrases” methodology, based on a simple grammar populated with a limited set of keywords. Results Under current functionality, this system detected 38 of 54 cases in the authors' gold standard set, of which 17 were true positives, for a sensitivity of 31%, a specificity of 98%, and a positive predictive value of 45%. Their proxy measure correlated with 70% of the ADRs in the gold standard. These values are comparable or superior to other systems described in the literature. Conclusions These results show that an automated system can detect ADRs with moderate sensitivity and high specificity, and has the potential to serve as the basis for a larger scale reporting system. PMID:17403760
Rodrigues, Maria Cristina Soares; de Oliveira, Cesar
ABSTRACT Objective: to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. Methods: an integrative review of studies published from January 2008 to December 2013, according to inclusion and exclusion criteria, in MEDLINE and EMBASE electronic databases were performed. Results: forty-seven full-text studies including 14,624,492 older adults (≥ 60 years) were analyzed: 24 (51.1%) concerning ADR, 14 (29.8%) DDI, and 9 studies (19.1%) investigating both DDI and ADR. We found a variety of methodological designs. The reviewed studies reinforced that polypharmacy is a multifactorial process, and predictors and inappropriate prescribing are associated with negative health outcomes, as increasing the frequency and types of ADRs and DDIs involving different drug classes, moreover, some studies show the most successful interventions to optimize prescribing. Conclusions: DDI and ADR among older adults continue to be a significant issue in the worldwide. The findings from the studies included in this integrative review, added to the previous reviews, can contribute to the improvement of advanced practices in geriatric nursing, to promote the safety of older patients in polypharmacy. However, more research is needed to elucidate gaps. PMID:27598380
Nikfarjam, Azadeh; Gonzalez, Graciela H
Rapid growth of online health social networks has enabled patients to communicate more easily with each other. This way of exchange of opinions and experiences has provided a rich source of information about drugs and their effectiveness and more importantly, their possible adverse reactions. We developed a system to automatically extract mentions of Adverse Drug Reactions (ADRs) from user reviews about drugs in social network websites by mining a set of language patterns. The system applied association rule mining on a set of annotated comments to extract the underlying patterns of colloquial expressions about adverse effects. The patterns were tested on a set of unseen comments to evaluate their performance. We reached to precision of 70.01% and recall of 66.32% and F-measure of 67.96%.
Nikfarjam, Azadeh; Gonzalez, Graciela H.
Rapid growth of online health social networks has enabled patients to communicate more easily with each other. This way of exchange of opinions and experiences has provided a rich source of information about drugs and their effectiveness and more importantly, their possible adverse reactions. We developed a system to automatically extract mentions of Adverse Drug Reactions (ADRs) from user reviews about drugs in social network websites by mining a set of language patterns. The system applied association rule mining on a set of annotated comments to extract the underlying patterns of colloquial expressions about adverse effects. The patterns were tested on a set of unseen comments to evaluate their performance. We reached to precision of 70.01% and recall of 66.32% and F-measure of 67.96%. PMID:22195162
Context: Drug-drug interactions(DDIs) are significant but avoidable causes of iatrogenic morbidity and hospital admission. Aim: To detect potential drug-drug interactions among medications received by hypertensive patients. Materials and Methods: Patients of both sex and all adult age groups, who were attending medicine out -patient department (OPD) of a tertiary care teaching rural hospital since last six months and were being prescribed antihypertensive drug/s for essential hypertension, were selected for the study. Hypertensive patient with co-morbities diabetes mellitus, ischemic heart diseases, congestive heart failure, and chronic renal diseases were also included in the study. Potential drug drug interactions were checked with medscape drug interaction software. Results: With the help of medscape drug interaction software, 71.50% prescriptions were identified having atleast one drug-drug interaction. Total 918 DDIs were found in between 58 drug pairs. 55.23% DDIs were pharmacodynamic, 4.79% pharmacokinetic type of DDIs. 32.24% DDIs were found affecting serum potassium level. 95.42% DDIs were found significant type of DDIs. Drug drug interaction between atenolol & amlodipine was the most common DDI (136) followed by metoprolol and amlodine (88) in this study. Atenolol and amlodipine ( 25.92%) was the most common drugs to cause DDIs in our study. Conclusion: We detected a significant number of drug drug interaction in hypertensive patients. These interactions were between antihypertensive agents or between hypertensive and drug for co-morbid condition. PMID:25584241
Bender, Ralf; Beckmann, Lars; Lange, Stefan
The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.
Royer, R J; Benichou, C
Under the auspices of the Council for International Organizations of Medical Sciences, a working group composed of representatives of seven multinational pharmaceutical manufacturers and six regulatory authorities developed and implemented a standardized method for reporting post-approval adverse drug reactions (ADR). The method is based on a set of uniform definitions and procedures and a single reporting form, and has been demonstrated to be feasible and effective. Regulators and manufacturers, in establishing requirements and systems for reporting of adverse drug reactions, should consider adopting this method.
Lavigne, Jill E.; McCarthy, Michael; Chapman, Richard; Petrilla, Allison; Knox, Kerry L.
Prescription drugs for many indications are labeled with warnings for potential risk of suicidal ideation or behavior. Exposures to prescription drugs labeled for adverse effects of suicidal behavior or ideation among 100 Air Force personnel who died by suicide between 2006 and 2009 are described. Air Force registry data were linked to…
Bénard-Laribière, Anne; Miremont-Salamé, Ghada; Pérault-Pochat, Marie-Christine; Noize, Pernelle; Haramburu, Françoise
To assess the incidence of hospital admissions related to adverse drug reactions (ADRs) in France and the frequency of preventable ADRs in France, a prospective study was conducted among a representative randomly selected sample of medical wards in public hospitals between December 2006 and June 2007; all patients admitted during a 2-week period were included. An ADR-related hospitalization case was defined as a hospital admission because of an ADR, and an independent committee reviewed and validated all potential cases. Preventability was assessed using the French ADR preventability scale. Data were extrapolated to the population of France. Among 2692 admissions, 97 were related to an ADR (incidence 3.6%, 95% confidence interval, CI [2.8-4.4]). Patients admitted for an ADR were significantly older than those admitted for other reasons (P < 0.001). A third (32.0%) of ADR-related hospitalizations were 'preventable', 16.5% 'potentially preventable'. Drug interactions accounted for 29.9% of ADR-related hospitalizations. The most frequent causes of ADR-related hospitalizations were vascular disorders (20.6%), mainly bleeding complications, central nervous system disorders (11.3%), gastrointestinal disorders, and general disorders (9.3%). Antithrombotic and antineoplastic agents were the most frequently involved (12.6% each), followed by diuretics and analgesics (9.0% each). Vitamin-K-antagonists (VKAs) were the most common drugs associated with admission. The estimated annual number of ADR-related hospitalizations in France was 143 915 (95% CI [112 063-175 766]). ADRs were a significant cause of hospital admission in 2006-2007, in particular those due to VKAs. As new oral anticoagulants (NOACs) have been marketed, more attention needs to be paid to ensure a safe use of antithrombotic agents.
Anderson, James G.; Jay, Stephen J.; Anderson, Marilyn; Hunt, Thaddeus J.
Background: The annual cost of morbidity and mortality due to medication errors in the U.S. has been estimated at $76.6 billion. Information technology implemented systematically has the potential to significantly reduce medication errors that result in adverse drug events (ADEs). Objective: To develop a computer simulation model that can be used to evaluate the effectiveness of information technology applications designed to detect and prevent medication errors that result in adverse drug effects. Methods: A computer simulation model was constructed representing the medication delivery system in a hospital. STELLA, a continuous simulation software package, was used to construct the model. Parameters of the model were estimated from a study of prescription errors on two hospital medical/surgical units and used in the baseline simulation. Five prevention strategies were simulated based on information obtained from the literature. Results: The model simulates the four stages of the medication delivery system: prescribing, transcribing, dispensing, and administering drugs. We simulated interventions that have been demonstrated in prior studies to decrease error rates. The results suggest that an integrated medication delivery system can save up to 1,226 days of excess hospitalization and $1.4 million in associated costs annually in a large hospital. The results of the analyses regarding the effects of the interventions on the additional hospital costs associated with ADEs are somewhat sensitive to the distribution of errors in the hospital, more sensitive to the costs of an ADE, and most sensitive to the proportion of medication errors resulting in ADEs. Conclusions: The results suggest that clinical information systems are potentially a cost-effective means of preventing ADEs in hospitals and demonstrate the importance of viewing medication errors from a systems perspective. Prevention efforts that focus on a single stage of the process had limited impact on the
Berreni, Aurélia; Montastruc, François; Bondon-Guitton, Emmanuelle; Rousseau, Vanessa; Abadie, Delphine; Durrieu, Geneviève; Chebane, Leila; Giroud, Jean-Paul; Bagheri, Haleh; Montastruc, Jean-Louis
Although self-medication is widely developed, there are few detailed data about its adverse drug reactions (ADRs). This study investigated the main characteristics of ADRs with self-medication recorded in the Midi-Pyrénées PharmacoVigilance between 2008 and 2014. Self-medication included first OTC drugs and second formerly prescribed drugs later used without medical advice (reuse of previously prescribed drugs). Among the 12 365 notifications recorded, 160 (1.3%) were related to SM with 186 drugs. Around three-forth of the ADRs were 'serious'. Mean age was 48.8 years with 56.3% females. The most frequent ADRs were gastrointestinal and neuropsychiatric and main drug classes involved NSAIDs, analgesics, and benzodiazepines. Phytotherapy-homeopathy accounted for 9.1% of drugs.
Masuko, Kayo; Tohma, Shigeto; Matsui, Toshihiro
Various medications are used for the treatment of rheumatoid arthritis (RA). Food-drug interactions may occur with concomitant ingestion of particular food. For example, methotrexate (MTX), the anchor drug in the therapeutic strategy against RA, is an antifolate agent. Excessive presence or absence of dietary folic acid may regulate MTX metabolism, possibly leading to unexpected adverse reactions. In this review, we focus on MTX, isoniazide and calcineurin inhibitors, and the implications of potential food-drug reactions in rheumatology, suggesting the important role of nutritional evaluations in RA patients.
Henriksson, Aron; Kvist, Maria; Dalianis, Hercules; Duneld, Martin
For the purpose of post-marketing drug safety surveillance, which has traditionally relied on the voluntary reporting of individual cases of adverse drug events (ADEs), other sources of information are now being explored, including electronic health records (EHRs), which give us access to enormous amounts of longitudinal observations of the treatment of patients and their drug use. Adverse drug events, which can be encoded in EHRs with certain diagnosis codes, are, however, heavily underreported. It is therefore important to develop capabilities to process, by means of computational methods, the more unstructured EHR data in the form of clinical notes, where clinicians may describe and reason around suspected ADEs. In this study, we report on the creation of an annotated corpus of Swedish health records for the purpose of learning to identify information pertaining to ADEs present in clinical notes. To this end, three key tasks are tackled: recognizing relevant named entities (disorders, symptoms, drugs), labeling attributes of the recognized entities (negation, speculation, temporality), and relationships between them (indication, adverse drug event). For each of the three tasks, leveraging models of distributional semantics - i.e., unsupervised methods that exploit co-occurrence information to model, typically in vector space, the meaning of words - and, in particular, combinations of such models, is shown to improve the predictive performance. The ability to make use of such unsupervised methods is critical when faced with large amounts of sparse and high-dimensional data, especially in domains where annotated resources are scarce.
Kadoyama, Kaori; Sakaeda, Toshiyuki; Tamon, Akiko; Okuno, Yasushi
The recent emergence of multidrug-resistant pathogens and/or pharmacokinetics-pharmacodynamics considerations may result in off-label use of a certain class of antibacterials, including tigecycline. This study was performed to clarify the safety profile of tigecycline in the user-derived manner and to compare it with the prescribing information provided by the manufacturer. Numerous spontaneous adverse event reports (AERs) submitted to the U.S. Food and Drug Administration (FDA) were analyzed after a revision of arbitrary drug names and the deletion of duplicated submissions. Standardized official pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Based on 22017956 co-occurrences, i.e., drug-adverse event pairs, found in 1644220 AERs from 2004 to 2009, 248 adverse events were suggested as tigecycline-associated ones. Adverse events with a relatively high frequency included nausea, vomiting, pancreatitis, hepatic failure, hypoglycemia, and increase in levels of alanine aminotransferase, bilirubin, alkaline phosphatase, aspartate aminotransferase, and gamma-glutamyltransferase. It is noted that cholestasis, jaundice, an increase in International Normalized Ratio, and Stevens-Johnson syndrome were also, although they were infrequent. The adverse events suggested were in agreement with information provided by the manufacturer, suggesting that off-label use hardly results in unexpected adverse events, presumably due to usage with extreme caution.
Croft, Ashley M; Herxheimer, Andrew
Background Mefloquine is a clinically important antimalaria drug, which is often not well tolerated. We critically reviewed 516 published case reports of mefloquine adverse effects, to clarify the phenomenology of the harms associated with mefloquine, and to make recommendations for safer prescribing. Presentation We postulate that many of the adverse effects of mefloquine are a post-hepatic syndrome caused by primary liver damage. In some users we believe that symptomatic thyroid disturbance occurs, either independently or as a secondary consequence of the hepatocellular injury. The mefloquine syndrome presents in a variety of ways including headache, gastrointestinal disturbances, nervousness, fatigue, disorders of sleep, mood, memory and concentration, and occasionally frank psychosis. Previous liver or thyroid disease, and concurrent insults to the liver (such as from alcohol, dehydration, an oral contraceptive pill, recreational drugs, and other liver-damaging drugs) may be related to the development of severe or prolonged adverse reactions to mefloquine. Implications We believe that people with active liver or thyroid disease should not take mefloquine, whereas those with fully resolved neuropsychiatric illness may do so safely. Mefloquine users should avoid alcohol, recreational drugs, hormonal contraception and co-medications known to cause liver damage or thyroid damage. With these caveats, we believe that mefloquine may be safely prescribed in pregnancy, and also to occupational groups who carry out safety-critical tasks. Testing Mefloquine's adverse effects need to be investigated through a multicentre cohort study, with small controlled studies testing specific elements of the hypothesis. PMID:11914150
Brown, S L; Parmentier, C M; Woo, E K; Vishnuvajjala, R L; Headrick, M L
OBJECTIVES: To characterize the adverse event reports on silicone gel breast implants (SGBIs), including death reports, submitted to the Food and Drug Administration (FDA) from 1984 through 1995 and to analyze changes in the type and complexity of reports following extensive media coverage of breast implants. METHODS: The authors analyzed mandatory and voluntary reports from the adverse events reporting system for medical devices at the FDA. RESULTS: In 1988, adverse event reports related to SGBIs accounted for 2.4% of the 14,473 mandatory reports entered into the FDA database on medical devices. In 1992, SGBI-related reports accounted for 30.3% of the total 66,476 mandatory reports of adverse events. The most frequently reported adverse event in 1988, before the widespread publicity on breast implants, was implant burst or rupture. In contrast, in 1992 the most frequently reported event was reaction, a term used to describe a range of adverse effects. CONCLUSIONS: The numbers of mandatory and voluntary reports of SGBI-related adverse events increased exponentially, as did the complexity of the reports, following publicity over the lack of safety data on breast implants and a short voluntary moratorium on their sale. A significant proportion of reports lacked information on specific medical symptoms or diagnoses. PMID:9847926
Black, Corri; Tagiyeva-Milne, Nara; Helms, Peter; Moir, Dorothy
Aims A systematic review of the literature published in English over 10 years was undertaken in order to describe the use of electronic healthcare data in the identification of potential adverse drug reactions (ADRs) in children. Methods MEDLINE and EMBASE were searched using MESH headings and text words. Titles, keywords and abstracts were checked for age <18 years, potential ADRs and electronic healthcare data. Information extracted included age, data source, pharmacovigilance method, medicines and ADRs. Studies were quality assessed. Results From 14 804 titles, 314 had a full text review and 71 were included in the final review. Fifty were published in North America, 10 in Scandinavia. Study size ranged from less than 1000 children to more than 10 million. Sixty per cent of studies used data from one source. Comparative observational studies were most commonly reported (66.2%) with 15% using passive surveillance. Electronic healthcare data set linkage and the quality of the data source were poorly reported. ADRs were classified using the International Classification of Disease (ICD10). Multi-system reactions were most commonly studied, followed by central nervous system and mental and behavioural disorders. Vaccines were most frequently prescribed followed by corticosteroids, general anaesthetics and antidepressants. Conclusions Routine electronic healthcare records were increasingly reported to be used for pharmacovigilance in children. This growing and important health protection activity could be enhanced by consistent reporting of studies to improve the identification, interpretation and generalizability of the evidence base. PMID:25819310
Vallano, A; Cereza, G; Pedròs, C; Agustí, A; Danés, I; Aguilera, C; Arnau, J M
Aim To describe the opinions of hospital physicians concerning problems regarding the spontaneous reporting of adverse drug reactions (ADRs) and ways to solve them. Methods A qualitative study was carried out. Fifteen focus groups were conducted among physicians working in a tertiary teaching hospital. A total of 208 physicians from different medical specialities participated. The focus group discussions were recorded by three different observers and the transcripts of each session were analysed for issues and themes emerging from the text. Results Four types of obstacles to spontaneous reporting were considered particularly important: (i) problems with the ADRs diagnosis; (ii) problems with the usual workload and lack of time; (iii) problems related to the organization and activities of the pharmacovigilance system; (iv) and problems related to potential conflicts. The potential solutions suggested for improving spontaneous reporting were to define the kind of ADRs which should be reported, to facilitate an easy contact and quick access to the hospital pharmacovigilance system, to facilitate information and support for reporting and feedback of pharmacovigilance activities. Conclusions The perception of the different obstacles by the hospital physicians is an important factor in determining the causes of the underreporting of ADRs and addressing these obstacles could lead to an improvement in spontaneous reporting. A closer relationship between the doctors and the pharmacovigilance centre is suggested as a means of solving these problems. More information is needed to improve the spontaneous reporting of ADRs in specialized healthcare. PMID:16305591
Karthik, Ramya; Karthik, K. S.; David, Chaya; Ameerunnisa; Keerthi, G.
Gastrointestinal disease is associated with alterations in the mouth or influence the course of the dental diseases, and the dental health care workers are expected to recognize, diagnose, and treat oral conditions associated with gastrointestinal diseases and also provide safe and appropriate dental care for afflicted individuals. Drugs used in the management of these diseases result in oral adverse effects and also are known to interact with those prescribed during dental care. Hence, this article has reviewed the drug considerations and guidelines for drug use during dental management of patients with gastrointestinal diseases. PMID:23066260
Gómez-Pavón, Javier; González García, Paloma; Francés Román, Inés; Vidán Astiz, Maite; Gutiérrez Rodríguez, José; Jiménez Díaz, Gregorio; Montero Fernández, Nuria Pilar; Alvarez Fernández, Baldomero; Jiménez Páez, José María
The elderly are one of the groups at greatest risk for adverse drugs reactions (ADR). The mean prevalence of these reactions in this population is 30%. Dementia is not an independent risk factor of ADR, but is the main condition that increases all risk factors (polypharmacy, comorbidity, inappropriate prescribing, drug-drug interactions, advanced age, and treatment adherence). The present article discusses revised and consensual recommendations for the prevention of ADR in the elderly, as well as recommendations specifically for dementia patients in relation to the management of comorbidity and cognitive, behavioral and psychological symptoms.
Raschi, Emanuel; Poluzzi, Elisabetta; Godman, Brian; Koci, Ariola; Moretti, Ugo; Kalaba, Marija; Bennie, Marion; Barbui, Corrado; Wettermark, Bjorn; Sturkenboom, Miriam; De Ponti, Fabrizio
Background Antipsychotics (APs) have been associated with risk of torsade de Pointes (TdP). This has important public health implications. Therefore, (a) we exploited the public FDA Adverse Event Reporting System (FAERS) to characterize their torsadogenic profile; (b) we collected drug utilization data from 12 European Countries to assess the population exposure over the 2005-2010 period. Methods FAERS data (2004-2010) were analyzed based on the following criteria: (1) ≥4 cases of TdP/QT abnormalities; (2) Significant Reporting Odds Ratio, ROR [Lower Limit of the 95% confidence interval>1], for TdP/QT abnormalities, adjusted and stratified (Arizona CERT drugs as effect modifiers); (3) ≥4 cases of ventricular arrhythmia/sudden cardiac death (VA/SCD); (4) Significant ROR for VA/SCD; (5) Significant ROR, combined by aggregating TdP/QT abnormalities with VA and SCD. Torsadogenic signals were characterized in terms of signal strength: from Group A (very strong torsadogenic signal: all criteria fulfilled) to group E (unclear/uncertain signal: only 2/5 criteria). Consumption data were retrieved from 12 European Countries and expressed as defined daily doses per 1,000 inhabitants per day (DID). Results Thirty-five antipsychotics met at least one criterium: 9 agents were classified in Group A (amisulpride, chlorpromazine, clozapine, cyamemazine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). In 2010, the overall exposure to antipsychotics varied from 5.94 DID (Estonia) to 13.99 (France, 2009). Considerable increment of Group A agents was found in several Countries (+3.47 in France): the exposure to olanzapine increased across all Countries (+1.84 in France) and peaked 2.96 in Norway; cyamemazine was typically used only in France (2.81 in 2009). Among Group B drugs, levomepromazine peaked 3.78 (Serbia); fluphenazine 1.61 (Slovenia). Conclusions This parallel approach through spontaneous reporting and drug utilization analyses highlighted drug- and
Federer, Callie; Yoo, Minjae
Abstract Drug adverse events (AEs) are a major health threat to patients seeking medical treatment and a significant barrier in drug discovery and development. AEs are now required to be submitted during clinical trials and can be extracted from ClinicalTrials.gov (https://clinicaltrials.gov/), a database of clinical studies around the world. By extracting drug and AE information from ClinicalTrials.gov and structuring it into a database, drug-AEs could be established for future drug development and repositioning. To our knowledge, current AE databases contain mainly U.S. Food and Drug Administration (FDA)-approved drugs. However, our database contains both FDA-approved and experimental compounds extracted from ClinicalTrials.gov. Our database contains 8,161 clinical trials of 3,102,675 patients and 713,103 reported AEs. We extracted the information from ClinicalTrials.gov using a set of python scripts, and then used regular expressions and a drug dictionary to process and structure relevant information into a relational database. We performed data mining and pattern analysis of drug-AEs in our database. Our database can serve as a tool to assist researchers to discover drug-AE relationships for developing, repositioning, and repurposing drugs. PMID:27631620
Federer, Callie; Yoo, Minjae; Tan, Aik Choon
Drug adverse events (AEs) are a major health threat to patients seeking medical treatment and a significant barrier in drug discovery and development. AEs are now required to be submitted during clinical trials and can be extracted from ClinicalTrials.gov ( https://clinicaltrials.gov/ ), a database of clinical studies around the world. By extracting drug and AE information from ClinicalTrials.gov and structuring it into a database, drug-AEs could be established for future drug development and repositioning. To our knowledge, current AE databases contain mainly U.S. Food and Drug Administration (FDA)-approved drugs. However, our database contains both FDA-approved and experimental compounds extracted from ClinicalTrials.gov . Our database contains 8,161 clinical trials of 3,102,675 patients and 713,103 reported AEs. We extracted the information from ClinicalTrials.gov using a set of python scripts, and then used regular expressions and a drug dictionary to process and structure relevant information into a relational database. We performed data mining and pattern analysis of drug-AEs in our database. Our database can serve as a tool to assist researchers to discover drug-AE relationships for developing, repositioning, and repurposing drugs.
The classical definition of clinical pharmacology is the study or the knowledge of the effects of drugs in humans. The activities of a clinical pharmacologist can vary from country to country, usually ranging from involvement in clinical trials, especially fundamental pharmacodynamic studies, to studies of pharmacokinetics and drug metabolism, to pharmacogenetics. Most clinical pharmacologists outside industry are in hospitals or university hospitals and research centres. In addition to research, this implies teaching of clinical pharmacology, and interacting with other medical staff: in the field of research, giving advice on clinical trials methodology and often managing a therapeutic drug monitoring centre. Some clinical pharmacologists have clinical departments with beds or consulting offices. Can there be another role for the clinical pharmacologist that would increase his or her usefulness for the medical community? Adverse drug reactions (ADRs) are remarkably complex events, related to drug effects, patient characteristics (background diseases, genetics), and drug/disease interactions. Evaluation of ADRs requires understanding of drug mechanisms and interactions, and of disease diagnostics, especially in the discussion of alternative diagnoses. This implies expertise as a pharmacologist and a clinician. In addition, because not all adverse reactions or interactions are in the Summary of Product Characteristics, and because problems arise long before they report in the literature, it is necessary for the clinical pharmacologist to have knowledge of ongoing regulatory processes, in addition to having access to the published literature. Helping clinicians cope with individual patient problems will also improve the clinical pharmacologist's integration into the healthcare process.
Shang, Ning; Xu, Hua; Rindflesch, Thomas C.; Cohen, Trevor
Pharmacovigilance involves continually monitoring drug safety after drugs are put to market. To aid this process; algorithms for the identification of strongly correlated drug/adverse drug reaction (ADR) pairs from data sources such as adverse event reporting systems or Electronic Health Records have been developed. These methods are generally statistical in nature, and do not draw upon the large volumes of knowledge embedded in the biomedical literature. In this paper, we investigate the ability of scalable Literature Based Discovery (LBD) methods to identify side effects of pharmaceutical agents. The advantage of LBD methods is that they can provide evidence from the literature to support the plausibility of a drug/ ADR association, thereby assisting human review to validate the signal, which is an essential component of pharmacovigilance. To do so, we draw upon vast repositories of knowledge that has been extracted from the biomedical literature by two Natural Language Processing tools, MetaMap and SemRep. We evaluate two LBD methods that scale comfortably to the volume of knowledge available in these repositories. Specifically, we evaluate Reflective Random Indexing (RRI), a model based on concept-level co-occurrence, and Predication-based Semantic Indexing (PSI), a model that encodes the nature of the relationship between concepts to support reasoning analogically about drug-effect relationships. An evaluation set was constructed from the Side Effect Resource 2 (SIDER2), which contains known drug/ADR relations, and models were evaluated for their ability to “rediscover” these relations. In this paper, we demonstrate that both RRI and PSI can recover known drug-adverse event associations. However, PSI performed better overall, and has the additional advantage of being able to recover the literature underlying the reasoning pathways it used to make its predictions. PMID:25046831
... adverse effects. Any person using a microbial pesticide in small-scale testing covered by this subpart who... potential unreasonable adverse effects. 172.57 Section 172.57 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Notification for...
... adverse effects. Any person using a microbial pesticide in small-scale testing covered by this subpart who... potential unreasonable adverse effects. 172.57 Section 172.57 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Notification for...
... adverse effects. Any person using a microbial pesticide in small-scale testing covered by this subpart who... potential unreasonable adverse effects. 172.57 Section 172.57 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Notification for...
Petrova, Guenka; Stoimenova, Assena; Dimitrova, Maria; Kamusheva, Maria; Petrova, Daniela; Georgiev, Ognian
Introduction: Adverse drug reactions can cause increased morbidity and mortality, and therefore information needs to be studied systematically. Little is known about the adverse drug reactions for chronic obstructive pulmonary disease therapy. The goal of this study is to assess the expectedness, seriousness and severity of adverse drug reactions during chronic obstructive pulmonary disease therapy based on their reporting in the national pharmacovigilance system. Methods: This was a prospective, observational, 1-year, real-life study about the pharmacotherapy of a sample of 390 chronic obstructive pulmonary disease patients. Prescribed medicines were systematized and national pharmacovigilance databases were searched for reported adverse drug reactions. The expectedness was evaluated through the review of the summary of product characteristics, the seriousness was evaluated by the clinicians based on the life threatening nature of the adverse drug reactions, and the severity was evaluated through Hartwig’s Severity Assessment Scale. Descriptive statistics of the reported adverse drug reactions was performed and the relative risk of developing an adverse drug reaction with all international non-proprietary names included in the analysis was calculated. Results: Results confirm that the chronic obstructive pulmonary disease is a disease with high appearance of adverse drug reactions, and causes many additional costs to the healthcare system. Unexpected and severe adverse drug reactions are frequent. A total of 4.8% of adverse drug reactions were evaluated as life threatening. Majority of adverse drug reactions are classified in Levels 1 (32.6%), 2 (26.4%) and 3 (19%) according to Hartwig’s Severity Assessment Scale. Approximately 22% of reported adverse drug reactions affect people’s everyday life to a greater extent and require additional therapy which might further increase the risk. The relative risk of developing an adverse drug reaction was highest for
Interrater agreement of two adverse drug reaction causality assessment methods: A randomised comparison of the Liverpool Adverse Drug Reaction Causality Assessment Tool and the World Health Organization-Uppsala Monitoring Centre system
Mehta, Ushma; Rossiter, Dawn P.; Maartens, Gary; Cohen, Karen
Introduction A new method to assess causality of suspected adverse drug reactions, the Liverpool Adverse Drug Reaction Causality Assessment Tool (LCAT), showed high interrater agreement when used by its developers. Our aim was to compare the interrater agreement achieved by LCAT to that achieved by another causality assessment method, the World Health Organization-Uppsala Monitoring Centre system for standardised case causality assessment (WHO-UMC system), in our setting. Methods Four raters independently assessed adverse drug reaction causality of 48 drug-event pairs, identified during a hospital-based survey. A randomised design ensured that no washout period was required between assessments with the two methods. We compared the methods’ interrater agreement by calculating agreement proportions, kappa statistics, and the intraclass correlation coefficient. We identified potentially problematic questions in the LCAT by comparing raters’ responses to individual questions. Results Overall unweighted kappa was 0.61 (95% CI 0.43 to 0.80) on the WHO-UMC system and 0.27 (95% CI 0.074 to 0.46) on the LCAT. Pairwise unweighted Cohen kappa ranged from 0.33 to 1.0 on the WHO-UMC system and from 0.094 to 0.71 on the LCAT. The intraclass correlation coefficient was 0.86 (95% CI 0.74 to 0.92) on the WHO-UMC system and 0.61 (95% CI 0.39 to 0.77) on the LCAT. Two LCAT questions were identified as significant points of disagreement. Discussion We were unable to replicate the high interrater agreement achieved by the LCAT developers and instead found its interrater agreement to be lower than that achieved when using the WHO-UMC system. We identified potential reasons for this and recommend priority areas for improving the LCAT. PMID:28235001
Genetically modified crops have the potential to eliminate hunger and starvation in millions of people, especially in developing countries because the genetic modification can produce large amounts of foods that are more nutritious. Large quantities are produced because genetically modified crops are more resistant to pests and drought. They also contain greater amounts of nutrients, such as proteins and vitamins. However, there are concerns about the safety of genetically modified crops. The concerns are that they may contain allergenic substances due to introduction of new genes into crops. Another concern is that genetic engineering often involves the use of antibiotic-resistance genes as "selectable markers" and this could lead to production of antibiotic-resistant bacterial strains that are resistant to available antibiotics. This would create a serious public health problem. The genetically modified crops might contain other toxic substances (such as enhanced amounts of heavy metals) and the crops might not be "substantially equivalent" in genome, proteome, and metabolome compared with unmodified crops. Another concern is that genetically modified crops may be less nutritious; for example, they might contain lower amounts of phytoestrogens, which protect against heart disease and cancer. The review of available literature indicates that the genetically modified crops available in the market that are intended for human consumption are generally safe; their consumption is not associated with serious health problems. However, because of potential for exposure of a large segment of human population to genetically modified foods, more research is needed to ensure that the genetically modified foods are safe for human consumption.
Giofrè, Chiara; Scicchitano, Francesca; Palleria, Caterina; Mazzitello, Carmela; Ciriaco, Miriam; Gallelli, Luca; Paletta, Laura; Marrazzo, Giuseppina; Leporini, Christian; Ventrice, Pasquale; Carbone, Claudia; Saullo, Francesca; Rende, Pierandrea; Menniti, Michele; Mumoli, Laura; Chimirri, Serafina; Patanè, Marinella; Esposito, Stefania; Cilurzo, Felisa; Staltari, Orietta; Russo, Emilio; De Sarro, Giovambattista
Introduction: Pharmacovigilance (PV) is designed to monitor drugs continuously after their commercialization, assessing and improving their safety profile. The main objective is to increase the spontaneous reporting of adverse drug reactions (ADRs), in order to have a wide variety of information. The Italian Drug Agency (Agenzia Italiana del Farmaco [AIFA]) is financing several projects to increase reporting. In Calabria, a PV information center has been created in 2010. Materials and Methods: We obtained data using the database of the National Health Information System AIFA relatively to Italy and Calabria in the year 2012. Descriptive statistics were performed to analyze the ADRs. Results: A total number of 461 ADRs have been reported in the year 2012 with an increase of 234% compared with 2011 (138 reports). Hospital doctors are the main source of this reporting (51.62%). Sorafenib (Nexavar®), the combination of amoxicillin/clavulanic acid and ketoprofen represent the drugs most frequently reported causing adverse reactions. Adverse events in female patients (61.83%) were more frequently reported, whereas the age groups “41-65” (39.07%) and “over 65” (27.9%) were the most affected. Conclusions: Calabria has had a positive increase in the number of ADRs reported, although it has not yet reached the gold standard set by World Health Organization (about 600 reports), the data have shown that PV culture is making inroads in this region and that PV projects stimulating and increasing PV knowledge are needed. PMID:24347984
Bousquet, Cédric; Sadou, Éric; Souvignet, Julien; Jaulent, Marie-Christine; Declerck, Gunnar
Although MedDRA has obvious advantages over previous terminologies for coding adverse drug reactions and discovering potential signals using data mining techniques, its terminological organization constrains users to search terms according to predefined categories. Adding formal definitions to MedDRA would allow retrieval of terms according to a case definition that may correspond to novel categories that are not currently available in the terminology. To achieve semantic reasoning with MedDRA, we have associated formal definitions to MedDRA terms in an OWL file named OntoADR that is the result of our first step for providing an "ontologized" version of MedDRA. MedDRA five-levels original hierarchy was converted into a subsumption tree and formal definitions of MedDRA terms were designed using several methods: mappings to SNOMED-CT, semi-automatic definition algorithms or a fully manual way. This article presents the main steps of OntoADR conception process, its structure and content, and discusses problems and limits raised by this attempt to "ontologize" MedDRA.
Hochberg, Alan M; Hauben, Manfred; Pearson, Ronald K; O'Hara, Donald J; Reisinger, Stephanie J
The optimum timing of drug safety data mining for a new drug is uncertain. The objective of this study was to compare cumulative data mining versus mining with sliding time windows. Adverse Event Reporting System data (2001-2005) were studied for 27 drugs. A literature database was used to evaluate signals of disproportionate reporting (SDRs) from an urn model data-mining algorithm. Data mining was applied cumulatively and with sliding time windows from 1 to 4 years in width. Time from SDR generation to the appearance of a publication describing the corresponding adverse event was calculated. Cumulative data mining and 1- to 2-year sliding windows produced the most SDRs for recently approved drugs. In the first postmarketing year, data mining produced SDRs an average of 800 days in advance of publications regarding the corresponding drug-event combination. However, this timing advantage reduced to zero by year 4. The optimum window width for sliding windows should increase with time on the market. Data mining may be most useful for early signal detection during the first 3 years of a drug's postmarketing life. Beyond that, it may be most useful for supporting or weakening hypotheses.
Rosli, Rosliana; Abd Aziz, Noorizan; Manan, Mohamed Mansor
Background Spontaneous reporting on adverse drug reactions (ADR) has been established in Malaysia since 1987, and although these reports are monitored by the Malaysia drug monitoring authority, the National Pharmaceutical Control Bureau, information about ADRs in the paediatric patient population still remains unexplored. The aims of this study, therefore, were to characterize the ADRs reported in respect to the Malaysian paediatric population and to relate the data to specific paediatric age groups. Methods Data on all ADRs reported to the National Pharmaceutical Control Bureau between 2000 and 2013 for individuals aged from birth to 17 years old were analysed with respect to age and gender, type of reporter, suspected medicines (using the Anatomical Therapeutic Chemical classification), category of ADR (according to system organ class) as well as the severity of the ADR. Results In total, 11,523 ADR reports corresponding to 22,237 ADRs were analysed, with half of these reporting one ADR per report. Vaccines comprised 55.7% of the 11,523 ADR reports with the remaining being drug related ADRs. Overall, 63.9% of ADRs were reported for paediatric patients between 12 and 17 years of age, with the majority of ADRs reported in females (70.7%). The most common ADRs reported were from the following system organ classes: application site disorders (32.2%), skin and appendages disorders (20.6%), body as a whole general disorders (12.8%) and central and peripheral nervous system disorders (11.2%). Meanwhile, ADRs in respect to anti-infectives for systemic use (2194/5106; 43.0%) were the most frequently reported across all age groups, followed by drugs from the nervous system (1095/5106; 21.4%). Only 0.28% of the ADR cases were reported as fatal. A large proportion of the reports were received from healthcare providers in government health facilities. Discussion ADR reports concerning vaccines and anti-infectives were the most commonly reported in children, and are mainly
Chan, Esther W; Liu, Kirin Q L; Chui, Celine S L; Sing, Chor-Wing; Wong, Lisa Y L; Wong, Ian C K
It is recognised that randomised controlled trials are not feasible for capturing rare adverse events. There is an increasing trend towards observational research methodologies using large population-based health databases. These databases offer more scope for adequate sample sizes, allowing for comprehensive patient characterisation and assessment of the associated factors. While direct causality cannot be established and confounders cannot be ignored, databases present an opportunity to explore and quantify rare events. The use of databases for the detection of rare adverse events in the following conditions, sudden death associated with attention deficit hyperactivity disorder (ADHD) treatment, retinal detachment associated with the use of fluoroquinolones and toxic epidermal necrolysis associated with drug exposure, are discussed as examples. In general, rare adverse events tend to have immediate and important clinical implications and may be life-threatening. An understanding of the causative factors is therefore important, in addition to the research methodologies and database platforms that enable the undertaking of the research. PMID:25060360
Wang, Chen; Zimmermann, Michael T; Prodduturi, Naresh; Chute, Christopher G; Jiang, Guoqian
Adverse drug events (ADEs) are a critical factor for selecting cancer therapy options. The underlying molecular mechanisms of ADEs associated with cancer therapy drugs may overlap with their antineoplastic mechanisms; an aspect of toxicity. In the present study, we develop a novel knowledge-driven approach that provides an ADE-based stratification (ADEStrata) of tumor mutations. We demonstrate clinical utility of the ADEStrata approach through performing a case study of breast invasive carcinoma (BRCA) patients receiving aromatase inhibitors (AI) from The Cancer Genome Atlas (TCGA) (n=212), focusing on the musculoskeletal adverse events (MS-AEs). We prioritized somatic variants in a manner that is guided by MS-AEs codified as 6 Human Phenotype Ontology (HPO) terms. Pathway enrichment and hierarchical clustering of prioritized variants reveals clusters associated with overall survival. We demonstrated that the prediction of per-patient ADE propensity simultaneously identifies high-risk patients experiencing poor outcomes. In conclusion, the ADEStrata approach could produce clinically and biologically meaningful tumor subtypes that are potentially predictive of the drug response to the cancer therapy drugs.
Mudzviti, Tinashe; Maponga, Charles C.; Khoza, Star; Ma, Qing; Morse, Gene D.
Background. The main objective was to determine the impact of herbal drug use on adverse drug reactions in patients on antiretroviral therapy (ART). Methodology. Patients receiving first-line ART from the national roll-out program participated in this cross-sectional study. Participants were interviewed and a data collection sheet was used to collect information from the corresponding medical record. Results. The majority (98.2%) of participants were using at least one herbal drug together with ART. The most common herbal remedies used were Allium Sativum (72.7%), Bidens pilosa (66.0%), Eucalyptus globulus (52.3%), Moringa oleifera (44.1%), Lippia javanica (36.3%), and Peltoforum africanum (34.3%). Two indigenous herbs, Musakavakadzi (OR = 0.25; 95% CI 0.076–0.828) and Peltoforum africanum (OR = 0.495; 95% CI 0.292–0.839) reduced the occurrence of adverse drug events. Conclusions. The use of herbal drugs is high in the HIV-infected population and there is need for pharmacovigilance programs to recognize the role they play in altering ADR profiles. PMID:22506106
Faich, G A; Castle, W; Bankowski, Z
A method for standardized postapproval adverse drug reaction (ADR) reporting has been developed and implemented by seven multinational pharmaceutical manufacturers and six regulatory authorities. This is based on a set of uniform definitions, procedures and a single reporting form, and has been demonstrated to be useful and effective. When regulators and manufacturers develop requirements and systems for ADR reporting they should consider adapting this method.
Harpaz, R; DuMouchel, W; Shah, N H; Madigan, D; Ryan, P; Friedman, C
An important goal of the health system is to identify new adverse drug events (ADEs) in the postapproval period. Datamining methods that can transform data into meaningful knowledge to inform patient safety have proven essential for this purpose. New opportunities have emerged to harness data sources that have not been used within the traditional framework. This article provides an overview of recent methodological innovations and data sources used to support ADE discovery and analysis.
Background Many biomedical relation extraction systems are machine-learning based and have to be trained on large annotated corpora that are expensive and cumbersome to construct. We developed a knowledge-based relation extraction system that requires minimal training data, and applied the system for the extraction of adverse drug events from biomedical text. The system consists of a concept recognition module that identifies drugs and adverse effects in sentences, and a knowledge-base module that establishes whether a relation exists between the recognized concepts. The knowledge base was filled with information from the Unified Medical Language System. The performance of the system was evaluated on the ADE corpus, consisting of 1644 abstracts with manually annotated adverse drug events. Fifty abstracts were used for training, the remaining abstracts were used for testing. Results The knowledge-based system obtained an F-score of 50.5%, which was 34.4 percentage points better than the co-occurrence baseline. Increasing the training set to 400 abstracts improved the F-score to 54.3%. When the system was compared with a machine-learning system, jSRE, on a subset of the sentences in the ADE corpus, our knowledge-based system achieved an F-score that is 7 percentage points higher than the F-score of jSRE trained on 50 abstracts, and still 2 percentage points higher than jSRE trained on 90% of the corpus. Conclusion A knowledge-based approach can be successfully used to extract adverse drug events from biomedical text without need for a large training set. Whether use of a knowledge base is equally advantageous for other biomedical relation-extraction tasks remains to be investigated. PMID:24593054
Harpaz, Rave; DuMouchel, William; Shah, Nigam H.; Madigan, David; Ryan, Patrick; Friedman, Carol
Introduction Discovery of new adverse drug events (ADEs) in the post-approval period is an important goal of the health system. Data mining methods that can transform data into meaningful knowledge to inform patient safety have proven to be essential. New opportunities have emerged to harness data sources that have not been used within the traditional framework. This article provides an overview of recent methodological innovations and data sources used in support of ADE discovery and analysis. PMID:22549283
Kanjanarat, Penkarn; Winterstein, Almut G; Johns, Thomas E; Hatton, Randy C; Gonzalez-Rothi, Ricardo; Segal, Richard
A literature review was conducted to identify the drug classes, types of errors, and types of adverse outcomes related to preventable adverse drug events (pADEs). Studies were identified by keyword search of MEDLINE and International Pharmaceutical Abstracts and by a manual search. The search was limited to peer-reviewed literature reporting pADEs in hospitalized patients and the frequencies of at least one pADE characteristic. The frequencies of pADEs and their characteristics were summarized using median and range. Ten studies published between 1994 and 2001 were included in the review. The reported median frequency of pADEs was 1.8% (range, 1.3-7.8%), and the median preventability rate of ADEs in the hospitals was 35.2% (range, 18.7-73.2%). Cardiovascular drugs were implicated for 17.9% of pADEs (range, 4.3-28.1%). Most pADEs occurred in the prescribing stage of the medication-use process and were dose related. Inappropriate prescribing decisions and patient monitoring were the most frequently identified causes of pADEs. The most common adverse outcomes were allergic reactions, hepatic or renal problems, cardiovascular problems, hematologic problems and bleeding, and central nervous system problems. Frequently reported examples of pADEs included antihypertensive overdose associated with bradycardia or hypotension, antiinfectives prescribed despite a history of allergy, warfarin overdose and inappropriate monitoring resulting in hemorrhage, and opioid overdose or underdose associated with respiratory depression or poor pain control, respectively. Despite the heterogeneity of pADEs, the results of this literature review suggest that a few types of drugs, errors, and adverse outcomes constitute a substantial proportion of pADEs. Targeting these high-priority areas could significantly reduce the overall frequency of pADEs.
Handler, Steven M.; Boyce, Richard D.; Ligons, Frank; Perera, Subashan; Nace, David A.; Hochheiser, Harry
Objective Although mobile devices equipped with drug reference software may help prevent adverse drug events (ADEs) in the nursing home (NH) by providing medication information at the point-of-care, little is known about their use and perceived benefits. The goal of this study was to conduct a survey of a nationally representative sample of NH physicians to quantify the use and perceived benefits of mobile devices in preventing ADEs in the NH setting. Design/Setting/Participants We surveyed physicians who attended the 2010 the AMDA Annual Symposium about their use of mobile devices and beliefs about the effectiveness of drug reference software in preventing ADEs. Results The overall net valid response rate was 70% (558/800) with 42% (236/558) using mobile devices to assist with prescribing in the NH. Physicians with ≤15 years clinical experience were 67% more likely to be mobile device users, compared to those with >15 years of clinical experience (odds ratio=1.68; 95% confidence interval=1.17-2.41; p=0.005). For those who used a mobile device to assist with prescribing, almost all (98%) reported performing an average of one or more drug look-ups per day, performed an average of 1-2 lookups per day for potential drug-drug interactions (DDIs), and most (88%) believed that drug reference software had helped to prevent at least one potential ADE in the preceding four-week period. Conclusions The proportion of NH physicians who use mobile devices with drug reference software, while significant, is lower than in other clinical environments. Our results suggest that NH physicians who use mobile devices equipped with drug reference software believe they are helpful for reducing ADEs. Further research is needed to better characterize the facilitators and barriers to adoption of the technology in the NH and its precise impact on NH ADEs. PMID:24094901
Fan, Kai; Sun, Xingzhi; Tao, Ying; Xu, Linhao; Wang, Chen; Mao, Xianling; Peng, Bo; Pan, Yue
Post-marketing pharmacovigilance is important for public health, as many Adverse Drug Events (ADEs) are unknown when those drugs were approved for marketing. However, due to the large number of reported drugs and drug combinations, detecting ADE signals by mining these reports is becoming a challenging task in terms of computational complexity. Recently, a parallel programming model, MapReduce has been introduced by Google to support large-scale data intensive applications. In this study, we proposed a MapReduce-based algorithm, for common ADE detection approach, Proportional Reporting Ratio (PRR), and tested it in mining spontaneous ADE reports from FDA. The purpose is to investigate the possibility of using MapReduce principle to speed up biomedical data mining tasks using this pharmacovigilance case as one specific example. The results demonstrated that MapReduce programming model could improve the performance of common signal detection algorithm for pharmacovigilance in a distributed computation environment at approximately liner speedup rates.
Olivier, Pascale; Caron, Jacques; Haramburu, Françoise; Imbs, Jean-Louis; Jonville-Béra, Annie-Pierre; Lagier, Georges; Sgro, Catherine; Vial, Thierry; Montastruc, Jean-Louis; Lapeyr-Mestre, Maryse
Adverse drug reactions (ADRs) have been recognised as an important cause of hospital admission. Most of these drug-related admissions were expected ADRs and, thus, partly preventable. However, as far as we know, the assessment of the preventability of ADRs was addressed in only two studies performed in France. In contrast, several other studies have been performed, mainly in the USA, and using different methods of assessing preventability. None of these methods were clearly evaluated with regard to reproducibility, validity or relevance. The purpose of this study was to initiate the validation of a French preventability scale. Here, we propose the first two phases of validation: the content validity and reliability of the scale. A working group of pharmacovigilance experts has been specifically established for this purpose. The content validity was assessed by collecting items representative of preventability. The choice and the formulation of items and a proposal of a score (global and for each item) were adopted after the consensus of the experts. A definitive version of the ADR preventability scale was used for the assessment of reliability. During the second phase, experts independently tested the new scale from observations of ADRs (49 central nervous system haemorrhages with antivitamine K). The concordance of the experts' judgements was calculated using two statistical methods (Kappa statistic and correlation coefficient). The content validity phase was performed during several workshops where experts discussed the choice and formulation of the best items. We decided to construct a scale with a small number of items, allowing a rapid evaluation of the preventability of ADRs. On the basis of a global score, four categories of preventability of ADRs ("preventable", "potentially preventable", "unclassable", "not preventable" ADRs) were proposed. The agreement of experts regarding the global score was low, with a poor correlation coefficient value (coefficient
Balmer, Nina V; Leist, Marcel
Prenatal exposure to environmental chemicals or drugs has been associated with functional or structural deficits and the development of diseases in later life. For example, developmental neurotoxicity (DNT) is triggered by lead, and this compound may predispose to neurodegenerative diseases in later life. The molecular memory for such late consequences of early exposure is not known, but epigenetic mechanisms (modification of the chromatin structure) could take this role. Examples and underlying mechanisms have been compiled here for the field of DNT. Moreover, we addressed the question as to what readout is suitable for addressing drug memory effects. We summarize how complex developmental processes can be modelled in vitro by using the differentiation of human stem cells. Although cellular models can never replicate the final human DNT phenotype, they can model the adverse effect that a chemical has on key biological processes essential for organ formation and function. Highly information-rich transcriptomics data may inform on these changes and form the bridge from in vitro models to human prediction. We compiled data showing that transcriptome analysis can indicate toxicity patterns of drugs. A crucial question to be answered in our systems is when and how transcriptome changes indicate adversity (as opposed to transient adaptive responses), and how drug-induced changes are perpetuated over time even after washout of the drug. We present evidence for the hypothesis that changes in the histone methylation pattern could represent the persistence detector of an early insult that is transformed to an adverse effect at later time-points in life.
Jha, Anshu Kumar; Gadgade, Akash; Shenoy, Ashok K.; Chowta, Mukta N.; Ramapuram, John T.
Context: The advancement and development of new drugs and treatment strategies increase the risk of unusual Adverse Events (AEs) in HIV patients. Aims: The objective of our study was to assess the incidence, types and nature of AEs in HIV positive subjects. Settings and Design: Patients with WHO stage IV disease irrespective of the CD4 cell count, or WHO stage III disease with a CD4 cell count <350 cell/cu. Mm, or, WHO stage I or II disease with a CD4 cell count of <200 cells/cu. mm, and on prior anti-retroviral therapy for not more than six months preceding the observation date, were included in the study. After initiation of therapy, the patients were examined for the occurrence any adverse events including the type and severity, or any other abnormal laboratory findings. Causality assessment of the adverse events was done using the Naranjo's scale. Results: Out of 327 patients studied prospectively, 43 patients developed AEs. Out of these, 23 (53.5%) were males and 20 (46.5%) were females. A total of 53 (16.21%) AEs were reported. Antitubercular drugs caused the maximum AEs (28.3%) followed by zidovudine (20.7%), nevirapine (15.0%) and efavirenz (5.6%). Stavudine, ethambutol, sulfamethoxazole and trimethoprim, and atazanavir were also responsible for 3.7% of AEs individually. Causality assessment done according to the Naranjo's scale revealed that 66.04% AEs were ‘probable’ and 33.96% were ‘possible’. Conclusions: Anemia, hepatitis and dermatological adverse effects are the most common AEs. Antitubercular drugs contributed significantly for the incidence of AEs in these patients. Frequency of AEs was slightly more in males compared to females. PMID:25657900
Hosoya, Ryuichiro; Ishii-Nozawa, Reiko; Kagaya, Hajime
Hiccups are occasionally experienced by most individuals. Although hiccups are not life-threatening, they may lead to a decline in quality of life. Previous studies showed that hiccups may occur as an adverse effect of certain medicines during chemotherapy. Furthermore, a male dominance in hiccups has been reported. However, due to the limited number of studies conducted on this phenomenon, debate still surrounds the few factors influencing hiccups. The present study aimed to investigate the influence of medicines and patient characteristics on hiccups using a large-sized adverse drug event report database and, specifically, the Japanese Adverse Drug Event Report (JADER) database. Cases of adverse effects associated with medications were extracted from JADER, and Fisher’s exact test was performed to assess the presence or absence of hiccups for each medication. In a multivariate analysis, we conducted a multiple logistic regression analysis using medication and patient characteristic variables exhibiting significance. We also examined the role of dexamethasone in inducing hiccups during chemotherapy. Medicines associated with hiccups included dexamethasone, levofolinate, fluorouracil, oxaliplatin, carboplatin, and irinotecan. Patient characteristics associated with hiccups included a male gender and greater height. The combination of anti-cancer agent and dexamethasone use was noted in more than 95% of patients in the dexamethasone-use group. Hiccups also occurred in patients in the anti-cancer agent-use group who did not use dexamethasone. Most of the medications that induce hiccups are used in chemotherapy. The results of the present study suggest that it is possible to predict a high risk of hiccups using patient characteristics. We confirmed that dexamethasone was the drug that has the strongest influence on the induction of hiccups. However, the influence of anti-cancer agents on the induction of hiccups cannot be denied. We consider the results of the
Tian, Xiao-Yin; Liu, Bing; Shi, Hao; Zhao, Zi-Ran; Zhou, Xi-Ping; Zhang, Tao; Sun, Qiu-Ning; Zuo, Ya-Gang
Cutaneous adverse drug reactions (ADRs) are common. However, no prospective study assessing cutaneous ADRs is available for Chinese populations. This study aimed to assess the incidence, manifestations, causative drugs, and other factors related to cutaneous ADRs. A total of 22,866 inpatients were surveyed prospectively from January to April 2012 at the Peking Union Medical College Hospital. Only cutaneous ADRs induced by systemic drugs were considered. Fifty cases were confirmed as cutaneous ADRs, for an estimated incidence of 2.2 per 1000 during this period (95 % confidence interval 1.6-2.8). Cases of cutaneous ADRs comprised 69 % females, while 63 % of all inpatients were female (χ (2) = 0.641, P = 0.427). The department of infectious diseases was the most frequently involved department. Morbilliform exanthema (40 %) was the most frequent cutaneous ADR, followed by urticaria (23.1 %). Anti-infection drugs (36.9 %) caused most cases of cutaneous ADRs, followed by iodinated contrast media (ICM, 18.5 %) and non-steroidal anti-inflammatory drugs (NSAIDs, 18.5 %). The most frequently associated disorders were cancer (24 %), infection (22 %), cardiovascular and cerebrovascular diseases (20 %), and autoimmune diseases (18 %). In this first prospective study assessing the incidence of cutaneous ADRs in China, anti-infection drugs were the most commonly involved drugs, followed by ICM and NSAIDs. No evidence of increased cutaneous ADR incidence in AIDS or SLE patients was observed. Our findings indicate that cancer and its treatments were often related to cutaneous ADRs in China.
Stadler, Th; Bader, M; Uckert, S; Staehler, M; Becker, A; Stief, C G
Sexual dysfunctions (SD) are adverse effects of common drug therapies that have rarely been considered in investigations so far. Possibly it is barely known that many widespread and frequently prescribed medications and drug therapies can have significant impact on vascular and nerval processes as well as on endocrinologic and psychoneuroendocrinologic systems and therefore can influence sexual functions. Impotence and disorders of the erectile function can mainly be caused by antidopaminergic mechanisms, whereas ejaculatory disorders and anorgasmia often can be explained by antiserotoninergic effects. Anticholinergic and adrenoloytic agents can also cause a particular impairment of erectile functions. The following considerations will show that the detection and treatment of SD (also in women!) should be given much more attention since drug-induced SDs occur predominantly in indications where a SD itself can be a symptom of the disease.
Finkelstein, Joseph; Chen, Qinlang; Adams, Hayden; Friedman, Carol
Academic literature provides rich and up-to-date information concerning adverse drug reactions (ADR), but it is time consuming and labor intensive for physicians to obtain information of ADRs from academic literature because they would have to generate queries, review retrieved articles and summarize the results. In this study, a method is developed to automatically detect and summarize ADRs from journal articles, rank them and present them to physicians in a user-friendly interface. The method studied ADRs for 6 drugs and returned on average 4.8 ADRs that were correct. The results demonstrated this method was feasible and effective. This method can be applied in clinical practice for assisting physicians to efficiently obtain information about ADRs associated with specific drugs. Automated summarization of ADR information from recent publications may facilitate translation of academic research into actionable information at point of care. PMID:27570654
Scoyni, R M; Aiello, L; Trani, I; Felli, B; Masin, A M R; Camponi, V; Dignazio, L; Cortese, M; Pacitti, M T; Carratelli, D; Morocutti, C
We report a brief discussion on a clinical case of a female patient, 85 years old, affected by severe cognitive impairment and chronic obstructive pulmonary disease (COPD). The patient was not taking drugs at home (apart from promazine: 10 drops when necessary to control her behavioral diseases). A previous neuropsychological evaluation had shown a severe cognitive impairment MMSE=16/30; ADL=3/6; IADL=0/8) due to multiple brain ischemic areas (confirmed in 2003 by MRI neuroimaging). When the patient was admitted to our center she was able to perform some basic activities of daily living such as eating and walking and was not too confused. She was included in cognitive rehabilitation groups. Since she showed signs of Parkinsonism, a therapy based on omeprazol 20mg, acetylsalicylic acid, donepezil 10mg, pramipexol 0.18 mg, nimodipine 10 drops, levodopa+carbidopa 100/25mg was started. A few days later she became sleepy during daytime and, once, she lost her balance and fell. She was not self-sufficient any more. At first this was attributed to a lung infection that the patient had, but her state continue after the infection was completely cured with appropriate antibiotics therapy. At that point an adverse drug reaction was suspected and therapy with pramipexol 0.18 mg was interrupted. In a few days the patient regained her previous level of consciousness and self-sufficiency. We consider this a typical case of complex management in a patient with dementia and comorbidity in which adverse drug reactions can play an important role in lowering the level of cognitive functions. In this case the relationship with the family of the patient was made difficult by the attitude of the patient's daughter who decided, after the onset of the adverse drug reaction, to interrupt her mother's stay in our center even at risk of the worst consequences.
Dorr, David A.; Burdon, Rachel; West, Dennis P.; Lagman, Jennifer; Georgopoulos, Christina; Belknap, Steven M.; McKoy, June M.; Djulbegovic, Benjamin; Edwards, Beatrice J.; Weitzman, Sigmund A.; Boyle, Simone; Tallman, Martin S.; Talpaz, Moshe; Sartor, Oliver; Bennett, Charles L.
Purpose Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB. Experimental Design sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed. Results Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P < 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P < 0.05). Some key clinical information was discrepant between the two sources. Conclusions The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients. PMID:19458059
... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Flagging of studies for potential... Provisions § 161.34 Flagging of studies for potential adverse effects. (a) Any person who submits a study of... registration, or to satisfy a requirement imposed under FIFRA sec. 3(c)(2)(B), must submit with the study...
... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Flagging of studies for potential... Provisions § 161.34 Flagging of studies for potential adverse effects. (a) Any person who submits a study of... registration, or to satisfy a requirement imposed under FIFRA sec. 3(c)(2)(B), must submit with the study...
... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Flagging of studies for potential... Provisions § 161.34 Flagging of studies for potential adverse effects. (a) Any person who submits a study of... registration, or to satisfy a requirement imposed under FIFRA sec. 3(c)(2)(B), must submit with the study...
Seebeck, J; Wulf, F; Sachs, B
In Germany, reports on adverse drug reactions (ADRs) are centrally collected and analyzed by the Federal Institute for Drugs and Medical Devices (BfArM). During routine analysis of ADR reports related to the antiobesity drug sibutramine, we repeatedly observed descriptions of its label*-inconsistent use (*European Summary of Product Characteristics (SmPC)). In order to quantify this observation, we analyzed all sibutramine-related ADR reports received by the BfArM so far. Using the same data source, we further analyzed the effect of a Dear Doctor Letter (DDL) which was distributed in 2002 in order to reinforce the label-consistent use of sibutramine. Out of a total of 170 identified reports, 104 were considered as suitable for further analysis. Of these, applying a catalogue of 24 SmPC-derived criteria, 34% (35 reports) contained information indicative of label-inconsistent use. The individual SmPC-criteria most often violated were (% of total analyzed reports): the recommended starting dose of 10 mg/day (9%), the body mass index (BMI)-related threshold permitting drug therapy (6%), and the contraindicated "history of drug abuse" (6%). The DDL was ineffective. The observed percentage of ADR reports, indicating a label-inconsistent use of sibutramine, is considered a signal for a therapeutic risk. This signal should be addressed in a drug utilization study investigating the use of sibutramine by means of a representative patient sample.
van Puijenbroek, Eugène; Diemont, Willem; van Grootheest, Kees
The primary aim of spontaneous reporting systems (SRSs) is the timely detection of unknown adverse drug reactions (ADRs), or signal detection. Generally this is carried out by a systematic manual review of every report sent to an SRS. Statistical analysis of the data sets of an SRS, or quantitative signal detection, can provide additional information concerning a possible relationship between a drug and an ADR. We describe the role of quantitative signal detection and the way it is applied at the Netherlands Pharmacovigilance Centre Lareb. Results of the statistical analysis are implemented in the traditional case-by-case analysis. In addition, for data-mining purposes, a list of associations of ADRs and suspected drugs that are disproportionally present in the database is periodically generated. Finally, quantitative signal generation can be used to study more complex relationships, such as drug-drug interactions and syndromes. The results of quantitative signal detection should be considered as an additional source of information, complementary to the traditional analysis. Techniques for the detection of drug interactions and syndromes offer a new challenge for pharmacovigilance in the near future.
Gallelli, Luca; Gallelli, Giuseppe; Codamo, Giuseppe; Argentieri, Angela; Michniewicz, Andzelika; Siniscalchi, Antonio; Stefanelli, Roberta; Cione, Erika; Caroleo, Maria C; Longo, Paola; De Sarro, Giovambattista
Generic formulations represent a way to reduce the costs of brand compounds when their patent is expired. While, the bio-equivalence in generic drugs is guaranteed, some excipients as well as dyes could be different and this could reduce the drug safety. Herein, we report the development of Adverse Drug Reactions (ADRs) in two patients after the switch from brand to generic formulations. We have tested cytochrome P450 enzymes expression as well as drug serum levels. None of these markers were altered. Checking deeply into both patient's medical history, they harbored poly-sensitivity or allergy to pollen and graminacea and used different active ingredients for different health problems coming from the same generic company Almus(®). This company used different dyes and excipients compared to the branded drugs made by distinguished companies. In conclusion, we strongly suggest to both pharmacists and physicians to be careful in giving the advice to change the drug, thinking to reduce health sanitary costs without considering the personal clinical history of each one. Paradoxically this behavior is causing other health issues, bringing to an increase of the overall costs for patients as well as for National Health System.
Background Antibiotics are the widely prescribed drugs for children and most likely to be related with adverse reactions. Record on adverse reactions and allergies from antibiotics considerably affect the prescription choices. We consider this a biomedical decision-making problem and explore hidden knowledge in survey results on data extracted from a big data pool of health records of children, from the Health Center of Osijek, Eastern Croatia. Results We applied and evaluated a k-means algorithm to the dataset to generate some clusters which have similar features. Our results highlight that some type of antibiotics form different clusters, which insight is most helpful for the clinician to support better decision-making. Conclusions Medical professionals can investigate the clusters which our study revealed, thus gaining useful knowledge and insight into this data for their clinical studies. PMID:25079450
Schwenk, Eric S; Goldberg, Stephen F; Patel, Ronak D; Zhou, Jon; Adams, Douglas R; Baratta, Jaime L; Viscusi, Eugene R; Epstein, Richard H
High-dose opioid administration is associated with significant adverse events. Evidence suggests that low-dose ketamine infusions improve perioperative analgesia over conventional opioid management, but usage is highly variable. Ketamine's adverse drug effects (ADEs) are well known, but their prevalence during low-dose infusions in a clinical setting and how often they lead to infusion discontinuation are unknown. The purposes of this study were 3-fold: (1) to identify patient factors associated with initiation of ketamine infusions during spine surgery, (2) to identify specific spine procedures in which ketamine has been used most frequently, and (3) to identify ADEs associated with postoperative ketamine infusions and which ADEs most frequently led to discontinuation. Spine surgery was chosen because of its association with moderate to severe pain and a relatively high use of ketamine infusions in this population at our hospital.
Pope, Harrison G.; Wood, Ruth I.; Rogol, Alan; Nyberg, Fred; Bowers, Larry
Despite the high prevalence of performance-enhancing drug (PED) use, media attention has focused almost entirely on PED use by elite athletes to illicitly gain a competitive advantage in sports, and not on the health risks of PEDs. There is a widespread misperception that PED use is safe or that adverse effects are manageable. In reality, the vast majority of PED users are not athletes but rather nonathlete weightlifters, and the adverse health effects of PED use are greatly underappreciated. This scientific statement synthesizes available information on the medical consequences of PED use, identifies gaps in knowledge, and aims to focus the attention of the medical community and policymakers on PED use as an important public health problem. PED users frequently consume highly supraphysiologic doses of PEDs, combine them with other PEDs and/or other classical drugs of abuse, and display additional associated risk factors. PED use has been linked to an increased risk of death and a wide variety of cardiovascular, psychiatric, metabolic, endocrine, neurologic, infectious, hepatic, renal, and musculoskeletal disorders. Because randomized trials cannot ethically duplicate the large doses of PEDs and the many factors associated with PED use, we need observational studies to collect valid outcome data on the health risks associated with PEDs. In addition, we need studies regarding the prevalence of PED use, the mechanisms by which PEDs exert their adverse health effects, and the interactive effects of PEDs with sports injuries and other high-risk behaviors. We also need randomized trials to assess therapeutic interventions for treating the adverse effects of PEDs, such as the anabolic-androgen steroid withdrawal syndrome. Finally, we need to raise public awareness of the serious health consequences of PEDs. PMID:24423981
Eyal, Sara; Rasaby, Sivan; Ekstein, Dana
People with epilepsy (PWE) may use prescription and over-the-counter (OTC) drugs for the treatment of concomitant diseases. Combinations of these drugs, as well as dietary supplements, with antiepileptic drugs (AEDs) may lead to reduced control of seizures and of coexisting medical conditions and increased risk of adverse drug reactions (ADRs). The aims of this study were to obtain comprehensive lists of medications, dietary supplements, botanicals, and specific food components used by adult PWE and to evaluate the potential for interactions involving AEDs and patients' awareness of such potential interactions. We conducted a prospective, questionnaire-based study of PWE attending the Hadassah-Hebrew University Epilepsy Clinic over a period of 7months. The questionnaire interview included the listing of medications, medicinal herbs, dietary supplements, and specific food components consumed and the knowledge of potential drug-drug interactions (DDIs), and it was conducted by a pharmacist. Drug-drug interactions were analyzed via the Micromedex online database. Out of 179 patients who attended the clinic over the study period, we interviewed 73 PWE, of which 71 were included in our final analysis. The mean number of AEDs consumed per subject was 1.7 (SD: 0.8, range: 1-4). Forty (56%) subjects were also treated with other prescription and/or OTC medications, and thirty-four (48%) took dietary supplements. Drug families most prone to DDIs involving AEDs included antipsychotic agents, selective serotonin reuptake inhibitors, and statins. Two-thirds of study participants (67%) knew that DDIs may lead to ADRs, but only half (56%) were aware of the potential for reduced seizure control. Only 44% always reported treatment with AEDs to medical professionals. This study provides for the first time a comprehensive picture of prescription and OTC drugs and food supplements used by PWE. Despite a considerable potential for DDIs involving AEDs, patient awareness is limited
Oronoz, Maite; Gojenola, Koldo; Pérez, Alicia; de Ilarraza, Arantza Díaz; Casillas, Arantza
The advances achieved in Natural Language Processing make it possible to automatically mine information from electronically created documents. Many Natural Language Processing methods that extract information from texts make use of annotated corpora, but these are scarce in the clinical domain due to legal and ethical issues. In this paper we present the creation of the IxaMed-GS gold standard composed of real electronic health records written in Spanish and manually annotated by experts in pharmacology and pharmacovigilance. The experts mainly annotated entities related to diseases and drugs, but also relationships between entities indicating adverse drug reaction events. To help the experts in the annotation task, we adapted a general corpus linguistic analyzer to the medical domain. The quality of the annotation process in the IxaMed-GS corpus has been assessed by measuring the inter-annotator agreement, which was 90.53% for entities and 82.86% for events. In addition, the corpus has been used for the automatic extraction of adverse drug reaction events using machine learning.
Anti-cancer drugs have relatively low effective rates and high frequencies of adverse reactions, occasionally leading to cessation of their treatments. Use of pharmacogenomic (PGx) information could be able to select the patients with high-response and less-adverse reactions, resulting in increase of patients' QOL and proper use of drugs. We have been collaborating with National Cancer Center for PGx analysis of anti-cancer drugs including irinotecan and gemcitabine in Japanese cancer patients. Irinotecan, now used for treatments of many cancers, is metabolically activated to SN-38 and then inactivated to SN-38 glucuronide by a UDP-glucuronosyltransferase UGT1A1. In the UGT1A1 gene, two representative genetic polymorphisms, *28 and *6, were detected at 0.138 and 0.167, respectively in 177 Japanese cancer patients. When the patients were homozygotes of *28 or *6, or compound heterozygotes of them, statistically significant decreases were observed in the SN-38 glucuronidation activity and increases in the rate of severe neutropenia, compared to those in the patients without *28 or *6. Our results and papers were cited in the Japanese package inserts of irinotecan. Gemcitabine was inactivated by cytidine deaminase (CDA) into 2'-2'-difluorodeoxyuridine. A CDA polymorphism 208G>A (Ala70Thr) was detected at 0.037 frequency in 256 Japanese cancer patients and associated with reduced gemcitabine clearance as well as increased frequency of severe neutropenia. In the 4 patients suffered from very severe bone marrow toxicities, 3 patients were homozygous CDA*3, suggesting that this polymorphism is exquisite for predicting severe adverse reactions by gemcitabine in Japanese.
Yu, Yun Mi; Shin, Wan Gyoon; Lee, Ju-Yeun; Choi, Soo An; Jo, Yun Hee; Youn, So Jung; Lee, Mo Se; Choi, Kwang Hoon
Purpose To evaluate the clinical manifestations and causative drugs associated with adverse drug reactions (ADRs) spontaneously reported by community pharmacists and to compare the ADRs by age. Methods ADRs reported to the Regional Pharmacovigilance Center of the Korean Pharmaceutical Association by community pharmacists from January 2013 to June 2014 were included. Causality was assessed using the WHO-Uppsala Monitoring Centre system. The patient population was classified into three age groups. We analyzed 31,398 (74.9%) ADRs from 9,705 patients, identified as having a causal relationship, from a total pool of 41,930 ADRs from 9,873 patients. Median patient age was 58.0 years; 66.9% were female. Results Gastrointestinal system (34.4%), nervous system (14.4%), and psychiatric (12.1%) disorders were the most frequent symptoms. Prevalent causative drugs were those for acid-related disorders (11.4%), anti-inflammatory products (10.5%), analgesics (7.2%), and antibacterials (7.1%). Comparisons by age revealed diarrhea and antibacterials to be most commonly associated with ADRs in children (p < 0.001), whereas dizziness was prevalent in the elderly (p < 0.001). Anaphylactic reaction was the most frequent serious event (19.7%), mainly associated with cephalosporins and non-steroidal anti-inflammatory drugs. Among 612 ADRs caused by nonprescription drugs, the leading symptoms and causative drugs were skin disorders (29.6%) and non-steroidal anti-inflammatory drugs (16.2%), respectively. Conclusions According to the community pharmacist reports, the leading clinical manifestations and causative drugs associated with ADRs in outpatients differed among age groups. PMID:26172050
MARTÍNEZ-MIR, I.; GARCÍA-LÓPEZ, M.; PALOP, V.; FERRER, J. M.; ESTAÑ, L.; RUBIO, E.; MORALES-OLIVAS, F. J.
1A total of 512 consecutive paediatric hospital admissions of children 2 years old or less were evaluated to assess the extent and pattern of admission caused by suspected adverse drug reactions (ADRs). The proportion of suspected ADRs related to hospital admissions was 4.3%. 2The organ-systems most commonly implicated were the central nervous system (40.5%), digestive system (16.7%), and skin and appendages (14.3%). Together, they accounted for 71.5% of admissions attributed to ADRs. The most common clinical manifestations inducing admission were convulsions (4 cases), dizziness (4), vomiting (3), and tremor, fever, itching and apnoea (2 cases each). 3The four classes of drugs most frequently suspected in admissions due to ADRs were respiratory drugs (35%), anti-infective agents (25%), drugs active on the central nervous system (15%) and drugs used in dermatology (10%). The most common drugs related to ADRs were a combination of chlorpheniramine, diphenhydramine, phenylephrine, guaiphenesin and salicylic acid (4 cases), followed by fenoterol, adrenaline, paracetamol, DTP vaccine and antipolio vaccine (2 cases each). 4There were no significant differences between children older and younger than 1 year (odds ratio 0.89; 95% CI 0.37–2.17) or between the sexes as regards hospital admittance due to suspected ADRs (odds ratio 1.94; 95% CI 0.72–5.42). 5The results of this kind of study may be influenced by patterns of drug utilization. Nevertheless, the lack of specific studies of drug effects in young children makes it desirable to carry out pharmacoepidemiological studies in this age group. PMID:8877022
Dahmke, Hendrike; Kupferschmidt, Hugo; Kullak-Ublick, Gerd A; Weiler, Stefan
Nalmefene (Selincro®) is a selective opioid receptor antagonist, licensed in April 2014 in Switzerland for the reduction of alcohol consumption in adults with a high drinking risk level. 200 reports of adverse drug reactions of nalmefene have been documented worldwide in the WHO global pharmacovigilance database between 7th March 1997 to 1st March 2015. In 21 cases (10,5%) nalmefene and an opioid were administered concomitantly, causing withdrawal symptoms. Until now, the regional pharmacovigilance center in Zurich received four cases of nalmefene combined with opioids. This combination should be avoided.
LaBute, Montiago X; Zhang, Xiaohua; Lenderman, Jason; Bennion, Brian J; Wong, Sergio E; Lightstone, Felice C
Late-stage or post-market identification of adverse drug reactions (ADRs) is a significant public health issue and a source of major economic liability for drug development. Thus, reliable in silico screening of drug candidates for possible ADRs would be advantageous. In this work, we introduce a computational approach that predicts ADRs by combining the results of molecular docking and leverages known ADR information from DrugBank and SIDER. We employed a recently parallelized version of AutoDock Vina (VinaLC) to dock 906 small molecule drugs to a virtual panel of 409 DrugBank protein targets. L1-regularized logistic regression models were trained on the resulting docking scores of a 560 compound subset from the initial 906 compounds to predict 85 side effects, grouped into 10 ADR phenotype groups. Only 21% (87 out of 409) of the drug-protein binding features involve known targets of the drug subset, providing a significant probe of off-target effects. As a control, associations of this drug subset with the 555 annotated targets of these compounds, as reported in DrugBank, were used as features to train a separate group of models. The Vina off-target models and the DrugBank on-target models yielded comparable median area-under-the-receiver-operating-characteristic-curves (AUCs) during 10-fold cross-validation (0.60-0.69 and 0.61-0.74, respectively). Evidence was found in the PubMed literature to support several putative ADR-protein associations identified by our analysis. Among them, several associations between neoplasm-related ADRs and known tumor suppressor and tumor invasiveness marker proteins were found. A dual role for interstitial collagenase in both neoplasms and aneurysm formation was also identified. These associations all involve off-target proteins and could not have been found using available drug/on-target interaction data. This study illustrates a path forward to comprehensive ADR virtual screening that can potentially scale with increasing number
Vazzana, M; Andreani, T; Fangueiro, J; Faggio, C; Silva, C; Santini, A; Garcia, M L; Silva, A M; Souto, E B
Tramadol hydrochloride (TrHC) is a synthetic analgesic drug exhibiting opioid and non-opioid properties, acting mainly on the central nervous system. It has been mostly used to treat pain, although its use to treat anxiety and depression has also been documented. These properties arise from the fact that they inhibit serotonin (5-HT) reuptake augmenting 5-HT concentration on the synaptic cleft. Despite this, TrHC has also been described to have several side effects which are mainly due to its fast metabolization and excretion which in turn requires multiple doses per day. To surpass this limitation, new pharmaceutical formulations are being developed intending the protection, target and sustained delivery as well as a reduction on daily dose aiming a reduction on the side effects. In the present work we have revised the efficacy, safety, biological and adverse effects of TrHC, and the added value of developing a novel drug delivery system for topical administration.
Weiner, Mark G.; Livshits, Alice; Carozzoni, Carol; McMenamin, Erin; Gibson, Gene; Loren, Alison W.; Hennessy, Sean
A difficult balance exists in the use of cancer chemotherapy in which the cytotoxic medicine must act on the cancer without causing neutropenic fever, a condition that is caused by over-suppression of the immune system. An improved understanding of dosing strategies as well as the use of medications to support the immune system has helped to reduce the likelihood of an admission for neutropenic fever following cancer chemotherapy. Therefore, as with any drug therapy, chemotherapy administration that is temporally associated with an unexpected hospitalization for neutropenia is an adverse drug event (ADE). Analogous to other informatics research to monitor and address the occurrence of ADEs, this work develops and validates the information systems infrastructure necessary to detect the occurrence of and analyze the factors contributing to chemotherapy associated ADEs.
Jiang, Guoqian; Solbrig, Harold R; Chute, Christopher G
A source of semantically coded Adverse Drug Event (ADE) data can be useful for identifying common phenotypes related to ADEs. We proposed a comprehensive framework for building a standardized ADE knowledge base (called ADEpedia) through combining ontology-based approach with semantic web technology. The framework comprises four primary modules: 1) an XML2RDF transformation module; 2) a data normalization module based on NCBO Open Biomedical Annotator; 3) a RDF store based persistence module; and 4) a front-end module based on a Semantic Wiki for the review and curation. A prototype is successfully implemented to demonstrate the capability of the system to integrate multiple drug data and ontology resources and open web services for the ADE data standardization. A preliminary evaluation is performed to demonstrate the usefulness of the system, including the performance of the NCBO annotator. In conclusion, the semantic web technology provides a highly scalable framework for ADE data source integration and standard query service.
Wang, Wei; Haerian, Krystl; Salmasian, Hojjat; Harpaz, Rave; Chase, Herbert; Friedman, Carol
Adverse drug events (ADEs) create a serious problem causing substantial harm to patients. An executable standardized knowledgebase of drug-ADE relations which is publicly available would be valuable so that it could be used for ADE detection. The literature is an important source that could be used to generate a knowledgebase of drug-ADE pairs. In this paper, we report on a method that automatically determines whether a specific adverse event (AE) is caused by a specific drug based on the content of PubMed citations. A drug-ADE classification method was initially developed to detect neutropenia based on a pre-selected set of drugs. This method was then applied to a different set of 76 drugs to determine if they caused neutropenia. For further proof of concept this method was applied to 48 drugs to determine whether they caused another AE, myocardial infarction. Results showed that AUROC was 0.93 and 0.86 respectively.
Jiang, Guoqian; Wang, Chen; Zhu, Qian; Chute, Christopher G.
Knowledge-driven text mining is becoming an important research area for identifying pharmacogenomics target genes. However, few of such studies have been focused on the pharmacogenomics targets of adverse drug events (ADEs). The objective of the present study is to build a framework of knowledge integration and discovery that aims to support pharmacogenomics target predication of ADEs. We integrate a semantically annotated literature corpus Semantic MEDLINE with a semantically coded ADE knowledgebase known as ADEpedia using a semantic web based framework. We developed a knowledge discovery approach combining a network analysis of a protein-protein interaction (PPI) network and a gene functional classification approach. We performed a case study of drug-induced long QT syndrome for demonstrating the usefulness of the framework in predicting potential pharmacogenomics targets of ADEs. PMID:24303306
Sims, Shannon A; Snow, Laverne A; Porucznik, Christina A
Healthcare safety and quality surveillance is increasingly conducted by public health agencies. We describe a biomedical informatics method that uses multiple public health data sources to perform surveillance of methadone-related adverse drug events. Data from Utah medical examiner records, vital statistics, emergency department encounter administrative data and a database of controlled substances prescriptions are used to examine trends in state-wide adverse events related to methadone. From 1997 to 2004, population-adjusted methadone prescriptions increased 727%, with evidence to suggest the rise in the methadone prescription rate is for treatment of pain, not addiction therapy. During the same period of time, population adjusted, accidental methadone-related deaths in medical examiner data increased 1770%. Population adjusted methadone-related emergency department encounters rose 612% from 1997 to 2003. Our results suggest that the increase in methadone prescription rates from 1997 to 2004 was accompanied by a concurrent increase in methadone-related morbidity and mortality. Although patient data is not linked between data sources, our results demonstrate that utilizing multiple public health data sources captures more cases and provides more clinical detail than individual data sources alone. Our approach is a successful biomedical informatics approach for surveillance of adverse events and utilizes widely available public health data sources, as well as an emerging source of public health data, controlled substance prescription registries.
Dimri, Deepak; Thapliyal, Swati; Thawani, Vijay
Introduction Cutaneous Adverse Drug Reactions (CADR) are the common drug induced adverse reactions which usually have wide range of manifestations and severity. Aim To describe the prevalence and clinical spectrum of CADR’s in a tertiary hospital of the Garhwal region in Uttarakhand, India. Materials and Methods All patients suspected of having CADRs reported in the various out-patient departments, and in-patients of HNB Base & Teaching Hospital, from 1st January 2012 to 31st December 2014 were retrospectively analysed. Drug history was recorded in a format specified in Indian National Pharmacovigilance Programme. Results Total 111 cases of CADRs were reported from Jan 2012 to Dec 2014. Mean age of patients was 33.34±18.7 years and maximum ADRs were reported in the age group of 20-39 years (36.9%). Female were affected more than male (W:M :: 66:45). Most of the ADRs were exanthematous eruptions (EE) type (33.3%). Medicine department reported maximum cases of CADRs (47.7%), followed by Dermatology. Most of the CADRs were reported with antimicrobial agents (69.4%). Significant associations of different types of various cutaneous reactions were observed in relation to the duration (in days) of ADRs (p = 0.038), types of outcome (p= 0.006), different departments (p= 0.014) and between different groups of medicines (p = 0.008). Conclusion CADRs have proved a significant problem in healthcare for decades. Major bulk of CADR result from physician prescribed drugs. Hence, awareness on part of the physician can help in timely detection of cutaneous reactions, thereby restricting damage from them. PMID:27437240
Mudzviti, Tinashe; Sibanda, Marvelous; Gavi, Samuel; Maponga, Charles Chiedza; Morse, Gene D.
Background Cutaneous adverse drug reactions (cADRs) can cause significant morbidity and distress in patients especially in the HIV infected population on antiretroviral therapy. Adverse Drug Reaction monitoring and ascertaining causality in resource limited settings still remains a challenge. This study was carried out to evaluate causality and measure incidence of cADRs in HIV infected patients on highly active antiretroviral therapy. The study was also designed to test a 3-step approach in the monitoring and evaluation of ADRs in resource limited settings. Methodology A retrospective patient medical records review was carried out at the Parirenyatwa Family Care Centre, (Harare, Zimbabwe). Cases of cADRs were reported to the Medicines Control Authority of Zimbabwe (Drug regulating body in Zimbabwe) for assessment and causality classification. Results Two hundred and twenty-one patient records were randomly selected and reviewed to determine if any diagnosis of cADRs was made by clinicians. Causality assessment revealed 13.1% of cADRs which were due to an offending agent in the antiretroviral therapy against an initial incidence of 17.6% which had been determined by the physicians. Conclusions cADRs had an incidence of 13.1% within the population under study due to non nucleoside reverse transcriptase inhibitors (NNRTIs). Most reactions were due to the NNRTIs which contributed 72.4 % of all cADRs. A panel of experts from the drug regulatory authority can be used as an implementation based mechanism in ascertaining causality objectively in settings where resources are constrained. PMID:23277506
Rosli, Rosliana; Dali, Ahmad Fauzi; Aziz, Noorizan Abd; Ming, Long Chiau; Manan, Mohamed Mansor
Spontaneous adverse drug reactions (ADRs) reporting is a useful source of drug safety information in infants as only adult patients are routinely tested in clinical trials. This study was aimed to evaluate the spontaneously reported ADRs using WHO Adverse Reaction Terminology and to identify the common drugs associated with ADRs in children under 2 years of age. A retrospective analysis of ADR data for children below 2 years old from 2000 to 2013 was conducted using the data extracted from Malaysia's national pharmacovigilance database, QUEST2 System. From 2000 to 2013, Malaysia's National Pharmaceutical Control Bureau received a total of 11,932 reports for children from various healthcare facilities in Malaysia. 14.0% (n = 1667) of the ADRs reported for those children were related to children under 2 years old. The data retrieved was analyzed in terms of age, gender, source of reporting, type of reporters, suspected medicines and characteristics of ADRs (category, onset, severity, and outcomes). A total of 1312 ADRs reported in 907 ADR reports were analyzed. The most common ADRs reported were skin appendage disorders (60.1%), and the most frequently reported symptoms were rash (n = 215), maculopapular rash (n = 206), urticaria (n = 169), erythematous rash (n = 76), and pruritus (n = 58). In general, drugs from antibacterials for systemic use (58.8%) appeared to be the most common contributors to ADRs in children below 2 years old. Penicillins and other β-Lactam Antibacterials accounted for more than 40% of all drugs implicated in ADRs. The majority of ADRs were subacute reactions that occurred within 24 h of exposure to the drug. A high proportion of ADRs was classified as mild, and most victims had no sequela. Only one fatality was seen. There were 10 cases for each symptom, namely erythema multiforme and Stevens-Johnson Syndrome, observed in this study. A large proportion of ADRs in children under 2 years old were mainly caused by drugs from antibacterial for
Rosli, Rosliana; Dali, Ahmad Fauzi; Aziz, Noorizan Abd.; Ming, Long Chiau; Manan, Mohamed Mansor
Spontaneous adverse drug reactions (ADRs) reporting is a useful source of drug safety information in infants as only adult patients are routinely tested in clinical trials. This study was aimed to evaluate the spontaneously reported ADRs using WHO Adverse Reaction Terminology and to identify the common drugs associated with ADRs in children under 2 years of age. A retrospective analysis of ADR data for children below 2 years old from 2000 to 2013 was conducted using the data extracted from Malaysia’s national pharmacovigilance database, QUEST2 System. From 2000 to 2013, Malaysia’s National Pharmaceutical Control Bureau received a total of 11,932 reports for children from various healthcare facilities in Malaysia. 14.0% (n = 1667) of the ADRs reported for those children were related to children under 2 years old. The data retrieved was analyzed in terms of age, gender, source of reporting, type of reporters, suspected medicines and characteristics of ADRs (category, onset, severity, and outcomes). A total of 1312 ADRs reported in 907 ADR reports were analyzed. The most common ADRs reported were skin appendage disorders (60.1%), and the most frequently reported symptoms were rash (n = 215), maculopapular rash (n = 206), urticaria (n = 169), erythematous rash (n = 76), and pruritus (n = 58). In general, drugs from antibacterials for systemic use (58.8%) appeared to be the most common contributors to ADRs in children below 2 years old. Penicillins and other β-Lactam Antibacterials accounted for more than 40% of all drugs implicated in ADRs. The majority of ADRs were subacute reactions that occurred within 24 h of exposure to the drug. A high proportion of ADRs was classified as mild, and most victims had no sequela. Only one fatality was seen. There were 10 cases for each symptom, namely erythema multiforme and Stevens–Johnson Syndrome, observed in this study. A large proportion of ADRs in children under 2 years old were mainly caused by drugs from antibacterial
Duarte-Silva, Daniela; Figueiras, Adolfo; Herdeiro, Maria T.; Teixeira Rodrigues, António; Silva Branco, Fábio; Polónia, Jorge; Figueiredo, Isabel V.
Objective The aim of this study was to design and validate a questionnaire to measure perceived symptoms associated with antihypertensive drugs (PERSYVE). Methods The PERSYVE development and validation included four stages: 1) item development (bibliographic review and questionnaire elaboration); 2) face and content validation; 3) field testing (pre-test); and 4) test-retest validation, assessment of internal consistency (Cronbach’s alpha) and reproducibility over time (intraclass correlation coefficient and Cohen’s kappa coefficient). Results PERSYVE is divided into six sections according to results obtained from the literature review: (1) drug adherence, (2) perceived symptoms and how they affect quality of life (five-point Likert scale), (3) communication with health professionals, (4) perception of symptoms as adverse reactions, (5) influence on therapy compliance, and (6) adoption of non-pharmacological methods for blood pressure control. Content and face validation of the questionnaire led to some vocabulary changes and the introduction of section 2.1. Field-testing (n=26) revealed high comprehensibility of the questions. The Cronbach's alpha, calculated for section 2 (five-point Likert scale) was 0.850. PERSYVE was reproducible (n=167): kappa values presented fair to substantial reproducibility and, in section 2, ICC values resulted in good to excellent reproducibility. Conclusion Results showed that PERSYVE is a well-structured, objective, patient-friendly, valid and reliable questionnaire. PERSYVE can be a very useful instrument in hypertensive patients’ monitoring and in the screening of adverse effects. PMID:25035716
Burgess, J L; Barnhart, S; Checkoway, H
A retrospective cohort study was conducted among an international group of 46 law enforcement chemists and 13 Washington State clandestine drug laboratory investigation team members with more than 2,800 combined investigations. Each participant completed a questionnaire concerning previous drug laboratory investigations and adverse health effects during response activities. Methamphetamine laboratories accounted for 81-97% of all responses. Total illness incident rates varied between 0.75-3.4% of responses. Most exposures were through inhalation, and many occurred in the years prior to use of personal protective equipment. Symptoms were primarily those of headache and respiratory, mucous membrane, and skin irritation. Most illness episodes occurred during the processing phase of laboratory responses, and none occurred during the entry phase. A majority of illness episodes occurred in laboratories with leak/spills, fire/explosion, or uncontrolled reactions. Responding to an active laboratory was associated with a 7 to 15-fold risk of becoming ill as compared with setup, in-transit, or former (equipment removed) laboratory responses. No other laboratories characteristics were consistently associated with a significantly elevated relative risk of adverse health effects.
Allegaert, Karel; van den Anker, Johannes N
Drug therapy is a powerful tool to improve outcome, but there is an urgent need to improve pharmacotherapy in neonates through tailored prevention and management of adverse drug reactions (ADRs). At present, infants commonly receive off-label drugs, at dosages extrapolated from those in children or adults. Besides the lack of labelling, inappropriate formulations, (poly)pharmacy, immature organ function and multiple illnesses further raise the risk for ADRs in neonates and infants. Pharmacovigilance to improve the prevention and management of ADRs needs to be tailored to neonates and infants. We illustrate this using prevention strategies for drug prescription and administration errors (e.g. formulation, bedside manipulation, access), detection through laboratory signalling or clinical outlier data (e.g. reference laboratory values, overall high morbidity), assessment through algorithm scoring (e.g. Naranjo or population specific), as well as understanding of the developmental toxicology (e.g. covariates, developmental pharmacology) to avoid re-occurrence and for development of guidelines. Such tailored strategies need collaborative initiatives to combine the knowledge and expertise of different disciplines, but hold promise to become a very effective tool to improve pharmacotherapy and reduce ADRs in infants. PMID:24862557
Liu, Mei; McPeek Hinz, Eugenia Renne; Matheny, Michael Edwin; Denny, Joshua C; Schildcrout, Jonathan Scott; Miller, Randolph A; Xu, Hua
Objective Medication safety requires that each drug be monitored throughout its market life as early detection of adverse drug reactions (ADRs) can lead to alerts that prevent patient harm. Recently, electronic medical records (EMRs) have emerged as a valuable resource for pharmacovigilance. This study examines the use of retrospective medication orders and inpatient laboratory results documented in the EMR to identify ADRs. Methods Using 12 years of EMR data from Vanderbilt University Medical Center (VUMC), we designed a study to correlate abnormal laboratory results with specific drug administrations by comparing the outcomes of a drug-exposed group and a matched unexposed group. We assessed the relative merits of six pharmacovigilance measures used in spontaneous reporting systems (SRSs): proportional reporting ratio (PRR), reporting OR (ROR), Yule's Q (YULE), the χ2 test (CHI), Bayesian confidence propagation neural networks (BCPNN), and a gamma Poisson shrinker (GPS). Results We systematically evaluated the methods on two independently constructed reference standard datasets of drug–event pairs. The dataset of Yoon et al contained 470 drug–event pairs (10 drugs and 47 laboratory abnormalities). Using VUMC's EMR, we created another dataset of 378 drug–event pairs (nine drugs and 42 laboratory abnormalities). Evaluation on our reference standard showed that CHI, ROR, PRR, and YULE all had the same F score (62%). When the reference standard of Yoon et al was used, ROR had the best F score of 68%, with 77% precision and 61% recall. Conclusions Results suggest that EMR-derived laboratory measurements and medication orders can help to validate previously reported ADRs, and detect new ADRs. PMID:23161894
Objective Automatic detection of Adverse Drug Reaction (ADR) mentions from text has recently received significant interest in pharmacovigilance research. Current research focuses on various sources of text-based information, including social media — where enormous amounts of user posted data is available, which have the potential for use in pharmacovigilance if collected and filtered accurately. The aims of this study are: (i) to explore natural language processing approaches for generating useful features from text, and utilizing them in optimized machine learning algorithms for automatic classification of ADR assertive text segments; (ii) to present two data sets that we prepared for the task of ADR detection from user posted internet data; and (iii) to investigate if combining training data from distinct corpora can improve automatic classification accuracies. Methods One of our three data sets contains annotated sentences from clinical reports, and the two other data sets, built in-house, consist of annotated posts from social media. Our text classification approach relies on generating a large set of features, representing semantic properties (e.g., sentiment, polarity, and topic), from short text nuggets. Importantly, using our expanded feature sets, we combine training data from different corpora in attempts to boost classification accuracies. Results Our feature-rich classification approach performs significantly better than previously published approaches with ADR class F-scores of 0.812 (previously reported best: 0.770), 0.538 and 0.678 for the three data sets. Combining training data from multiple compatible corpora further improves the ADR F-scores for the in-house data sets to 0.597 (improvement of 5.9 units) and 0.704 (improvement of 2.6 units) respectively. Conclusions Our research results indicate that using advanced NLP techniques for generating information rich features from text can significantly improve classification accuracies over existing
Machado-Alba, Jorge Enrique; Ruiz, Andrés Felipe; Machado-Duque, Manuel Enrique
This study describes the adverse drug reactions (ADRs) and their incidence in patients with rheumatoid arthritis who were treated in the Colombian health system. A retrospective cohort study was conducted using information from all patients who were diagnosed with rheumatoid arthritis and attended specialized health care centers in the cities of Bogotá, Cali, Manizales, Medellin, and Pereira between 1 December 2009 and 30 August 2013. The ADRs were obtained from medical records and the pharmacovigilance system registry and sorted by frequency and affected tissue according to World Health Organization Adverse Reaction Terminology (WHO-ART). A total of 949 reports of ADRs were obtained from 419 patients (32.8 ADRs per 100 patient-years); these patients were from a cohort of 1,364 patients being treated for rheumatoid arthritis and followed up for an average of 23.8 months (± 12.9). The cohort was mostly female (366, 87.4%) and had a mean age of 52.7 years (± 13.1). The highest numbers of ADRs were reported following the use of tocilizumab, rituximab, and infliximab (28.8, 23.1, and 13.3 reports per 100 patient-years respectively). The most frequently reported ADRs were elevated transaminase levels and dyspepsia. Overall, 87.7% of ADRs were classified as type A, 36.6% as mild, 40.7% as moderate, and 22.7% as severe. As a result, 73.2% of patients who experienced an ADR stopped taking their drugs. The occurrence of ADRs in patients treated for rheumatoid arthritis is common, especially in those associated with the use of biotechnologically produced anti-rheumatic drugs. This outcome should be studied in future research and monitoring is needed to reduce the risks in these patients.
Wahlang, Julie Birdie; Laishram, Purnima Devi; Brahma, Dhriti Kumar; Sarkar, Chayna; Lahon, Joonmoni; Nongkynrih, Banylla Shisha
Background: An adverse drug reaction (ADR) is defined by World Health Organization (WHO) as ‘Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy’. ADRs associated with cancer chemotherapy warrant analysis on their severity and preventability. The outcome would create awareness among health care providers and prevent their recurrence. We have performed a hospital-based prospective observational study designed to analyze the pattern of ADRs to chemotherapeutic agents in cancer patients of a tertiary care hospital. Methods: A total of 119 cancer patients were monitored for suspected ADRs during the course of chemotherapy from November 2014 to December 2015. Clinical events were recorded and analyzed with regard to the demographics and drug details of the patients. Results: A total of 106 ADRs were recorded from 119 cases. The ADRs commonly encountered included constipation, nausea, vomiting, alopecia and hematological changes. Cisplatin, cyclophosphamide, paclitaxel and 5-FU were used for the treatment of commonly found cancers in this region affecting the lungs, esophagus and lymphomas. Naranjo’s causality assessment showed 86.7% possible (score 4) and 13.2% probable (score 5–6). Severity of adverse reactions showed 77.4% mild, 18.9% moderate and 3.8% severe. A total of 45.3% of ADRs were preventable reactions such as nausea, vomiting and constipation. Conclusions: This study highlights the role of active monitoring as an important tool for early detection, assessment and timely management of ADRs in patients undergoing cancer chemotherapy. The observed ADRs were preventable although ADRs such as hiccough, anemia, neutropenia and alopecia were not preventable.
Hei, T K; Liu, S X; Hall, E J
Potential oncogenicity must be a factor of concern in the design and development of novel bioreductive drugs. In the present studies, the cytotoxicity and oncogenic transforming potential of a series of heterocyclic mono-N-oxides, designed to be used as bioreductive drugs, were examined using the mouse C3H 10T1/2 cell system. Exponential phase cultures of 10T1/2 cells were treated with graded doses of the bioreductive drugs for a 4 h period, either in air or hypoxia, at 37 degrees C. After treatment, cultures were replated for both survival and transformation assays. The fused pyrazine mono-N-oxide RB 90740 and its N-deoxy analogue, RB 92816, demonstrated a dose-dependent cytotoxicity and oncogenic transforming potency under aerobic conditions. Similarly, the indoloquinone E09 and the structurally related mitomycin C demonstrated dose dependence in both toxicity and oncogenic transforming potential. The most cytotoxic aromatic-N-oxides tested, RB 92816, also demonstrated the highest oncogenic transformation incidence. In hypoxia, the bioreductive metabolites of RB 90740 were substantially more cytotoxic and induced a higher oncogenic transformation yield than the drug in air. These data are consistent with the structure-activity relationship for bioreductive drugs in that heterocyclic-N-oxides with reactive side chains such as RB 92816 are cytotoxic and potentially carcinogenic.
Walker, Lauren M; Tran, Susan; Robinson, John W
Men with prostate cancer (PCa) frequently undergo androgen deprivation therapy (ADT), typically in the form of a depot injection of luteinizing hormone-releasing hormone agonists (LHRHa). LHRHa are associated with many adverse effects (eg, hot flashes, sexual dysfunction, loss of muscle mass, osteopenia, metabolic syndrome), which drastically impact patient quality of life. This literature review, which includes a comprehensive table documenting prevalence rates, provides a quick reference for health care professionals involved in the care of men undergoing ADT with LHRHa. Primary sources were acquired from PubMed using the search terms "androgen deprivation therapy" and each potentially adverse effect (eg, "androgen deprivation therapy and hot flashes"). Commonly cited review articles were also examined for citations of original studies containing prevalence rates. More than 270 articles were reviewed. In contrast to many existing reviews, rates are cited exclusively from original sources. The prevalence rates, obtained from original sources, suggest that more than half of documented adverse effects are experienced by as many as 40% or more of patients. A critique of the literature is also provided. Although there is a vast literature of both original and review articles on specific adverse effects of LHRHa, the quality of research on prevalence rates for some adverse effects is subpar. Many review articles contain inaccuracies and do not cite original sources. The table of prevalence rates will serve as a quick reference for health care providers when counseling patients and will aid in the development of evidence-based patient education materials.
Chan, Sze Ling; Ang, Xiaohui; Sani, Levana L.; Ng, Hong Yen; Winther, Michael D.; Liu, Jian Jun; Brunham, Liam R.
Aims Adverse drug reactions (ADRs) contribute to poorer patient outcomes and additional burden to the healthcare system. However, data on the true burden, relevant types and drugs causing ADRs are lacking. The aim of this study was to determine the prevalence of ADR‐related hospitalization in the general adult population in Singapore and to investigate their characteristics. Methods We prospectively recruited 1000 adult patients with unplanned admission to a large tertiary‐care hospital. Two independent reviewers evaluated all suspected ADRs for causality, type, severity and avoidability. The prevalence of ADR‐related hospitalization was calculated based on ‘definite’ and ‘probable’ ADRs. Logistic regression was used to evaluate predictors for having an ADR at admission. Results The prevalence of all ADRs at admission was 12.4% (95% CI: 10.5–14.6%) and ADRs causing admission was 8.1% (95% CI: 6.5–10.0%). The most common ADRs were gastrointestinal‐related. The most common drug category causing ADRs were cardiovascular drugs. Patients with ADRs had a longer length of stay than those who did not (median 4 vs. 3 days, P = 1.70 × 10−3). About 30% of ADRs at admission were caused by at least one drug with a clinical annotation in the Pharmacogenomics KnowledgeBase (PharmGKB), suggesting that some of these ADRs may have been predicted by pharmacogenetic testing. Conclusions We have quantified the burden and characteristics of clinically impactful ADRs in the Singaporean general adult population. Our results will provide vital information for efforts in reducing ADRs through targeted vigilance, patient education and pharmacogenomics in Singapore. PMID:27640819
Casadei Gardini, Andrea; Tenti, Elena; Masini, Carla; Nanni, Oriana; Scarpi, Emanuela; Valgiusti, Martina; Restuccia, Silvia; Gallani, Maria Laura; Palazzini, Simonetta; Bianchini, Erica; Menozzi, Silvia; Maugeri, Antonio; Amadori, Dino; Minguzzi, Martina; Frassineti, Giovanni Luca
Antiblastic drugs have a high number of potential side-effects. Paradoxically, according to the National Network of Pharmacovigilance, the number of reported adverse reactions to these agents is proportionally lower than that registered for non antiblastic drugs. Critical phenomena such as treatment interruptions and significant dose reductions within the first two months of use may be indicators of adverse drug reactions. The aim of the present study was to increase our knowledge of pharmacovigilance to facilitate the actions taken to improve the risk-benefit profile of cancer drugs and, consequently, their safety. This retrospective observational survey was carried out on prescriptions from 1st January 2012 to 31st December 2012.Dose reductions of more than 10% during the first 90 days of therapy were considered as a surrogate indicator of an adverse reaction. Dose interruptions during the first 60 days of therapy were taken into consideration. Of the12,472 patients 1,248 underwent a dose reduction. The drugs that most often required a dose reduction were paclitaxel and oxaliplatin (17.4% and 17.3%, respectively), docetaxel (14.8%), carboplatin (15%), fluorouracil (10.7%) and, among oral medications, capecitabine (6.9%). Of the 1896 patients treated with the same drugs, 9.7% interrupted treatment. Patients required a lower dose reduction than that reported by other authors. Around 15% of cases underwent a 30% dose reduction within three months of starting therapy, indicating a possible adverse reaction. Constant monitoring of dose prescription and continuous training of medical and nursing staff are clearly needed to increase awareness of the importance of reporting adverse events.
Singh, Anshi; Bhatt, Parloop
Despite comprehensive and stringent phases of clinical trials and surveillance efforts, unexpected and serious adverse drug reactions (ADRs) repeatedly occur after the drug is marketed. ADR reporting is an important aspect of an efficient and effective pharmacovigilance program. Although Medwatch, Yellow Card, CDSCO form, etc. are the protocol forms of ADR collection and reports, a number of countries design and use their respective ADR forms. This review compares similarities and dissimilarities of 13 ADR forms of countries representing their geographical location. This study extracted 73 data elements mentioned in 13 different ADR forms. Only 13 elements were common. An ADR form of Malaysia and Canada covers the highest number of data 43, while Brazil falls to the opposite end with a number of 17 data elements in lieu with the Generic ADR Form. The result of this review highlights 58 data elements of the proposed generic ADR form which ensures that requisite reporting information essential for correct causality assessment of ADRs are included. The proposed “Generic ADR form” could be adopted worldwide mandatorily for reporting any/all ADRs associated with marketed drugs. PMID:23129957
Phillips-Howard, P. A.; Bjorkman, A. B.
Serious adverse reactions during malaria chemoprophylaxis are reviewed. Three drugs considered to have caused serious reactions in recent years are pyrimethamine/sulfadoxine (Fansidar), pyrimethamine/dapsone (Maloprim) and amodiaquine. These reactions are principally independent of dose and cannot be determined during screening for optimal doses. However, host factors may precipitate dose-dependent reactions, some of which could be avoided with improvements in drug licensing. Since serious and life-threatening reactions are relatively rare (between 1:1000 and 1:20,000), Phase I to III trials cannot identify them. Reliance must therefore be placed on Phase IV post-marketing studies, including ongoing reviews of national registers, and specially tailored studies to identify the risk using prescription-event monitoring in high-risk populations. Occasionally, medical-record linkage, case-control and cohort studies may provide supportive data. Although large numbers of travellers must, of necessity, be exposed to a drug before relatively rare reactions are identified, the ascertainment of risk using post-marketing surveillance was prevented by the following five deficiencies: lack of awareness of early alerts, inadequate use of national registers, poor attention to epidemiological and statistical rigour, inadequate verification of denominators, and inadequacy of data records. Recommendations are given for minimizing such errors in the future. PMID:2208562
Vozoris, Nicholas T; Wang, Xuesong; Fischer, Hadas D; Bell, Chaim M; O'Donnell, Denis E; Austin, Peter C; Stephenson, Anne L; Gill, Sudeep S; Rochon, Paula A
We evaluated risk of adverse respiratory outcomes associated with incident opioid use among older adults with chronic obstructive pulmonary diseases (COPD).This was a retrospective population-based cohort study using a validated algorithm applied to health administrative data to identify adults aged 66 years and older with COPD. Inverse probability of treatment weighting using the propensity score was used to estimate hazard ratios comparing adverse respiratory outcomes within 30 days of incident opioid use compared to controls.Incident opioid use was associated with significantly increased emergency room visits for COPD or pneumonia (HR 1.14, 95% CI 1.00-1.29; p=0.04), COPD or pneumonia-related mortality (HR 2.16, 95% CI 1.61-2.88; p<0.0001) and all-cause mortality (HR 1.76, 95% CI 1.57-1.98; p<0.0001), but significantly decreased outpatient exacerbations (HR 0.88, 95% CI 0.83-0.94; p=0.0002). Use of more potent opioid-only agents was associated with significantly increased outpatient exacerbations, emergency room visits and hospitalisations for COPD or pneumonia, and COPD or pneumonia-related and all-cause mortality.Incident opioid use, and in particular use of the generally more potent opioid-only agents, was associated with increased risk for adverse respiratory outcomes, including respiratory-related mortality, among older adults with COPD. Potential adverse respiratory outcomes should be considered when prescribing new opioids in this population.
Toropov, Andrey A; Toropova, Alla P; Rasulev, Bakhtiyor F; Benfenati, Emilio; Gini, Giuseppina; Leszczynska, Danuta; Leszczynski, Jerzy
Classification data related to the Liver-Related Adverse Effects of Drugs have been studied with the CORAL software (http://www.insilico.eu/coral). Two datasets which contain compounds with two serum enzyme markers of liver toxicity: alanine aminotransferase (ALT, n=187) and aspartate aminotransferase (AST, n=209) are analyzed. Statistical quality of the prediction for ALT activity is n=35, Sensitivity = 0.5556, Specificity = 0.8077, and Accuracy = 0.7429. In the case of AST activity the prediction is characterized by n=42, Sensitivity = 0.6875, Specificity = 0.7692, and Accuracy = 0.7381. A number of structural alerts which can be related to the studied activities are revealed. It is the first attempt to build up the classification QSAR model by means of the Monte Carlo technique based on representation of the molecular structure by SMILES using the CORAL software.
Harpaz, Rave; Callahan, Alison; Tamang, Suzanne; Low, Yen; Odgers, David; Finlayson, Sam; Jung, Kenneth; LePendu, Paea; Shah, Nigam H
Text mining is the computational process of extracting meaningful information from large amounts of unstructured text. It is emerging as a tool to leverage underutilized data sources that can improve pharmacovigilance, including the objective of adverse drug event (ADE) detection and assessment. This article provides an overview of recent advances in pharmacovigilance driven by the application of text mining, and discusses several data sources-such as biomedical literature, clinical narratives, product labeling, social media, and Web search logs-that are amenable to text mining for pharmacovigilance. Given the state of the art, it appears text mining can be applied to extract useful ADE-related information from multiple textual sources. Nonetheless, further research is required to address remaining technical challenges associated with the text mining methodologies, and to conclusively determine the relative contribution of each textual source to improving pharmacovigilance.
Sudo, Chie; Azuma, Yu-ichiro; Maekawa, Keiko; Kaniwa, Nahoko; Sai, Kimie; Saito, Yoshiro
Spontaneous reports on suspected serious adverse events caused by medicines from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated by the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety features. Although causal relationship between the medicine and the adverse event is not evaluated, and one incidence may be redundantly reported, this information would be useful to roughly grasp the current movements of drug-related serious adverse events, We searched open-source data of the spontaneous reports publicized by Pharmaceutical and Medical Devices Agency for 4 serious adverse events (interstitial lung disease, rhabdomyolysis, anaphylaxis, and Stevens-Johnson syndrome/toxic epidermal necrolysis) from 2004 to 2010 fiscal year (for 2010, from April 1 st to January 31th). Major drug-classes suspected to the adverse events were antineoplastics for interstitial lung disease, hyperlipidemia agents and psychotropics for rhabdomyolysis, antibiotics/chemotherapeutics, antineoplastics and intracorporeal diagnostic agents for anaphylaxis (anaphylactic shock, anaphylactic reactions, anaphylactoid shock and anaphylactoid reactions), and antibiotics/chemotherapeutics, antipyretics and analgesics, anti-inflammatory agents/common cold drugs, and antiepileptics for Stevens-Johnson syndrome/toxic epidermal necrolysis. These results would help understanding of current situations of the 4 drug-related serious adverse events in Japan.
Steele, Megan L; Axtner, Jan; Happe, Antje; Kröz, Matthias; Matthes, Harald; Schad, Friedemann
Background. In Europe, mistletoe extracts are widely used as a complementary cancer therapy. We assessed the safety of subcutaneous mistletoe as a conjunctive therapy in cancer patients within an anthroposophic medicine setting in Germany. Methods. A multicentre, observational study was performed within the Network Oncology. Suspected mistletoe adverse drug reactions (ADRs) were described by frequency, causality, severity, and seriousness. Potential risk factors, dose relationships and drug-drug interactions were investigated. Results. Of 1923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38°C). ADRs were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%). All were nonserious. Logistic regression analysis revealed that expected effects were more common in females, while immunoreactivity decreased with increasing age and tumour stage. No risk factors were identified for ADRs. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrent with conventional therapies. Conclusion. The results of this study indicate that mistletoe therapy is safe. ADRs were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe.
Steele, Megan L.; Happe, Antje; Kröz, Matthias; Matthes, Harald; Schad, Friedemann
Background. In Europe, mistletoe extracts are widely used as a complementary cancer therapy. We assessed the safety of subcutaneous mistletoe as a conjunctive therapy in cancer patients within an anthroposophic medicine setting in Germany. Methods. A multicentre, observational study was performed within the Network Oncology. Suspected mistletoe adverse drug reactions (ADRs) were described by frequency, causality, severity, and seriousness. Potential risk factors, dose relationships and drug-drug interactions were investigated. Results. Of 1923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38°C). ADRs were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%). All were nonserious. Logistic regression analysis revealed that expected effects were more common in females, while immunoreactivity decreased with increasing age and tumour stage. No risk factors were identified for ADRs. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrent with conventional therapies. Conclusion. The results of this study indicate that mistletoe therapy is safe. ADRs were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe. PMID:24672577
Palaian, Subish; Ibrahim, Mohamed I.M.; Mishra, Pranaya
The pharmacovigilance program in Nepal is less than a decade old, and is hospital centered. This study highlights the findings of a community based pharmacovigilance program involving the community pharmacists. Objectives: To collect the demographic details of the patients experiencing adverse drug reactions (ADR) reported by the community pharmacists; to identify the common drugs causing the ADRs, the common types of ADRs; and to carry out the causality, severity and preventability assessments of the reported ADRs. Methods: The baseline Knowledge-Attitude-Practices (KAP) of 116 community pharmacists from Pokhara valley towards drug safety was evaluated using a validated (Cronbach alpha=0.61) KAP questionnaire having 20 questions [(knowledge 11, attitude 5 and practice 4) maximum possible score 40]. Thirty community pharmacists with high scores were selected for three training sessions, each session lasting for one to two hours, covering the basic knowledge required for the community pharmacists for ADR reporting. Pharmacist from the regional pharmacovigilance center visited the trained community pharmacists every alternate day and collected the filled ADR reporting forms. Results: Altogether 71 ADRs, from 71 patients (37 males) were reported. Antibiotics/ antibacterials caused 42% (n=37) of the total ADRs followed by non steroidal anti-inflammatory drugs [25% (n=22)]. Ibuprofen/paracetamol combination accounted for ten ADRs. The most common type of ADR was itching [17.2 % (n=20), followed by generalized edema [8.6 % (n=10)]. In order to manage the ADRs, the patients needed medical treatment in 69% (n=49) of the cases. Over two third (69%) of the ADRs had a ‘possible’ association with the suspected drugs and a high percentage (70.4%) were of ‘mild (level 2)’ type. Nearly two third [64.7 % (n=46)] of the ADRs were ‘definitely preventable’. Conclusion: The common class of drugs known to cause ADRs was antibacterial/ antibiotics. Ibuprofen/ Paracetamol
Prajapati, Kinjal; Desai, Mira; Shah, Samidh; Panchal, Jigar; Kapadia, Jigar; Dikshit, Ramkumar
Objective: The objective of this study was to analyze the various aspects of serious adverse drug reactions (serious ADRs) such as clinical presentation, causality, severity, and preventability occurring in a hospital setting. Materials and Methods: All serious ADRs reported from January 2010 to May 2015 at ADR Monitoring Centre, Department of Pharmacology, B. J. Medical College and Civil Hospital, Ahmedabad, were selected as per the World health Organization –Uppsala Monitoring Center (WHO-UMC) criteria. A retrospective analysis was carried out for clinical presentation, causality (as per the WHO-UMC scale and Naranjo's algorithm), severity (Hartwig and Siegel scale), and preventability (Schumock and Thornton criteria). Results: Out of 2977 ADRs reported, 375 were serious in nature. The most common clinical presentation involved was skin and appendageal disorders (71, 18.9%). The common causal drug group was antitubercular (129, 34.4%) followed by antiretroviral (76, 20.3%) agents. The criteria for the majority of serious ADRs were intervention to prevent permanent impairment or damage (164, 43.7%) followed by hospitalization (158, 42.1%). Majority of the serious ADRs were continuing (191, 50.9%) at the time of reporting, few recovered (101, 26.9%), and two were fatal. The majority of serious ADRs were categorized as possible (182, 48.8%) followed by probable (173, 46.1%) in nature. Conclusion: Antitubercular, antiretroviral, and antimicrobial drugs were the most common causal drug groups for serious ADRs. This calls for robust ADR monitoring system and education of patients and prescribers for identification and effective management. PMID:27843794
Mihajlovic, Silvija; Gauthier, Jeremie; MacDonald, Erika
Background: Adverse drug events (ADEs) occurring in hospital inpatients can have serious implications. The ability to identify and prioritize patients at higher risk of ADEs could help pharmacists to optimize their impact as members of the patient care team. Objective: To identify risk factors, patient characteristics, and medications associated with a higher likelihood of ADEs in adult inpatients through an overview of reviews on this topic. Data Sources: Systematic reviews and narrative reviews or guidelines identified through a search of MEDLINE and the Cochrane Database of Systematic Reviews (limited to articles published from 1995 to June 4, 2015), as well as a grey literature search. Study Selection and Data Extraction: For inclusion in this overview, a review had to discuss patient characteristics or risk factors associated with ADEs, medications associated with ADEs, or drug–drug interactions associated with ADEs, in adult inpatients. Articles retrieved by the literature search were screened for eligibility by a single reviewer. Data Synthesis: Eleven articles were deemed eligible for inclusion in this overview: 4 systematic reviews and 7 narrative reviews or guidelines. Their results were described narratively. Older age and polypharmacy were the most frequently cited risk factors associated with ADEs in hospital inpatients. Renal impairment, female sex, and decline in cognition were also frequently reported as being associated with ADEs. Medication classes reported to be associated with ADEs during the hospital stay included anticoagulants, anti-infectives/antibiotics, antidiabetic agents, analgesics (including opioids and nonsteroidal anti-inflammatory drugs), and cardiovascular drugs (including antihypertensive agents, diuretics, and digoxin). Two publications reported on preventable ADEs in hospital inpatients; the medications associated with preventable ADEs were consistent with those reported above. Conclusions: The risk factors, patient
Rydberg, Diana M.; Holm, Lennart; Engqvist, Ida; Fryckstedt, Jessica; Lindh, Jonatan D.; Stiller, Carl-Olav; Asker-Hagelberg, Charlotte
Purpose To identify the prevalence and preventability of adverse drug reactions (ADRs) in an emergency ward setting in a tertiary hospital in Sweden and to what extent the detected ADRs were reported to the Medical Product Agency (MPA). Methods In this prospective cross sectional observational study, 706 patients admitted to one of the Emergency Wards, at the Karolinska University Hospital in Solna, Stockholm during September 2008 –September 2009, were included. The electronic patient records were reviewed for patients’ demographic parameters, prevalence of possible ADRs and assessment of their preventability. In addition, the extent of formal and required ADR reporting to national registers was studied. Results Approximately 40 percent of the patient population had at least one possible ADR (n = 284). In the multivariable regression model, age and number of drugs were significantly associated with risk of presenting with an ADR (p<0.01 and p<0.001, respectively). Sex was not identified as a significant predictor of ADRs (p = 0.27). The most common ADRs were cardiovascular, followed by electrolyte disturbances, and hemorrhage. In 18 percent of the patient population ADRs were the reason for admission or had contributed to admission and 24% of these ADRs were assessed as preventable. The under-reporting of ADRs to the MPA was 99%. Conclusions ADRs are common in Emergency Medicine in tertiary care in Sweden, but under-reporting of ADRs is substantial. The most frequent ADRs are caused by cardiovascular drugs, and significantly associated with age and number of drugs. However, only a minority of the detected serious ADRs contributing to admission could have been avoided by increased risk awareness. PMID:27622270
Background Adverse drug reactions (ADR) are a substantial cause of hospital admissions. We conducted a nationwide study to estimate the burden of hospital admissions for ADRs in Spain during a six-year period (2001-2006) along with the associated total health cost. Methods Data were obtained from the national surveillance system for hospital data (Minimum Basic Data Set) maintained by the Ministry of Health and Consumer Affairs, and covering more than 95% of Spanish hospitals. From these admissions we selected all hospitalization that were code as drug-related (ICD-9-CM codes E), but intended forms of overdoses, errors in administration and therapeutics failure were excluded. The average number of hospitalizations per year, annual incidence of hospital admissions, average length of stay in the hospital, and case-fatality rate, were calculated. Results During the 2001-2006 periods, the total number of hospitalized patients with ADR diagnosis was 350,835 subjects, 1.69% of all acute hospital admissions in Spain. The estimated incidence of admissions due to ADR decreased during the period 2001-2006 (p < 0.05). More than five percent of patients (n = 19,734) died during an ADR-related hospitalization. The drugs most commonly associated with ADR-related hospitalization were antineoplastic and immunosuppressive drugs (n = 75,760), adrenal cortical steroids (n = 47,539), anticoagulants (n = 26,546) and antibiotics (n = 22,144). The costs generated by patients in our study increased by 19.05% between 2001 and 2006. Conclusions Approximately 1.69% of all acute hospital admissions were associated with ADRs. The rates were much higher for elderly patients. The total cost of ADR-related hospitalization to the Spanish health system is high and has increased between 2001 and 2006. ADRs are an important cause of admission, resulting in considerable use of national health system beds and a significant number of deaths. PMID:20942906
Manini, Alex F.; Hoffman, Robert S.; Stimmel, Barry; Vlahov, David
Objectives It was recently demonstrated that adverse cardiovascular events (ACVE) complicate a high proportion of hospitalizations for patients with acute drug overdoses. The aim of this study was to derive independent clinical risk factors for ACVE in patients with acute drug overdoses. Methods This prospective cohort study was conducted over 3 years at two urban university hospitals. Patients were adults with acute drug overdoses enrolled from the ED. In-hospital ACVE was defined as any of myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest. Results There were 1,562 patients meeting inclusion/exclusion criteria (mean age, 41.8 years; female, 46%; suicidal, 38%). ACVE occurred in 82 (5.7%) patients (myocardial injury, 61; shock, 37; dysrhythmia, 23; cardiac arrests, 22) and there were 18 (1.2%) deaths. On univariate analysis, ACVE risk increased with age, lower serum bicarbonate, prolonged QTc interval, prior cardiac disease, and altered mental status. In a multivariable model adjusting for these factors as well as patient sex and hospital site, independent predictors were: QTc > 500 msec (3.8% prevalence, odds ratio [OR] 27.6), bicarbonate < 20 mEql/L (5.4% prevalence, OR 4.4), and prior cardiac disease (7.1% prevalence, OR 9.5). The derived prediction rule had 51.6% sensitivity, 93.7% specificity, and 97.1% negative predictive value; while presence of two or more risk factors had 90.9% positive predictive value. Conclusions The authors derived independent clinical risk factors for ACVE in patients with acute drug overdose, which should be validated in future studies as a prediction rule in distinct patient populations and clinical settings. PMID:25903997
Niedrig, David Franklin; Hoppe, Liesa; Mächler, Sarah; Russmann, Heike; Russmann, Stefan
Objective Benzodiazepines and “Z-drug” GABA-receptor modulators (BDZ) are among the most frequently used drugs in hospitals. Adverse drug events (ADE) associated with BDZ can be the result of preventable medication errors (ME) related to dosing, drug interactions and comorbidities. The present study evaluated inpatient use of BDZ and related ME and ADE. Methods We conducted an observational study within a pharmacoepidemiological database derived from the clinical information system of a tertiary care hospital. We developed algorithms that identified dosing errors and interacting comedication for all administered BDZ. Associated ADE and risk factors were validated in medical records. Results Among 53,081 patients contributing 495,813 patient-days BDZ were administered to 25,626 patients (48.3%) on 115,150 patient-days (23.2%). We identified 3,372 patient-days (2.9%) with comedication that inhibits BDZ metabolism, and 1,197 (1.0%) with lorazepam administration in severe renal impairment. After validation we classified 134, 56, 12, and 3 cases involving lorazepam, zolpidem, midazolam and triazolam, respectively, as clinically relevant ME. Among those there were 23 cases with associated adverse drug events, including severe CNS-depression, falls with subsequent injuries and severe dyspnea. Causality for BDZ was formally assessed as ‘possible’ or ‘probable’ in 20 of those cases. Four cases with ME and associated severe ADE required administration of the BDZ antagonist flumazenil. Conclusions BDZ use was remarkably high in the studied setting, frequently involved potential ME related to dosing, co-medication and comorbidities, and rarely cases with associated ADE. We propose the implementation of automated ME screening and validation for the prevention of BDZ-related ADE. PMID:27711224
Ghattaoraya, Gurpreet S; Dundar, Yenal; González-Galarza, Faviel F; Maia, Maria Helena Thomaz; Santos, Eduardo José Melo; da Silva, Andréa Luciana Soares; McCabe, Antony; Middleton, Derek; Alfirevic, Ana; Dickson, Rumona; Jones, Andrew R
Human leukocyte antigens (HLA) are an important family of genes involved in the immune system. Their primary function is to allow the host immune system to be able to distinguish between self and non-self peptides-e.g. derived from invading pathogens. However, these genes have also been implicated in immune-mediated adverse drug reactions (ADRs), presenting a problem to patients, clinicians and pharmaceutical companies. We have previously developed the Allele Frequency Net Database (AFND) that captures the allelic and haplotype frequencies for these HLA genes across many healthy populations from around the world. Here, we report the development and release of the HLA-ADR database that captures data from publications where HLA alleles and haplotypes have been associated with ADRs (e.g. Stevens-Johnson Syndrome/toxic epidermal necrolysis and drug-induced liver injury). HLA-ADR was created by using data obtained through systematic review of the literature and semi-automated literature mining. The database also draws on data already present in AFND allowing users to compare and analyze allele frequencies in both ADR patients and healthy populations. The HLA-ADR database provides clinicians and researchers with a centralized resource from which to investigate immune-mediated ADRs.Database URL: http://www.allelefrequencies.net/hla-adr/.
Lawton, Kitta; Skjoet, Peter
One way to reduce adverse drug events (ADEs) is to empower the patient to participate in the control of medication. This empowerment can be supported in different ways by making knowledge and information available to the patient. This study examines the usefulness and safety of two different systems on the background of a paper-based medication list presenting prescribed medicine presently used in hospitals in Copenhagen. Each of the systems examined aims to reduce ADEs but presents information in different levels of detail, and anticipates different level of prior knowledge from the patient: a Web-based prototype presenting medication, lab-results and alerts, and a cell phone-based prototype presenting alerts. Six patients were introduced to each of the systems by performing small tasks and subsequently interviewed. The patients found the paper-based medication list useful and comprehensive for control of own prescribed medication. The Web-based prototype also proved to be useful, but drug and lab values were hard to correlate, and the alerts were hard to understand. The cell phone-based prototype proved less useful as the patients were challenged to vision the applicability of the system. Furthermore, it is a safety issue that the information the alert is based upon, stems from the patient alone. We conclude that, in order for the Web-based system as well as the cell phone system to empower patient and increase patient safety, further development of the systems is necessary.
Miller, Paul E.; Mannis, Mark J.
Abstract This article reviews ocular adverse events (AEs) reported in association with administration of antibody–drug conjugates (ADCs) in human clinical trials. References reporting ocular toxicity or AEs associated with ADCs were collected using online publication searches. Articles, abstracts, or citations were included if they cited ocular toxicities or vision-impairing AEs with a confirmed or suspected association with ADC administration. Twenty-two references were found citing ocular or vision-impairing AEs in association with ADC administration. All references reported use of ADCs in human clinical trials for treatment of various malignancies. The molecular target and cytotoxic agent varied depending on the ADC used. Ocular AEs affected a diversity of ocular tissues. The most commonly reported AEs involved the ocular surface and included blurred vision, dry eye, and corneal abnormalities (including microcystic corneal disease). Most ocular AEs were not severe (≤ grade 2) or dose limiting. Clinical outcomes were not consistently reported, but when specified, most AEs improved or resolved with cessation of treatment or with ameliorative therapy. A diverse range of ocular AEs are reported in association with administration of ADCs for the treatment of cancer. The toxicologic mechanism(s) and pathogenesis of such events are not well understood, but most are mild in severity and reversible. Drug development and medical professionals should be aware of the clinical features of these events to facilitate early recognition and intervention in the assessment of preclinical development programs and in human clinical trials. PMID:26539624
Bhuvaneswar, Chaya G; Baldessarini, Ross J; Harsh, Veronica L; Alpert, Jonathan E
The article critically reviews selected, clinically significant, adverse endocrine and metabolic effects associated with psychotropic drug treatments, including hyperprolactinaemia, hyponatraemia, diabetes insipidus, hypothyroidism, hyperparathyroidism, sexual dysfunction and virilization, weight loss, weight gain and metabolic syndrome (type 2 diabetes mellitus, dyslipidaemia and hypertension). Such effects are prevalent and complex, but can be managed clinically when recognized. They encourage continued critical assessment of benefits versus risks of psychotropic drugs and underscore the importance of close coordination of psychiatric and general medical care to improve long-term health of psychiatric patients. Options for management of hyperprolactinaemia include lowering doses, switching to agents such as aripiprazole, clozapine or quetiapine, managing associated osteoporosis, carefully considering the use of dopamine receptor agonists and ruling out stress, oral contraceptive use and hypothyroidism as contributing factors. Disorders of water homeostasis may include syndrome of inappropriate antidiuretic hormone (SIADH), managed by water restriction or slow replacement by hypertonic saline along with drug discontinuation. Safe management of diabetes insipidus, commonly associated with lithium, involves switching mood stabilizer and consideration of potassium-sparing diuretics. Clinical hypothyroidism may be a more useful marker than absolute cut-offs of hormone values, and may be associated with quetiapine, antidepressant and lithium use, and managed by thyroxine replacement. Hyper-parathyroidism requires comprehensive medical evaluation for occult tumours. Hypocalcaemia, along with multiple other psychiatric and medical causes, may result in decreased bone density and require evaluation and management. Strategies for reducing sexual dysfunction with psychotropics remain largely unsatisfactory. Finally, management strategies for obesity and metabolic syndrome
Background Adverse drug reactions (ADRs) are recognised as a common cause of hospital admissions, and they constitute a significant economic burden for hospitals. Hospital-based ADR monitoring and reporting programmes aim to identify and quantify the risks associated with the use of drugs provided in a hospital setting. This information may be useful for identifying and minimising preventable ADRs and may enhance the ability of prescribers to manage ADRs more effectively. The main objectives of this study were to evaluate ADRs that occurred during inpatient stays at the Hospital Geral de Palmas (HGP) in Tocantins, Brazil, and to facilitate the development of a pharmacovigilance service. Methods A prospective study was conducted at HGP over a period of 8 months, from January 2009 to August 2009. This observational, cross-sectional, descriptive study was based on an analysis of medical records. Several parameters were utilised in the data evaluation, including patient demographics, drug and reaction characteristics, and reaction outcomes. The reaction severity and predisposing factors were also assessed. Results The overall incidence of ADRs in the patient population was 3.1%, and gender was not found to be a risk factor. The highest ADR rate (75.8%) was found in the adult age group 15 to 50 years, and the lowest ADR rate was found in children aged 3 to 13 years (7.4%). Because of the high frequency of ADRs in orthopaedic (25%), general medicine (22%), and oncology (16%) patients, improved control of the drugs used in these specialties is required. Additionally, the nurse team (52.7%) registered the most ADRs in medical records, most likely due to the job responsibilities of nurses. As expected, the most noticeable ADRs occurred in skin tissues, with such ADRs are more obvious to medical staff, with rashes being the most common reactions. Metamizole, tramadol, and vancomycin were responsible for 21, 11.6, and 8.4% of ADRs, respectively. The majority of ADRs had
Kraft, W K; Waldman, S A
Governmental agencies overseeing pharmaceutical products use a risk/benefit approach to analyse data and make regulatory decisions. Comprehensive public dissemination of the safety profile of pharmaceutical products is part of an overall strategy for reducing risk associated with the use of any medical product. In the US, reports of postmarketing surveillance of approved drugs are in the public domain. Some, but not all, of the information in drug interaction studies is available to the public through the Freedom of Information Act (FOIA). However, there are concerns over the misuse of these data for commercial or other gain. The need to protect intellectual property and foster innovation in drug development, and concerns of legal liability are often cited as reasons to limit full public access to data from drug development studies. In contrast, intellectual freedom. public safety, and a mandate for transparent decision-making processes by regulatory agencies are issues that support open access to these data. Ultimately. concern for the public safety justifies open access to postmarketing surveillance data, and to a lesser degree, data regarding drug interactions in marketed products, and should outweigh the potential loss of competitive advantage by pharmaceutical companies.
Ohyama, Katsuhiro; Inoue, Michiko
Selective beta-adrenergic drugs are used clinically to treat various diseases. Because of imperfect receptor selectivity, beta-adrenergic drugs cause some adverse drug events by stimulating other adrenergic receptors. To examine the association between selective beta-adrenergic drugs and blood pressure elevation, we reviewed the Japanese Adverse Drug Event Reports (JADERs) submitted to the Japan Pharmaceuticals and Medical Devices Agency. We used the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms extracted from Standardized MedDRA queries for hypertension to identify events related to blood pressure elevation. Spontaneous adverse event reports from April 2004 through May 2015 in JADERs, a data mining algorithm, and the reporting odds ratio (ROR) were used for quantitative signal detection, and assessed by the case/non-case method. Safety signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. A total of 2021 reports were included in this study. Among the nine drugs examined, significant signals were found, based on the 95%CI for salbutamol (ROR: 9.94, 95%CI: 3.09-31.93) and mirabegron (ROR: 7.52, 95%CI: 4.89-11.55). The results of this study indicate that some selective beta-adrenergic drugs are associated with blood pressure elevation. Considering the frequency of their indications, attention should be paid to their use in elderly patients to avoid adverse events.
Gramec, Darja; Peterlin Mašič, Lucija; Sollner Dolenc, Marija
Thiophene is a five-membered, sulfur-containing heteroaromatic ring commonly used as a building block in drugs. It is considered to be a structural alert, as its metabolism can lead to the formation of reactive metabolites. Thiophene S-oxides and thiophene epoxides are highly reactive electrophilic thiophene metabolites whose formation is cytochrome P450-dependent. These reactive thiophene-based metabolites are quite often responsible for drug-induced hepatotoxicity. Tienilic acid is an example of a thiophene-based drug that was withdrawn from the market after only a few months of use, due to severe cases of immune hepatitis. However, inclusion of the thiophene moiety in drugs does not necessarily result in toxic effects. The presence of other, less toxic metabolic pathways, as well as an effective detoxification system in our body, protects us from the bioactivation potential of the thiophene ring. Thus, the presence of a structural alert itself is insufficient to predict a compound's toxicity. The question therefore arises as to which factors significantly influence the toxicity of thiophene-containing drugs. There is no easy way to answer this question. However, the findings presented here indicate that, for a number of reasons, daily dose and alternative metabolic pathways are important factors when predicting toxicity and will therefore be discussed together with examples.
Stevenson, Jennifer M; Williams, Josceline L; Burnham, Thomas G; Prevost, A Toby; Schiff, Rebekah; Erskine, S David; Davies, J Graham
Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR.
Stevenson, Jennifer M; Williams, Josceline L; Burnham, Thomas G; Prevost, A Toby; Schiff, Rebekah; Erskine, S David; Davies, J Graham
Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR. PMID:25278750
Alopecia is a dermatological condition with limited therapeutic options. Only two drugs, finasteride and minoxidil, are approved by FDA for alopecia treatment. However, little is known about the differences in adverse effects between these two drugs. We examined the clinical reports submitted to the FDA Adverse Event Reporting System (FAERS) from 2004 to 2014. For both female and males, finasteride was found to be more associated with reproductive toxicity as compared to minoxidil. Among male alopecia cases, finasteride was significantly more concurrent with several forms of sexual dysfunction. Among female alopecia cases, finasteride was significantly more concurrent with harm to fetus and disorder of uterus. In addition, drug-gene network analysis indicated that finasteride could profoundly disturb pathways related to sex hormone signaling and oocyte maturation. These findings could provide clues for subsequent toxicological research. Taken together, this analysis suggested that finasteride could be more liable to various reproductive adverse effects. Some of these adverse effects have yet to be warned in FDA-approved drug label. This information can help improve the treatment regimen of alopecia and post-marketing regulation of drug products. PMID:27738338
Momo, Kenji; Homma, Masato; Matsumoto, Sayaka; Sasaki, Tadanori; Kohda, Yukinao
The drug-drug interactions of tizanidine and cytochrome (CYP) P450 1A2 inhibitors, which potentially alter the hepatic metabolism of tizanidine, were investigated by retrospective survey of medical records with regard to prescription. One thousand five hundred sixty-three patients treated with tizanidine at University of Tsukuba Hospital were investigated. Of those, 713 patients (45.6%) were treated with coadministration of tizanidine and CYP1A2 inhibitors (37 drugs). The patients who received a combination of tizanidine and CYP1A2 inhibitors were characterized as elderly, having multiple diseases, and taking a large number of comedications (over 10 drugs) for a long period as compared with the patients who did not receive CYP1A2 inhibitors. Tizanidine-induced adverse effects were examined in 100 patients treated with coadministration of tizanidine and 8 CYP1A2 inhibitors. Adverse effects (e.g., drowsiness: 10 patients; low blood pressure: 9 patients; low heart rate: 9 patients) were observed in 23 patients (23%) 8±10 days after CYP1A2 inhibitors were coadministered. The patients with tizanidine-induced adverse effects were of older age (64.3±9.8 vs. 57.5±18.1 years, p<0.05) and received a higher daily dose of tizanidine (3.00±0.74 vs. 2.56±0.86 mg/day, p<0.05) than the patients without adverse effects. The present results suggest that coadministration of tizanidine and CYP1A2 inhibitors enhances tizanidine-induced adverse effects, especially in elderly patients treated with a higher dose of tizanidine.
Alexander, Stephen P H
In this review, I will consider the dual nature of Cannabis and cannabinoids. The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the 'abuse' of Cannabis outside the clinic. The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma. As with every other medicinal drug of course, the 'trick' will be to maximise the benefit and minimise the cost. After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit.
Giordano, Giuseppe N.; Ohlsson, Henrik; Kendler, Kenneth S.; Sundquist, Kristina; Sundquist, Jan
Aims Exposure to extraordinary traumatic experience is one acknowledged risk factor for drug use. We aim to analyse the influence of potentially life-changing childhood stressors, experienced second-hand, on later drug use disorder in a national population of Swedish adolescent and young adults (aged 15–26 years). Design We performed Cox Proportional Hazard regression analyses, complemented with co-relative pair comparisons. Setting Sweden Participants All individuals in the Swedish population born 1984 to 1995, who were registered in Sweden at the end of the calendar year they turned 14 years of age. Our follow-up time (Mean: 6.2 years; Range 11 years) started at the year they turned 15 and continued to December 2011 (N=1,409,218). Measurements Our outcome variable was drug use disorder, identified from medical, legal and pharmacy registry records. Childhood stressors, as per DSM-IV stressor criteria, include death of an immediate family member and second-hand experience of diagnoses of malignant cancer, serious accidental injury, and victim of assault. Other covariates include parental divorce, familial psychological well-being, and familial drug and alcohol use disorders. Findings After adjustment for all considered confounders, individuals exposed to childhood stressors ‘parental death’ or ‘parental assault’ had over twice the risk of drug use disorder than those who were not (HR = 2.63 (2.23–3.09) and 2.39 (2.06–2.79), respectively). Conclusions Children under 15 who experience second-hand an extraordinary traumatic event (such as a parent or sibling being assaulted, diagnosed with cancer, or dying) appear to have approximately twice the risk of developing a drug use disorder than those who do not. PMID:24612271
... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Drugs with potential for abuse. 314.104 Section 314.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... and Abbreviated Applications § 314.104 Drugs with potential for abuse. The Food and...
... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Drugs with potential for abuse. 314.104 Section 314.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... and Abbreviated Applications § 314.104 Drugs with potential for abuse. The Food and...
Subiela, José D; Dapena, Elida
Adverse drug reactions (ADRs) represent the first cause of change of the first-line highly active antiretroviral therapy (HAART) regimen, therefore, they constitute the main limiting factor in the long-term follow up of HIV patients in treatment. A retrospective study was carried out in a specialized center in Lara State, Venezuela, including 99 patients over 18 years of age who had change of first-line HAART regimen due to ADRs, between 2010 and 2013. The aims of this research were to describe the sociodemographic and clinical variables, frequency of ADRs related to change of HAART, duration of the first-line HAART regimen, to determine the drugs associated with ARVs and to identify the risk factors. The ADRs constituted 47.5% of all causes of change of first-line HAART regimen, the median duration was 1.08±0.28 years. The most frequent ADRs were anemia (34.3%), hypersensitivity reactions (20.2%) and gastrointestinal intolerance (13.1%). The most frequent ARV regimen type was the protease inhibitors-based regimen (59.6%), but zidovudine was the ARV most linked to ADRs (41.4%). The regression analysis showed increased risk of ADRs in singles and students in the univariate analysis and heterosexuals and homosexuals in multivariate analysis; and decreased risk in active workers. The present work shows the high prevalence of ADRs in the studied population and represents the first case-based study that describes the pharmacoepidemiology of a cohort of HIV-positive patients treated in Venezuela.
Boland, Mary Regina; Jacunski, Alexandra; Lorberbaum, Tal; Romano, Joseph; Moskovitch, Robert; Tatonetti, Nicholas P.
Small molecules are indispensable to modern medical therapy. However, their use may lead to unintended, negative medical outcomes commonly referred to as adverse drug reactions (ADRs). These effects vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. Current methods rely on clinical trials and post-market surveillance programs to find novel ADRs; however, clinical trials are limited by small sample size, while post-market surveillance methods may be biased and inherently leave patients at risk until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods. In particular, network analysis allows researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large-scale observational health data to predict ADRs in both individual patients and global populations. In this review, we explore the rapid expansion of systems pharmacology in the study of ADRs. We enumerate the existing methods and strategies and illustrate progress in the field with a model framework that incorporates crucial data elements, such as diet and comorbidities, known to modulate ADR risk. Using this framework, we highlight avenues of research that may currently be underexplored, representing opportunities for future work. PMID:26559926
Süsskind, M.; Thürmann, P. A.; Lüke, C.; Jeschke, E.; Tabali, M.; Matthes, H.; Ostermann, T.
Background. Anthroposophic medicine is one of the widely used approaches of complementary and alternative medicine. However, few prospective studies have generated safety data on its use. Objectives. We aimed to assess adverse drug reactions (ADRs) caused by anthroposophical medicines (AMEDs) in the anthroposophical Community Hospital Havelhoehe, GERMANY. Study Design and Methods. Between May and November 2007, patients of six medical wards were prospectively assessed for ADRs. Suspected ADRs occurring during hospitalization were documented and classified in terms of organ manifestation (WHO SOC-code), causality (according to the Uppsala Monitoring Centre WHO criteria), and severity. Only those ADRs with a severity of grade 2 and higher according to the CTCAE classification system are described here. Results. Of the 3,813 patients hospitalized, 174 patients (4.6%) experienced 211 ADRs (CTCAE grade 2/3 n = 191, 90.5%, CTCAE grade 4/5 n = 20, 9.5%) of which 57 ADRs (27.0%) were serious. The median age of patients with ADRs (62.1% females) was 72.0 (IQR: 61.0; 80.0). Six patients (0.2%) experienced six ADRs (2.8% of ADRs) caused by eight suspected AMEDs, all of which were mild reactions (grade 2). Conclusion. Our data show that ADRs caused by AMEDs occur rarely and are limited to mild symptoms. PMID:22315630
Berthe, Anaïs; Fronteau, Clémentine; Le Fur, Éloïse; Morin, Caroline; Huon, Jean-François; Rouiller-Furic, Isabelle; Berlioz-Thibal, Marielle; Berrut, Gilles; Lepelletier, Aline
Iatrogenic effects represent a large part of emergency admissions among elderly people. Throughout the care pathway of a patient, whether he is at home or hospitalized, many different health professionals are involved regarding the patient's medication. Medication reconciliation is one way to prevent adverse drug events at all care transitions for every patient by eliminating undocumented intentional discrepancies and unintentional discrepancies in the patient's medication. The aim of this article is to present the different activities of clinical pharmacy developed since 2011 in a follow up and rehabilitation geriatric care service, including medication reconciliation activity. Monitoring of this activity started in March 2014, indicators show that almost 90% of patients were reconciled at admission and discharge from the geriatric unit. Physicians and pharmacists play an active role in reviewing, managing and monitoring a patient's medication. Care coordination and communication among the many members of the medical care team have become one of the greatest challenges healthcare professionals face. At the time of discharge, the patient also plays a key role in medication reconciliation and should be educated when it's possible on the importance of managing medication information. Finally, the hospital pharmacist's role is to keep the primary care physicians and community pharmacists informed about medication changes.
Boland, Mary Regina; Jacunski, Alexandra; Lorberbaum, Tal; Romano, Joseph D; Moskovitch, Robert; Tatonetti, Nicholas P
Small molecules are indispensable to modern medical therapy. However, their use may lead to unintended, negative medical outcomes commonly referred to as adverse drug reactions (ADRs). These effects vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. Current methods rely on clinical trials and postmarket surveillance programs to find novel ADRs; however, clinical trials are limited by small sample size, whereas postmarket surveillance methods may be biased and inherently leave patients at risk until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods. In particular, network analysis allows researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large-scale observational health data to predict ADRs in both individual patients and global populations. In this review, we explore the rapid expansion of systems pharmacology in the study of ADRs. We enumerate the existing methods and strategies and illustrate progress in the field with a model framework that incorporates crucial data elements, such as diet and comorbidities, known to modulate ADR risk. Using this framework, we highlight avenues of research that may currently be underexplored, representing opportunities for future work.
Yasuda, Kie; Miyoshi, Yoko; Tachibana, Makiko; Namba, Noriyuki; Miki, Kazunori; Nakata, Yukiko; Takano, Toru; Ozono, Keiichi
Abstract. Graves’ disease (GD) accounts for a large proportion of pediatric hyperthyroidism, and the first-line treatment is antithyroid drug (ATD) therapy. Methimazole (MMI) is effective in most patients but is associated with significant adverse events (AEs). We reviewed the medical records of GD patients (n = 56) with onset age of <15 yr and investigated the relationship between MMI dose and AEs. The study population comprised 11 male and 45 female patients and the median age at diagnosis was 11 yr. All patients were initially treated with ATDs. Among the 52 patients initially treated with MMI, 20 received a low dose, and 32 received a high dose of MMI (< 0.7 vs ≥ 0.7 mg/kg/day, respectively). AEs occurred in 20% of the patients in the low-dose MMI group, and in 50% patients in the high-dose MMI group (p = 0.031). A greater variety of AEs was observed in the high-dose group. Neutropenia and rash were observed in both groups. With treatment transition to low-dose MMI according to the Japanese Society for Pediatric Endocrinology guidelines, we expect a decrease in the incidence of AEs in future. However, we should be careful as neutropenia and rash can occur independently of the MMI dose. PMID:28203042
Khan, Kashifullah; Khan, Amer Hayat; Sulaiman, Syed Azhar; Soo, Chow Ting; Akhtar, Ali
In the current study we explored the occurrence of adverse drug reactions (ADRs) to antiretroviral therapy among human immune-deficiency virus (HIV)/AIDS patients. We concluded an observational retrospective study in all patients who were diagnosed with HIV infection and were receiving highly active antiviral therapy from Jan. 2007 to Dec. 2012 at Hospital Pulau Pinang, Malaysia. Patient socio-demographic details along with clinical features and susceptible ADRs were observed during the study period. Out of 743 patients, 571 (76.9%) were men, and 172 (23.1%) were women. Overall 314 (42.2%) patients experienced ADRs. A total of 425 ADRs were reported, with 311 (73.1%) occurring in men and 114 (26.8%) in women, with a significant statistical relationship (P value (P) = 0.02, OR = 1.21). Overall 239 (56.2%) ADRs were recorded among Chinese, 94 (22.1%) in Malay, and 71 (16.7%) in Indian patients, which had a statistically significant association with ADRs (P = 0.05, OR = 1.50). Out of a total 425 among ADRs, lipodystrophy was recorded in 151 (35.5%) followed by skin rashes in 80 (18.8%), anemia in 74 (17.4%), and peripheral neuropathy in 27 (6.3%) patients. These findings suggest a need of intensive monitoring of ADRs in HIV treatment centres across Malaysia.
Deshpande, Rushikesh Prabhakar; Motghare, Vijay Motiram; Padwal, Sudhir Laxman; Pore, Rakesh Ramkrishna; Bhamare, Chetanraj Ghanshyam; Deshmukh, Vinod Shivaji; Pise, Harshal Nutan
Objectives The study was carried out with the aim of evaluation of the adverse drug reaction profile of anti-snake venom serum (ASV) in a rural tertiary care hospital. Methods An observational study was conducted in SRTR Medical College, Ambajogai, Maharashtra, India. A total number of 296 indoor case papers of snake bite from February to September 2011 and June to August 2012 were retrieved from the record section and the antivenom reactions were assessed. In addition, basic epidemiological data and prescribing practices of ASV were also analyzed. Results Vasculotoxic snake bites were more common (50.61%) than neuroparalytic ones (22.56%). Mild envenomation was the commonest presentation. A total of 92 (56.10%) patients who received ASV suffered from antivenom reactions. The most common nature of reaction was chills, rigors (69.56%) followed by nausea and vomiting (34.8%). 10-15% patients suffered from moderate to severe reactions like hypotension and sudden respiratory arrest. We did not find any dose response relationship of ASV to risk of reactions (odds ratio 0.37). Intradermal sensitivity test was performed in about 72% cases. Conclusion Our study showed a higher incidence of reactions to ASV at our institute. PMID:24396245
Alagoz, O; Durham, D; Kasirajan, K
We evaluated the cost-effectiveness of one-time pharmacogenomic testing for preventing adverse drug reactions (ADRs) over a patient's lifetime. We developed a Markov-based Monte Carlo microsimulation model to represent the ADR events in the lifetime of each patient. The base-case considered a 40-year-old patient. We measured health outcomes in life years (LYs) and quality-adjusted LYs (QALYs) and estimated costs using 2013 US$. In the base-case, one-time genetic testing had an incremental cost-effectiveness ratio (ICER) of $43,165 (95% confidence interval (CI) is ($42,769,$43,561)) per additional LY and $53,680 per additional QALY (95% CI is ($53,182,$54,179)), hence under the base-case one-time genetic testing is cost-effective. The ICER values were most sensitive to the average probability of death due to ADR, reduction in ADR rate due to genetic testing, mean ADR rate and cost of genetic testing.
Tanti, A; Serracino-Inglott, A; Borg, J J
The Maltese Medicines Authority was tasked with developing a reporting form that captures high-quality case information on adverse drug reactions (ADRs) and medication errors in order to fulfil its public-health obligations set by the European Union (EU) legislation on pharmacovigilance. This paper describes the process of introducing the first combined ADR/medication error reporting form in the EU for health-care professionals, the analysis of reports generated by it and the promotion of the system. A review of existing ADR forms was carried out and recommendations from the European Medicines Agency and World Health Organization audits integrated. A new, combined ADR/medication error reporting form was developed and pilot tested based on case studies. The Authority's quality system (ISO 9001 certified) was redesigned and a promotion strategy was deployed. The process used in Malta can be useful for countries that need to develop systems relative to ADR/medication error reporting and to improve the quality of data capture within their systems.
Du, Wei; Lehr, Victoria Tutag; Lieh-Lai, Mary; Koo, Winston; Ward, Robert M; Rieder, Michael J; Van Den Anker, John N; Reeves, Jaxk H; Mathew, Merene; Lulic-Botica, Mirjana; Aranda, Jacob V
Critically ill newborns in neonatal intensive care units (NICUs) are at greater risk of developing adverse drug reactions (ADRs). Differentiation of ADRs from reactions associated with organ dysfunction/immaturity is difficult. Current ADR algorithm scoring was established arbitrarily without validation in infants. The study objective was to develop a valid and reliable algorithm to identify ADRs in the NICU. Algorithm development began with a 24-item questionnaire for data collection on 100 previously suspected ADRs. Five pediatric pharmacologists independently rated cases as definite, probable, possible, and unlikely ADRs. Consensus "gold standard" was reached via teleconference. Logistic regression and iterative C programs were used to derive the scoring system. For validation, 50 prospectively collected ADR cases were assessed by 3 clinicians using the new algorithm and the Naranjo algorithm. Weighted kappa and intraclass correlation coefficient (ICC) were used to compare validity and reliability of algorithms. The new algorithm consists of 13 items. Kappa and ICC of the new algorithm were 0.76 and 0.62 versus 0.31 and 0.43 for the Naranjo algorithm. The new algorithm developed using actual patient data is more valid and reliable than the Naranjo algorithm for identifying ADRs in the NICU population. Because of the relatively small and nonrandom samples, further refinement and additional testing are needed.
Berman, S M; Kuczenski, R; McCracken, J T; London, E D
Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential. Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse
Shirkey, H C
This is a review of known periods in utero during which drugs alter the process of growth; effects may be shown on the fetus or the newborn and vary with the stage of development of the fetus when exposed. Other variables are the mother and the placenta. There is no safe animal screening mechanism, the human test is by ordeal, and more clinical monitoring and reporting are needed. Cancer chemotherapeutic agents exert their maximal effects on rapidly dividing cells and are therefore hazardous during pregnancy; the greatest risk is in the 1st trimester. In the thalidomide experience the critical days were the 22nd and 23rd days after conception. Masculinizing drugs such as testosterone and other androgenic steroids have been implicated as affecting the female fetus when given early in pregnancy. Oral contraceptives taken by an already pregnant woman are a hazard because of these progestational agents. Progesterone alone is unlikely to cause masculinization but other progestins may cause such changes. Carcinogenesis may develop later in females born of mothers who are treated with diethylstilbestrol to prevent miscarriage. Many antithyroid drugs have caused neonatal goiter. Maternal ingestion of iodides during pregnancy (preparations for treating asthma, cough syrups, radio-contrast media used in diagnoses) is the most frequent cause. Goiter is relatively common in infants whose mothers were treated with propylthiouracil and other antithyroid drugs, yet they usually show normal thyroid function. However, hypothyroidism with cretinism can occur. Lithium, used in psychiatry and as a salt substitute, may alter iodine metabolism and thyroid gland function. It also passes into the milk to continue the potential toxicity. Teratogenic effects in experimental animals suggest other possible effects on infants from lithium and similar drugs.
Summary: How can I quickly find the key events in a pathway that I need to monitor to predict that a/an beneficial/adverse event/outcome will occur? This is a key question when using signaling pathways for drug/chemical screening in pharma-cology, toxicology and risk assessment. ...
Bellet, Florelle; Asfari, Hadyl; Souvignet, Julien; Texier, Nathalie; Jaulent, Marie-Christine; Beyens, Marie-Noëlle; Burgun, Anita; Bousquet, Cédric
Background The underreporting of adverse drug reactions (ADRs) through traditional reporting channels is a limitation in the efficiency of the current pharmacovigilance system. Patients’ experiences with drugs that they report on social media represent a new source of data that may have some value in postmarketing safety surveillance. Objective A scoping review was undertaken to explore the breadth of evidence about the use of social media as a new source of knowledge for pharmacovigilance. Methods Daubt et al’s recommendations for scoping reviews were followed. The research questions were as follows: How can social media be used as a data source for postmarketing drug surveillance? What are the available methods for extracting data? What are the different ways to use these data? We queried PubMed, Embase, and Google Scholar to extract relevant articles that were published before June 2014 and with no lower date limit. Two pairs of reviewers independently screened the selected studies and proposed two themes of review: manual ADR identification (theme 1) and automated ADR extraction from social media (theme 2). Descriptive characteristics were collected from the publications to create a database for themes 1 and 2. Results Of the 1032 citations from PubMed and Embase, 11 were relevant to the research question. An additional 13 citations were added after further research on the Internet and in reference lists. Themes 1 and 2 explored 11 and 13 articles, respectively. Ways of approaching the use of social media as a pharmacovigilance data source were identified. Conclusions This scoping review noted multiple methods for identifying target data, extracting them, and evaluating the quality of medical information from social media. It also showed some remaining gaps in the field. Studies related to the identification theme usually failed to accurately assess the completeness, quality, and reliability of the data that were analyzed from social media. Regarding
Lau, Iris; Kirkwood, Allison
Background: An adverse drug event (ADE) is a noxious, unintended response to a drug, occurring at doses used in humans for prophylaxis, diagnosis, or treatment of disease or for modification of physiological function. ADEs account for about one-quarter of all adverse events in Canadian hospitals. Canadian data on specific types of ADEs and commonly implicated drugs are lacking. In particular, there is a paucity of data on ADEs that occur during hospital admissions. Objectives: The primary objective was to identify the incidence of ADEs in a sample of adult general medicine inpatients over a 1-year period. The secondary objective was to identify the 5 drugs most frequently responsible for ADEs in this setting. Methods: A retrospective chart analysis was conducted for general medicine patients discharged from St Paul’s Hospital in Vancouver, British Columbia, from January to December 2011. ADEs were identified using the Institute for Healthcare Improvement (IHI) Trigger Tool for Measuring Adverse Drug Events. The Naranjo criteria were applied to assess causality, and a physician independently authenticated the ADEs for preventability and harm using the categories of harm set out by the US National Coordinating Council for Medication Error Reporting and Prevention. Results: Of the 204 patient encounters reviewed, 15 involved ADEs, which represented an incidence of 7% over the 1-year study period. The 5 drugs most frequently implicated in ADEs were vancomycin, ciprofloxacin, ceftriaxone, piperacillin–tazobactam, and moxifloxacin. Conclusions: The rate of ADEs during hospital admissions was substantial. These events may necessitate additional investigations and interventions and may prolong the hospital stay. The authors do not recommend the IHI Trigger Tool for Measuring Adverse Drug Events for efficient prospective detection of ADEs in manual chart reviews. Possible modifications to improve the utility of this tool might include incorporating it into a compatible
AIM: To investigate the nature and severity of AE related to sacral neurostimulation (SNS). METHODS: Based on Pubmed and Embase searches, we identified published trials and case series of SNS for fecal incontinence (FI) and extracted data on adverse events, requiring an active intervention. Those problems were operationally defined as infection, device removal explant or need for lead and/or generator replacement. In addition, we analyzed the Manufacturer and User Device Experience registry of the Federal Drug Administration for the months of August - October of 2015. Events were included if the report specifically mentioned gastrointestinal (GI), bowel and FI as indication and if the narrative did not focus on bladder symptoms. The classification, reporter, the date of the recorded complaint, time between initial implant and report, the type of AE, steps taken and outcome were extracted from the report. In cases of device removal or replacement, we looked for confirmatory comments by healthcare providers or the manufacturer. RESULTS: Published studies reported adverse events and reoperation rates for 1954 patients, followed for 27 (1-117) mo. Reoperation rates were 18.6% (14.2-23.9) with device explants accounting for 10.0% (7.8-12.7) of secondary surgeries; rates of device replacement or explant or pocket site and electrode revisions increased with longer follow up. During the period examined, the FDA received 1684 reports of AE related to SNS with FI or GI listed as indication. A total of 652 reports met the inclusion criteria, with 52.7% specifically listing FI. Lack or loss of benefit (48.9%), pain or dysesthesia (27.8%) and complication at the generator implantation site (8.7%) were most commonly listed. Complaints led to secondary surgeries in 29.7% of the AE. Reoperations were performed to explant (38.2%) or replace (46.5%) the device or a lead, or revise the generator pocket (14.6%). Conservative management changes mostly involved changes in stimulation
Background In spite of enhanced control efforts, malaria remains a major public health problem causing close to a million deaths annually. With support from several donors, large amounts of artemisinin-based combination therapy (ACT) are being deployed in endemic countries raising safety concerns as little is known about the use of ACT in several of the settings where they are deployed. This project was undertaken to profile the provenance of the pharmacovigilance reporting of all anti-malarials, including ACT to the WHO adverse drug reaction (ADR) database (Vigibase™) over the past 40 years. Methods The WHO Programme for International Drug Monitoring, the Uppsala Monitoring Centre (UMC) provided anonymized extracts of Vigibase™ covering the period 1968-2008. All countries in the programme were clustered according to their malaria control phase and income status. The number of individual case safety reports (ICSRs) of anti-malarials was analyzed according to those clusters. Results From 1968 to 2008, 21,312 ICSRs suspecting anti-malarials were received from 64 countries. Low-income countries, that are also malaria-endemic (categorized as priority 1 countries) submitted only 1.2% of the ICSRs. Only 60 out of 21,312 ICSRs were related to ACT, 51 of which were coming from four sub-Saharan African countries. Although very few ICSRs involved artemisinin-based compounds, many of the adverse events reported were potentially serious. Conclusions This paper illustrates the low reporting of ADRs to anti-malarials in general and ACT in particular. Most reports were submitted by non-endemic and/or high-income countries. Given the current mix of large donor funding, the insufficient information on safety of these drugs, increasing availability of ACT and artemisinin-based monotherapies in public and private sector channels, associated potential for inappropriate use and finally a pipeline of more than 10 new novel anti-malarials in various stages of development, the
Böhm, Ingrid; Nairz, Knud; Morelli, John N; Keller, Patricia Silva Hasembank; Heverhagen, Johannes T
Purpose To test the hypothesis that the incomplete diagnosis "iodine allergy" is a possibly dangerous concept for patients under routine radiologic conditions. Materials and Methods 300 patients with a history of an "iodine allergy" were retrospectively screened and compared with two age-, sex-, and procedure-matched groups of patients either diagnosed with a nonspecific "iodine contrast medium (ICM) allergy" or an allergy to a specific ICM agent. For all groups, the clinical symptoms of the most recent past adverse drug reaction (ADR), prophylactic actions taken for subsequent imaging, and ultimate outcome were recorded and analyzed. Results The diagnosis "iodine allergy" was not otherwise specified in 84.3 % patients. For this group, in most cases, the symptoms of the previous ADRs were not documented. In contrast, the type of ADR was undocumented in only a minority of patients in the comparison groups. In the group of patients with an "iodine allergy" the percentage of unenhanced CT scans was greater than within the other two groups (36.7 % vs. 28.7 %/18.6 %). ADRs following prophylactic measures were only observed in the "iodine allergy" group (OR of 9.24 95 % CI 1.16 - 73.45; p < 0.04). Conclusion This data confirms the hypothesis that the diagnosis "iodine allergy" is potentially dangerous and results in uncertainty in clinical management and sometimes even ineffective prophylactic measures. Key points · The term "iodine allergy" is imprecise, because it designates allergies against different substance classes, such as disinfectants with complexed iodine and contrast media containing covalently bound iodine.. · There is a clear correlation between the exactness of the diagnosis - from the alleged "iodine allergy" to "contrast media allergy" to naming the exact culprit CM - and the quality of documentation of the symptoms.. · Management of patients diagnosed with "iodine allergy" was associated with uncertainty leading to
Liabeuf, Sophie; Masmoudi, Kamel; Scailteux, Lucie-Marie; Moragny, Julien; Masson, Henri; Brnet-Dufour, Valérie; Andrejak, Michel; Gras-Champel, Valérie
Abstract Although drug therapy is inherently associated with the risk of adverse drug reactions (ADRs), some of these events are preventable. The estimated proportion of preventable ADRs varies from one study or clinical context to another. Bleeding caused by antithrombotic agents (and particularly vitamin K antagonists, VKAs) constitutes one of the most frequent causes of ADR-related hospitalization. Hence, the objective of the present study was to adapt and validate an ADR preventability score for bleeding due to VKAs and evaluate the preventability of bleeding in 906 consecutive hospitalized, VKA-treated adult patients with a risk of major bleeding (defined as an international normalized ratio ≥5) over a 2-year period. A specific preventability scale for VKA-associated bleeding was developed by adapting a published tool. Overall, 241 of the 906 patients in the study experienced at least 1 VKA-associated bleeding event. The scale's reliability was tested by 2 different evaluators. The inter-rater reliability (evaluated by calculation of Cohen's kappa) ranged from “good” to “excellent.” Lastly, the validated scale was used to assess the preventability of the VKA-associated bleeding. We estimated that bleeding was preventable or potentially preventable in 109 of the 241 affected patients (45.2%). We have developed a useful, reliable tool for evaluating the preventability of VKA-associated bleeding. Application of the scale in a prospective study revealed that a high proportion of VKA-associated bleeding events in hospitalized, at-risk adult patients were preventable or potentially preventable. PMID:27684801
Wang, S F; Zhan, S Y
Electronic healthcare databases have become an important source for active surveillance of drug safety in the era of big data. The traditional epidemiology research designs are needed to confirm the association between drug use and adverse events based on these datasets, and the selection of the comparative control is essential to each design. This article aims to explain the principle and application of each type of control selection, introduce the methods and parameters for method comparison, and describe the latest achievements in the batch processing of control selection, which would provide important methodological reference for the use of electronic healthcare databases to conduct post-marketing drug safety surveillance in China.
Kose, Eiji; Uno, Kana; Hayashi, Hiroyuki
Typical antipsychotics are easily expressed as adverse events such as extrapyramidal symptom (EPS). On the other hand, incidence of adverse events due to atypical antipsychotics is low. Therefore, currently, atypical antipsychotics are widely used to treat schizophrenia. However, it has been reported that there is no difference in the frequency of EPS in atypical and typical antipsychotics. This study aimed to evaluate the expression profile of EPS in atypical and typical antipsychotics treatment using the Japanese Adverse Drug Event Report (JADER) database. We analyzed reports of EPS in the JADER database and calculated the reporting odds ratio (ROR) of antipsychotics potentially associated with EPS. We applied the Weibull shape parameter to time-to-event data in the JADER database. Consequently, there was little information to distinguish between the ROR of atypical and typical antipsychotics. A significant difference related to the time of onset of EPS in both antipsychotics was not recognized. However, when comparing each drug, Paliperidone, Perospirone, Blonanserin, and Aripiprazole were relatively developed as EPS in the early stage. On the other hand, Risperidone, Clozapine, Olanzapine, and Quetiapine were developed as EPS not only at an early stage but also after long-term use. In addition, this finding was suggested from the result of the cumulative incidence of EPS in each drug and of the time-to-onset analysis using Weibull distribution. These findings may contribute to future clinical practice because we revealed the expression profile of EPS in treatment with atypical and typical antipsychotics.
Harden, Cynthia L
Antiepileptic drug (AED) exposure in utero has been associated with major congenital malformations (MCMs) and adverse cognitive outcomes in the offspring of women with epilepsy (WWE). However, determining the exact risk and the relative risks of AEDs for these outcomes has been challenging, and only in recent years has improved study designs enabled us to get a clearer picture of the risks. Still, there is a startling lack of information for many of the newer and widely used AEDs. At this point of time, studies clearly show that valproate (VPA) as a part of polytherapy or when used as a monotherapy is associated with an increased risk of MCMs, and that it poses about threefold the risk of carbamazepine (CBZ). It is unclear if any other AEDs studied pose an increased risk of MCM occurrence; in the best available large study the absolute rates of MCMs with other several other AEDs were not different from untreated WWE. The absolute risks have been reported as CBZ 2.2%, lamotrigine (LTG) 3.2%, phenytoin (PHT) 3.7%, untreated WWE 3.5%, with VPA as the outlier at 6.2%. In utero VPA exposure is also associated with a risk of lower verbal intelligence quotient (IQ) in children, at approximately 10 points lower than controls. CBZ appears to pose no risk to cognitive outcome, and there is some evidence that PHT and phenobarbital (PB) may be associated with risk of reduced cognitive outcome. Polytherapy is associated with greater risk than monotherapy for both MCMs and cognitive outcome. Although more information is needed and hopefully will be obtained from ongoing prospective studies, it is clear that WWE taking VPA and planning pregnancy should have a discussion with their physician about considering changing to another AED before pregnancy, if possible.
Background Reporting of adverse drug reactions (ADRs) has traditionally been the sole province of healthcare professionals. In the European Union, more countries have allowed consumers to report ADRs directly to the regulatory agencies. The aim of this study was to characterize ADRs reported by European consumer for nervous system medications. Methods ADRs reported by consumers for nervous system medications (ATC group N) from 2007 to 2011 and located in the European ADR database, EudraVigilance, were analysed. Data were categorized with respect to age and sex, category and seriousness of reported ADRs and medications. The unit of analysis was one ADR. Results We located 4766 ADRs reported for nervous system medications, and one half of these were serious including 19 deaths. Less than 5% of ADRs were reported in children. Totally, 58% of ADRs were reported for women, 42% for men. The majority of reported ADRs were of the types “nervous system disorders” (18% of total ADRs) followed by “psychiatric disorders” (18% of total ADRs) and “general disorders” (15% of total ADRs) which also were the system organ classes in which the majority of serious ADRs were found. ADR reports encompassed medicines from the therapeutic groups: antiepileptics (ATC group N03) (36% of total ADRs), parasympathomimetics (ATC group N07) (22% of total ADRs) and antidepressants ATC group N06A (9% of total ADRs). Antiepileptics were the therapeutic group with the highest share of serious ADRs (60%) followed by antidepressants (15%). Many serious ADRs were reported for pregabalin and varenicline. Conclusions The majority of ADRs from nervous system mediations reported by consumers that were identified from the EudraVigilance database were serious. The value of consumer reports in pharmacovigilance still remains unclarified. PMID:23763896
Blandizzi, Corrado; De Paolis, Barbara; Colucci, Rocchina; Lazzeri, Gloria; Baschiera, Fabio; Del Tacca, Mario
This study investigates the mechanisms accounting for the adverse cholinergic effects of the antitumour drug irinotecan. The activity of irinotecan and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), was assayed in models suitable for pharmacological studies on cholinergic system. Irinotecan moderately inhibited human or electric eel acetylcholinesterase activity, SN-38 had no effect, whereas physostigmine blocked both the enzymes with high potency and efficacy. Irinotecan and SN-38 did not affect spontaneous or electrically-induced contractile activity of human colonic muscle. Acetylcholine and dimethylphenylpiperazinium (DMPP) caused phasic contractions or relaxations, respectively. Physostigmine enhanced the motor responses elicited by electrical stimulation. Although irinotecan and SN-38 did not modify the basal contractile activity of guinea-pig ileum longitudinal muscle strips, irinotecan 100 μM moderately enhanced cholinergic twitch contractions. Acetylcholine or DMPP caused phasic contractions, whereas physostigmine enhanced the twitch responses. Electrically-induced [3H]-acetylcholine release was reduced by irinotecan (100 μM) or physostigmine (0.1 μM). Intravenous irinotecan stimulated gastric acid secretion in rats, but no effects were obtained with SN-38, physostigmine or i.c.v. irinotecan. Hypersecretion induced by irinotecan was partly prevented by ondansetron, and unaffected by capsazepine. In the presence of atropine, vagotomy and systemic or vagal ablation of capsaicin-sensitive afferent fibres, irinotecan did not stimulate gastric secretion. The present results indicate that irinotecan and SN-38 do not act as specific acetylcholinesterase blockers or acetylcholine receptor agonists. It is rather suggested that irinotecan promotes a parasympathetic discharge to peripheral organs, mediated by capsaicin-sensitive vagal afferent fibres, and that serotonin 5-HT3 receptors are implicated in the genesis of vago-vagal reflex
Kiguba, Ronald; Karamagi, Charles; Bird, Sheila M
We sought to determine the prevalence at admission and incidence during hospitalization of antibiotic-associated suspected adverse drug reactions (aa-ADRs) among Ugandan inpatients; and to characterize these aa-ADRs. We conducted a prospective cohort study of 762 consented adults admitted on medical and gynecological wards of the 1790-bed Mulago National Referral Hospital. Thirty percent were known HIV-seropositive (232/762). Nineteen percent (148/762; 95% CI: 17-22%) of inpatients experienced at least one aa-ADR. At hospital admission, 6% (45/762; 95% CI: 4-8%) of patients had at least one aa-ADR; and 15% (45/300; 11-20%) of those who had received antibiotics in the 4-weeks preadmission. Twenty-four (53%) of these 45 patients had serious aa-ADRs. The incidence of aa-ADRs was 19% (117/629; 95% CI: 16-22%) of patients who received antibiotics [community-acquired: 9% (27/300; 95% CI: 6-13%); hospital-acquired: 16% (94/603; 95% CI: 13-19%)]: 39 (33%) of 117 patients had serious aa-ADRs. Of 269 aa-ADRs, 115 (43%) were community-acquired, 66 (25%) probable/definite, 171 (64%) preventable, 86 (32%) serious, and 24 (9%) rare. Ceftriaxone was the most frequently implicated for serious hospital-acquired aa-ADRs. Cotrimoxazole, isoniazid, rifampicin, ethambutol, and pyrazinamide were the most frequently linked to serious community-acquired aa-ADRs. Fatal jaundice (isoniazid), life-threatening difficulty in breathing with shortness of breath (rifampicin) and disabling itchy skin rash with numbness of lower swollen legs (ethambutol, isoniazid) were observed. Pharmaceutical quality testing of implicated antibiotics could be worthwhile. Periodic on-ward collection and analysis of antibiotic-safety-data standardized by consumption is an efficient method of tracking antibiotics with 1%-risk for serious aa-ADRs.
Pugsley, Michael K; Authier, Simon; Curtis, Michael J
Cationic compounds are diverse and atypical therapeutic substances. In the present study we examined whether a prototypical class effect of cationic drugs in the cardiovascular system exists and whether this might be predictable on the basis of chemistry. The dose-dependent effects of cationic compounds of varying molecular weights and charge were examined on the blood pressure (BP), heart rate (HR) and the ECG in anesthetized rats. The compounds examined were protamine, hexadimethrine, tetraethylammonium (TEA), low molecular weight poly-L-lysine (LMW-PLL) and high molecular weight PLL (HMW-PLL). All of the compounds examined except TEA produced a dose-dependent reduction in BP. No changes occurred in HR even when high doses were administered. The ECG effects of these cationic compounds included a dose-dependent prolongation of the QT interval, especially at higher doses. All compounds transiently decreased the size of the P-wave after i.v. bolus administration whereas only protamine and hexadimethrine prolonged the PR and QRS intervals and only at the highest dose (32 mg/kg) administered. All cationic compounds, except TEA and saline, evoked ventricular premature beats (VPB), and protamine and HMW-PLL also evoked brief episodes of ventricular tachycardia (VT). The incidence and frequency of arrhythmias was not dose-dependent and no animals experienced protracted episodes of arrhythmia incidence. These dose dependent effects of the polycationic compounds tested suggest a collective mechanism of action that relates the effect of charge of the compound to the onset and persistence of observed cardiovascular toxicity, and adverse cardiovascular effect risk appears to be predictable on this basis.
Tripathi, Raakhi Kaliprasad; Jalgaonkar, Sharmila Vinayak; Sarkate, Pankaj V.; Rege, Nirmala Narayan
Objectives: Underreporting and poor quality of adverse drug reaction (ADR) reports pose a challenge for the Pharmacovigilance Program of India. A module to impart knowledge and skills of ADR reporting to MBBS students was developed and evaluated. Materials and Methods: The module consisted of (a) e-mailing an ADR narrative and online filling of the “suspected ADR reporting form” (SARF) and (b) a week later, practical on ADR reporting was conducted followed by online filling of SARF postpractical at 1 and 6 months. SARF was an 18-item form with a total score of 36. The module was implemented in the year 2012–2013. Feedback from students and faculty was taken using 15-item prevalidated feedback questionnaires. The module was modified based on the feedback and implemented for the subsequent batch in the year 2013–2014. The evaluation consisted of recording the number of students responding and the scores achieved. Results: A total of 171 students in 2012–2013 batch and 179 in 2013–2014 batch participated. In the 2012–2013 batch, the number of students filling the SARF decreased from basal: 171; 1 month: 122; 6 months: 17. The average scores showed improvement from basal 16.2 (45%) to 26.4 (73%) at 1 month and to 27.3 (76%) at 6 months. For the 2013–2014 batch, the number (n = 179) remained constant throughout and the average score progressively increased from basal 10.5 (30%) to 27.8 (77%) at 1 month and 30.3 (84%) at 6 months. Conclusion: This module improved the accuracy of filling SARF by students and this subsequently will led to better ADR reporting. Hence, this module can be used to inculcate better ADR reporting practices in budding physicians. PMID:28031613
Martins, H H; Alonso, N B; Vidal-Dourado, M; Carbonel, T D; de Araújo Filho, G M; Caboclo, L O; Yacubian, E M; Guilhoto, L M
We report the results of administration of the Portuguese-Brazilian translation of the Liverpool Adverse Events Profile (LAEP) to 100 patients (mean age=34.5, SD=12.12; 56 females), 61 with symptomatic partial epilepsy (SPE) and 39 with idiopathic generalized epilepsy (IGE) (ILAE, 1989) who were on a stable antiepileptic drug (AED) regimen and being treated in a Brazilian tertiary epilepsy center. Carbamazepine was the most commonly used AED (43.0%), followed by valproic acid (32.0%). Two or more AEDs were used by 69.0% of patients. The mean LAEP score (19 questions) was 37.6 (SD=13.35). The most common adverse effects were sleepiness (35.0%), memory problems (35.0%), and difficulty in concentrating (25.0%). Higher LAEP scores were associated with polytherapy with three or more AEDs (P=0.005), female gender (P<0.001), older age (P<0.001), and uncontrolled seizures (P=0.045). The intraclass coefficient (test-retest reliability) for LAEP overall score was 0.848 (95% CI=0.782-0.895), with a range from 0.370 (unsteadiness) to 0.750 (memory problems). Cronbach's α coefficient (internal consistency) was 0.903. The LAEP was highly correlated with Quality of Life in Epilepsy-31 inventory (r=-0.804, P>0.001) and Hospital Anxiety and Depression Scale (Depression: r=0.637, P<0.001; Anxiety: r=0.621, P<0.001) dimensions. LAEP overall scores were similar in people with SPE and IGE and were not helpful in differentiating adverse effects in these two groups. Clinical variables that influenced global LAEP were seizure frequency (P=0.050) and generalized tonic-clonic seizures in the last month (P=0.031) in the IGE group, and polytherapy with three or more AEDs (P=0.003 and P=0.003) in both IGE and SPE groups.
Galbiati, Valentina; Papale, Angela; Kummer, Elena; Corsini, Emanuela
Hypersensitivity drug reactions (HDRs) are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug-induced adverse effects, and include immune-mediated (“allergic”) and non-immune-mediated (“pseudo allergic”) reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon. We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells. PMID:27462271
Jiang, Guoqian; Wang, Liwei; Liu, Hongfang; Solbrig, Harold R; Chute, Christopher G
A semantically coded knowledge base of adverse drug events (ADEs) with severity information is critical for clinical decision support systems and translational research applications. However it remains challenging to measure and identify the severity information of ADEs. The objective of the study is to develop and evaluate a semantic web based approach for building a knowledge base of severe ADEs based on the FDA Adverse Event Reporting System (AERS) reporting data. We utilized a normalized AERS reporting dataset and extracted putative drug-ADE pairs and their associated outcome codes in the domain of cardiac disorders. We validated the drug-ADE associations using ADE datasets from SIDe Effect Resource (SIDER) and the UMLS. We leveraged the Common Terminology Criteria for Adverse Event (CTCAE) grading system and classified the ADEs into the CTCAE in the Web Ontology Language (OWL). We identified and validated 2,444 unique Drug-ADE pairs in the domain of cardiac disorders, of which 760 pairs are in Grade 5, 775 pairs in Grade 4 and 2,196 pairs in Grade 3.
Meyer, Charles; Behm, Nicole; Brown, Emily; Copeland, Nathanial K; Sklar, Marvin J
Adverse drug reactions (ADRs) to antibiotics complicate the management of any infection, particularly opportunistic infections in advanced HIV as some ADRs are potentiated by HIV. Trimethoprim-sulfamethoxazole (TMP-SMX) causes ADRs in 40-80% of HIV infected individuals, compared to 3-5% in the general population. The incidence and severity of ADRs among HIV infected individuals appear to increase as they progress from latent infection to AIDS. We present a single case report of a 55-year-old African American male found to have an otherwise asymptomatic acute HIV infection who developed an ADR to TMP-SMX, despite having previously tolerating the medication. The proposed mechanisms for the increased incidence of sulfa hypersensitivity reactions among HIV infected individuals focus on either (1) HIV-induced changes in the immune function driven by falling levels of CD4 cells or (2) other HIV-specific factors correlated with rising viral load. To our knowledge this is the first reported case of new sulfa hypersensitivity in primary HIV and may provide clinical evidence to support the correlation between viral load and ADRs to TMP-SMX without a severely diminished CD4 count, though further research is necessary. This case also demonstrates a rare and easily overlooked presentation of HIV that may aid in early diagnosis.
Yang, Y; Chen, S; Yang, F; Zhang, L; Alterovitz, G; Zhu, H; Xuan, J; Yang, X; Luo, H; Mu, J; He, L; Luo, X; Xing, Q
Clindamycin causes cutaneous adverse drug reactions (cADRs), sometimes with the mechanisms of pathogenicity or risk factors unknown. This study aims to assess whether HLA alleles are associated with clindamycin-related cADRs in the Han Chinese population. We performed an association study of 12 subjects with clindamycin-related cADRs, 279 controls and 26 clindamycin-tolerant subjects. Subjects who received clindamycin through intravenous drip were analyzed separately. Unbiased, in silico docking was conducted. We found 6 out of 12 clindamycin-induced cADR patients carried HLA-B*51:01, and all of them received clindamycin via intravenous drip (6/9). The carrier frequency of HLA-B*51:01 is significantly higher compared with the control group (P=0.0006; OR=9.731, 95% CI: 2.927-32.353) and the clindamycin-tolerant group (OR=24.000, 95% CI: 3.247-177.405). In silico docking showed clindamycin is potentially more stable inside HLA-B*51:01 protein. Our results suggested, for the first time, that HLA-B*51:01 is a risk allele for clindamycin-related cADRs in Han Chinese, especially when clindamycin is administered via intravenous drip.The Pharmacogenomics Journal advance online publication, 16 August 2016; doi:10.1038/tpj.2016.61.
Zhang, Xiaoyan; Hamadeh, Issam S; Song, Shuang; Katz, Joseph; Moreb, Jan S; Langaee, Taimour Y; Lesko, Lawrence J; Gong, Yan
Osteonecrosis of the jaw (ONJ) is a serious adverse drug event that was initially reported with intravenous bisphosphonates (BPs) and more recently with other classes of drugs such as receptor activator of NF-κB ligand (RANKL) inhibitor, antiangiogenic agents, and mammalian target of rapamycin (m-TOR) inhibitors. The purpose of this study is to analyze the ONJ cases and the associated drugs in the US Food and Drug Administration's adverse event reporting system (FAERS). The FAERS database was queried for the adverse drug events reported from the first quarter of 2010 to the first quarter of 2014. The reporting odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each queried drug. A total of 17,119 unique ONJ cases were identified. In the overall analysis, the drugs with the highest reporting ORs were BPs: pamidronate (OR = 498.9), zoledronate (OR = 171.7), and alendronate (OR = 63.6), whereas denosumab had lower ORs than all the BPs except for etidronate. The antiangiogenic and m-TOR inhibitors had the lowest ORs. In cancer patients who were treated for prevention of skeletal-related events (SREs), the reporting ORs for zoledronate and denosumab were 125.2 and 4.9, respectively. In patients with osteoporosis, the ORs were 1.1 (1.0-1.18) for zoledronate and 0.63 (0.56-0.70) for denosumab, respectively. Our analysis of the FAERS database showed that the intravenous BPs were associated with the highest risk for ONJ, RANKL inhibitor was associated with risk comparable to BPs used for osteoporosis such as etidronate, and the antiangiogenic agents and m-TOR inhibitors were associated with the lowest risk for ONJ. The high risk for ONJ with zoledronate and denosumab was mainly observed in those who were treated for prevention of SREs, whereas there was limited evidence for such risk in those who were treated for osteoporosis.
Kennedy-Dixon, Tracia-Gay; Gossell-Williams, Maxine; Hall, Jannel; Anglin-Brown, Blossom
Objective: To identify major potential drug-drug interactions (DDIs) on prescriptions filled at the University Health Centre Pharmacy, Mona Campus, Jamaica. Methods: This investigation utilised a cross-sectional analysis on all prescriptions with more than one drug that were filled at the Health Centre Pharmacy between November 2012 and February 2013. Potential DDIs were identified using the online Drug Interactions Checker database of Drugs.com. Results: During the period of the study, a total of 2814 prescriptions were analysed for potential DDIs. The prevalence of potential DDIs found during the study period was 49.82%. Major potential DDIs accounted for 4.7 % of the total number of interactions detected, while moderate potential DDIs and minor potential DDIs were 80.8 % and 14.5 % respectively. The three most frequently occurring major potential DDIs were amlodipine and simvastatin (n=46), amiloride and losartan (n=27) and amiloride and lisinopril (n=16). Conclusion: This study has highlighted the need for educational initiatives to ensure that physicians and pharmacists collaborate in an effort to minimise the risks to the patients. These interactions are avoidable for the most part, as the use of online tools can facilitate the selection of therapeutic alternatives or guide decisions for closer patient monitoring and thus reduce the risks of adverse events. PMID:26759615
Böhm, Ruwen; von Hehn, Leocadie; Herdegen, Thomas; Klein, Hans-Joachim; Bruhn, Oliver; Petri, Holger; Höcker, Jan
Pharmacovigilance contributes to health care. However, direct access to the underlying data for academic institutions and individual physicians or pharmacists is intricate, and easily employable analysis modes for everyday clinical situations are missing. This underlines the need for a tool to bring pharmacovigilance to the clinics. To address these issues, we have developed OpenVigil FDA, a novel web-based pharmacovigilance analysis tool which uses the openFDA online interface of the Food and Drug Administration (FDA) to access U.S. American and international pharmacovigilance data from the Adverse Event Reporting System (AERS). OpenVigil FDA provides disproportionality analyses to (i) identify the drug most likely evoking a new adverse event, (ii) compare two drugs concerning their safety profile, (iii) check arbitrary combinations of two drugs for unknown drug-drug interactions and (iv) enhance the relevance of results by identifying confounding factors and eliminating them using background correction. We present examples for these applications and discuss the promises and limits of pharmacovigilance, openFDA and OpenVigil FDA. OpenVigil FDA is the first public available tool to apply pharmacovigilance findings directly to real-life clinical problems. OpenVigil FDA does not require special licenses or statistical programs. PMID:27326858
Amin, Mohammad Nurul; Khan, Tahir Mehmood; Dewan, Syed Masudur Rahman; Islam, Mohammad Safiqul; Moghal, Mizanur Rahman
Objectives To assess community pharmacists'/pharmacy technicians' knowledge and perceptions about adverse drug reactions (ADRs) and barriers towards the reporting of such reactions in Dhaka, Bangladesh. Method A cross-sectional study was planned to approach potential respondents for the study. A self-administered questionnaire was delivered to community pharmacists/pharmacy technicians (N=292) practising in Dhaka, Bangladesh. Results The overall response to the survey was 69.5% (n=203). The majority of the sample was comprised of pharmacy technicians (152, 74.9%) who possessed a diploma in pharmacy, followed by pharmacists (37, 18.2%) and others (12, 5.9%). Overall, 72 (35.5%) of the respondents disclosed that they had experienced an ADR at their pharmacy, yet more than half (105, 51.7%) were not familiar with the existence of an ADR reporting body in Bangladesh. Exploring the barriers to the reporting of ADRs, it was revealed that the top four barriers to ADR reporting were ‘I do not know how to report (Relative Importance Index (RII)=0.998)’, ‘reporting forms are not available (0.996)’, ‘I am not motivated to report (0.997)’ and ‘Unavailability of professional environment to discuss about ADR (RII=0.939)’. In addition to these, a majority (141, 69.46%) were not confident about the classification of ADRs (RII=0.889) and were afraid of legal liabilities associated with reporting ADRs (RII=0.806). Moreover, a lack of knowledge about pharmacotherapy and the detection of ADRs was another major factor hindering their reporting (RII=0.731). Conclusions The Directorate of Drug Administration in Bangladesh needs to consider the results of this study to help it improve and simplify ADR reporting in Bangladeshi community pharmacy settings. PMID:27489151
Castillo-Carandang, Nina T; Juban, Noel R; Amarillo, Maria Lourdes; Tagle, Maria Pamela; Baja, Emmanuel S
Background Paper-based adverse drug reaction (ADR) reporting has been in practice for more than 6 decades. Health professionals remain the primary source of reports, while the value of patients’ reporting is yet unclear. With the increasing popularity of using electronic gadgets in health, it is expected that the electronic transmission of reports will become the norm within a few years. Objective The aims of this study are to investigate whether short messaging service or texting can provide an alternative or supplemental method for ADR reporting given the increasing role of mobile phones in health care monitoring; to determine the usefulness of texting in addition to paper-based reporting of ADRs by resident physicians; and to describe the barriers to ADR reporting and estimate the cost for setting up and maintaining a texting-computer reporting system. Methods This was a pre-post cross-sectional study that measured the number of ADRs texted by 51 resident physicians for 12 months from the Department of Obstetrics and Gynecology and the Department of Adult Medicine of a tertiary government hospital in Manila, Philippines, with 1350-bed capacity. Reports were captured by a texting-computer reporting system. Prior to its implementation, key informant interview and focus group discussion were conducted. Baseline information and practice on the existing paper-based reporting system were culled from the records of the hospital’s Pharmacy and Therapeutics Committee. A postintervention survey questionnaire was administered at the end of 12 months. Results Only 3 ADRs were texted by 51 resident physicians in 12 months (reporting rate 3/51 or 6%). By contrast, 240 ADRs from the paper-based reporting system from 848 resident physicians of the study hospital were collected and tabulated (reporting rate 240/848 or 28.3%). Texting ADRs was not efficient because of power interruption, competition with the existing paper-based reporting system, and unforeseen expiration of
During 1988, the Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED) coordinated a pilot study aimed at evaluating the feasibility of a system for spontaneous monitoring of adverse drug reactions in dermatological practice in Italy. Approximately 400 dermatologists were asked to collaborate, and 141 agreed to the study. Procedures similar to those well established in other surveillance programs (including the use of standard forms and standardized assessment procedure) were adopted. In a 2-month period 775 reports were collected, of which 711 were maintained after careful evaluation. The general profile of the adverse reactions reported was in accordance with the experience derived by other spontaneous surveillance programs. The main purpose of spontaneous reporting systems is the identification of new reactions, and a model analysis was proposed, in our study, with reference to skin reactions to bamifylline. The demonstration of the feasibility of a drug-monitoring program in Italy, where little tradition exists in the area, is the most important result of our study.
Kalogirou, Eleni-Marina; Katsoulas, Nikolaos; Tosios, Konstantinos I; Lazaris, Andreas C; Sklavounou, Alexandra
Leflunomide is a member of the disease modifying anti-rheumatic drugs group used as a treatment modality in active rheumatoid and psoriatic arthritis. "Oral ulcers" are reported in 3-5% of leflunomide medicated rheumatoid arthritis patients with adverse events, but they are not described in detail in the literature. We present a case of an ulcer in the tongue of a rheumatoid arthritis patient managed with leflunomide and contemplate on its pathogenesis. Key words:Leflunomide, oral ulcer, DHODH.
Adhyapak, M S; Kachole, M S
Throughout the world, herbal medicines are consumed by most of the patients without considering their adverse effects. Many herbal medicines/plant extracts have been reported to interact with the natural blood clotting system. In continuation to this effort, thirty medicinal plant extracts were allowed to interact with citrated human blood and the clotting time was measured after re-calcification in vitro using Lee and White method. The aq. leaf ext. of Syzygium cumini and Camellia sinensis significantly prolonged the clotting time. In response to the prothrombin time and activated partial thromboplastin time tests, the ext. of C. sinensis showed normal APTT and marginally prolonged the PT to 16.7 s (control-15.2 s) while S. cumini showed normal PT but significantly prolonged the APTT to 66.9 s (control-20.7 s). This suggests that, C. sinensis acts on the extrinsic pathway while S. cumini on the intrinsic pathway. There are some common herbal formulations that are frequently used by the patients which contain above plant materials, like, Syzygium cumin in anti-diabetic formulations, while the ext. of C. sinensis is consumed frequently as beverage in many part of the world. Hence, patients having known bleeding tendency or haemophilia disease should take into account the interaction potential of these plants with the natural blood clotting system while taking herbal formulations containing above plants; specially, the patients suffering from intrinsic pathway factor deficiency should keep a limit on the consumption of S. cumini while extrinsic pathway factor deficiency patients should limit C. sinensis. Also, the medical practitioners should consider the patient's food consumption history before doing any major surgical procedures.
Skvrce, Nikica Mirosević; Bozina, Nada; Sarinić, Viola Macolić; Tomić, Sinisa
Hydroxymethylglutaryl-CoA reductase inhibitors (statins) are drugs used in the treatment of chronic diseases and frequently in concomitant therapy with many other drugs. Therefore, the risk of adverse drug reactions (ADRs), especially those caused by interactions is high. Aim of the study was to describe and analyze ADRs caused by statins reported to Croatian Agency from March 2005 to December 2008, and to emphasize reasons of their occurrence. 136 of statin ADRs were reported. 12 % of all reported statins' ADRs were caused by interactions, which is higher than percent (5.6%) of interactions caused by all other drugs in 2005 and 2006. Proportion of serious ADRs related to administered dose and thus preventable was higher than proportion of all ADRs caused by statins (p = 0.003). Most serious ADRs could have been prevented with better understanding of interactions and by use of pharmacogenomics in identifying patients that are because of genetic predisposition more sensitive to standard doses.
Du, Dongyi; Goldsmith, John; Aikin, Kathryn J; Encinosa, William E; Nardinelli, Clark
In 2007 the federal government began requiring drug makers to include in their print direct-to-consumer advertisements information for consumers on how to contact the Food and Drug Administration directly, either by phone or through the agency's website, to report any adverse events that they experienced after taking a prescription drug. Adverse events can range from minor skin problems like itching to serious injuries or illness that result in hospitalization, permanent disability, or even death. Even so, current rates of adverse event reporting are low. We studied adverse event reports about 123 drugs that came from patients before and after the enactment of the print advertising requirement and estimated that requirement's impact with model simulations. We found that if monthly spending on print direct-to-consumer advertising increased from zero to $7.7 million per drug, the presence of the Food and Drug Administration contact information tripled the increase in patient-reported adverse events, compared to what would have happened in the absence of the law. However, the absolute monthly increase was fewer than 0.24 reports per drug, suggesting that the public health impact of the increase was small and that the adverse event reporting rate would still be low. The study results suggest that additional measures, such as more publicity about the Adverse Event Reporting System or more consumer education, should be considered to promote patient reporting of adverse events.
Gahr, Maximilian; Freudenmann, Roland W; Connemann, Bernhard J; Hiemke, Christoph; Schönfeldt-Lecuona, Carlos
Early studies suggested that the centrally acting non-opioid and non-steroidal analgesic flupirtine (FLP) has no potential for abuse. However, FLP's agonistic effects at the GABAA receptor might prime addictive behaviors, and literature provides some anecdotal reports on FLP abuse/dependence. To shed more light on this topic we acquired and evaluated data obtained from a national German pharmacovigilance database. We analyzed all reports of FLP abuse/dependence that were recorded in the database of the German Federal Institute for Drugs and Medical Devices (BfArM). A total of n = 48 reports of FLP abuse/dependence could be identified (mean age 45 years, 62.5% female). First reports were submitted to BfArM in 1991 with increasing numbers of annual reports from the year 2006 on. Mean daily FLP dosage was 805 mg (range 200-3,000 mg). Current or previous substance abuse/dependence was reported in 21% and 17%, respectively. Mean duration of FLP abuse/dependence until report to BfArM was 23 months (range 1-84 months). Withdrawal syndromes after discontinuation of FLP were reported in n = 9 (19%). Our findings strengthen the hypothesis that FLP features a potential to cause addictive behaviors. Female sex, age >40 years, and long-term FLP-treatment may be possible risk factors for the development of FLP abuse/dependence.
Jackson, Richard George; Ball, Michael; Ibrahim, Zina M.; Broadbent, Matthew; Dzahini, Olubanke; Stewart, Robert; Johnston, Caroline; Dobson, Richard J. B.
Objectives Electronic healthcare records (EHRs) are a rich source of information, with huge potential for secondary research use. The aim of this study was to develop an application to identify instances of Adverse Drug Events (ADEs) from free text psychiatric EHRs. Methods We used the GATE Natural Language Processing (NLP) software to mine instances of ADEs from free text content within the Clinical Record Interactive Search (CRIS) system, a de-identified psychiatric case register developed at the South London and Maudsley NHS Foundation Trust, UK. The tool was built around a set of four movement disorders (extrapyramidal side effects [EPSEs]) related to antipsychotic therapy and rules were then generalised such that the tool could be applied to additional ADEs. We report the frequencies of recorded EPSEs in patients diagnosed with a Severe Mental Illness (SMI) and then report performance in identifying eight other unrelated ADEs. Results The tool identified EPSEs with >0.85 precision and >0.86 recall during testing. Akathisia was found to be the most prevalent EPSE overall and occurred in the Asian ethnic group with a frequency of 8.13%. The tool performed well when applied to most of the non-EPSEs but least well when applied to rare conditions such as myocarditis, a condition that appears frequently in the text as a side effect warning to patients. Conclusions The developed tool allows us to accurately identify instances of a potential ADE from psychiatric EHRs. As such, we were able to study the prevalence of ADEs within subgroups of patients stratified by SMI diagnosis, gender, age and ethnicity. In addition we demonstrated the generalisability of the application to other ADE types by producing a high precision rate on a non-EPSE related set of ADE containing documents. Availability The application can be found at http://git.brc.iop.kcl.ac.uk/rmallah/dystoniaml. PMID:26273830
Dubus, Jean-Christophe; Bavoux, Françoise; Boyer-Gervoise, Marie-José; Jean-Pastor, Marie-Josèphe; Chalumeau, Martin
Objective To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. Design The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. Setting Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. Patients The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. Results The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. Conclusion Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence. PMID:21818391
Pasqualetti, Giuseppe; Tognini, Sara; Calsolaro, Valeria; Polini, Antonio; Monzani, Fabio
The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied by potential harm, even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse drug reactions considering comorbidity, poly-therapy, physiological changes affecting the pharmacokinetics and pharmacodynamics of many drugs and, in some cases, poor compliance due to cognitive impairment and/or depression. In this setting, drug–drug interaction may represent a serious and even life-threatening clinical condition. Moreover, the inability to distinguish drug-induced symptoms from a definitive medical diagnosis often results in addition of yet another drug to treat the symptoms, which in turn increases drug–drug interactions. Cognitive enhancers, including acetylcholinesterase inhibitors and memantine, are the most widely prescribed agents for Alzheimer’s disease (AD) patients. Behavioral and psychological symptoms of dementia, including psychotic symptoms and behavioral disorders, represent noncognitive disturbances frequently observed in AD patients. Antipsychotic drugs are at high risk of adverse events, even at modest doses, and may interfere with the progression of cognitive impairment and interact with several drugs including anti-arrhythmics and acetylcholinesterase inhibitors. Other medications often used in AD patients are represented by anxiolytic, like benzodiazepine, or antidepressant agents. These agents also might interfere with other concomitant drugs through both pharmacokinetic and pharmacodynamic mechanisms. In this review we focus on the most frequent drug–drug interactions, potentially harmful, in AD patients with behavioral symptoms considering both physiological and pathological changes in AD patients, and potential pharmacodynamic/pharmacokinetic drug interaction mechanisms. PMID:26392756
Kannan, Bhaskar; Nagella, Amrutha Bindu; Sathia Prabhu, A; Sasidharan, Gopalakrishnan M; Ramesh, A S
Background: Drug-drug interactions (DDIs) are very common adverse events in health care delivery settings. The use of electronic pharmacopeias can potentially reduce the incidence of DDIs, but they are often thought to be cumbersome to use. This study is aimed at studying the incidence of potential DDIs in a surgical department, where a limited number of drugs are used in stereotyped combinations. We also compared two popular drug compendia in detecting potential DDIs. Methods: The prescriptions of selected patients were entered into Epocrates® and Medscape® for Android smartphones. Potential DDIs were generated and their categories were noted. The warnings generated by Epocrates® were compared with those generated by Medscape® and an agreement index was calculated. Results: Three hundred and thirty-one patients were included for analysis who had received a total of 2,878 drug orders. The incidence of potential DDIs was very high - 89% of all prescriptions. Phenytoin was the drug most commonly implicated, followed by furosemide. Of the DDIs detected, 0.14% were potentially serious and the drug combinations were contraindicated. There was a significant discrepancy between the categories of potential DDIs detected by Epocrates® and Medscape®. No clinically significant DDI was detected in any patient in this cohort. Conclusions: Despite routinely using only a limited number of drugs in stereotyped combinations, prescriptions in surgical departments may not be immune from a significant incidence of DDIs. The use of free apps could reduce the incidence of DDIs, enhance patient safety, and also aid in educating trainees. PMID:28018756
Fujiwara, Masakazu; Kawasaki, Yohei; Yamada, Hiroshi
Background Rapid dissemination of information regarding adverse drug reactions is a key aspect for improving pharmacovigilance. There is a possibility that unknown adverse drug reactions will become apparent through post-marketing administration. Currently, although there have been studies evaluating the relationships between a drug and adverse drug reactions using the JADER database which collects reported spontaneous adverse drug reactions, an efficient approach to assess the association between adverse drug reactions of drugs with the same indications as well as the influence of demographics (e.g. gender) has not been proposed. Methods and Findings We utilized the REAC and DEMO tables from the May 2015 version of JADER for patients taking antidepressant drugs (SSRI, SNRI, and NaSSA). We evaluated the associations using association analyses with an apriori algorithm. Support, confidence, lift, and conviction were used as indicators for associations. The highest score in adverse drug reactions for SSRI was obtained for "aspartate aminotransferase increased", "alanine aminotransferase increased", with values of 0.0059, 0.93, 135.5, and 13.9 for support, confidence, lift and conviction, respectively. For SNRI, "international normalized ratio increased", "drug interaction" were observed with 0.0064, 1.00, 71.9, and NA. For NaSSA, "anxiety", "irritability" were observed with 0.0058, 0.80, 49.9, and 4.9. For female taking SSRI, the highest support scores were observed in "twenties", "suicide attempt", whereas "thirties", "neuroleptic malignant syndrome" were observed for male. Second, for SNRI, "eighties", "inappropriate antidiuretic hormone secretion" were observed for female, whereas "interstitial lung disease" and "hepatitis fulminant" were for male. Finally, for NaSSA, "suicidal ideation" was for female, and "rhabdomyolysis" was for male. Conclusions Different combinations of adverse drug reactions were noted between the antidepressants. In addition, the reported
Pan, Jian-Bo; Ji, Nan; Pan, Wen; Hong, Ru; Wang, Hao; Ji, Zhi-Liang
Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. - Highlights: • A novel computational framework was developed for mechanistic study of SADRs. • Off-targets of drugs were identified in large scale and in a high-throughput manner. • SADRs like cardiac disorders were systematically explored in molecular networks. • A number of ADR-associated proteins were identified.
Wallach, Izhar; Jaitly, Navdeep; Lilien, Ryan
Adverse drug reactions (ADR), also known as side-effects, are complex undesired physiologic phenomena observed secondary to the administration of pharmaceuticals. Several phenomena underlie the emergence of each ADR; however, a dominant factor is the drug's ability to modulate one or more biological pathways. Understanding the biological processes behind the occurrence of ADRs would lead to the development of safer and more effective drugs. At present, no method exists to discover these ADR-pathway associations. In this paper we introduce a computational framework for identifying a subset of these associations based on the assumption that drugs capable of modulating the same pathway may induce similar ADRs. Our model exploits multiple information resources. First, we utilize a publicly available dataset pairing drugs with their observed ADRs. Second, we identify putative protein targets for each drug using the protein structure database and in-silico virtual docking. Third, we label each protein target with its known involvement in one or more biological pathways. Finally, the relationships among these information sources are mined using multiple stages of logistic-regression while controlling for over-fitting and multiple-hypothesis testing. As proof-of-concept, we examined a dataset of 506 ADRs, 730 drugs, and 830 human protein targets. Our method yielded 185 ADR-pathway associations of which 45 were selected to undergo a manual literature review. We found 32 associations to be supported by the scientific literature. PMID:20808786
dos Santos, Wendel Mombaque; Secoli, Silvia Regina; Padoin, Stela Maris de Mello
ABSTRACT Objective: to investigate potential drug-drug interactions (PDDI) in patients with HIV infection on antiretroviral therapy. Methods: a cross-sectional study was conducted on 161 adults with HIV infection. Clinical, socio demographic, and antiretroviral treatment data were collected. To analyze the potential drug interactions, we used the software Micromedex(r). Statistical analysis was performed by binary logistic regression, with a p-value of ≤0.05 considered statistically significant. Results: of the participants, 52.2% were exposed to potential drug-drug interactions. In total, there were 218 potential drug-drug interactions, of which 79.8% occurred between drugs used for antiretroviral therapy. There was an association between the use of five or more medications and potential drug-drug interactions (p = 0.000) and between the time period of antiretroviral therapy being over six years and potential drug-drug interactions (p < 0.00). The clinical impact was prevalent sedation and cardiotoxicity. Conclusions: the PDDI identified in this study of moderate and higher severity are events that not only affect the therapeutic response leading to toxicity in the central nervous and cardiovascular systems, but also can interfere in tests used for detection of HIV resistance to antiretroviral drugs. PMID:27878224
McGregor, I S; Callaghan, P D; Hunt, G E
Addictive drugs can profoundly affect social behaviour both acutely and in the long-term. Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology. In this review we focus on the 'social neuropeptide' oxytocin and its possible role in acute and long-term effects of commonly used drugs. Oxytocin regulates social affiliation and social recognition in many species and modulates anxiety, mood and aggression. Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects. Oxytocin interacts with the mesolimbic dopamine system to facilitate sexual and social behaviour, and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behaviour. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behaviour. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems. Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders.
Cleck, Jessica N; Blendy, Julie A
Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle. We also discuss both animal and human studies that suggest treating the stress-related aspects of drug addiction is likely to be an important contributing factor to a long-lasting recovery from this disorder.
Bogetti-Salazar, Michele; González-González, Cesar; Juárez-Cedillo, Teresa; Sánchez-García, Sergio; Rosas-Carrasco, Oscar
OBJECTIVE: To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. METHOD: This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug interactions (contraindicated/severe) (n=64) and those with non-severe drug-drug interactions (moderate/minor/absent) (n=117). Additional socio-demographic, clinical and caregiver data were included. Potential drug-drug interactions were identified using Micromedex Drug Reax 2.0® database. RESULTS: A total of 181 patients were enrolled, including 57 men (31.5%) and 124 women (68.5%) with a mean age of 80.11±8.28 years. One hundred and seven (59.1%) patients in our population had potential drug-drug interactions, of which 64 (59.81%) were severe/contraindicated. The main severe potential drug-drug interactions were caused by the combinations citalopram/anti-platelet (11.6%), clopidogrel/omeprazole (6.1%), and clopidogrel/aspirin (5.5%). Depression, the use of a higher number of medications, dementia severity and caregiver burden were the most significant factors associated with severe potential drug-drug interactions. CONCLUSIONS: Older people with dementia experience many severe potential drug-drug interactions. Anti-depressants, antiplatelets, anti-psychotics and omeprazole were the drugs most commonly involved in these interactions. Despite their frequent use, anti-dementia drugs were not involved in severe potential drug-drug interactions. The number and type of medications taken, dementia severity and depression in patients in addition to caregiver burden should be considered to avoid possible drug interactions in this population. PMID:26872079
Mason, Jennifer; Pirmohamed, Munir; Nunn, Tony
The use of unlicensed and off-label medicines in children is common because trials in children have not usually been performed during the drug development process. Consequently, the information available to paediatricians may not always be as detailed or as robust as that available when prescribing a medicine that is licensed for an approved indication. This has led to concerns that children may be receiving drugs at dosages that either lack efficacy or present safety problems. The latter in particular has received a great deal of attention. In this narrative review, we have evaluated the use of off-label and unlicensed medicines in children and whether and how frequently this predisposes to adverse drug reactions.
Anastasio, Thomas J.
The leading hypothesis on Alzheimer Disease (AD) is that it is caused by buildup of the peptide amyloid-β (Aβ), which initially causes dysregulation of synaptic plasticity and eventually causes destruction of synapses and neurons. Pharmacological efforts to limit Aβ buildup have proven ineffective, and this raises the twin challenges of understanding the adverse effects of Aβ on synapses and of suggesting pharmacological means to prevent them. The purpose of this paper is to initiate a computational approach to understanding the dysregulation by Aβ of synaptic plasticity and to offer suggestions whereby combinations of various chemical compounds could be arrayed against it. This data-driven approach confronts the complexity of synaptic plasticity by representing findings from the literature in a course-grained manner, and focuses on understanding the aggregate behavior of many molecular interactions. The same set of interactions is modeled by two different computer programs, each written using a different programming modality: one imperative, the other declarative. Both programs compute the same results over an extensive test battery, providing an essential crosscheck. Then the imperative program is used for the computationally intensive purpose of determining the effects on the model of every combination of ten different compounds, while the declarative program is used to analyze model behavior using temporal logic. Together these two model implementations offer new insights into the mechanisms by which Aβ dysregulates synaptic plasticity and suggest many drug combinations that potentially may reduce or prevent it. PMID:24847263
Umeda, Maki; Kawakami, Norito; Kessler, Ronald C; Miller, Elizabeth
Using data derived from the World Mental Health Japan Survey (n = 1,186), this study examined the intergenerational continuity of potentially injurious physical discipline of children in a community sample from Japan with a special focus on the confounding effects of 11 other types of childhood adversities (CAs) and the intervening effects of mental disorders and socioeconomic status. Bivariate analyses revealed that having experienced physical discipline as children and five other CAs was significantly associated with the use of physical discipline as parents in the Japanese community examined. However, childhood physical discipline was the only CA that remained significant after adjusting for the other CAs. The association of childhood physical discipline with adult perpetration was independent of the respondents' mental disorders and household income. No significant gender differences were found in the associations between childhood physical discipline and adult perpetration. The current study on Japan provided empirical support consistent with results found in other countries regarding the intergenerational transmission of child physical abuse.
Umeda, Maki; Kawakami, Norito; Kessler, Ronald C.; Miller, Elizabeth
Using data derived from the World Mental Health Japan Survey (n = 1,186), this study examined the intergenerational continuity of potentially injurious physical discipline of children in a community sample from Japan with a special focus on the confounding effects of 11 other types of childhood adversities (CAs) and the intervening effects of mental disorders and socioeconomic status. Bivariate analyses revealed that having experienced physical discipline as children and five other CAs was significantly associated with the use of physical discipline as parents in the Japanese community examined. However, childhood physical discipline was the only CA that remained significant after adjusting for the other CAs. The association of childhood physical discipline with adult perpetration was independent of the respondents’ mental disorders and household income. No significant gender differences were found in the associations between childhood physical discipline and adult perpetration. The current study on Japan provided empirical support consistent with results found in other countries regarding the intergenerational transmission of child physical abuse. PMID:26478655
Kesselheim, Aaron S; Tan, Yongtian Tina; Darrow, Jonathan J; Avorn, Jerry
Specialty drugs are notable among prescription drugs in that they offer the possibility of substantial clinical improvement, come with important risks of adverse events and mortality, can be complex to manufacture or administer, and are usually extremely costly. The Food and Drug Administration (FDA) plays a critical role in ensuring that patients who could benefit from specialty drugs have access to them in a timely fashion. In this article we review the different strategies that the FDA can use to approve and influence the post-approval prescribing of specialty drugs. When specialty drugs show promise in early clinical trials, the FDA can expedite the drugs' availability to patients through expanded access programs and expedited approval pathways that speed regulatory authorization. After approval, to ensure that specialty drugs are directed to the patients who are most likely to benefit from them, the FDA can limit the scope of the drugs' indications, encourage the development of companion diagnostic tests to indicate which patients should receive the drugs, or require that manufacturers subject them to Risk Evaluation and Mitigation Strategies to ensure that their use is appropriately limited to a restricted population that is aware of the drugs' risks and benefits. Implementing these existing regulatory approaches can promote timely patient access to specialty drugs while preventing expensive and potentially inappropriate overuse.
The Boston Collaborative Drug Surveillance Program started in 1966 and conducted epidemiologic research to quantify the potential adverse effects of prescription drugs, utilizing in-hospital monitoring.
Tavakoli-Ardakani, Maria; Kazemian, Kaveh; Salamzadeh, Jamshid; Mehdizadeh, Mahshid
Cancer patients are more susceptible to adverse drug-drug interactions (DDIs) due to receiving multiple medications especially chemotherapy medications, hormonal agents and supportive care drugs. The aim of this study is to describe the prevalence of potential DDIs and to identify risk factors for these potential interactions in hospitalized cancer patients in a developing country. A cross-sectional study conducted by reviewing charts of 224 consecutive in hospitalized patients in hematology-oncology ward of a teaching hospital in Tehran, during a 12 month period from July 2009 to July 2010. “Drug Interaction Facts 2008, 2009: The Authority on Drug Interactions” was used for screening the potential drug-drug interactions. Potential interactions were classified by levels of severity and documentation. The median age of patients was 50 years, the length of hospital stay for patient was 5 days and the number of drugs per patient was 8 drugs. Two hundred and twenty-eight potential interactions were detected. Nearly 14% of the interactions were major and 60% were moderate. Approximately 9% and 10% potential interactions were graded as established and probable. In multivariate analysis, being older than 61 years old, suffering from hematologic cancer, source of cancer in different specific organs (esophagus, testis and cervices more than other sources), and number of ordered drugs for patients were independent predictors of having at least one potential DDI in hospital order. Suffering from hematologic cancer, source of cancer in different organs, length of hospital stay and number of ordered drugs for patients were independent predictors for number of interactions per patients. Having a DDI seems to be more likely to occur in patients older than 61 years old. Hematologic cancers, having more medications in physician’s order, longer length of hospital stay, esophageal cancer, testicular cancer and cervical cancer have related to having a DDI and also having more
Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L
Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated.
Gurmesa, Lense Temesgen
Background. Adverse drug reactions are global problems of major concern. Adverse drug reaction reporting helps the drug monitoring system to detect the unwanted effects of those drugs which are already in the market. Aims. To assess the knowledge, attitude, and practice of health care professionals working in Nekemte town towards adverse drug reaction reporting. Methods and Materials. A cross-sectional study design was conducted on a total of 133 health care professionals by interview to assess their knowledge, attitude, and practice using structured questionnaire. Results. Of the total respondents, only 64 (48.2%), 56 (42.1%), and 13 (9.8%) health care professionals have correctly answered the knowledge, attitude, and practice assessment questions, respectively. Lack of awareness and knowledge on what, when, and to whom to report adverse drug reactions and lack of commitments of health care professionals were identified as the major discouraging factors against adverse drug reaction reporting. Conclusion. This study has revealed that the knowledge, attitude, and practice of the health care professionals working in Nekemte town towards spontaneous adverse drug reaction reporting were low that we would like to recommend the concerned bodies to strive on the improvement of the knowledge, attitude, and practice status of health care professionals. PMID:28042569
Raheel, Syed Ahamed; Kujan, Omar Bashar; Tarakji, Bassel; Umar, Dilshad; Ibrahim, Salah
Drug reactions are a group of reactionary lesions generally show their manifestations in the oral cavity. The drug reactions may vary from local rashes to well-developed swellings in the oral cavity especially involving the gingiva. Most of the drug reactions are asymptomatic and commonly triggered from the active metabolite of a drug used for a long time. Nager syndrome is a group of acrofacial dysostosis that usually results in craniofacial and limb malformations. The craniofacial defects are very similar to the mandibulofacial dysostosis. A very early intervention is needed for the habilitation of the patient especially when it is concerned with speech and language development. This paper reports a case of a 32-year-old female with craniofacial, limb, and skeletal abnormalities along with a drug-induced gingival hyperplasia. PMID:27144155
Small, Serena S; Badke, Katherin; Wickham, Maeve E; Bailey, Chantelle; Chruscicki, Adam; Ackerley, Christine; Balka, Ellen; Hohl, Corinne M
Background Adverse drug events (ADEs) are unintended and harmful events related to medication use. Up to 30% of serious ADEs recur within six months because culprit drugs are unintentionally represcribed and redispensed. Improving the electronic communication of ADE information between care providers, and across care settings, has the potential to reduce recurrent ADEs. Objective We aim to describe the methods used to design Action ADE, a novel electronic ADE reporting system that can be leveraged to prevent unintentional reexposures to harmful drugs in British Columbia, Canada. Methods To develop the new system, our team will use action research and participatory design, approaches that employ social scientific research methods and practitioner participation to generate insights into work settings and problem resolution. We will develop a systematic search strategy to review existing ADE reporting systems identified in academic and grey literature, and analyze the content of these systems to identify core data fields used to communicate ADE information. We will observe care providers in the emergency departments and on the wards of two urban tertiary hospitals and one urban community hospital, in one rural ambulatory care center, and in three community pharmacies in British Columbia, Canada. We will also conduct participatory workshops with providers to understand their needs and priorities related to communicating ADEs and preventing erroneous represcribing or redispensing of culprit medications. These methods will inform the iterative development of a preliminary paper-based reporting form, which we will then pilot test with providers in a real-world setting. Results This is an ongoing project with results being published as analyses are completed. The systematic review has been completed; field observations, focus groups, and pilot testing of a preliminary paper-based design are ongoing. Results will inform the development of software that will enable
Graham, Timothy A.D.; Kushniruk, Andre W.; Bullard, Michael J.; Holroyd, Brian R.; Meurer, David P.; Rowe, Brian H.
Introduction Clinical decision support systems (CDSS) have the potential to reduce adverse medical events, but improper design can introduce new forms of error. CDSS pertaining to community acquired pneumonia and neutropenic fever were studied to determine whether usability of the graphical user interface might contribute to potential adverse medical events. Methods Automated screen capture of 4 CDSS being used by volunteer emergency physicians was analyzed using structured methods. Results 422 events were recorded over 56 sessions. In total, 169 negative comments, 55 positive comments, 130 neutral comments, 21 application events, 34 problems, 6 slips, and 5 mistakes were identified. Three mistakes could have had life-threatening consequences. Conclusion Evaluation of CDSS will be of utmost importance in the future with increasing use of electronic health records. Usability engineering principles can identify interface problems that may lead to potential medical adverse events, and should be incorporated early in the software design phase. PMID:18998968
Jiang, L.H; Gamper, N; Beech, D.J
Mammals contain 28 genes encoding Transient Receptor Potential (TRP) proteins. The proteins assemble into cationic channels, often with calcium permeability. Important roles in physiology and disease have emerged and so there is interest in whether the channels might be suitable therapeutic drug targets. Here we review selected members of three subfamilies of mammalian TRP channel (TRPC5, TRPM2 and TRPA1) that show relevance to sensing of adversity by cells and biological systems. Summarized are the cellular and tissue distributions, general properties, endogenous modulators, protein partners, cellular and tissue functions, therapeutic potential, and pharmacology. TRPC5 is stimulated by receptor agonists and other factors that include lipids and metal ions; it heteromultimerises with other TRPC proteins and is involved in cell movement and anxiety control. TRPM2 is activated by hydrogen peroxide; it is implicated in stress-related inflammatory, vascular and neurodegenerative conditions. TRPA1 is stimulated by a wide range of irritants including mustard oil and nicotine but also, controversially, noxious cold and mechanical pressure; it is implicated in pain and inflammatory responses, including in the airways. The channels have in common that they show polymodal stimulation, have activities that are enhanced by redox factors, are permeable to calcium, and are facilitated by elevations of intracellular calcium. Developing inhibitors of the channels could lead to new agents for a variety of conditions: for example, suppressing unwanted tissue remodeling, inflammation, pain and anxiety, and addressing problems relating to asthma and stroke. PMID:21291387
Lahue, Betsy J.; Pyenson, Bruce; Iwasaki, Kosuke; Blumen, Helen E.; Forray, Susan; Rothschild, Jeffrey M.
Background Harmful medication errors, or preventable adverse drug events (ADEs), are a prominent quality and cost issue in healthcare. Injectable medications are important therapeutic agents, but they are associated with a greater potential for serious harm than oral medications. The national burden of preventable ADEs associated with inpatient injectable medications and the associated medical professional liability (MPL) costs have not been previously described in the literature. Objective To quantify the economic burden of preventable ADEs related to inpatient injectable medications in the United States. Methods Medical error data (MedMarx 2009–2011) were utilized to derive the distribution of errors by injectable medication types. Hospital data (Premier 2010–2011) identified the numbers and the types of injections per hospitalization. US payer claims (2009–2010 MarketScan Commercial and Medicare 5% Sample) were used to calculate the incremental cost of ADEs by payer and by diagnosis-related group (DRG). The incremental cost of ADEs was defined as inclusive of the time of inpatient admission and the following 4 months. Actuarial calculations, assumptions based on published literature, and DRG proportions from 17 state discharge databases were used to derive the probability of preventable ADEs per hospitalization and their annual costs. MPL costs were assessed from state- and national-level industry reports, premium rates, and from closed claims databases between 1990 and 2011. The 2010 American Hospital Association database was used for hospital-level statistics. All costs were adjusted to 2013 dollars. Results Based on this medication-level analysis of reported harmful errors and the frequency of inpatient administrations with actuarial projections, we estimate that preventable ADEs associated with injectable medications impact 1.2 million hospitalizations annually. Using a matched cohort analysis of healthcare claims as a basis for evaluating incremental
Kawaguchi, Yoshiaki; Maruno, Atsuko; Kawashima, Yohei; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya
The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.
Palamar, Joseph J.; Fenstermaker, Michael; Kamboukos, Dimitra; Ompad, Danielle C.; Cleland, Charles M.; Weitzman, Michael
Objectives There is debate about whether marijuana (cannabis) use is more dangerous than alcohol use. Although difficult to make objective comparisons, research is needed to compare relative dangers in order to help inform preventive efforts and policy. Methods Data were analyzed from a nationally representative sample of high school seniors in the Monitoring the Future study (2007–2011; Weighted n = 7437; modal age: 18) who reported lifetime use of alcohol or marijuana. Students were asked to indicate whether they experienced various adverse psychosocial outcomes resulting from use of each substance. We examined which outcomes were more prevalent for each substance. Results Compared to alcohol use, marijuana use was more commonly reported to compromise relationships with teachers or supervisors, result in less energy or interest, and result in lower school or job performance. Compared to marijuana use, alcohol was more commonly reported to compromise relationships with friends and significant others; it was also reported to lead to more regret (particularly among females), and driving unsafely. Marijuana users were more likely to report no adverse outcomes. Females and white students were more likely to report various adverse outcomes and higher frequency use of each substance also increased occurrences of reported adverse outcomes. Conclusions Marijuana and alcohol are associated with unique adverse psychosocial outcomes. Outcomes differ by sex and race/ethnicity, and perception or experience of outcomes may also be related to legal status and associated stigma. Public health interventions may be more effective by focusing on harm reduction strategies for these drug-specific outcomes. PMID:25169838
Polton, Gerry A; Elwood, Clive M
This report describes recurrent respiratory distress following vincristine administration to a cat with chronic lymphocytic leukaemia. The cat was treated with a combination of vincristine, chlorambucil and prednisolone with initial success. After approximately 4 months, dyspnoea developed within 6 h of vincristine administration. Emergency therapy was instituted resulting in a full recovery. Further vincristine was administered; dyspnoea was similarly noted after all but one of these treatments. Dyspnoeic episodes were not attributable to alterations in vincristine dose or method of administration. The repeated temporal association was consistent with a suspected adverse drug reaction to vincristine.
Kalogirou, Eleni-Marina; Tosios, Konstantinos I.; Lazaris, Andreas C.; Sklavounou, Alexandra
Leflunomide is a member of the disease modifying anti-rheumatic drugs group used as a treatment modality in active rheumatoid and psoriatic arthritis. “Oral ulcers” are reported in 3-5% of leflunomide medicated rheumatoid arthritis patients with adverse events, but they are not described in detail in the literature. We present a case of an ulcer in the tongue of a rheumatoid arthritis patient managed with leflunomide and contemplate on its pathogenesis. Key words:Leflunomide, oral ulcer, DHODH. PMID:28210457
Eriksson, Robert; Aagaard, Lise; Jensen, Lars Juhl; Borisova, Liza; Hørlück, Dorte; Brunak, Søren; Hansen, Ebba Holme
Pharmaceutical product information (PI) supplied by the regulatory authorities serves as a source of information on safe and effective use of drugs. The objectives of this study were to qualitatively and quantitatively compare PIs for selected drugs marketed in both Denmark and the USA with respect to consistency and discrepancy of listed adverse drug reaction (ADR) information. We compared individual ADRs listed in PIs from Denmark and the USA with respect to type and frequency. Consistency was defined as match of ADRs and of ADR frequency or match could not be ruled out. Discrepancies were defined as ADRs listed only in one country or listed with different frequencies. We analyzed PIs for 40 separate drugs from ten therapeutic groups and assigned the 4003 identified ADRs to System Organ Classes (Medical Dictionary for Regulatory Activities [MedDRA] terminology). Less than half of listed ADRs (n = 1874; 47%) showed consistency. Discrepancies (n = 2129; 53%) were split into ADRs listed only in the USA (n = 1558; 39%), ADRs listed only in Denmark (n = 325; 8%) and ADRs listed with different frequencies (n = 246; 6%). The majority of listed ADRs were of the type "gastrointestinal disorders" and "nervous system disorders". Our results show great differences in PIs for drugs approved in both Denmark and the USA illuminating concerns about the credibility of the publicly available PIs. The results also represent an argument for further harmonization across borders to improve consistency between authority-supplied information.
Tatonetti, NP; Denny, JC; Murphy, SN; Fernald, GH; Krishnan, G; Castro, V; Yue, P; Tsau, PS; Kohane, I; Roden, DM; Altman, RB
The lipid-lowering agent pravastatin and the antidepressant paroxetine are among the most widely prescribed drugs in the world. Unexpected interactions between them could have important public health implications. We mined the US Food and Drug Administration’s (FDA’s) Adverse Event Reporting System (AERS) for side-effect profiles involving glucose homeostasis and found a surprisingly strong signal for comedication with pravastatin and paroxetine. We retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received comedication with these two drugs, using data in electronic medical record (EMR) systems of three geographically distinct sites. We assessed the mean random blood glucose levels before and after treatment with the drugs. We found that pravastatin and paroxetine, when administered together, had a synergistic effect on blood glucose. The average increase was 19 mg/dl (1.0 mmol/l) overall, and in those with diabetes it was 48 mg/dl (2.7 mmol/l). In contrast, neither drug administered singly was associated with such changes in glucose levels. An increase in glucose levels is not a general effect of combined therapy with selective serotonin reuptake inhibitors (SSRIs) and statins. PMID:21613990
What started as a trickle of new agents that help the body's immune system fight cancer has now become a flood, despite some daunting adverse effects. This report discusses the new drugs, indications, and combinations that continue to emerge.
Johnson, Robert B.; And Others
A brief historical review of attempts to control the abuse of drugs introduces a series of tables listing pertinent information about drugs of potential abuse. Each table provides the common commercial and slang names for the drugs, their medical and legal classification, their potential for emotional and physical dependence, whether the user…
Rottenkolber, Dominik; Schmiedl, Sven; Rottenkolber, Marietta; Thuermann, Petra A; Hasford, Joerg
Therapy for adverse drug reactions (ADRs) often results in the application of blood components. This study aims to assess the demand for blood components and the resulting economic burden (hospital perspective) in German hospitals induced by ADRs leading to admissions to departments of internal medicine. In this prospective study, ADRs leading to hospitalization were surveyed in four regional pharmacovigilance centres in Germany during the years 2000-2007. ADRs assessed as 'possible', 'likely' or 'very likely' were included. Market prices for blood components and hospitalization data were determined by desktop research. A probabilistic sensitivity analysis was performed. A total of 6099 patients were admitted to internal medicine departments because of an outpatient ADR of whom 1165 patients (19.1%; mean age, 73.0 ± 13.0 years) required treatment with blood components owing to major bleeding events. Overall consumption was 4185 erythrocyte concentrates (EC), 426 fresh frozen plasma (FFP) and 48 thrombocyte (TC) units. On the basis of statistical hospital data, we estimated a nationwide demand of approximately 132,020 EC, 13,440 FFP and 1515 TC units, resulting in total costs of €12.66 million per year for all German hospitals. Some 19.2% of all ADR cases were assessed as preventable. Theoretically, a nationwide decreased demand for blood components and a savings potential of €2.43 million per year could be achieved by preventing ADRs in Germany. Blood components are used in one-fifth (mainly gastrointestinal bleeding) of all ADRs, leading to hospitalizations in internal medicine departments. Both blood demand and hospital procurement costs can be significantly lowered by preventing ADRs.
Theile, Dirk; Hohmann, Nicolas; Kiemel, Dominik; Gattuso, Giuseppe; Barreca, Davide; Mikus, Gerd; Haefeli, Walter Emil; Schwenger, Vedat; Weiss, Johanna
Adverse drug interactions due to grapefruit juice are well known prompting warnings even in drug labels. Similar issues have not been reported for clementines and available data is scarce, despite of genetic descent. We observed substantially increased tacrolimus trough concentrations in a renal transplant patient consuming high clementine amounts and, thus, scrutinised the effects of clementine juice on drug metabolism and drug transporters in vitro and compared it to the effects of mandarin and grapefruit juice. All citrus juices profoundly induced several drug transporters and drug metabolising enzymes, whereas the effects of grapefruit juice were most pronounced (e.g. 156-fold and 34-fold induction of cytochrome P450 (CYP) 3A4 mRNA by grapefruit juice and clementine juice, respectively). However, the juices also inhibited e.g. CYP3A4, raising the question which effect prevails in vivo. Using an enzymatic activity assay, we demonstrated that at least in vitro CYP3A4 inhibition prevails for both grapefruit and clementine juice, whereas for CYP1A2 induction appears to predominate. Thus, inhibition of CYP3A4 is presumably the underlying reason for the observed increase in the concentrations of the CYP3A4 substrate tacrolimus in the patient. Taken together, our data indicate that clementine juice as well as grapefruit juice and to a lesser extent also mandarin juice can induce several important drug metabolising enzymes and drug transporters, but also inhibit some of these proteins. Our data indicate that clementine juice similar to grapefruit juice bears the potential for profound interactions with drugs potentially leading to adverse drug effects e.g. through over-exposure to CYP3A4 substrates.
Roemer, F W; Hayes, C W; Miller, C G; Hoover, K; Guermazi, A
Despite promising results, the U.S. Food and Drug Administration (FDA) put on hold trials assessing anti-nerve growth factor (a-NGF) compounds due to concerns over accelerated rates of OA progression. The mechanism of these events is unclear but joint adverse events were observed particularly in patients using a-NGFs in combination with non-steroidal anti-inflammatory drugs (NSAIDs), suggesting that the significantly greater analgesic effect of these separate classes of drugs prompted patients to permit increased joint load without experiencing the usual pain that would limit joint stress. Development of a-NGF drugs is continuing with stringent safety criteria included in future trials as a-NGF therapies offer potential as the first new class of analgesics in many years. Potential imaging joint safety findings and exclusionary criteria for eligibility for the large weight bearing joints were presented in parts I and II of this atlas. The shoulder as a non-weight bearing joint is likely to be less affected by increased loading due to efficacious pain reduction. However, it remains prone to degeneration especially due to concomitant rotator cuff pathology and previous trauma and inflammatory disorders. This third part of the atlas illustrates imaging findings relevant for eligibility and potential joint safety findings such as osteonecrosis, incidental findings such as large cystic lesions, inflammatory disorders, bone marrow disorders and metastases.
Klein, Thomas W; Newton, Catherine A
Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.
Carey, Jennifer L; Nader, Nathalie; Chai, Peter R; Carreiro, Stephanie; Griswold, Matthew K; Boyle, Katherine L
A large number of medications and medical devices removed from the market by the US Food and Drug Administration over the past 4 decades specifically posed greater health risks to women. This article reviews the historical background of sex and gender in clinical research policy and describes several approved drugs and devices targeted for use in women that have caused major morbidity and mortality. The intended population for the medications and devices, population affected, approval process, and the basic and legal actions taken against the medication/drug company are also discussed. It is recognized that women are still at risk for harm from unsafe medications and devices, and continued improvements in legislation that promotes inclusion of sex and gender into the design and analysis of research will improve safety for both men and women.
Somaini, L; Donnini, C; Manfredini, M; Raggi, M A; Saracino, M A; Gerra, M L; Amore, M; Leonardi, C; Serpelloni, G; Gerra, G
Epidemiological and clinical data show frequent associations between adverse childhood experiences (ACEs) and substance abuse susceptibility particularly in adolescents. A large body of evidences suggests that the possible dysregulation of neuroendocrine responses as well as neurotransmitters function induced by childhood traumatic experiences and emotional neglect could constitute one of the essential biological changes implementing substance abuse vulnerability. Moreover, genotype variables and its environment interactions have been associated with an increased risk for early onset substance abuse. In this paper we present several data that support the hypothesis of the involvement of hypothalamus-pituitary-adrenal (HPA) axis in mediating the combined effect of early adverse experiences and gene variants affecting neurotransmission. The presented data also confirm the relationship between basal plasma levels of cortisol and ACTH, on the one hand, and retrospective measures of neglect during childhood on the other hand: the higher the mother and father neglect (CECA-Q) scores are, the higher the plasma levels of the two HPA hormones are. Furthermore, such positive relationship has been proved to be particularly effective and important when associated with the "S" promoter polymorphism of the gene encoding the 5-HTT transporter, both in homozygote and heterozygote individuals.
Junqueira, Daniela Rezende Garcia; Carvalho, Maria das Graças; Perini, Edson
Heparin is a natural agent with antithrombotic action, commercially available for therapeutic use as unfractionated heparin and low molecular weight heparin. Heparin-induced thrombocytopenia (HIT) is a serious adverse reaction to heparin that promotes antibody-mediated platelet activation. HIT is defined as a relative reduction in platelet count of 50% (even when the platelet count at its lowest level is above>150 x 10(9)/L) occurring within five to 14 days after initiation of the therapy. Thrombocytopenia is the main feature that directs the clinical suspicion of the reaction and the increased risk of thromboembolic complications is the most important and paradoxical consequence. The diagnosis is a delicate issue, and requires a combination of clinical probability and laboratory tests for the detection of platelet activation induced by HIT antibodies. The absolute risk of HIT has been estimated between 1% and 5% under treatment with unfractionated heparin, and less than 1% with low molecular weight heparin. However, high-quality evidence about the risk of HIT from randomized clinical trials is scarce. In addition, information on the frequency of HIT in developing countries is not widely available. This review aims to provide a better understanding of the key features of this reaction and updated information on its frequency to health professionals and other interested parties. Knowledge, familiarity, and access to therapeutic options for the treatment of this adverse reaction are mandatory to minimize the associated risks, improving patient safety.
Shiny, T N; Mahajan, Vikram K; Mehta, Karaninder S; Chauhan, Pushpinder S; Rawat, Ritu; Sharma, Rajni
AIM To evaluate the utility of patch test and cross-sensitivity patterns in patients with adverse cutaneous drug reactions (ACDR) from common anticonvulsants. METHODS Twenty-four (M:F = 13:11) patients aged 18-75 years with ACDR from anticonvulsants were patch tested 3-27 mo after complete recovery using carbamazepine, phenytoin, phenobarbitone, lamotrigine, and sodium valproate in 10%, 20% and 30% conc. in pet. after informed consent. Positive reactions persisting on D3 and D4 were considered significant. RESULTS Clinical patterns were exanthematous drug rash with or without systemic involvement (DRESS) in 18 (75%), Stevens-Johnsons syndrome/toxic epidermal necrolysis (SJS/TEN) overlap and TEN in 2 (8.3%) patients each, SJS and lichenoid drug eruption in 1 (4.2%) patient each, respectively. The implicated drugs were phenytoin in 14 (58.3%), carbamazepine in 9 (37.5%), phenobarbitone in 2 (8.3%), and lamotrigine in 1 (4.7%) patients, respectively. Twelve (50%) patients elicited positive reactions to implicated drugs; carbamazepine in 6 (50%), phenytoin alone in 4 (33.3%), phenobarbitone alone in 1 (8.3%), and both phenytoin and phenobarbitone in 1 (8.33%) patients, respectively. Cross-reactions occurred in 11 (92%) patients. Six patients with carbamazepine positive patch test reaction showed cross sensitivity with phenobarbitone, sodium valproate and/or lamotrigine. Three (75%) patients among positive phenytoin patch test reactions had cross reactions with phenobarbitone, lamotrigine, and/or valproate. CONCLUSION Carbamazepine remains the commonest anticonvulsant causing ACDRs and cross-reactions with other anticonvulsants are possible. Drug patch testing appears useful in DRESS for drug imputability and cross-reactions established clinically.
Patel, Tejas K; Bhabhor, Prakash H; Desai, Nimisha; Shah, Saurabh; Patel, Parvati B; Vatsala, Ela; Panigrahi, Sanjibani
The epidemiological data are limited for the spontaneous adverse drug reaction (ADR) reporting system in psychiatry and its comparison with intensive monitoring studies in terms of causative drugs, seriousness, preventability and drug interactions. This spontaneous ADR reporting study was carried out over a period of three years in the psychiatry department. We adopted WHO definition for an ADR, Naranjo's algorithm for causality, WHO-ADR terminology for the labeling of involved organ-system, International conference on harmonisation (ICH) E2A guidelines for seriousness, modified Schumock and Thornton's criteria for preventability and Medscape drug interaction checker for drug interactions. Two subgroup analyses were performed to find out the risk factors for the serious and preventable reactions. A total of 97 ADRs from 67 patients were included for analysis. The incidence of 'overall' and 'serious ADRs were 0.69% (95% CI: 0.54%, 0.88%) and 0.18% (95% CI: 0.12-0.29%), respectively. The females experienced more ADRs than males. The most commonly reported ADR, incriminated pharmacology group and drug, were extrapyramidal movement disorders (22.68%), atypical antipsychotics (35.62%) and escitalopram (13.91%), respectively. One out of five and one out three reactions were considered as 'serious' and 'preventable', respectively. The drug interactions contributed in 34.02% reactions. The factors significantly associated with 'serious' reactions were typical antipsychotics [OR: 5.47 (1.68, 17.87)], central and peripheral nervous system disorders [OR: 24.00 (5.12, 112.5)] and extrapyramidal reactions [OR: 14.03 (4.43, 44.43)]. The polypharmacy [OR: 5.85 (1.90, 18.03)] was significantly associated with 'preventable' reactions. The spontaneous reporting system is efficient to detect serious reactions and preventable reactions.
Maxey, Dawn M; Ivy, D Dunbar; Ogawa, Michelle T; Feinstein, Jeffrey A
Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.
Fisher, Robert S; Ho, Jet
Use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs (AEDs). Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and therefore seizure control. In emergency situations, administration via rectal, nasal or buccal mucosa can deliver the drug more quickly than can oral administration. Slow-release oral forms and rectal forms of AEDs are already approved for use, nasal and buccal administration is currently off-label and skin patches for AEDs are an attractive but currently hypothetical option. Therapies under development may result in the delivery of AEDs directly to the regions of the brain involved in seizures. Experimental protocols are underway to allow continuous infusion of potent excitatory amino acid antagonists into the CSF. In experiments with animal models of epilepsy, AEDs have been delivered successfully to seizure foci in the brain by programmed infusion pumps, acting in response to computerised EEG seizure detection. Inactive prodrugs can be given systemically and activated at the site of the seizure focus by locally released compounds. One such drug under development is DP-VPA (or DP16), which is cleaved to valproic acid (sodium valproate) by phospholipases at the seizure focus. Liposomes and nanoparticles are engineered micro-reservoirs of a drug, with attached antibodies or receptor-specific binding agents designed to target the particles to a specific region of the body. Liposomes in theory could deliver a high concentration of an AED to a seizure focus. Penetration of the blood-brain barrier can be accomplished by linking large particles to iron transferrin or biological toxins that can cross the barrier. In the near future, it is likely that cell transplants that generate neurotransmitters and neuromodulators will accomplish renewable endogenous drug delivery. However, the survival and viability of transplanted cells have yet to be demonstrated
Ekins, Sean; Coffee, Megan
In the search for treatments for the Ebola Virus, multiple screens of FDA drugs have led to the identification of several with promising in vitro activity. These compounds were not originally developed as antivirals and some have been further tested in mouse in vivo models. We put forward the opinion that some of these drugs could be evaluated further and move into the clinic as they are already FDA approved and in many cases readily available. This may be important if there is a further outbreak in future and no other therapeutic is available. PMID:25789163
Most regulatory authorities require that developers of genetically engineered insect-resistant (GEIR) crops evaluate the potential for these crops to have adverse impacts on valued non-target organisms (NTOs), i.e., organisms not intended to be controlled by the trait. In many cases, impacts to NTOs...
Langman, Michael J S
This article reviews the clinical and epidemiological features of conventional non-steroidal anti-inflammatory drug (NSAID) related peptic ulcer complications, and the associated risk factors. The degree of gastrointestinal toxicity varies widely between the available drugs and with dose of each. The risk of ulcer complications can however be reduced, and perhaps completely removed, by using the lowest dose of the least toxic member of the class. Enteric coating and other delayed release formulations have not been shown to reduce risk. Estimates of the imposed disease burden have varied widely, in part through assuming that risks in selected patient groups will necessarily translate to the general population. Nevertheless, the imposed disease burden is one of the largest associated with current drug treatment. Associated risk factors such as prior ulcer, corticosteroid use and concurrent aspirin as well as general cardiovascular disease will raise the likelihood of an ulcer complication in NSAID takers and non-takers. Therefore, strategies dependent on substituting COX-selective drugs will then be only partially successful.
Mugoša, Snežana; Djordjević, Nataša; Djukanović, Nina; Protić, Dragana; Bukumirić, Zoran; Radosavljević, Ivan; Bošković, Aneta; Todorović, Zoran
The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6) poor metabolizer alleles (*3, *4, *5, and *6) on a Montenegrin population and its impact on developing adverse drug reactions (ADRs) of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients' medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9%) patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001), with ADRs' occurrence significantly correlating with slower CYP2D6 metabolism. Our study showed that the adverse reactions to β-blockers could be predicted by the length of hospitalization, CYP2D6 poor metabolizer phenotype, and the concomitant use of other CYP2D6-metabolizing drugs. Therefore, in hospitalized patients with polypharmacy CYP2D6 genotyping might be useful in detecting those at risk of ADRs.
Mugoša, Snežana; Djordjević, Nataša; Djukanović, Nina; Protić, Dragana; Bukumirić, Zoran; Radosavljević, Ivan; Bošković, Aneta; Todorović, Zoran
The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6) poor metabolizer alleles (*3, *4, *5, and *6) on a Montenegrin population and its impact on developing adverse drug reactions (ADRs) of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients’ medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9%) patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001), with ADRs’ occurrence significantly correlating with slower CYP2D6 metabolism. Our study showed that the adverse reactions to β-blockers could be predicted by the length of hospitalization, CYP2D6 poor metabolizer phenotype, and the concomitant use of other CYP2D6-metabolizing drugs. Therefore, in hospitalized patients with polypharmacy CYP2D6 genotyping might be useful in detecting those at risk of ADRs. PMID:27536078
Antonen, J A; Markula, K P; Pertovaara, M I; Pasternack, A I
Trimethoprim-associated systemic reactions, including aseptic meningitis, have been reported to be very rare adverse drug reactions. Patients with Sjögren's syndrome have been overrepresented, but no epidemiological surveys of the reaction have been conducted. To study the overall frequency of adverse drug reactions, and especially trimethoprim-associated reactions, we interviewed 85 primary Sjögren's syndrome patients and compared the results with those of 45 similarly interviewed osteoarthritis patients. Antimicrobial allergy was more common among Sjögren's syndrome patients than in osteoarthritis patients (46% vs. 27%). Eleven Sjögren's syndrome patients (13%), but no osteoarthritis patient, had experienced at least a partial, non-allergic systemic reaction with trimethoprim. Of them five (6%) had had a full-blown systemic reaction including both chills/fever and headache/backache and at least one of the following: malaise, vomiting, dizziness, confusion or meningeal irritation. Our findings confirm that allergic reactions to antimicrobials are frequent in Sjögren's syndrome. In addition to allergic reactions Sjögren's syndrome patients are prone to a specific trimethoprim-associated systemic reaction. This should be remembered when prescribing antimicrobials.
Myers, Bronwyn; McLaughlin, Katie A; Wang, Shuai; Blanco, Carlos; Stein, Dan J
Stress sensitization, whereby CA lowers tolerance to later stressors, has been proposed as a potential mechanism explaining the association between exposure to childhood adversities (CA) and drug use disorders in adulthood. However, this mechanism remains untested. This paper begins to address this gap through exploring associations between CA exposure and stressful events in adulthood for predicting drug use disorders. We used data drawn from Wave 2 of the U.S. National Epidemiological Survey of Alcohol and Related Conditions (n = 34,653) to explore whether the association between past-year stressful life events and the 12-month prevalence of disordered cannabis, stimulant, and opiate use varied by the number of types of CA that an individual was exposed to. Past-year stressful life events were associated with an increased risk of cannabis, stimulant, and opiate use disorders among men and women. Exposure to CA was associated with increased risk for disordered cannabis use among men and women and opiate use among men only. Finally, we found significant associations between exposure to CA and past-year stressful life events in predicting disordered drug use, but only for women in relation to disordered stimulant and opiate use. Findings are suggestive of possible stress sensitization effects in predicting disordered stimulant and opiate use among women. Implications of these findings for the prevention and treatment of drug use disorders and for future research are discussed.
Myers, Bronwyn; McLaughlin, Katie A.; Wang, Shuai; Blanco, Carlos; Stein, Dan J.
Stress sensitization, whereby CA lowers tolerance to later stressors, has been proposed as a potential mechanism explaining the association between exposure to childhood adversities (CA) and drug use disorders in adulthood. However this mechanism remains untested. This paper begins to address this gap through exploring associations between CA exposure and stressful events in adulthood for predicting drug use disorders. We used data drawn from Wave 2 of the U.S. National Epidemiological Survey of Alcohol and Related Conditions (n=34,653) to explore whether the association between past-year stressful life events and the 12-month prevalence of disordered cannabis, stimulant and opiate use varied by the number of types of CA that an individual was exposed to. Past-year stressful life events were associated with an increased risk of cannabis, stimulant and opiate use disorders among men and women. Exposure to CA was associated with increased risk for disordered cannabis use among men and women and opiate use among men only. Finally, we found significant associations between exposure to CA and past year stressful life events in predicting disordered drug use, but only for women in relation to disordered stimulant and opiate use. Findings are suggestive of possible stress sensitization effects in predicting disordered stimulant and opiate use among women. Implications of these findings for the prevention and treatment of drug use disorders and for future research are discussed. PMID:25134042
Rumyantsev, N A; Kukes, V G; Kazakov, R E; Rumyantsev, A A; Sychev, D A
The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors' experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.
Davis, Jesse; Costa, Vítor Santos; Peissig, Peggy; Caldwell, Michael; Berg, Elizabeth; Page, David
Learning from electronic medical records (EMR) is challenging due to their relational nature and the uncertain dependence between a patient's past and future health status. Statistical relational learning is a natural fit for analyzing EMRs but is less adept at handling their inherent latent structure, such as connections between related medications or diseases. One way to capture the latent structure is via a relational clustering of objects. We propose a novel approach that, instead of pre-clustering the objects, performs a demand-driven clustering during learning. We evaluate our algorithm on three real-world tasks where the goal is to use EMRs to predict whether a patient will have an adverse reaction to a medication. We find that our approach is more accurate than performing no clustering, pre-clustering, and using expert-constructed medical heterarchies. PMID:25285329
Hisham, Mohamed; Sivakumar, Mundilipalayam N.; Senthil Kumar, R. S.; Nandakumar, P.
A 52-year-old obese gentleman presented to the hospital with complaints of fever and shortness of breath for 10 days. He was admitted in the ward and treated for acute exacerbation of asthma. He was shifted to the Intensive Care Unit (ICU) for persistent fever, neck swelling, airway obstruction and desaturation. Ludwig's angina was suspected and computed tomography of neck confirmed it. A difficult airway was anticipated and preceded with surgical tracheostomy. The patient had hypersensitivity reactions to piperacillin/tazobactam; hence, he was treated with clindamycin and metronidazole. The patient improved and was discharged after five days of ICU stay and 12 days of hospitalization. This case summarizes the rare incidence of Ludwig's angina with antibiotic adverse reactions. If angioneurotic edema is coincidental with features of Ludwig's angina, it becomes more challenging. Early identification, securing the airway, and antibiotic administration are the keystone to better survival.
Zhao, Yueqin; Yi, Min; Tiwari, Ram C
A likelihood ratio test, recently developed for the detection of signals of adverse events for a drug of interest in the FDA Adverse Events Reporting System database, is extended to detect signals of adverse events simultaneously for all the drugs in a drug class. The extended likelihood ratio test methods, based on Poisson model (Ext-LRT) and zero-inflated Poisson model (Ext-ZIP-LRT), are discussed and are analytically shown, like the likelihood ratio test method, to control the type-I error and false discovery rate. Simulation studies are performed to evaluate the performance characteristics of Ext-LRT and Ext-ZIP-LRT. The proposed methods are applied to the Gadolinium drug class in FAERS database. An in-house likelihood ratio test tool, incorporating the Ext-LRT methodology, is being developed in the Food and Drug Administration.
Luo, Jake; Cisler, Ron A.
We systematically compared the adverse effects of cancer drugs to detect event outliers across different clinical trials using a data-driven approach. Because many cancer drugs are toxic to patients, better understanding of adverse events of cancer drugs is critical for developing therapies that could minimize the toxic effects. However, due to the large variabilities of adverse events across different cancer drugs, methods to efficiently compare adverse effects across different cancer drugs are lacking. To address this challenge, we present an exploration study that integrates multiple adverse event reports from clinical trials in order to systematically compare adverse events across different cancer drugs. To demonstrate our methods, we first collected data on 186,339 clinical trials from ClinicalTrials.gov and selected 30 common cancer drugs. We identified 1602 cancer trials that studied the selected cancer drugs. Our methods effectively extracted 12,922 distinct adverse events from the clinical trial reports. Using the extracted data, we ranked all 12,922 adverse events based on their prevalence in the clinical trials, such as nausea 82%, fatigue 77%, and vomiting 75.97%. To detect the significant drug outliers that could have a statistically high possibility of causing an event, we used the boxplot method to visualize adverse event outliers across different drugs and applied Grubbs’ test to evaluate the significance. Analyses showed that by systematically integrating cross-trial data from multiple clinical trial reports, adverse event outliers associated with cancer drugs can be detected. The method was demonstrated by detecting the following four statistically significant adverse event cases: the association of the drug axitinib with hypertension (Grubbs’ test, P < 0.001), the association of the drug imatinib with muscle spasm (P < 0.001), the association of the drug vorinostat with deep vein thrombosis (P < 0.001), and the association of the drug
Luo, Jake; Cisler, Ron A
We systematically compared the adverse effects of cancer drugs to detect event outliers across different clinical trials using a data-driven approach. Because many cancer drugs are toxic to patients, better understanding of adverse events of cancer drugs is critical for developing therapies that could minimize the toxic effects. However, due to the large variabilities of adverse events across different cancer drugs, methods to efficiently compare adverse effects across different cancer drugs are lacking. To address this challenge, we present an exploration study that integrates multiple adverse event reports from clinical trials in order to systematically compare adverse events across different cancer drugs. To demonstrate our methods, we first collected data on 186,339 clinical trials from ClinicalTrials.gov and selected 30 common cancer drugs. We identified 1602 cancer trials that studied the selected cancer drugs. Our methods effectively extracted 12,922 distinct adverse events from the clinical trial reports. Using the extracted data, we ranked all 12,922 adverse events based on their prevalence in the clinical trials, such as nausea 82%, fatigue 77%, and vomiting 75.97%. To detect the significant drug outliers that could have a statistically high possibility of causing an event, we used the boxplot method to visualize adverse event outliers across different drugs and applied Grubbs' test to evaluate the significance. Analyses showed that by systematically integrating cross-trial data from multiple clinical trial reports, adverse event outliers associated with cancer drugs can be detected. The method was demonstrated by detecting the following four statistically significant adverse event cases: the association of the drug axitinib with hypertension (Grubbs' test, P < 0.001), the association of the drug imatinib with muscle spasm (P < 0.001), the association of the drug vorinostat with deep vein thrombosis (P < 0.001), and the association of the drug afatinib
Aljadhey, Hisham; Mahmoud, Mansour A; Ahmed, Yusuf; Sultana, Razia; Zouein, Salah; Alshanawani, Sulafah; Mayet, Ahmed; Alshaikh, Mashael K; Kalagi, Nora; Al Tawil, Esraa; El Kinge, Abdul Rahman; Arwadi, Abdulmajid; Alyahya, Maha; Murray, Michael D; Bates, David
Objectives To determine the incidence of adverse drug events (ADEs) and assess their severity and preventability in four Saudi hospitals. Design Prospective cohort study. Setting The study included patients admitted to medical, surgical and intensive care units (ICUs) of four hospitals in Saudi Arabia. These hospitals include a 900-bed tertiary teaching hospital, a 400-bed private hospital, a 1400-bed large government hospital and a 350-bed small government hospital. Participants All patients (≥12 years) admitted to the study units over 4 months. Primary and secondary outcome measures Incidents were collected by pharmacists and reviewed by independent clinicians. Reviewers classified the identified incidents as ADEs, potential ADEs (PADEs) or medication errors and then determined their severity and preventability. Results We followed 4041 patients from admission to discharge. Of these, 3985 patients had complete data for analysis. The mean±SD age of patients in the analysed cohort was 43.4±19.0 years. A total of 1676 ADEs were identified by pharmacists during the medical chart review. Clinician reviewers accepted 1531 (91.4%) of the incidents identified by the pharmacists (245 ADEs, 677 PADEs and 609 medication errors with low risk of causing harm). The incidence of ADEs was 6.1 (95% CI 5.4 to 6.9) per 100 admissions and 7.9 (95% CI 6.9 to 8.9) per 1000 patient-days. The occurrence of ADEs was most common in ICUs (149 (60.8%)) followed by medical (67 (27.3%)) and surgical (29 (11.8%)) units. In terms of severity, 129 (52.7%) of the ADEs were significant, 91 (37.1%) were serious, 22 (9%) were life-threatening and three (1.2%) were fatal. Conclusions We found that ADEs were common in Saudi hospitals, especially in ICUs, causing significant morbidity and mortality. Future studies should focus on investigating the root causes of ADEs at the prescribing stage, and development and testing of interventions to minimise harm from medications. PMID:27406640
Bronzaft, Arline L.
Research linking loud sounds to hearing loss in youngsters is now widespread, resulting in the issuance of warnings to protect children's hearing. However, studies attesting to the adverse effects of intrusive sounds and noise on children's overall mental and physical health and well-being have not received similar attention. This, despite the…
The current approach to assessing adverse effects of chemicals in the environment is largely based on a battery of in-vivo study methods and a limited number of accepted in-silico approaches. For most substances the pool of data from which to predict ecosystem effects is limited ...
Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena
Cysteamine is an amino thiol with the chemical formula HSCH2CH2NH2. Endogenously, cysteamine is derived from coenzyme A degradation, although its plasma concentrations are low. Most experience with cysteamine as a drug originates from the field of the orphan disease cystinosis, in which cysteamine is prescribed to decrease intralysosomal cystine accumulation. However, over the years, the drug has been used for several other applications both in vitro and in vivo. In this article, we review the different applications of cysteamine, ending with an overview of ongoing clinical trials for new indications, such as neurodegenerative disorders and nonalcoholic fatty liver disease (NAFLD). The recent development of an enteric-coated cysteamine formulation makes cysteamine more patient friendly and will extend its applicability for both old and new indications.
Schwengber, Alex; Prado, Héctor J; Zilli, Darío A; Bonelli, Pablo R; Cukierman, Ana L
Drug loaded buckypapers based on different types of carbon nanotubes (CNTs) were prepared and characterized in order to evaluate their potentialities for the design of novel transdermal drug delivery systems. Lab-synthesized CNTs as well as commercial samples were employed. Clonidine hydrochloride was used as model drug, and the influence of composition of the drug loaded buckypapers and processing variables on in vitro release profiles was investigated. To examine the influence of the drug nature the evaluation was further extended to buckypapers prepared with flurbiprofen and one type of CNTs, their selection being based on the results obtained with the former drug. Scanning electronic microscopy images indicated that the model drugs were finely dispersed on the CNTs. Differential scanning calorimetry, and X-ray diffraction pointed to an amorphous state of both drugs in the buckypapers. A higher degree of CNT-drug superficial interactions resulted in a slower release of the drug. These interactions were in turn affected by the type of CNTs employed (single wall or multiwall CNTs), their functionalization with hydroxyl or carboxyl groups, the chemical structure of the drug, and the CNT:drug mass ratio. Furthermore, the application of a second layer of drug free CNTs on the loaded buckypaper, led to decelerate the drug release and to reduce the burst effect.
McDonough, Ryan; Streletzky, Kiril; Bayachou, Mekki; Peiris, Pubudu
The temperature dependent volume phase change of cross-linked amphiphilic molecules (microgels) suggests their use as drug delivery vesicles. Drug particles aggregate in the slightly hydrophobic microgel interior. They are stored in equilibrium until the critical temperature (Tv) is reached where the volume phase change limits available space, thus expelling the drugs. This loading property of hydroxypropylcellulose (HPC) microgels was tested using amperometric analytical techniques. Small molecules inside microgels do not approach the electrode surface, which decreases current signal. A room temperature (Troom) flow amperometric measurement comparing microgel/paracetamol solution with control paracetamol samples yielded about 20 percent concentration reduction in the microgel sample. Results from the steady-state electrochemical experiment confirm the 20 percent concentration drop in the microgel sample compared to the control sample at Troom. Using the steady-state experiment with a cyclic temperature ramp from Troom to beyond Tv showed that the paracetamol concentration change between the temperature extremes was greater for the microgels than for the controls. An evolving aspect of the study is the characterization of microgel shrinkage from in situ, temperature controlled liquid AFM images as compared to previously completed DLS characterization of the same microgel sample.
Liu, Mei; Hu, Yong; Tang, Buzhou
Drugs are an important part of today's medicine, designed to treat, control, and prevent diseases; however, besides their therapeutic effects, drugs may also cause adverse effects that range from cosmetic to severe morbidity and mortality. To identify these potential drug safety issues early, surveillance must be conducted for each drug throughout its life cycle, from drug development to different phases of clinical trials, and continued after market approval. A major aim of pharmacovigilance is to identify the potential drug-event associations that may be novel in nature, severity, and/or frequency. Currently, the state-of-the-art approach for signal detection is through automated procedures by analyzing vast quantities of data for clinical knowledge. There exists a variety of resources for the task, and many of them are textual data that require text analytics and natural language processing to derive high-quality information. This chapter focuses on the utilization of text mining techniques in identifying potential safety issues of drugs from textual sources such as biomedical literature, consumer posts in social media, and narrative electronic medical records.
Miller, Laurence L.
Intracranial self-stimulation (ICSS) is a behavioral procedure in which operant responding is maintained by pulses of electrical brain stimulation. In research to study abuse-related drug effects, ICSS relies on electrode placements that target the medial forebrain bundle at the level of the lateral hypothalamus, and experimental sessions manipulate frequency or amplitude of stimulation to engender a wide range of baseline response rates or response probabilities. Under these conditions, drug-induced increases in low rates/probabilities of responding maintained by low frequencies/amplitudes of stimulation are interpreted as an abuse-related effect. Conversely, drug-induced decreases in high rates/probabilities of responding maintained by high frequencies/amplitudes of stimulation can be interpreted as an abuse-limiting effect. Overall abuse potential can be inferred from the relative expression of abuse-related and abuse-limiting effects. The sensitivity and selectivity of ICSS to detect abuse potential of many classes of abused drugs is similar to the sensitivity and selectivity of drug self-administration procedures. Moreover, similar to progressive-ratio drug self-administration procedures, ICSS data can be used to rank the relative abuse potential of different drugs. Strengths of ICSS in comparison with drug self-administration include 1) potential for simultaneous evaluation of both abuse-related and abuse-limiting effects, 2) flexibility for use with various routes of drug administration or drug vehicles, 3) utility for studies in drug-naive subjects as well as in subjects with controlled levels of prior drug exposure, and 4) utility for studies of drug time course. Taken together, these considerations suggest that ICSS can make significant contributions to the practice of abuse potential testing. PMID:24973197
Wang, Lv; Wu, Ning; Zhao, Tai-Yun; Li, Jin
Drug addiction places a significant burden on society and individuals. Proteomics and metabolomics approaches pave the road for searching potential biomarkers to assist the diagnosis and treatment. This review summarized putative drug addiction-related biomarkers in proteomics and metabolomics studies and discussed challenges and prospects in future studies. Alterations of several hundred proteins and metabolites were reported when exposure to abused drug, which enriched in energy metabolism, oxidative stress response, protein modification and degradation, synaptic function and neurotrasmission, etc. Hsp70, peroxiredoxin-6 and α- and β-synuclein, as well as n-methylserotonin and purine metabolites, were promising as potential biomarker for drug addiction.
Avillach, Paul; Dufour, Jean-Charles; Diallo, Gayo; Salvo, Francesco; Joubert, Michel; Thiessard, Frantz; Mougin, Fleur; Trifirò, Gianluca; Fourrier-Réglat, Annie; Pariente, Antoine; Fieschi, Marius
Objectives The aim of this research was to automate the search of publications concerning adverse drug reactions (ADR) by defining the queries used to search MEDLINE and by determining the required threshold for the number of extracted publications to confirm the drug/event association in the literature. Methods We defined an approach based on the medical subject headings (MeSH) ‘descriptor records’ and ‘supplementary concept records’ thesaurus, using the subheadings ‘chemically induced’ and ‘adverse effects’ with the ‘pharmacological action’ knowledge. An expert-built validation set of true positive and true negative drug/adverse event associations (n=61) was used to validate our method. Results Using a threshold of three of more extracted publications, the automated search method presented a sensitivity of 90% and a specificity of 100%. For nine different drug/event pairs selected, the recall of the automated search ranged from 24% to 64% and the precision from 93% to 48%. Conclusions This work presents a method to find previously established relationships between drugs and adverse events in the literature. Using MEDLINE, following a MeSH approach to filter the signals, is a valid option. Our contribution is available as a web service that will be integrated in the final European EU–ADR project (Exploring and Understanding Adverse Drug Reactions by integrative mining of clinical records and biomedical knowledge) automated system. PMID:23195749
Background The new European pharmacovigilance legislation has been suggested as marking the beginning of a new chapter in drug safety, making patients an important part of pharmacovigilance. In Sweden since 2008 it has been possible for consumers to report adverse drug reactions (ADRs) to the Medical Products Agency (MPA), and these reports are now understood as an increasingly valuable contribution in the monitoring of safety aspects in medicines. Already in 2002 it was possible to report experiences with medicines to the non-profit and independent organization Consumer Association for Medicines and Health (KILEN) through a web-based report form with an opportunity to describe ADR experiences in free text comments. The aim of this study was to qualitatively analyze the free text comments appended to consumer reports on antidepressant medication. Methods All reports of suspected adverse reactions regarding antidepressant medications submitted from January 2002 to April 2009 to KILEN’s Internet-based reporting system in Sweden were analyzed according to reported narrative experience(s). Content analysis was used to interpret the content of 181 reports with free text comments. Results Three main categories emerged from the analyzed data material: (1) Experiences of drug treatment with subcategories (a) Severe psychiatric adverse reactions, and (b) Discontinuation symptoms; (2) Lack of communication and (3) Trust and distrust. A majority of the reports to KILEN were from patients experiencing symptoms of mental disturbances (sometimes severe) affecting them in many different ways, especially during discontinuation. Several report included narratives of patients not receiving information of potential ADRs from their doctor, but also that there were no follow-ups of the treatment. Trust was highlighted as especially important and some patients reported losing confidence in their doctor when they were not believed about the suspected ADRs they experienced, making them
El Emam, Khaled; Samet, Saeed; Arbuckle, Luk; Tamblyn, Robyn; Earle, Craig; Kantarcioglu, Murat
Background There is limited capacity to assess the comparative risks of medications after they enter the market. For rare adverse events, the pooling of data from multiple sources is necessary to have the power and sufficient population heterogeneity to detect differences in safety and effectiveness in genetic, ethnic and clinically defined subpopulations. However, combining datasets from different data custodians or jurisdictions to perform an analysis on the pooled data creates significant privacy concerns that would need to be addressed. Existing protocols for addressing these concerns can result in reduced analysis accuracy and can allow sensitive information to leak. Objective To develop a secure distributed multi-party computation protocol for logistic regression that provides strong privacy guarantees. Methods We developed a secure distributed logistic regression protocol using a single analysis center with multiple sites providing data. A theoretical security analysis demonstrates that the protocol is robust to plausible collusion attacks and does not allow the parties to gain new information from the data that are exchanged among them. The computational performance and accuracy of the protocol were evaluated on simulated datasets. Results The computational performance scales linearly as the dataset sizes increase. The addition of sites results in an exponential growth in computation time. However, for up to five sites, the time is still short and would not affect practical applications. The model parameters are the same as the results on pooled raw data analyzed in SAS, demonstrating high model accuracy. Conclusion The proposed protocol and prototype system would allow the development of logistic regression models in a secure manner without requiring the sharing of personal health information. This can alleviate one of the key barriers to the establishment of large-scale post-marketing surveillance programs. We extended the secure protocol to account for
Vasapollo, Piero; Cione, Erika; Luciani, Filippo; Gallelli, Luca
Selective agents able to locate and identify unique targets represent a crucial aspect of modern pharmacology. The exclusive location of sodium-glucose co-transporter-2 (SGLUT2) on kidneys prompt companies to develop SGLT2 inhibitors that today are the latest class of drugs for diabetes treatment. In particular, canagliflozin blocks the re-absorption of glucose in the kidney lowering blood glucose levels by increasing glucose excretion. We report a 61-year old woman who developed an intense and severe pruritus during the treatment with canagliflozin. Clinical and laboratory findings excluded the presence of systemic or skin diseases able to induce pruritus. The discontinuation of canagliflozin and the treatment with pioglitazone/metformin fixed combination induced a remission of pruritus. This case emphasizes the need to consider pruritus as a differential diagnosis during the treatment with canagliflozin.
Elkalmi, Ramadan; Hassali, Mohamed Azmi; Al-lela, Omar Qutaiba; Jawad Awadh, Ammar Ihsan; Al-Shami, Abdul Kareem; Jamshed, Shazia Qasim
Objective: The objective of this study was to explore the knowledge of the general population towards ADR and their reporting system. Methods: An anonymous, self-administered questionnaire (15 items) was designed. The questionnaire was subjected to face validity and content validity. The reliability coefficient was found to be 0.71. This study recruited proportionately large convenience sample of the general public in Penang. Interviews using a structured questionnaire were conducted over a week period in August 2009. The recommended sample size was calculated to be 368. Results: Three hundred thirty-four responses were received. Slightly more than half of the respondents were in the age group of 18-25 years (53.6%; n = 179). When asked about the sources of their medication majority of them reported medical doctor (85.6%), whereas small number (34.7%) reported community pharmacists as sources of medications. Three-quarter of the respondents (77.2%) get their information about the side-effects of drugs from physicians, followed by pharmacist (44.6%). More than half of the respondents (65.6%, n = 219) reported unawareness about the existence of ADR center set up by the Ministry of Health. Conclusion: Respondents reflected inadequate knowledge on ADR reporting. This needs to be corrected as the trend of future pharmacovigilance is toward the patient. Moreover, the new trend seems to be more appropriate as the patient is the group of the people who are directly affected from the ADR of a particular drug and not the health-care providers. Furthermore, the patient will be informed about the economic implications of not reporting ADR. It is recommended that government agencies, like MADRAC needs to find ways to increase patient- reported ADR cases. PMID:24082699
Charles, Krista; Cannon, Margaret; Hall, Robert; Coustasse, Alberto
Computerized provider order entry (CPOE) systems allow physicians to prescribe patient services electronically. In hospitals, CPOE essentially eliminates the need for handwritten paper orders and achieves cost savings through increased efficiency. The purpose of this research study was to examine the benefits of and barriers to CPOE adoption in hospitals to determine the effects on medical errors and adverse drug events (ADEs) and examine cost and savings associated with the implementation of this newly mandated technology. This study followed a methodology using the basic principles of a systematic review and referenced 50 sources. CPOE systems in hospitals were found to be capable of reducing medical errors and ADEs, especially when CPOE systems are bundled with clinical decision support systems designed to alert physicians and other healthcare providers of pending lab or medical errors. However, CPOE systems face major barriers associated with adoption in a hospital system, mainly high implementation costs and physicians’ resistance to change. PMID:25593568
Alecu, Iulian; Bousquet, Cedric; Mougin, Fleur; Jaulent, Marie-Christine
The WHO-ART and MedDRA terminologies used for coding adverse drug reactions (ADR) do not provide formal definitions of terms. In order to improve groupings, we propose to map ADR terms to equivalent Snomed CT concepts through UMLS Metathesaurus. We performed such mappings on WHO-ART terms and can automatically classify them using a description logic definition expressing their synonymies. Our gold standard was a set of 13 MedDRA special search categories restricted to ADR terms available in WHO-ART. The overlapping of the groupings within the new structure of WHO-ART on the manually built MedDRA search categories showed a 71% success rate. We plan to improve our method in order to retrieve associative relations between WHO-ART terms.
Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Sporozo ite infection of the liver is the first obl igate step of the Plasmodium...goal is to find drugs that prevent or control liver infection. Development of such drugs will be faci l itated by identification of parasite proteins...required for l iver infection. These proteins are potential drug targets for development of therapies that restrict Plasmodium liver infection. The
Vinogradov, Serguei; Wei, Xin
Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs. PMID:22471722
Liu, Hongfang; Nambisan, Priya
Background Drug repurposing (defined as discovering new indications for existing drugs) could play a significant role in drug development, especially considering the declining success rates of developing novel drugs. Typically, new indications for existing medications are identified by accident. However, new technologies and a large number of available resources enable the development of systematic approaches to identify and validate drug-repurposing candidates. Patients today report their experiences with medications on social media and reveal side effects as well as beneficial effects of those medications. Objective Our aim was to assess the feasibility of using patient reviews from social media to identify potential candidates for drug repurposing. Methods We retrieved patient reviews of 180 medications from an online forum, WebMD. Using dictionary-based and machine learning approaches, we identified disease names in the reviews. Several publicly available resources were used to exclude comments containing known indications and adverse drug effects. After manually reviewing some of the remaining comments, we implemented a rule-based system to identify beneficial effects. Results The dictionary-based system and machine learning system identified 2178 and 6171 disease names respectively in 64,616 patient comments. We provided a list of 10 common patterns that patients used to report any beneficial effects or uses of medication. After manually reviewing the comments tagged by our rule-based system, we identified five potential drug repurposing candidates. Conclusions To our knowledge, this is the first study to consider using social media data to identify drug-repurposing candidates. We found that even a rule-based system, with a limited number of rules, could identify beneficial effect mentions in patient comments. Our preliminary study shows that social media has the potential to be used in drug repurposing. PMID:27311964
Gräns, Albin; Sandblom, Erik; Kiessling, Anders; Axelsson, Michael
The use of fish models in biomedical research is increasing. Since behavioural and physiological consequences of surgical procedures may affect experimental results, these effects should be defined and, if possible, ameliorated. Thus, the use of post-surgical analgesia should be considered after invasive procedures also in fish, but presently, little information exists on the effects of analgesics in fish. This study assessed the effects of an opioid drug, buprenorphine (0.05 mg/kg IM), on resting ventilation and heart rates during 7 days of postsurgical recovery in rainbow trout (Oncorhynchus mykiss) at 10°C by non-invasively recording bioelectric potentials from the fish via electrodes in the water. Baseline ventilation and heart rates were considerably lower compared to previously reported values for rainbow trout at 10°C, possibly due to the non-invasive recording technique. Buprenorphine significantly decreased both ventilation and heart rates further, and the effects were most pronounced at 4-7 days after anaesthesia, surgical procedures and administration of the drug. Somewhat surprisingly, the same effects of buprenorphine were seen in the two control groups that had not been subject to surgery. These results indicate that the reductions in ventilation and heart rates are not caused by an analgesic effect of the drug, but may instead reflect a general sedative effect acting on both behaviour as well as e.g. central control of ventilation in fishes. This resembles what has previously been demonstrated in mammals, although the duration of the drug effect is considerably longer in this ectothermic animal. Thus, before using buprenorphine for postoperative analgesic treatment in fish, these potentially adverse effects need further characterisation.
Romana, Bilquis; Batger, Mellissa; Prestidge, Clive A; Colombo, Gaia; Sonvico, Fabio
Statins are effective lipid lowering agents traditionally used for the primary and secondary prevention of cardiovascular disease. Statins also exert a range of pleiotropic effects that make them attractive candidates for use in a wide range of disorders, in particular inflammatory and immune mediated conditions. However, the exploitation of such pleiotropic effects has been greatly hindered by poor bioavailability and adverse effects on muscles and the liver at higher doses. Nanotechnology is often suggested as the solution to this problem, as it enables an increased bioavailability of statins. Moreover, colloidal carriers can offer targeted drug delivery approaches that enable localised biological effects of statins, further reducing their potential for unwanted toxicity and adverse effects. This article reviews the available evidences for the increased potential of statin therapy when administered in nano-formulations such as nanocrystals, nanoparticles, liposomes, micelles and various nano-enabled devices.
Angamo, Mulugeta Tarekegn; Chalmers, Leanne; Curtain, Colin M; Bereznicki, Luke R E
Adverse drug reactions (ADRs) are one of the leading causes of hospital admissions and morbidity in developed countries and represent a substantial burden on healthcare delivery systems. However, there is little data available from low- and middle-income countries. This review compares the prevalence and characteristics of ADR-related hospitalisations in adults in developed and developing countries, including the mortality, severity and preventability associated with these events, commonly implicated drugs and contributing factors. A literature search was conducted via PubMed, Scopus, Web of Science, Embase, ProQuest and Google Scholar to find articles published in English from 2000 to 2015. Relevant observational studies were included. The median (with interquartile range [IQR]) prevalence of ADR-related hospitalisation in developed and developing countries was 6.3 % (3.3-11.0) and 5.5 % (1.1-16.9), respectively. The median proportions of preventable ADRs in developed and developing countries were 71.7 % (62.3-80.0) and 59.6 % (51.5-79.6), respectively. Similarly, the median proportions of ADRs resulting in mortality in developed and developing countries were 1.7 % (0.7-4.8) and 1.8 % (0.8-8.0), respectively. Commonly implicated drugs in both settings were antithrombotic, non-steroidal anti-inflammatory and cardiovascular drugs. Older age, female gender, number of medications, renal impairment and heart failure were reported to be associated with an increased risk for ADR-related hospitalisation in both settings while HIV/AIDS was implicated in developing countries only. The majority of ADRs were preventable in both settings, highlighting the importance of improving medication use, particularly in vulnerable patient groups such as the elderly, patients with multiple comorbidities and, in developing countries, patients with HIV/AIDS.
Pathak, Anuj Kumar; Dokania, Shambhu; Mohan, Lalit; Dikshit, Harihar
Introduction Pharmacovigilance (PV) is related to detection, assessment, understanding and prevention of Adverse Drug Reactions (ADRs) which are incurred when drug is made available in the market and used in different physiological conditions. In many countries, ADRs ranks among the top ten leading cause of morbidity and mortality. There is a lack of formal culture for monitoring and reporting of ADRs in India, with ADR reporting rate being only 1% as compared to 5% in world. This type of academic detailing activity helps to create awareness of ADR reporting in the institutions. Aim This study was planned to evaluate and analyse the incidence and patterns of ADRs in various inpatient and outpatient departments of hospital. Materials and Methods This was an observational, retrospective and record based study conducted by analysing the spontaneous ADR forms, collected over a period of 12 months (September 2014 to August 2015) at Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India. Results During the period of one year, 292 ADR forms were collected from 4,34,965 patients attending OPD and inpatients of the hospital. Incidence of ADR was 0.67 per thousand patients and average of around 24 ADR collected per month. Male:Female ratio was 1.30. Adolescent (16-30 yr) was the most common age group affected. Department of Skin and VD reported the maximum number of ADRs (33.22%), followed by the Departments of Oncology (18.84%). Antibiotics were the most common drug implicated followed by anticancer drugs. Conclusion ADR reporting is an ongoing and continuous process. Studies from the institute helps to identify and rectify the problems related to ADR reporting. Pitfalls can be addressed by creating awareness among physicians and the patients to achieve finally the goal of Pharmacovigilant India. PMID:27656459
Miguel-Arias, Domingo; Pereiro Gómez, César; Bermejo Barrera, Ana M; López de Abajo Rodríguez, Benito; Sobrido Prieto, María
The aim of this research is to study all people who died in the Autonomous Community of Galicia from acute death after drugconsumption (ADR) in which there was judicial intervention during the period from 1997 to 2011, according to inclusion and exclusión criteria established by the National Drug Plan for the entire national territory. Sociodemographic and clinical characteristics of deceased subjects were studied, in order to identify key risk factors and/or vulnerable populations.A total of 805 deaths were recorded. The distribution by provinces and municipalities corresponds to the areas of greatest population, incidence of consumption and proximity to the coast. The average age of these patients was 34.34 years, with a gradual increase over years. Most of them were male (91.2%) and single (47.7). 43.5% of the deceased habitually used the parenteral route of administration and 36.4% had positive HIV serology. The most frequently-detected substances corresponded to opiates (heroin: 61.3%, methadone: 35.6%), followed by cocaine (53.7%), although the most common pattern was that of poly-consumption. ADR mortality figures remain relatively stable throughout the study period. The predominant pattern is that of males, opiates and a long history of consumption.
Unoki, M.; Kumamoto, K.; Harris, C.C.
Recent emerging evidence suggests that ING family proteins play roles in carcinogenesis both as oncogenes and tumor suppressor genes depending on the family members and on cell status. Previous results from non-physiologic overexpression experiments showed that all five family members induce apoptosis or cell cycle arrest, thus it had been thought until very recently that all of the family members function as tumor suppressor genes. Therefore restoration of ING family proteins in cancer cells has been proposed as a treatment for cancers. However, ING2 knockdown experiments showed unexpected results: ING2 knockdown led to senescence in normal human fibroblast cells and suppressed cancer cell growth. ING2 is also overexpressed in colorectal cancer, and promotes cancer cell invasion through an MMP13 dependent pathway. Additionally, it was reported that ING2 has two isoforms, ING2a and ING2b. Although expression of ING2a predominates compared with ING2b, both isoforms confer resistance against cell cycle arrest or apoptosis to cancer cells, thus knockdown of both isoforms is critical to remove this resistance. Taken together, these results suggest that ING2 can function as an oncogene in some specific types of cancer cells, indicating restoration of this gene in cancer cells could cause cancer progression. Because knockdown of ING2 suppresses cancer cell invasion and induces apoptosis or cell cycle arrest, ING2 may be an anticancer drug target. In this brief review, we discuss possible clinical applications of ING2 with the latest knowledge of molecular targeted therapies. PMID:19442116
Park, Joong-Min; Hwang, In Gyu; Suh, Suk-Won; Chi, Kyong-Choun
TS-1 is an oral anti-cancer agent for gastric cancer with a high response rate and low toxicity. We report a case of long-term drug retention of TS-1 causing interstitial lung disease (ILD) as a fatal adverse reaction. A 65-year-old woman underwent a total gastrectomy with pathologic confirmation of gastric adenocarcinoma. She received 6 cycles of TS-1 and low-dose cisplatin for post-operative adjuvant chemotherapy followed by single-agent maintenance therapy with TS-1. After 8 months, the patient complained of a productive cough with sputum and mild dyspnea. A pulmonary evaluation revealed diffuse ILD in the lung fields, bilaterally. In spite of discontinuing chemotherapy and the administration of corticosteroids, the pulmonary symptoms did not improve, and the patient died of pulmonary failure. TS-1-induced ILD can be caused by long-term drug retention that alters the lung parenchyma irreversibly, the outcome of which can be life-threatening. Pulmonary evaluation for early detection of disease is recommended.
Chen, Yen-Chia; Huang, Hsien-Hao; Fan, Ju-Sing; Chen, Min-Hui; Hsu, Teh-Fu; Yen, David Hung-Tsang; Huang, Mu-Shung; Wang, Chien-Ying; Huang, Chun-I; Lee, Chen-Hsen
To compare the proportion, seriousness, preventability of adverse drug events (ADEs) between the older adults (≥ 65 years old) and younger adults (<65 years old) presenting to the emergency department (ED), we conducted a prospective observational cohort study of patients 18 years and older presenting to the ED. For all ED visits between March 1, 2009, and Feb 28, 2010, investigators identified ADEs and assessed cases using the Naranjo adverse drug reaction probability scale. Outcomes (proportion, seriousness, and preventability of ADE, length of ED stay, and hospitalization) and associated variables were measured and compared between younger and older adults. The results showed that of 58,569 ED visits, 295 older adults, and 157 younger adults were diagnosed as having an ADE and included in our analysis. The proportion of ADEs leading to ED visits in the older group, 14.3 per 1000 (295/20,628), was significantly higher than the younger group of 4.1 per 1000 (157/37,941). The older group with ADE had a longer ED stay (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.9-6.4 for stay ≥ 24 hours) and larger proportion of preventable ADEs (OR 2.2, 95% CI 1.4-3.6) than the younger group, but there was no significant difference in terms of serious ADEs (OR 0.6, 95% CI 0.3-1.3 for fatal and life threatening) and hospitalization (OR 1.5, 95% CI 0.9-2.6) between the 2 groups. In addition, patients in the older group were more likely to be male, to have symptoms of fatigue or altered mental status, to involve cardiovascular, renal, and respiratory systems, and to have higher Charlson comorbidity index scores, higher number of prescription medications, and higher proportion of unintentional overdose. In conclusion, the proportion of ADE-related ED visits in older adults was higher than younger adults, and many of these were preventable. The most common drug categories associated with preventable ADEs in the older adults were antithrombotic agents, antidiabetic
Saleem, Ammara; Akhtar, Muhammad Furqan; Mushtaq, Muhammed Fahd; Saleem, Muhammad; Muhammad, Syed Taqi; Akhtar, Bushra; Sharif, Ali; Peerzada, Sohaib
Viral hepatitis, an inflammatory liver disease, is caused by various genotypes of hepatitis C viruses (HCV). Hepatitis C slowly sprouts into fibrosis, which progresses to cirrhosis. Over a prolonged period of time compensated cirrhosis can advance to decompensated cirrhosis culminating in hepatic failure and death. Conventional treatment of HCV involves the administration of interferons. However, association of interferon with the adverse drug reactions led to the development of novel anti-HCV drugs given as monotherapy or in combination with the other drugs. Advances in drug delivery systems (DDS) improved the pharmacokinetic profile and stability of drugs, ameliorated tissue damages on extravasation and increased the targeting of affected sites. Liposomes and lipid based vehicles have been employed with polyethylene glycol (PEG) so as to stabilize the formulations as PEG drug complex. Sofosbuvir, a novel anti-HCV drug, is administered as monotherapy or in combination with daclatasvir, ledipasivir, protease inhibitors, ribavirin and interferon for the treatment of HCV genotypes 1, 2 and 3. These drug combinations are highly effective in eradicating the interferon resistance, recurrent HCV infection in liver transplant, concurrent HIV infection and preventing interferon related adverse effects. Further investigations to improve drug targeting and identification of new drug targets are highly warranted due to the rapid emergence of drug resistance in HCV. PMID:28096788
Saleem, Ammara; Akhtar, Muhammad Furqan; Mushtaq, Muhammed Fahd; Saleem, Muhammad; Muhammad, Syed Taqi; Akhtar, Bushra; Sharif, Ali; Peerzada, Sohaib
Viral hepatitis, an inflammatory liver disease, is caused by various genotypes of hepatitis C viruses (HCV). Hepatitis C slowly sprouts into fibrosis, which progresses to cirrhosis. Over a prolonged period of time compensated cirrhosis can advance to decompensated cirrhosis culminating in hepatic failure and death. Conventional treatment of HCV involves the administration of interferons. However, association of interferon with the adverse drug reactions led to the development of novel anti-HCV drugs given as monotherapy or in combination with the other drugs. Advances in drug delivery systems (DDS) improved the pharmacokinetic profile and stability of drugs, ameliorated tissue damages on extravasation and increased the targeting of affected sites. Liposomes and lipid based vehicles have been employed with polyethylene glycol (PEG) so as to stabilize the formulations as PEG drug complex. Sofosbuvir, a novel anti-HCV drug, is administered as monotherapy or in combination with daclatasvir, ledipasivir, protease inhibitors, ribavirin and interferon for the treatment of HCV genotypes 1, 2 and 3. These drug combinations are highly effective in eradicating the interferon resistance, recurrent HCV infection in liver transplant, concurrent HIV infection and preventing interferon related adverse effects. Further investigations to improve drug targeting and identification of new drug targets are highly warranted due to the rapid emergence of drug resistance in HCV.
Levoe, S. Nikki; Flannery, Brenna M.; Brignolo, Laurie; Imai, Denise M.; Koehne, Amanda; Austin, Adam T.; Bruun, Donald A.; Tancredi, Daniel J.; Lein, Pamela J.
Repeated subcutaneous (s.c.) injection is a common route of administration in chronic studies of neuroactive compounds. However, in a pilot study we noted a significant incidence of skin abnormalities in adult male Long-Evans rats receiving daily s.c. injections of peanut oil (1.0 ml/kg) in the subscapular region for 21 d. Histopathological analyses of the lesions were consistent with a foreign body reaction. Subsequent studies were conducted to determine factors that influenced the incidence or severity of skin abnormalities, and whether these adverse skin reactions influenced a specific neurobehavioral outcome. Rats injected daily for 21 d with food grade peanut oil had an earlier onset and greater incidence of skin abnormalities relative to rats receiving an equal volume (1.0 ml/kg/d) of reagent grade peanut oil or triglyceride of coconut oil. Skin abnormalities in animals injected daily with peanut oil were increased in animals housed on corncob versus paper bedding. Comparison of animals obtained from different barrier facilities exposed to the same injection paradigm (reagent grade peanut oil, 1.0 ml/kg/d s.c.) revealed significant differences in the severity of skin abnormalities. However, animals from different barrier facilities did not perform differently in a Pavlovian fear conditioning task. Collectively, these data suggest that environmental factors influence the incidence and severity of skin abnormalities following repeated s.c. injections, but that these adverse skin responses do not significantly influence performance in at least one test of learning and memory. PMID:25705100
Khasawneh, Fadi T.; Shankar, Gollapudi S.
The use of atypical antipsychotic agents has rapidly increased in the United States and worldwide in the last decade. Nonetheless, many health care practitioners do not appreciate the significance of the cardiovascular side effects that may be associated with their use and the means to minimize them. Thus, atypical antipsychotic medications can cause cardiovascular side effects such as arrhythmias and deviations in blood pressure. In rare cases, they may also cause congestive heart failure, myocarditis, and sudden death. Patients with schizophrenia have a higher risk of cardiovascular mortality than healthy individuals, possibly because of excessive smoking, the underlying disorder itself, or a combination of both factors. Increased awareness of these potential complications can allow pharmacists and physicians to better manage and monitor high risk patients. Accurate assessments are very important to avoid medications from being given to patients inappropriately. Additionally, monitoring patients regularly via blood draws and checking blood pressure, heart rate, and electrocardiogram can help catch any clinical problems and prevent further complications. Finally, patient and family-member education, which pharmacists in particular can play key roles in, is central for the management and prevention of side effects, which is known to reflect positively on morbidity and mortality in these patients. PMID:24649390
Oehme, Ann-Kathrin; Rashed, Asia N.; Hefele, Barbara; Wong, Ian C. K.; Rascher, Wolfgang; Neubert, Antje
Background In recent years, efforts have been made to improve paediatric drug therapy. The aim of this research was to investigate any changes regarding the frequency and nature of adverse drug reactions (ADRs) in hospitalized children in one paediatric general medical ward over a 9-year period. Methodology Two prospective observational cohort studies were conducted at a large University hospital in Germany in 1999 and 2008, respectively. Children aged 0–18 years admitted to the study ward during the study periods were included. ADRs were identified using intensive chart review. Uni- and multivariable regression has been used for data analysis. Results A total of 520 patients (574 admissions) were included [1999: n = 144 (167); 2008: n = 376 (407)]. Patients received a total of 2053 drugs [median 3, interquartile range (IQR) 2–5]. 19% of patients did not receive any medication. Median length of stay was 4 days (IQR 3–7; range 1–190 days) with a significantly longer length of stay in 1999. The overall ADR incidence was 13.1% (95% CI, 9.8–16.3) varying significantly between the two study cohorts [1999: 21.9%, 95% CI, 14.7–29.0; 2008: 9.2%, 95% CI, 5.9–12.5 (p<0.001)]. Antibacterials and corticosteroids for systemic use caused most of the ADRs in both cohorts (1999; 2008). Exposure to systemic antibacterials decreased from 62.9% to 43.5% whereas exposure to analgesics and anti-inflammatory drugs increased from 17.4% to 45.2%, respectively. The use of high risk drugs decreased from 75% to 62.2%. In 1999, 45.7% and in 2008 96.2% of ADRs were identified by treating clinicians (p<0.001). Conclusions Between 1999 and 2008, the incidence of ADRs decreased significantly. Improved treatment strategies and an increased awareness of ADRs by physicians are most likely to be the cause for this positive development. Nevertheless further research on ADRs particularly in primary care and the establishment of prospective pharmacovigilance systems are still
Schwab, Matthias; Schäffeler, Elke; Marx, Claudia; Fischer, Christine; Lang, Thomas; Behrens, Christoph; Gregor, Michael; Eichelbaum, Michel; Zanger, Ulrich M; Kaskas, Bernd A
The efficacy of the immunosuppressants azathioprine and 6-mercaptopurine has been well established in the therapy of inflammatory bowel diseases (IBD). However, its use has been complicated by a high incidence of serious adverse drug reactions such as hematotoxicity, hepatotoxicity, pancreatitis and gastrointestinal disturbances. Whereas azathioprine-related pancytopenia has been clearly linked to thiopurine S-methyltransferase (TPMT) polymorphism limited data are available to explain gastrointestinal side effects. In a retrospective analysis of 93 adults with IBD and azathioprine therapy both phenotyping and genotyping was used to explore systematically the relationship between TPMT and azathioprine-related adverse reactions. At time of inclusion, 69 patients were still receiving azathioprine therapy and had never experienced side effects. Azathioprine had been withdrawn in 10 patients for non-medical reasons or lack of response and 14 patients (15%) had stopped medication or were on reduced dose due to severe azathioprine-related side effects. Nine of these 14 patients had developed gastrointestinal side effects (hepatotoxicity, n = 3; pancreatitis, n = 3; others, n = 3), but their normal red blood cell TPMT activities were in accordance to TPMT wild-type. TPMT deficiency in one patient had led to pancytopenia whereas only two of the remaining four patients with hematotoxicity displayed an intermediate phenotype of TPMT. This study demonstrates that azathioprine-related gastrointestinal side effects are independent of the TPMT polymorphism. Nevertheless pharmacogenetic testing for TPMT prior to commencing thiopurine therapy should become routine practice in order to avoid severe hematotoxicity in TPMT deficient patients and lowering the incidence of hematological side effects in individuals heterozygous for TPMT.
Carrasco-Garrido, P; Hernández-Barrera, V; Esteban-Hernández, J; Jiménez-Trujillo, I; Álvaro-Meca, A; López de Andrés, A; de Miguel Diez, J; Rodríguez Barrios, J M; Muñoz Robles, J A; Jiménez-García, R
Objective To describe and analyse hospitalisations for adverse drug reactions (ADRs) involving anticoagulants. We also analysed the progress of the reactions over time, the factors related with ADRs. Design A retrospective, descriptive, epidemiological study. Setting This study used the Spanish National Hospital Discharge Database (Conjunto Mínimo Básico de Datos, CMBD), over a 4-year period. Participants We selected CMBD data corresponding to hospital discharges with a diagnosis of ADRs to anticoagulants (International Classification of Diseases-Ninth Revision, Clinical Modification (ICD-9-CM) code E934.2) in any diagnostic field during the study period. Main outcome measures We calculated the annual incidence of ADRs to anticoagulants according to sex and age groups. The median lengths of hospital stay and in-hospital mortality (IHM) were also estimated for each year studied. Bivariate analyses of the changes in variables according to year were based on Poisson regression. IHM was analysed using logistic regression models. The estimates were expressed as ORs and their 95% CI. Results During the study period, 50 042 patients were hospitalised because of ADRs to anticoagulants (6.38% of all ADR-related admissions). The number of cases increased from 10 415 in 2010 to 13 891 in 2013. Cumulative incidence of ADRs to anticoagulants was significantly higher for men than women and in all age groups. An adjusted multivariate analysis revealed that IHM did not change significantly over time. We observed a statistically significant association between IHM and age, with the highest risk for the ≥85 age group (OR 2.67; 95% CI 2.44 to 2.93). Conclusions The incidence of ADRs to anticoagulants in Spain increased from 2010 to 2013, and was significantly higher for men than women and in all age groups. Older patients were particularly susceptible to being hospitalised with an adverse reaction to an anticoagulant. PMID:28073793
Walenga, Jeanine M; Thethi, Indermohan; Lewis, Bruce E
The topic of adverse effects of drugs is now receiving due attention in both the lay and medical communities. For drugs of the coagulation disorder class, such as anticoagulants and antiplatelet agents, the obvious adverse effects are bleeding from a dose too high and thrombosis from a dose too low. However, these drugs have other potential adverse effects that are not directly related to blood coagulation, yet cannot be dismissed due to their medical importance. There has been a recent advancement of several new drugs in this category and this number will soon grow as more drugs are reaching the end of their clinical trials. This article will discuss the nonhemostatic adverse effects of anticoagulants and antiplatelet drugs. As the adverse effects of bleeding and thrombosis will be excluded, this article will be in contrast to the typical discussions on the anticoagulant and antiplatelet drug classes.
Sharma, Sonam; Mehra, Neelesh Kumar; Jain, Keerti; Jain, Narendra Kumar
The main aim of the present investigation was to explore the effect of functionalization on drug delivery potential of carbon nanotubes (CNTs) and to compare the in vitro and in vivo cancer targeting potential of doxorubicin HCL (DOX)-loaded ox-/multi-walled CNTs (MWCNTs), DOX-loaded PEG-MWCNTs and DOX-loaded FA-PEG-MWCNTs. The DOX/PEG-FA-MWCNTs showed enhanced cytotoxicity and were most preferentially taken up by the cancerous cells. The obtained results also support the extended resistance time and sustained release profile of drug-loaded surface-engineered MWCNTs. Overall, we concluded that the developed MWCNTs nanoformulations have higher cancer targeting potential.
Omoruyi, F O; Budiaman, A; Eng, Y; Olumese, F E; Hoesel, J L; Ejilemele, A; Okorodudu, A O
In this study, the effect of phytic acid supplement on streptozotocin-induced diabetic rats was investigated. Diabetic rats were fed rodent chow with or without phytic acid supplementation for thirty days. Blood and organ samples were collected for assays. The average food intake was the highest and the body weight gain was the lowest in the group fed phytic acid supplement compared to the diabetic and normal control groups. There was a downward trend in intestinal amylase activity in the group fed phytic acid supplement compared to the other groups. The spike in random blood glucose was the lowest in the same group. We noted reduced serum triglycerides and increased total cholesterol and HDL cholesterol levels in the group fed phytic acid supplement. Serum alkaline phosphatase and alanine amino transferase activities were significantly (P < 0.05) increased by phytic acid supplementation. Systemic IL-1 β level was significantly (P < 0.05) elevated in the diabetic control and supplement treated groups. The liver lipogenic enzyme activities were not significantly altered among the groups. These results suggest that phytic acid supplementation may be beneficial in the management of diabetes mellitus. The observed adverse effect on the liver may be due to the combined effect of streptozotocin-induced diabetes and phytic acid supplementation.
Magalhães, Paulo; Alves, Gilberto; Llerena, Adrián; Falcão, Amílcar
Venlafaxine (VEN) is one of the safest and most effective drugs used in the treatment of selective serotonin reuptake inhibitors-resistant depression, and thereby it is nowadays one of the most commonly prescribed antidepressants. Nevertheless, patients treated with antidepressant drugs including VEN have exhibited large inter-individual variability in drug outcomes, possibly due to the influence of genetic and nongenetic factors on the drug pharmacokinetics and/or pharmacodynamics. Among them, an increased interest has emerged over the last few years on the genetic and/or phenotypic profile for drug-metabolizing cytochrome P450 isoenzymes and drug transporters such as potential predictive pharmacokinetic-based biomarkers of the variability found in drug biodisposition and antidepressant response. The integration of some of these key therapeutic biomarkers with classic therapeutic drug monitoring constitutes a promising way to individualization of VEN's pharmacotherapy, offering to clinicians the ability to better predict and manage pharmacological treatments to maximize the drug effectiveness. Thus, this review provides an extensive discussion of the pharmacokinetics of VEN focusing in particular on metabolism issues, without forgetting the clinically relevant sources of pharmacokinetics variability (mainly the genetic sources) and aiming on the identification of phenotypic and/or genetic biomarkers for therapy optimization.
Tragni, Elena; Casula, Manuela; Pieri, Vasco; Favato, Giampiero; Marcobelli, Alberico; Trotta, Maria Giovanna; Catapano, Alberico Luigi
The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes “two prescriptions in the same day”, and concomitant medication “the prescription of two drugs with overlapping coverage”. A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ≥70 years. On average, subjects involved in pDDIs received ≥10 drugs. The odds of exposure were more frequently higher for age ≥65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use
Kiguba, Ronald; Karamagi, Charles; Bird, Sheila M
Objectives To determine the incidence and risk factors of hospital-acquired suspected adverse drug reactions (ADRs) among Ugandan inpatients. We also constructed risk scores to predict and qualitatively assess for peculiarities between low-risk and high-risk ADR patients. Methods Prospective cohort of consented adults admitted on medical and gynaecological wards of the 1790-bed Mulago National Referral Hospital. Hospital-acquired suspected ADRs were dichotomised as possible (possible/probable/definite) or not and probable (probable/definite) or not, using the Naranjo scale. Risk scores were generated from coefficients of ADR risk-factor logistic regression models. Results The incidence of possible hospital-acquired suspected ADRs was 25% (194/762, 95% CI: 22% to 29%): 44% (85/194) experienced serious possible ADRs. The risk of probable ADRs was 11% (87/762, 95% CI 9% to 14%): 46% (40/87) had serious probable ADRs. Antibacterials-only (51/194), uterotonics-only (21/194), cardiovascular drugs-only (16/194), antimalarials-only (12/194) and analgesics-only (10/194) were the most frequently implicated. Treatment with six or more conventional medicines during hospitalisation (OR=2.31, 95% CI 1.29 to 4.15) and self-reported herbal medicine use during the 4 weeks preadmission (OR=1.96, 95% CI 1.22 to 3.13) were the risk factors for probable hospital-acquired ADRs. Risk factors for possible hospital-acquired ADRs were: treatment with six or more conventional medicines (OR=2.72, 95% CI 1.79 to 4.13), herbal medicine use during the 4 weeks preadmission (OR=1.68, 95% CI 1.16 to 2.43), prior 3 months hospitalisation (OR=1.57, 95% CI 1.09 to 2.26) and being on gynaecological ward (OR=2.16, 95% CI 1.36 to 3.44). More drug classes were implicated among high-risk ADR-patients, with cardiovascular drugs being the most frequently linked to possible ADRs. Conclusions The risk of hospital-acquired suspected ADRs was higher with preadmission herbal medicine use and treatment with
Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng
Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.
Greenwich Bay is an urbanized embayment of Narragansett Bay potentially impacted by multiple stressors. The present study identified the important stressors affecting Greenwich Bay benthic fauna. First, existing data and information were used to confirm that the waterbody was imp...