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.
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.
Verma, Rajesh; Vasudevan, Biju; Pragasam, Vijendran
Severe cutaneous drug reactions are one of the commonest medical challenges presenting to an emergency room in any hospital. The manifestations range from maculopapular rash to severe systemic symptoms like renal failure and cardiovascular compromise. Toxic epidermal necrolysis, erythroderma, drug rash with eosinophilia and systemic symptoms, acute generalised exanthematous pustulosis and drug induced vasculitis are the common cutaneous drug reactions which can have severe morbidity and even mortality. Careful history taking of the lag period after drug intake and associated symptoms, along with detailed examination of the skin, mucosa and various systems, help in early diagnosis of these reactions. Early stoppage of the incriminating drug, specific therapy including corticosteroids, cyclosporine and intravenous immunoglobulin depending on the case along with supportive therapy and local measures help in salvaging most patients. An overview of these important cutaneous drug reactions along with their management is being reviewed in this article. PMID:24600147
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
Drago, F; Cogorno, L; Agnoletti, A F; Parodi, A
The objective of this retrospective study was to verify whether peripheral eosinophilia (PE) may be a marker of severity for adverse cutaneous drug reactions (ACDR). We investigated for PE in sixty-three patients diagnosed as adverse cutaneous drug reactions. All the patients underwent blood tests at baseline visit. Only patients that showed a very likely connection between ACDR and the suspected causative drug were induced in the study. We found that 11 out of 63 patients (17%) presented PE for values ≥ 0.6 x 10(9) cells/l or for a percentage of total leukocytes ≥ 6%. These 11 patients compared to patients without eosinophilia had a longer recovery time, they showed diffuse severe cutaneous reactions and they all needed a systemic therapy compared to the 41% of patients without eosinophilia. These outcomes prompt us to believe that peripheral eosinophilia may be an index of severity for adverse cutaneous drug reactions. Therefore, we suggest physicians to always detect the presence of peripheral eosinophilia in order to not underestimate the reaction and to promptly start an appropriate therapy.
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
Patel, Tejas K; Thakkar, Sejal H; Sharma, DC
Background: Epidemiological data is limited for cutaneous adverse drug reactions (CADRs) in India. Most of the Indian studies have small sample size and are of limited duration. Aims: The aim of this study is to analyze CADRs with reference to the causative drugs and their clinical characteristics in Indian population. Materials and Methods: As per selection criteria, electronic databases were searched for publications describing CADRs from January-1995 to April-2013 by two independent investigators. Data of the causative drugs and clinical characteristics were extracted and summarized by absolute numbers, percentages, ranges, and means as presented by the authors. The subgroup analysis of causative drugs was performed for causality assessment, severe or nonsevere reactions and occurrence of common CADRs. Studies showing “definite” and “probable” categories of causality analysis were labeled as “definite and probable causality (DPC) studies”. The other included studies were labeled as “non-DPC studies”. Results: Of 8337 retrieved references, 18 prospective studies were selected for analysis. The pooled incidence was 9.22/1000 total among outpatient and inpatient cases. Commonly observed reactions were maculopapular rash (32.39%), fixed drug eruptions (FDEs) (20.13%), urticaria (17.49%) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (6.84%). The major causative drug groups were antimicrobials (45.46%), nonsteroidal anti-inflammatory drugs (NSAIDs) (20.87%) and anti-epileptic drugs (14.57%). Commonly implicated drugs were sulfa (13.32%), β-lactams (8.96%) and carbamazepine (6.65%). High frequency of CADRs is observed with anti-epileptic drugs in DPC studies only. Carbamazepine, phenytoin and fluoroquinolones had higher severe to nonsevere cutaneous reaction ratio than other drugs. Antimicrobials were the main causative drugs for maculopapular rash, FDEs and SJS/TEN, and NSAIDs for the urticaria. The mortality for overall CADRs, SJS
Soria, Angèle; Barbaud, Annick; Assier, Haudrey; Avenel-Audran, Martine; Tétart, Florence; Raison-Peyron, Nadia; Amarger, Stéphanie; Girardin, Pascal; Francès, Camille
Currently used antimalarial drugs (AM) are hydroxychloroquine and chloroquine, which are prescribed for many autoimmune disorders. The value of skin tests on cutaneous adverse drug reactions (CADR) with AM remains unknown. The main objective of this retrospective study is to know whether skin tests for AM are useful and how to manage the recovery of AM therapy in these patients. All patients referred for suspected CADR secondary to AM between 2001 and 2014 in eight French dermatology centers were retrospectively reviewed. We report herein a retrospective series of 20 patients with CADR and AM involvement. Skin tests, performed in 14/20 patients, were negative in all cases. Six patients had an oral provocation test with recurrence of CADR in 1 case. We encourage dermatologists to perform oral provocation tests in nonsevere CADR in order to allow AM rechallenge at progressive doses. © 2015 S. Karger AG, Basel.
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.
Ding, Wen Yi; Lee, Chew Kek; Choon, Siew Eng
Adverse drug reactions are most commonly cutaneous in nature. Patterns of cutaneous adverse drug reactions (ADRs) and their causative drugs vary among the different populations previously studied. Our aim is to determine the clinical pattern of drug eruptions and the common drugs implicated, particularly in severe cutaneous ADRs in our population. This study was done by analyzing the database established for all adverse cutaneous drug reactions seen from January 2001 until December 2008. A total of 281 cutaneous ADRs were seen in 280 patients. The most common reaction pattern was maculopapular eruption (111 cases, 39.5%) followed by Stevens-Johnson Syndrome (SJS: 79 cases, 28.1%), drug reaction with eosinophilia and systemic symptoms (DRESS: 19 cases, 6.8%), toxic epidermal necrolysis (TEN: 16 cases, 5.7 %), urticaria/angioedema (15 cases, 5.3%) and fixed drug eruptions (15 cases, 5.3%). Antibiotics (38.8%) and anticonvulsants (23.8%) accounted for 62.6% of the 281 cutaneous ADRs seen. Allopurinol was implicated in 39 (13.9%), carbamazepine in 29 (10.3%), phenytoin in 27 (9.6%) and cotrimoxazole in 26 (9.3%) cases. Carbamazepine, allopurinol and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 24.0%, 18.8% and 12.5% respectively of the 96 cases seen whereas DRESS was mainly caused by allopurinol (10 cases, 52.6%) and phenytoin (3 cases, 15.8%). The reaction patterns and drugs causing cutaneous ADRs in our population are similar to those seen in other countries although we have a much higher proportion of severe cutaneous ADRs probably due to referral bias, different prescribing habit and a higher prevalence of HLA-B*1502 and HLA-B*5801 which are genetic markers for carbamazepine-induced SJS/TEN and allopurinol-induced SJS/TEN/DRESS respectively. The most common reaction pattern seen in our study population was maculopapular eruptions. Antibiotics, anticonvulsants and NSAIDs were the most frequently implicated drug groups. Carbamazepine
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
Latha, S; Choon, S E
Cutaneous adverse drug reactions (cADRs) are common. There are only few studies on the incidence of cADRs in Malaysia. To determine the incidence, clinical features and risk factors of cADRs among hospitalized patients. A prospective study was conducted among medical inpatients from July to December 2014. A total of 43 cADRs were seen among 11 017 inpatients, yielding an incidence rate of 0.4%. cADR accounted for hospitalization in 26 patients. Previous history of cADR was present in 14 patients, with 50% exposed to the same drug taken previously. Potentially lifethreatening severe cutaneous adverse reactions (SCAR), namely drug reaction with eosinophilia and systemic symptoms (DRESS: 14 cases) and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN: 6 cases) comprise almost 50% of cADRs. The commonest culprit drug group was antibiotics (37.2%), followed by anticonvulsants (18.6%). Cotrimoxazole, phenytoin and rifampicin were the main causative drugs for DRESS. Anticonvulsants were most frequently implicated in SJS/TEN (66.7%). Most cases had "probable" causality relationship with suspected drug (69.8%). The majority of cases were of moderate severity (65.1%), while 18.6% had severe reaction with 1 death recorded. Most cases were not preventable (76.7%). Older age (> 60 years) and mucosal involvement were significantly associated with a more severe reaction. The incidence of cADRs was 0.4%, with most cases classified as moderate severity and not preventable. The commonest reaction pattern was DRESS, while the main culprit drug group was antibiotics. Older age and mucosal membrane involvement predicts a severe drug reaction.
Danza, Alvaro; López, Maynés; Vola, Magdalena; Alvarez-Rocha, Alfredo
Adverse cutaneous reactions to Drugs (CDRs) are of particular interest among all adverse Drug reactions (ADR) due to their frequency, potential severity and because of the importance of an early diagnosis. Antimicrobial agents, anticonvulsants and non-steroidal anti-inflammatory Drugs are the Drugs associated to the highest risk of CDRs. To assess CDRs in hospitalized patients and identify the Drugs involved. All patients hospitalized in the Hospital de Clínicas in Montevideo, Uruguay, with suspected CDRs, detected during one year, were included in this prospective study. The imputability was established using the Karch and Lasagna algorithm modified by Naranjo. We analyzed age, gender, Drugs involved, causal disease, severity, latency and evolution. Seventeen patients, aged 17 to 85 years (15 females) with CDRs were identifed. Twelve had morbilliform exanthemas, four had reactions with eosinophilia and systemic symptoms and one had a Stevens Johnson syndrome. The Drugs involved were antimicrobials in nine cases, hypouricemic agents in four cases, anticonvulsants in three cases and aspartic insulin in one. Twelve patients had a life threatening reaction and one required admission to the intensive care unit. No deaths occurred. CDRs were more common in women and most of them were caused by antimicrobial agents.
Imbesi, S; Allegra, A; Calapai, G; Musolino, C; Gangemi, S
Lenalidomide is an immunomodulatory drug (IMiD) used principally in the treatment of multiple myeloma (MM), myelodysplastic syndromes (MS) and amyloidosis. Adverse reactions related to lenalidomide include myelosuppression (mainly neutropenia but also thrombocytopenia), gastrointestinal problems, skin eruption, atrial fibrillation and asthenia, decreased peripheral blood stem cell yield during stem cell collection, venous thromboembolism, and secondary malignances. In this review we focused our attention on the cutaneous adverse reactions to lenalidomide.
Mittal, Niti; Gupta, Mahesh; Singla, Mohit
Medication-related adverse events, apart from causing significant morbidity and mortality, increase the healthcare cost burden and lead to early treatment discontinuations. Knowing the fact that cutaneous adverse drug reactions (cADRs) are most frequent, this study was conducted with an aim to describe their clinical profiles and preventive strategies. All adverse drug reaction (ADR) forms filled from January 2012 to January 2013 were scrutinised and forms with cADRs analysed and assessed for causality, preventability and severity. Of 400 ADR forms, 109 included cADRs. Sixty-eight percent patients were males and mean ± SD age was 35 ± 18 years. Rash, Steven-Johnson syndrome and toxic epidermal necrolysis were the most common presentations. Most frequent culprit drugs included antibiotics and anti-inflammatory agents. Causality was probable or possible in majority. Ninety percent cases were "not preventable". Majority of the patients had mild to moderate reactions and recovered completely after medical management. Pharmacovigilance, with special attention to monitoring and reporting of cADRs must be encouraged. As major bulk of cADRs result from physician prescribed drugs, awareness on part of the physician can help in their timely detection and management, thereby restricting the associated damage.
Adler, N R; Graudins, L V; Aung, A K
We read with interest Teo et al.'s recently published article examining cutaneous adverse drug reactions (cADR) referred to an inpatient liaison dermatology service.(1) The authors assessed the number and types of cADR encountered and subsequent documentation.(1) The diagnosis and management of cADR has been recognised by NICE Guidelines on Drug Allergy as a high-priority area for quality improvement.(2) We commend Teo and colleagues(1) for examining an essential, yet often overlooked, component of health service quality. We would like to further highlight the importance of risk communication, documentation and patient-centred care, aspects that are imperative for severe cADR. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Weinborn, Marie; Barbaud, Annick; Truchetet, Francois; Beurey, Philippe; Germain, Lucie; Cribier, Bernard
Few studies have been published on the histopathology of cutaneous adverse drug reactions (CADR), and most of these lack information on skin allergological tests. The histopathology of drug reaction with eosinophilia and systemic symptoms (DRESS) is also seldom described. The purpose of our study was to examine six types of well-documented CADR (maculopapular exanthema, DRESS, fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis [TEN], and acute generalized exanthematous pustulosis) using histopathology and immunohistochemistry to evaluate the expression of granulysin, a key molecule in TEN. We retrospectively included 106 skin biopsies performed in proven cases of CADR (by chronological investigation, single attributable drug, or/and skin tests). All slides were reviewed, and microscopic changes were analyzed using a standardized form. Granulysin expression was studied by immunohistochemistry. In DRESS, we observed spongiosis, edema, and basal vacuolization, with rare necrotic keratinocytes and constant lymphocytic infiltrate in the superficial dermis. Eosinophils were often present, and pustules were found in 15% of cases. Necrotic keratinocytes are often absent in maculopapular exanthema. Granulysin was expressed in six types of CADR with a trend toward more intense expression in DRESS and TEN. We detailed further about the histopathology of DRESS. Granulysin expression was observed in all CADR with a marked overlap of expression pattern between the six types. © 2016 The International Society of Dermatology.
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
Ke, Ching-Hua; Chung, Wen-Hung; Wen, Yen-Hsia; Huang, Yaw-Bin; Chuang, Hung-Yi; Tain, You-Lin; Wang, Yu-Ching Lily; Wu, Cheng-Chih; Hsu, Chien-Ning
Patients with an HLA-B*58:01 allele have an increased risk of developing severe cutaneous adverse drug reactions (SCAR) when treated with allopurinol. Although one-off pharmacogenetic testing may prevent life-threatening adverse drug reactions, testing prior to allopurinol initiation incurs additional costs. The study objective was to evaluate the cost-effectiveness of HLA-B*58:01 screening compared with using other available urate-lowering agents (ULA). A decision-analytical model was used to compare direct medical costs and effectiveness [including lifetime saved, quality-adjusted life-yrs (QALY) gained] in treating new patients with the following options: (1) genetic screening followed by allopurinol prescribing for noncarriers of HLA-B*58:01, (2) prescribing benzbromarone without screening, (3) prescribing febuxostat without screening, and (4) prescribing allopurinol without screening. A 1-year time frame and third-party payer perspective were modeled for both the entire cohort (base-case) and for the subgroup of patients with chronic kidney disease (CKD). The incremental cost-effectiveness ratio of genetic screening prior to ULA therapy was estimated as New Taiwan (NT) $234,610 (US$7508) per QALY gained in the base-case cohort. For patients with CKD, it was estimated as NT$230,925 (US$7390) per QALY. The study results were sensitive to the probability of benzbromarone/febuxostat-related hypersensitivity, and a negative predicted value of genotyping. HLA-B*58:01 screening gave good value for money in preventing allopurinol-induced SCAR in patients indicated for ULA therapy. In addition to the costs of genotyping, it is important to monitor ULA safety closely in adopting HLA-B*58:01 screening in practice.
Trubiano, Jason A; Aung, Ar Kar; Nguyen, Mary; Fehily, Sasha R; Graudins, Linda; Cleland, Heather; Padiglione, Alex; Peleg, Anton Y
The difference in clinical presentation, causality assessments, and outcomes of patients with delayed antibiotic-associated cutaneous adverse drug reactions (AA-cADR) and nonantibiotic-associated (NA)-cADR is ill defined. We examined the etiology of AA-cADR, with regard to the type of antibiotic exposure, allergy labeling, and patient outcomes, in comparison with NA-cADR. A retrospective observational inpatient cohort study of cADR was performed from January 2004 to August 2014. Patients were divided into AA-cADR and NA-cADR groups for analysis. cADR was defined as erythema multiforme, fixed drug eruption, acute generalized erythematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS), drug-associated linear IgA disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Of the 84 patients with cADR, 48% were AA-cADR. Male sex (60% vs 32%, P = .004), median length of stay (14.5 vs 11 days, P = .05), median Charlson comorbidity index (3 vs 1, P = .03), and inpatient mortality (20% vs 5%, P = .04) were higher in AA-cADR compared with NA-cADR. The median drug latency was lower in AA-cADR (6 vs 20 days, P = .001). Sulfonamide antibiotics and glycopeptides were implicated in 20% of AA-cADR. DRESS was more frequently reported in AA-cADR. After cADR diagnosis, further antibiotic therapy was administered in 64% of patients, higher in AA-cADR (75%, 30 of 40) compared with NA-cADR (55%, 24 of 44) (P = .06). Fluoroquinolones (53% vs 21%, P = .02), glycopeptides (vancomycin and teicoplanin; 70% vs 38%, P = .05), and carbapenems (33% vs 13%, P = .11) were used more commonly in AA-cADR. Antibiotics were the cause of cADR requiring hospital admission in 48% of episodes, and were associated with longer length of stay, higher age-adjusted Charlson comorbidity index, shorter drug latency, and mortality. In AA-cADR, glycopeptide and sulfonamide antibiotic exposure predominated. Copyright © 2016 American Academy of Allergy, Asthma & Immunology
Graudins, Linda Velta; Ly, Jenny; Trubiano, Jason; Aung, Ar Kar
To determine the gaps in practice regarding appropriate ADR documentation and risk communication for patients diagnosed with severe cutaneous adverse drug reactions (CADR). This was a retrospective observational cohort study conducted using hospital coding and databases to identify inpatients diagnosed with CADR from January 2004 to August 2014. Hospital discharge summaries, ADR reports and pharmacy dispensing records were reviewed for ADR documentation. Patients still living in Australia and who did not opt out of being contacted were invited to be surveyed by telephone to determine their understanding of recommendations, re-exposure rates and long-term effects. Of 85 patients identified, median age was 59 (IQR 44-72) years and 47.1% were male. The most common diagnosis was TENS (49.4%). Ten patients (11.8%) died as inpatients. Of the 81 patients with a drug-related causality, 47 (58%) had appropriate documentation in all three required medical record platforms. Of the 56 eligible patients, 38 (67.9%) were surveyed; 13% had no information provided upon discharge and 26.3% patients had a mismatch in knowledge of implicated medications. No surveyed patient had a relapse of CADR, but 23.7% had a subsequent unrelated allergic reaction. Thirteen patients (34.2%) reported long-term effects. We found gaps in the accuracy of ADR documentation and communication of risk at discharge, which indicated risks to patient safety. Electronic systems are being developed to improve documentation. Written information about CADR is being provided at discharge to improve patient understanding and knowledge. © 2016 The British Pharmacological Society.
Tan-Koi, Wei Chuen; Sung, Cynthia; Chong, Yong Yeow; Lateef, Aisha; Pang, Shiu Ming; Vasudevan, Archana; Aw, Derrick; Lui, Nai Lee; Lee, Shan Xian; Ren, Ee Chee; Koay, Evelyn Sc; Tay, Yong Kwang; Lim, Yen Loo; Lee, Haur Yueh; Dong, Di; Loke, Celine; Tan, Liesbet; Limenta, Michael; Lee, Edmund Jd; Toh, Dorothy; Chan, Cheng Leng
The Health Sciences Authority launched a pharmacogenetics initiative in 2008 to facilitate evaluation of pharmacogenetics associations pertinent for Chinese, Malays and Indians in Singapore. The aim was to reduce the incidence and unpredictability of serious adverse drug reactions, with a focus on serious skin adverse drug reactions. This paper describes the gathering of evidence and weighing of factors that led to different genotyping recommendations for HLA-B*15:02 with carbamazepine and HLA-B*58:01 with allopurinol, despite both having strong genetic associations. Translation of pharmacogenomics at a national level requires careful deliberation of the prevalence of at-risk allele, strength of genetic associations, positive predictive value, cost-effectiveness and availability of alternative therapies. Our experience provides a perspective on translating genomic discoveries in advancing drug safety.
Lehloenya, R J; Todd, G; Wallace, J; Ngwanya, M R; Muloiwa, R; Dheda, K
The incidence of cutaneous adverse drug reactions (CADRs) to first-line antituberculosis drugs (FLTDs) is higher in HIV-tuberculosis coinfection. However, the utility of patch testing to identify the offending drug in this patient subgroup has been poorly studied. To identify drugs causing adverse drug reactions in patients with HIV-tuberculosis coinfection. Fourteen consecutive patients underwent diagnostic work-up (patch testing followed by a skin prick test and an oral rechallenge) to pinpoint the offending drug after developing FLTD-associated CADR, which included drug rash with eosinophilia and systemic symptoms (n = 12), Stevens-Johnson syndrome (SJS, n = 1) and toxic epidermal necrolysis/SJS overlap (n = 1). A positive reaction to any of the three diagnostic modalities eliminated that drug from the regimen. Once patients were clinically stable postreaction, sequential and additive rechallenge with FLTDs was initiated. Eleven of the 14 participants with FLTD-associated CADR were HIV infected (median CD4 count 149 cells mm(-3) ). In this subgroup, patch testing resulted in generalized systemic reactions in 10 of 11 patients (91%). These included rash in 10 of 13 reactions (77%), eosinophilia in eight (62%), transaminitis in seven (54%) and fever in five (38%). Isoniazid caused six of 13 (46%) generalized systemic reactions, rifampicin four (31%), ethambutol two (15%) and pyrazinamide one reaction. Using the Common Terminology Criteria for Adverse Events, five of 13 reactions were mild, six were moderate and two were severe. There were no life-threatening or fatal reactions. In HIV-infected persons with tuberculosis-associated CADR, although patch-testing reactions to FLTD are common and tend to be associated with systemic features, they are not life threatening or fatal. These data inform clinical practice in HIV-endemic settings. © 2016 British Association of Dermatologists.
Manuyakorn, Wiparat; Siripool, Khanitha; Kamchaisatian, Wasu; Pakakasama, Samart; Visudtibhan, Anannit; Vilaiyuk, Soamarat; Rujirawat, Thidarat; Benjaponpitak, Suwat
Aromatic anticonvulsant-induced severe cutaneous adverse drug reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrosis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), are fatal immune-mediated adverse drug reactions. CYP2C19, a cytochrome P450 isoform, plays a role in metabolic rate of aromatic anticonvulsant. HLA-B*1502 has also been demonstrated to be associated with carbamazepine-induced SJS-TEN. Forty case patients who were diagnosed with SCARs after initiation of phenobarbital (PB), phenytoin (PHT), or carbamazepine (CBZ) for 1-8 wk and forty control patients who received PB, PHT, or CBZ at least 2 months with no adverse drug reactions were enrolled in the study. The genotypes of CYP2C19*1, CYP2C19*2, and HLA-B*1502 were analyzed using allele-specific polymerase chain reaction technique. Clinical characteristics of SCARs patients who used different drugs were also analyzed. There was no significant difference in sex, onset of symptoms, laboratory results, treatment, and length of stay among patients with SCARs due to PB, PHT, or CBZ. The patients with CYP2C19*2 variant had a trend to have a likelihood to develop SCARs more than the patients with CYP2C19 wild type (OR = 2.5, 95% CI (0.96-67.3) p = 0.06). In subgroup analysis, the patients with CYP2C19*2 variant were at four times increased risk of SCARs from phenobarbital more than the patients with CYP2C19 wild type (OR = 4.5, 95% CI (1.17-17.37) p < 0.03). There was no association between the HLA-B*1502 and aromatic anticonvulsant-induced severe cutaneous adverse reactions (SCARs). CYP2C19*2 variant may play a role in the genetic predisposition of SCARs from phenobarbital. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.
Choon, Siew-Eng; Lai, Nai-Ming
The prevalence, clinical patterns, and causative drugs of cutaneous adverse drug reactions (cADR) vary among the different populations previously studied. To determine the prevalence, the clinical patterns of drug eruptions, and the common drugs implicated, particularly in severe cADR such as Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms (DRESS) in our population. We analyzed the database established for all cADR seen by the department of Dermatology from January 2001 till December 2010. A total of 362 cADR were seen among 42 170 new clinic attendees, yielding an incidence rate of 0.86%. The most common reaction pattern seen was maculopapular eruption (153 cases) followed by SJS/TEN (110 cases) and DRESS (34 cases). Antibiotics was the most commonly implicated drug group (146 cases) followed by anticonvulsants (81 cases) and antigout drugs (50 cases). The most frequently implicated drug was allopurinol (50 cases). Carbamazepine, allopurinol, and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 21.8%, 20.9%, and 12.7%, respectively, of the 110 cases seen, whereas DRESS was mainly caused by allopurinol (15 cases). Mortality rates for TEN, SJS, and DRESS were 28.6%, 2.2%, and 5.9%, respectively. The low rate of cADR with a high proportion of severe reactions observed in this study was probably due to referral bias. Otherwise, the reaction patterns and drugs causing cADR in our population were similar to those seen in other countries. Carbamazepine, allopurinol, and cotrimoxazole were the three main causative drugs of SJS/TEN in our population.
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. PMID:28396847
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.
Daud, Adil; Algazi, Alain; Gubens, Matthew; Luna, Sara Alcántara; Lin, Kevin; Quaglino, Pietro; Rappersberger, Klemens; Ortiz-Urda, Susana
IMPORTANCE Immunomodulatory anticancer drugs, such as the anti–programmed death-1 drug pembrolizumab, have shown promising results in trials, and more patients will receive such treatments. Little is known about cutaneous adverse events (AEs) caused by these drugs and their possible correlation with treatment response. OBJECTIVE To describe the frequency and spectrum of cutaneous AEs linked with pembrolizumab and their possible correlation with treatment response. DESIGN, SETTING, AND PARTICIPANTS A single-institution, retrospective medical record review was conducted of patients with cancer who were treated with pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83 consecutive patients who were enrolled in 2 clinical trials, received at least 1 dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped according to the following therapeutic regimen for pembrolizumab: 43 received 10 mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma. Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted from March 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES Occurrence, severity, and type of cutaneous AEs, as well as disease progression and response to pembrolizumab treatment. RESULTS Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma. Survival analyses showed that patients who developed cutaneous AEs had significantly longer progression-free intervals in all 3 groups (pembrolizumab, 10 mg/kg, every 3 weeks, P = .001; pembrolizumab, 10 mg/kg, every 2 weeks, P = .003; pembrolizumab, 2 mg/kg, every 3
Shuster, Marina; Do, Daihung; Nambudiri, Vinod
A 50-year-old woman presented with diffuse, intensely pruritic pink-red papules on her trunk and extremities three weeks after starting combination therapy with ribavirin, telaprevir, and interferon. She also had cervical lymphadenopathy, fever, eosinophilia, and transaminitis consistent with a severe drug reaction to telaprevir. She was started on high potency topical steroids under inpatient observation and recovered within two weeks. Severe cutaneous eruptions secondary to telaprevir have resulted in black-box warnings for potentially fatal skin reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN). Because these reactions carry acute mortality rates of 10%, prompt detection and treatment with steroids are important. As such, physicians should be aware of these potentially lethal side effects.
Naldi, L; Crotti, S
Cutaneous reactions represent in many surveillance systems, the most frequent adverse events attributable to drugs. The spectrum of clinical manifestations is wide and virtually encompasses any known dermatological disease. The introduction of biological agents and so-called targeted therapies has further enlarged the number of reaction patterns especially linked with cytokine release or in balance. The frequency and clinical patterns of cutaneous reactions are influenced by drug use, prevalence of specific conditions (e.g., HIV infection) and pharmacogenetic traits of a population, and they may vary greatly among the different populations around the world. Studies of reaction rates in cohorts of hospitalized patients revealed incidence rates ranging from, 1 out 1000 to 2 out 100 of all hospitalized patients. For drugs such as aminopenicillines and sulfamides the incidence of skin reactions is in the order of 3-5 cases out of 100 exposed people. Although the majority of cutaneous reactions are mild and self-limiting, there are reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) which are associated with significant morbidity and mortality. Surveillance systems routed on sound epidemiologic methodology, are needed to raise signals and to assess risks associated with specific reactions and drug exposures. Identification of risk factors for adverse reactions and appropriate genetic screening of groups at higher risk may improve the outcomes of skin reactions.
Bensaïd, Benoît; Valeyrie-Allanore, Laurence; Lebrun-Vignes, Bénédicte; Nicolas, Jean-François
Cutaneous adverse drug reactions (CADR) are delayed hypersensivities. Their clinical presentation and severity are very diverse ranging from the frequent and benign exanthemas to the rare but severe CADR involving deep organs in the case of drug reaction with eosinophilia and systemic symptoms (DRESS) or leading to skin bulla and epidermal detachment in toxic epidermal necrolysis. The main differential diagnoses are infections, especially viral ones, which could give clinical symptoms identical to those occurring in CADR.
Callen, Jeffrey P
Many new drugs are entering the marketplace and although some cutaneous reactions might be noted in the preclinical evaluation, some of the reactions, particularly those that are rare, will not be noted until the drugs enter widespread use. In addition, distinctive reactions may occur, as is the case with epidermal growth factor-receptor inhibitors. Careful observation and evaluation might result in a better understanding of "naturally" occurring skin disease.
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.
Cortese, Irene; Ohayon, Joan; Fenton, Kaylan; Lee, Chyi-Chia; Raffeld, Mark; Cowen, Edward W.; DiGiovanna, John J.
Objective: To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multiple sclerosis treated with daclizumab high-yield process (DAC-HYP). Methods: A total of 31 participants in an institutional review board–approved open-label phase I study of DAC-HYP (NCT01143441) were prospectively evaluated over 42 months for development of cutaneous AEs. Participants provided written informed consent. Fifteen participants were naive to anti-CD25 therapy (cohort B), while 16 had received daclizumab (Zenapax; Hoffmann-La Roche) IV for 4–9 years (mean 5.8 years) prior to enrollment (cohort A). Immunohistochemistry was performed on pretreatment and posttreatment skin biopsies of normal-appearing skin (cohort B only) and on lesional biopsies in participants presenting with rash (both cohorts). Results: Cutaneous AEs occurred in 77% of patients, the majority presenting with patches of eczema requiring no treatment. Moderate to severe rash developed in 6 participants (19%) and required discontinuation of DAC-HYP in 4 (13%). More severe rashes presented psoriasiform phenotype, but lesional biopsies lacked features of either psoriasis or drug hypersensitivity eruptions. Instead, irrespective of clinical severity, lesional biopsies showed nonspecific features of eczematous dermatitis, but with prominent CD56+ lymphocytic infiltrates. Pretreatment and posttreatment biopsies of normal-appearing skin demonstrated no histopathologic changes. Conclusions: Observed cutaneous AEs are likely related to the immunomodulatory effects DAC-HYP exerts on innate lymphoid cells, including natural killer cells. Vigilance and timely management of skin reactions may prevent treatment discontinuation in participants with severe rash. PMID:26843560
Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR).
Kano, Yoko; Tohyama, Mikiko; Aihara, Michiko; Matsukura, Setsuko; Watanabe, Hideaki; Sueki, Hirohiko; Iijima, Masafumi; Morita, Eishin; Niihara, Hiroyuki; Asada, Hideo; Kabashima, Kenji; Azukizawa, Hiroaki; Hashizume, Hideo; Nagao, Keisuke; Takahashi, Hayato; Abe, Riichiro; Sotozono, Chie; Kurosawa, Michiko; Aoyama, Yumi; Chu, Chia-Yu; Chung, Wen-Hung; Shiohara, Tetsuo
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse drug reaction caused by specific drug. It is characterized by visceral organ involvement and reactivation of various human herpesviruses. Although sporadic reports have documented certain conditions that appear after the resolution of DIHS/DRESS, little information is available on sequelae after resolution of DIHS/DRESS in a large patient population. The Asian Research Committee on Severe Cutaneous Adverse Reactions, comprised of doctors from Japan and Taiwan, conducted a survey on sequelae and deterioration of the underlying disease in patients with DIHS/DRESS. This was achieved by directly interviewing patients who had been followed-up by experts or through a questionnaire mailed to patients. Questions were asked about new onset cardiovascular disease, collagen disease or autoimmune disease, gastrointestinal disease, renal disease, respiratory disease, neoplasms, and other diseases such as herpes zoster and diabetes mellitus, as well as deterioration of the underlying disease. A total of 145 patients were analyzed in this study. The following newly developed diseases after recovery from DIHS/DRESS were observed: Graves' disease (n = 2), Hashimoto's disease (n = 3), painless thyroiditis (n = 2), fulminant type 1 diabetes mellitus (n = 5), and infectious diseases (n = 7). Several DIHS/DRESS patients with pre-existing renal dysfunction required lifelong hemodialysis. DIHS/DRESS is a condition that increases the risk of new onset of disease. Long-term observation of DIHS/DRESS can provide an opportunity to investigate substantial diseases from onset to the full-blown stage. Patients with DIHS/DRESS require careful long-term follow-up. © 2015 Japanese Dermatological Association.
Adler, N R; Aung, A K; Ergen, E N; Trubiano, J; Goh, M S Y; Phillips, E J
Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. Our understanding of several aspects of SCAR syndromes has evolved considerably over the last decade. This review explores evolving knowledge of the immunopathogenic mechanisms, pharmacogenomic associations, in vivo and ex vivo diagnostics for causality assessment, and medication cross-reactivity data related to SCAR syndromes. Given the rarity and severity of these diseases, multidisciplinary collaboration through large international, national and/or multicentre networks to collect prospective data on patients with SCAR syndromes should be prioritized. This will further enhance a systematized framework for translating epidemiological, clinical and immunopathogenetic advances into preventive efforts and improved outcomes for patients. © 2017 British Association of Dermatologists.
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.
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…
Becker, Daniel E.
The potential for interactions with current medications should always be considered when administering or prescribing any drug. Considering the staggering number of drugs patients may be taking, this task can be daunting. Fortunately, drug classes employed in dental practice are relatively few in number and therapy is generally brief in duration. While this reduces the volume of potential interactions, there are still a significant number to be considered. This article will review basic principles of drug interactions and highlight those of greatest concern in dental practice. PMID:21410363
Callen, J P
Subacute cutaneous lupus erythematosus (SCLE) is a subset of cutaneous lupus erythematosus with unique immunologic and clinical features. The first description dates back to 1985 when a series of five patients were found to have hydrochlorothiazide-induced SCLE. Since that time, at least 40 other drugs have been implicated in the induction of SCLE.
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
Ishak, Rim; Abbas, Ossama
Penicillamine is a well-known heavy metal chelator, classically used in the treatment of Wilson disease, rheumatoid arthritis, and cystinuria. From a dermatologic standpoint, penicillamine was found to be useful in the treatment of systemic sclerosis. The successful therapeutic uses of penicillamine have been hindered by its numerous adverse effects, both cutaneous and extra-cutaneous. It is a unique drug since it provokes a diversity of dermatologic manifestations that include (1) acute hypersensitivity reactions, (2) dermopathies characterized by elastic fiber abnormalities including elastosis perforans serpiginosa and pseudo-pseudoxanthoma elasticum, (3) autoimmune disorders such as pemphigus and penicillamine-induced lupus erythematosus-like syndrome, and (4) miscellaneous dermatoses that result from undefined mechanisms. These cutaneous adverse effects may correlate with the dosage and duration of penicillamine therapy as well as the disease being treated.
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.
Various adverse cutaneous reactions may occur as a result of exposure to wood dust or solid woods. These include allergic contact dermatitis, irritant contact dermatitis and, more rarely, contact urticaria, photoallergic and phototoxic reactions. Also cases of erythema multiforme-like reactions have been reported. Contact dermatitis, both allergic and irritant, is most frequently provoked by exotic woods, e.g. wood of the Dalbergia spp., Machaerium scleroxylon or Tectona grandis. Cutaneous reactions are usually associated with manual or machine woodworking, in occupational setting or as a hobby. As a result of exposure to wood dust, airborne contact dermatitis is often diagnosed. Cases of allergic contact dermatitis due to solid woods of finished articles as jewelry or musical instruments have also been reported. The aim of the paper is to present various adverse skin reactions related to exposure to woods, their causal factors and sources of exposure, based on the review of literature.
Dao, Ro-Lan; Su, Shih-Chi
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCAR) which are majorly caused by drugs. Though the incidence rate is low, SCAR sometimes can be life-threatening and leads to lifelong sequelae. Many pharmacogenomic associations in immune and nonimmune related genes with the development of SCAR have been discovered recently and the pharmacogenetic tests have been applied to prevent specific drug-induced SCAR. In this review, we discuss the recent advances of pharmacogenomics in SCAR. PMID:25938070
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.
Khumalo, Nonhlanhla P; Jessop, Susan; Ehrlich, Rodney
To identify studies of the prevalence of cutaneous complications of hairdressing in (1) hairdressers and the general population and (2) those more common in people of African ancestry. Three versions of MEDLINE were searched from January 1966 through December 2004 and with a repeated search in August 2005 using 2 groups of search terms: group 1, terms used for hair care and specific study designs: survey, cross-sectional study, and cohort study; group 2, the terms African hair, Afro-Caribbean hair, African American hair, central centrifugal cicatricial alopecia, acne keloidalis nuchae, traction alopecia, and synonyms for each. All identified cross-sectional and cohort studies of cutaneous adverse effects were included and their quality assessed using criteria developed by Radulescu et al. Four studies used either questionnaires or patch testing to estimate the prevalence of cutaneous adverse effects of hair chemicals in the general population and found a prevalence of contact dermatitis, secondary to use of hair dye, of 5.3% and of allergy to paraphenylenediamine of 0.1% to 2.3%. Working as a hairdresser is associated with a prevalence of contact dermatitis ranging from 16.4% in larger cohort studies that included a clinical examination to 80% in the smaller, questionnaire-based studies. Three studies of people of African ancestry found a prevalence of acne keloidalis nuchae ranging from 1.3% to 13.7% and of traction alopecia of 1%. None of these were in the general population. Working as a hairdresser is associated with an increased risk of contact allergy and/or hand dermatitis. Studies of skin disorders of individuals of African ancestry are needed to quantify the health burden and clarify causal variables of these disorders. It is not clear how much the unique shape of the African hair follicle contributes to the development of these conditions.
van der Bent, S A S; Wolkerstorfer, A; Rustemeyer, T
Tattooing involves the introduction of exogenous pigment into the dermis. Worldwide, tattoos are one of the most popular forms of permanent body art. In the Netherlands, 8-10% of the population older than 12 years old has a tattoo. A wide variety of cutaneous adverse effects can occur in tattoos, these can cause serious symptoms. However, recognition and appropriate knowledge of diagnosis and treatment is still frequently insufficient in many medical practitioners. The first case concerns a 57-year-old female, who developed an itching swelling in the red part of a tattoo on the left arm. Histology of a punch biopsy showed a pseudolymphomatous reaction. This plaque-like allergic reaction was successfully treated with intralesional injection of corticosteroids. Here we described four cases of cutaneous adverse reactions to tattoos. Allergic reactions in tattoos can present in a wide variety of clinical and histological patterns. The symptoms are often chronic itch and can appear weeks, months or years after placing the tattoo. Allergic reactions are uniformly manifested in one particular colour. Clinically, the reactions can present in a plaque-like, hyperkeratotic or rarely ulcerative or generalised reaction. In spite of changes to the compounds in tattoo inks, allergic reactions are still mostly observed to red ink. Treatment options are topical corticosteroids, intralesional injection of corticosteroids, laser treatment or dermatome shaving.
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.
Nieweg, Omgo E; Gallegos-Hernández, José Francisco
The treatment of cutaneous melanoma has historically been essentially surgical. Much progress has been made in this area, and the resection margins have been established based on tumour depth. Candidates are also identified for lymphadenectomy, avoiding the morbidity of the procedure in patients who do not require it. But little progress has been made in systemic treatment, since the 70's when the use of dacarbazine was introduced for the treatment of patients with tumour progression or distant metastasis, with disappointing results. Despite this, Dacarbazine has been the most used drug to the present. Three years ago, two new drugs were introduced, one of them based on the target therapy and other one in the immunotherapy, offering, with the obtained results, an alternative in the treatment of cutaneous melanoma The objectives of this article are to show the pathways of these drugs, to describe the current role of surgery in cutaneous melanoma, with the arrival of these drugs, as well as to know the therapeutic alternatives that are emerging for the cutaneous melanoma based on scientific evidence. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.
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
Fricke-Galindo, I; Jung-Cook, H; LLerena, A; López-López, M
Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients' quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.
Bircher, Andreas J; Scherer, Kathrin
Drugs may elicit a considerable variety of clinical signs, often affecting the skin and the mucous membranes. The most common are maculopapular exanthemas and urticaria, more rarely pustules, bullae vasculitic lesions, and lichenoid lesions may also be observed. Apart from the morphology, the chronology of the occurrence and the evolution of single skin lesions and exanthema are also paramount in the clinical diagnosis of cutaneous drug hypersensitivity. Often, the skin represents the only organ manifestation; however, it may be the herald for a systemic involvement of internal organs, such as in severe drug-induced hypersensitivity syndromes or anaphylaxis.
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.
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.
Bock, Vanessa L; Friedlander, Michael; Waring, Dale; Kossard, Steven; Wood, Glenda K
Hormonal therapy with either tamoxifen or aromatase inhibitors is commonly used to treat women with breast cancer in both the adjuvant and recurrent disease setting. Cutaneous adverse reactions to these drugs have been rarely reported in the literature. We report an unusual case of urticarial vasculitis following the aromatase inhibitor anastrozole that localised to the unilateral trunk and mastectomy scar, and review the literature on the cutaneous adverse effects of hormonal therapy for breast cancer.
Souissi, Amel; Fenniche, Samy; Benmously, Rym; Ben Jannet, Sélima; Marrak, Hayet; Mokhtar, Inçaf
Cutaneous adverse drug reactions correspond to adverse effects with cutaneous expression resulting from the systemic penetration of a drug in the body. The aim of this study is to evaluate the various clinical pictures of RCM, their epidemiologic characteristics as well as the different causative drugs, through a retrospective hospital series. It is about a retrospective study about all the patients consulting and/or hospitalized for suspicion of an adverse cutaneous drug reaction led to the service of dermatology of the teaching hospital Habib Thameur of Tunis over a 3-year period (from January 2002 to December 2004). The diagnosis was based on a beam of clinical and anamnestic arguments. Only the patients having a positive pharmacovigilance investigation were retained. 28 patients were retained for this study. The macular and papular exanthema represented the most frequent clinical aspects followed by acute urticaria and fixed drug eruption. The antibiotics represented the most causative drugs followed by analgesics and non steroidal anti-inflammatory. We record a lower frequency of cutaneous adverse drug reactions in comparison with the literature. We also find a high frequency of severe forms and stress on the difficulties encountered in the identification of the causativele drugs. Though, a close cooperation between the various hospital structures and pharmacovigilance centers is mandatory.
Yuan, Jing; Guo, Sheng; Hall, David; Cammett, Anna M; Jayadev, Supriya; Distel, Manuel; Storfer, Stephen; Huang, Zimei; Mootsikapun, Piroon; Ruxrungtham, Kiat; Podzamczer, Daniel; Haas, David W
Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening.
Yuan, Jing; Guo, Sheng; Hall, David; Cammett, Anna M.; Jayadev, Supriya; Distel, Manuel; Storfer, Stephen; Huang, Zimei; Mootsikapun, Piroon; Ruxrungtham, Kiat; Podzamczer, Daniel; Haas, David W.
Objective Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. Design We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Methods Cases and controls were matched 1 : 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. Results We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Conclusion Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening. PMID
Nanau, Radu M; Neuman, Manuela G
Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Su, Shih-Chi; Hung, Shuen-Iu; Fan, Wen-Lang; Dao, Ro-Lan; Chung, Wen-Hung
Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine. PMID:27854302
Su, Shih-Chi; Hung, Shuen-Iu; Fan, Wen-Lang; Dao, Ro-Lan; Chung, Wen-Hung
Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine.
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
Walling, Hobart W; Swick, Brian L
Fixed drug eruption (FDE) is an uncommon medication-induced cutaneous reaction. A case of fluconazole-induced FDE is described. A 64-year-old woman presented with eight ovoid hyperpigmented patches on the arms, palm and lower leg that had recurred multiple times at the identical sites at seemingly random intervals over the prior six months. The clinicopathologic diagnosis strongly favored FDE, though the culprit medication remained elusive. Further evaluation and oral rechallenge confirmed the diagnosis of FDE to fluconazole. The patient had not related the eruption to this medication due to the short courses of therapy and prior use without incident. FDE to fluconazole has only been rarely reported in the literature. The presentation and evaluation of FDE is reviewed.
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.
Gamba, Chiara; Schroeder, Jan; Citterio, Antonella; Cazzaniga, Simone; Rivolta, Alma Lisa; Vighi, Giuseppe
Adverse drug reactions affecting the skin have particular relevance as they may cause significant mortality and a possible modification of the benefit/risk profile of the concerned drug. The following entities are of special importance: Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and drug rash with eosinophilia and systemic symptoms (DRESS). On the above mentioned reactions we focused our surveillance programme in the Lombardy region, the REACT-Lombardia project. The REACT registry involved 22 hospital-based dermatological centres, collecting, from April 2009 up to March 2014, a total of 72 cases of SJS-TEN, 17 cases of AGEP and 9 cases of DRESS. Allopurinol was the drug associated with the largest number of cases of SJS/TEN (21 cases) followed by paracetamol (8 cases), levofloxacine (6 cases) and carbamazepine (4 cases). The risk for specific drug exposures was estimated by employing drug utilization data expressed as Defined Daily Doses (DDD). Mortality rate from SJS-TEN was 21%. Together with the registry, a "hub and spoke" clinical network for the management of severe cutaneous reactions was established with the Burn Unit of Niguarda Ca' Granda Hospital as the reference center for the most critical patients.
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
de Las Salas, Roxana; Díaz-Agudelo, Daniela; Burgos-Flórez, Francisco Javier; Vaca, Claudia; Serrano-Meriño, Dolores Vanessa
The occurrence of adverse drug reactions is an important issue due to the lack of drug safety data in children. To describe the Adverse Drug Reactions in inpatient children under 6 years of age in two general pediatrics wards located in Barranquilla, Colombia. 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. 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). 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.
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.
Hannaford, P C
Five hundred patients were asked whether they were allergic to any medicines. The description given of any stated reaction was assessed to see whether an important adverse drug reaction was likely to have occurred. The patients' records were also examined for collaborative evidence. Poor documentation often made it difficult to confirm the patient's claim of drug sensitivity. A total of 89 patients may have suffered from important adverse reactions to 113 drugs. Full documentation of adverse reactions is important, but only eight patients carried any information to warn others of their sensitivities. Patients should be asked about any drug sensitivities and, if appropriate, given written confirmation of them. A quick, simple method of doing this would be to provide patients' with a plastic card, similar to a credit card, with instructions and details of the reaction written on it with an indelible pen.
Salami, T A T; Asalu, A F; Samuel, S O
Adverse cutaneous drug eruptions are dreaded complication of drug use and this is more so when it occurs in the setting of human immune virus (HIV) infection and acquired immune deficiency syndrome (AIDS). This study aims to look at the prevalence of cutaneous drug eruptions in adult Nigerians with HIV/AIDS and find out the etiological agents, outcome, and prognosis of such occurrence in Irrua Specialist Teaching Hospital, Irrua Edo State Nigeria. A retrospective study of cutaneous drug eruptions in patients with HIV/AIDS managed in this centre over the past five years (between January 2001 and December 2005 prior to initiation of antiretroviral therapy) was carried out. A total of 900 patients with HIV/AIDS were managed during this period (antiretroviral treatment was not available during this period). Twenty five of these patients (2.8%) not had cutaneous drug eruptions (2.8%). Erythema multiforme major or Steven Johnson Syndrome (SJS)-40% and Toxic epidermal necrolysis (TEN)-20% were the most frequent types of adverse cutaneous drug events found while combination antituberculosis agent of Isoniazid/Thiacethazone (64%) and anti malarial Sulphadoxine/Pyrimethamine (20%) were the notable culprit drugs found to be responsible for these. There was a 20% fatality rate. Treatment of tuberculosis which is the most common AIDS presenting illness with anti tuberculosis regimen that includes thiacethazone and the ready availability of anti malarials over the counter without prescription are responsible for the findings of this study. Avoiding drugs such as those found to be culprit agents in this study in patients with HIV/AIDS; right prescription practice by health practitioners as well as more intense health education of the public on the hazards of self prescription will all go a long way in minimising the occurrence of these events.
Ikeda, Hiroko; Takahashi, Yukitoshi; Yamazaki, Etsuko; Fujiwara, Tateki; Kaniwa, Nahoko; Saito, Yoshiro; Aihara, Michiko; Kashiwagi, Mariko; Muramatsu, Masaaki
Carbamazepine (CBZ) is frequently used for treating epilepsy, but this drug causes cutaneous adverse drug reactions (cADRs) that may range from mild to severe. It is reported recently that the human leukocyte antigen HLA-B*1502 is associated with Stevens-Johnson syndrome (SJS) induced by CBZ in Han Chinese. We examined HLA class I in 15 Japanese patients who fulfilled the diagnostic criteria for CBZ-induced cADRs (mild in 10 and severe = SJS in 5). HLA-B*1518, HLA-B*5901 and HLA-C*0704 alleles showed higher relative risks (above 10.0) for severe cADRs. The haplotype (HLA-A*2402-B*5901-C*0102) had high relative risk (16.09) for severe cADRs. In patients with severe cADRs, frequencies of HLA-A*1101, HLA-A*3303, HLA-B*1501, HLA-B*4403, HLA-B*5101, HLA-B*5201, HLA-C*0702, and HLA-C*1202 alleles are relatively lower than in the Japanese population. These data may suggest that HLA-B*5901 is one of the candidate markers for CBZ-induced SJS in Japanese.
Hauben, Manfred; Hung, Eric; Hsieh, Wen-Yaw
Background: Severe cutaneous adverse reactions (SCARs) are prominent in pharmacovigilance (PhV). They have some commonalities such as nonimmediate nature and T-cell mediation and rare overlap syndromes have been documented, most commonly involving acute generalized exanthematous pustulosis (AGEP) and drug rash with eosinophilia and systemic symptoms (DRESS), and DRESS and toxic epidermal necrolysis (TEN). However, they display diverse clinical phenotypes and variations in specific T-cell immune response profiles, plus some specific genotype–phenotype associations. A question is whether causation of a given SCAR by a given drug supports causality of the same drug for other SCARs. If so, we might expect significant intercorrelations between SCARs with respect to overall drug-reporting patterns. SCARs with significant intercorrelations may reflect a unified underlying concept. Methods: We used exploratory factor analysis (EFA) on data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) to assess reporting intercorrelations between six SCARs [AGEP, DRESS, erythema multiforme (EM), Stevens–Johnson syndrome (SJS), TEN, exfoliative dermatitis (ExfolDerm)]. We screened the data using visual inspection of scatterplot matrices for problematic data patterns. We assessed factorability via Bartlett’s test of sphericity, Kaiser-Myer-Olkin (KMO) statistic, initial estimates of communality and the anti-image correlation matrix. We extracted factors via principle axis factoring (PAF). The number of factors was determined by scree plot/Kaiser’s rule. We also examined solutions with an additional factor. We applied various oblique rotations. We assessed the strength of the solution by percentage of variance explained, minimum number of factors loading per major factor, the magnitude of the communalities, loadings and crossloadings, and reproduced- and residual correlations. Results: The data were generally adequate for factor analysis
Sekhon, Sahil; Nedorost, Susan T
Adverse drug reactions result in a substantial number of hospital admissions and inpatient events. Diagnosis usually is made with clinical judgment and circumstantiality without diagnostic testing. Furthermore, even in situations where diagnostic testing is performed, no safe gold standard tests exist. Oral rechallenge is currently the gold standard but carries the risk of recrudescence of severe allergic symptoms. Other tests include skin prick tests, the lymphocyte transformation test, immunohistochemistry, and patch testing. This article provides a review of patch testing in cases of adverse drug reactions and presents new data on this topic.
Ahmad, Syed Rizwanuddin
The Food and Drug Administration (FDA) is responsible not only for approving drugs but also for monitoring their safety after they reach the market. The complete adverse event profile of a drug is not known at the time of approval because of the small sample size, short duration, and limited generalizability of pre-approval clinical trials. This report describes the FDA's postmarketing surveillance system, to which many clinicians submit reports of adverse drug events encountered while treating their patients. Despite its limitations, the spontaneous reporting system is an extremely valuable mechanism by which hazards with drugs that were not observed or recognized at the time of approval are identified. Physicians are strongly encouraged to submit reports of adverse outcomes with suspect drugs to the FDA, and their reports make a difference. The FDA is strengthening its postmarketing surveillance with access to new data sources that have the potential to further improve the identification, quantification, and subsequent management of drug risk. PMID:12534765
Ahmad, Syed Rizwanuddin
The Food and Drug Administration (FDA) is responsible not only for approving drugs but also for monitoring their safety after they reach the market. The complete adverse event profile of a drug is not known at the time of approval because of the small sample size, short duration, and limited generalizability of pre-approval clinical trials. This report describes the FDA's postmarketing surveillance system, to which many clinicians submit reports of adverse drug events encountered while treating their patients. Despite its limitations, the spontaneous reporting system is an extremely valuable mechanism by which hazards with drugs that were not observed or recognized at the time of approval are identified. Physicians are strongly encouraged to submit reports of adverse outcomes with suspect drugs to the FDA, and their reports make a difference. The FDA is strengthening its postmarketing surveillance with access to new data sources that have the potential to further improve the identification, quantification, and subsequent management of drug risk.
Kim, Sae-Hoon; Lee, Kyung Wha; Song, Woo-Jung; Kim, Sang-Heon; Jee, Young-Koo; Lee, Sang-Min; Kang, Hye-Ryun; Park, Heung-Woo; Cho, Sang-Heon; Park, Seong-Ho; Min, Kyung-Up; Chang, Yoon-Seok
Although the US FDA recommends screening for HLA-B*1502 allele in most of Asian ancestry before initiating carbamazepine therapy, the HLA associations with carbamazepine hypersensitivity in non-Chinese Asian populations remain unclear. This study investigated the association between the HLA class I genotype and carbamazepine-induced severe cutaneous adverse reaction (SCAR) in Koreans. Twenty-four patients who had developed carbamazepine-induced SCAR (7 Stevens-Johnson syndrome (SJS), 17 drug hypersensitivity syndrome (HSS)), 50 carbamazepine-tolerant controls from the Korean Pharmacogenetic Adverse Drug Reaction Research Network and data of 485 Korean general population from a previously published study were recruited. HLA-A, -B, and -C genotyping was performed by direct DNA sequence analysis. Only one of the seven SJS patients was positive for the B*1502 allele, but the frequency of B*1511 was much higher in the patients with CBZ-SJS than in the CBZ-tolerant control patients (P=0.011, P(c)=not significant; OR=18.0(2.3-141.2)). The frequencies of A*3101 in carbamazepine-induced HSS and SCAR were significantly higher than those in carbamazepine-tolerant controls (P(c)=0.011, OR=8.8(2.5-30.7) and P(c)=0.013, OR=7.3(2.3-22.5), respectively). The frequencies of B*1511 in carbamazepine-SJS and A*3101 in carbamazepine-HSS/SCAR were significantly higher than those in the general population. HLA-B*1502 does not seem to be an effective predictive marker for carbamazepine-induced SCAR, while HLA-B*1511 and A*3101 was associated with carbamazepine-induced SJS and HSS/SCAR respectively in the Korean population. Copyright © 2011 Elsevier B.V. All rights reserved.
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
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.
Kolb-Mäurer, Annette; Goebeler, Matthias; Mäurer, Mathias
Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS) patient treated with interferon-β who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs.
Kolb-Mäurer, Annette; Goebeler, Matthias; Mäurer, Mathias
Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS) patient treated with interferon-β who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs. PMID:26147425
Brickel, Neil; Shaikh, Haris; Kirkham, Andrew; Davies, Greg; Chalker, Michelle; Yoshida, Pascal
Pharmacovigilance presents many challenges, particularly when managing unpredictable, rare conditions, eg, severe cutaneous adverse reactions (SCARs). Such rare events are often only detected from spontaneous reports, which present their own limitations, particularly during a prolonged global launch schedule. GlaxoSmithKline's routine pharmacovigilance includes regular reviews of global adverse event (AE) reports and aggregate data from a central safety database. Lamotrigine is one of the several antiepileptic drugs associated with SCARs. After identification of increased rates of fatal SCAR cases with lamotrigine in Japan between September and December 2014, this analysis investigated the global incidence of fatal SCARs with lamotrigine and explored whether known risk factors may have contributed to these cases. Global fatal SCAR cases reported with lamotrigine administration from launch until January 2015 were reviewed for evidence of temporal association with dosing and the presence of risk factors, including comorbidities, concomitant medications, and noncompliance with the prescribing information (PI). Worldwide, the estimated cumulative exposure to lamotrigine was >8.4 million patient-years. Globally, there were 54,513 AE reports for lamotrigine, of which 3,454 (6.3%) concerned SCARs. Of these, 122 (3.5%) had a fatal outcome (attributable and nonattributable to lamotrigine), equating to 0.01 fatal SCARs per 1,000 patient-years. In Japan (estimated cumulative exposure 141,000 patient-years), 17 fatal SCARs were reported (attributable and nonattributable), equating to 0.12 per 1,000 patient-years. Seventy-one percent of fatal SCAR cases in Japan showed evidence of noncompliance with the recommended dosing regimen; in 65% of the cases, a delay in discontinuation of lamotrigine after early signs of hypersensitivity was reported. Despite a number of limitations inherent in comparing spontaneous report data, this analysis highlights the need for adherence to the
Saksit, Niwat; Tassaneeyakul, Wichittra; Nakkam, Nontaya; Konyoung, Parinya; Khunarkornsiri, Usanee; Chumworathayi, Pansu; Sukasem, Chonlaphat; Suttisai, Sumitra; Piriyachananusorn, Napacha; Tiwong, Pawinee; Chaiyakunapruk, Nathorn; Sawanyawisuth, Kittisak; Rerkpattanapipat, Ticha; Tassaneeyakul, Wongwiwat
Allopurinol is one of the most common causes of severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). This study identified the risk factors associated with the development of allopurinol-induced SCARs in a Thai population. Eighty-six allopurinol-induced SCARs (i.e. 19 DRESS and 67 SJS/TEN) and 182 allopurinol-tolerant patients were enrolled in the study. The HLA-B*58:01 allele was determined. Clinical and medicinal data were collected. Results from multivariate analysis showed that only the HLA-B*58:01 and female sex were identified as risk factors of allopurinol-induced SCARs in this Thai population. Patients who carried the HLA-B*58:01 allele were at a higher risk of allopurinol-induced DRESS [odds ratio (OR)=149.2, 95% confidence interval (CI)=24.0-∞, P<1.00×10]. Similar results were observed in allopurinol-induced SJS/TEN (OR=175.0, 95% CI=44.3-690.9, P=1.69×10). The risk of allopurinol-induced SCARs in women was higher than that in men (OR=4.6, 95% CI=1.4-15.6, P=1.44×10). The overall mortality rate of allopurinol-induced SCARs was 11.39% and a higher mortality rate was observed in elderly women. Among the risk factors identified, the HLA-B*58:01 allele had the greatest impact on the development of both phenotypes of allopurinol-induced SCARs in this studied Thai population. In case HLA-B*58:01 genotyping cannot be accessed, close monitoring of allopurinol usage, especially in elderly women with impaired renal function, is necessary to reduce the mortality rate of these life-threatening SCARs.
Bascones-Martinez, Antonio; Mattila, Riikka; Gomez-Font, Rafael; Meurman, Jukka H
The main objectives are to present the different adverse effects of the immunomodulatory drugs that can impair the quality of life of the immunosuppressed patients and study the impact of immunomodulation 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. We review current data on the new immunomodulatory drugs from the oral health perspective based on open literature search of the topic. 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. 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.
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
Lo Russo, Lucio; Guida, Laura; Di Masi, Maria; Buccelli, Claudio; Giannatempo, Giovanni; Di Fede, Olga; Di Lorenzo, Pierpaolo; Lo Muzio, Lorenzo
Several drugs may have a number of adverse reactions (ADRs) involving the oro-facial region. The dose of the drug and the time required for the reaction to take place are relevant parameters; nonetheless, ADRs mechanisms are not always known and ADRs are not always predictable since aspects other than drug pharmacodynamics and/or pharmacokinetics, as well as various interacting variables contribute to the final outcome. All tissues and many functions of the oral cavity can be affected. In particular, salivary function is frequently involved and hypo-salivation is the main manifestation; several mucosal lesions with different morphology (ulcerations, vesiculobullous lesions, white lesions, pigmentations, swelling) are also possible. Taste, sensation and trigeminal function alterations have been reported and the recent evidence regarding the occurrence of jawbones osteonecrosis, especially in bisphosphonates treated patients, is increasing. Clinical management may be quite difficult due to the multiplicity of involved classes of drugs and substances (dental materials, foods), the variety of affected tissues and functions, the type of produced lesions and disturbances, the complexity of related pathogenetic mechanisms (if known), the difficulties in assessing causality and managing drug withdrawal and/or dose adjustment, as well as in establishing specific treatments, if any. In this paper the most common and significant oral ADRs, their related aspects and importance (including medico-legal implications) for health care providers will be discussed.
Ara, M; Pastushenko, E
As new antiangiogenic therapies have been introduced and added to the therapeutic arsenal against various types of cancer, previously unknown adverse effects have been detected. These effects negatively impact patients' quality of life and can even make it necessary to suspend treatment. Adverse skin reactions occur in 90% of patients treated with angiogenesis inhibitors. In some cases, a correlation has been observed between the severity of reactions and treatment efficacy and tumor response. It is therefore extremely important that dermatologists be able to recognize and manage these reactions. Moreover, in order to avoid the unjustified withdrawal of potentially life-extending treatments, dermatologists must be able to differentiate between non-life-threatening reactions and life-threatening reactions that necessitate the suspension of treatment. In this review article, we analyze the main cutaneous adverse effects of the most common antiangiogenic agents. Copyright © 2013 Elsevier España, S.L.U. y AEDV. All rights reserved.
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.
Rongioletti, F; Burlando, M; Parodi, A
In recent years, the use of biologic drugs has greatly changed the therapy of psoriasis and psoriatic arthritis, but they have some adverse effects. In particular, skin lesions induced by anti-tumor necrosis factor (TNF) and anti-interleukin (IL) 12/23 drug (ustekinumab) have been reported with an increased incidence, highlighting the importance of the skin as a major target of the side effects of these drugs. There is a wide spectrum of skin lesions of different morphology and etiology that includes skin lesions directly related to drug administration, the development of cutaneous immune-mediated conditions and cutaneous infections. The aim of this review is to revisit the literature data on inflammatory/infectious skin adverse effects of biologics both anti-TNF-α inhibitors and anti-IL 12/23 antagonists and to report and update our personal data on inflammatory/infectious side effects in patients with psoriasis/psoriatic arthritis treated with biologics.
Iten, F; Reichling, J; Saller, R
The significantly increased sales figures many phytopharmaceuticals have achieved during the last years prove the confidence that a great part of the population has in herbal remedies. This is primarily due to the wide-spread opinion that herbal remedies are free from side-effects. The long tradition and presumed 'natural' origin are no guarantee for safety in the treatment with herbal remedies. Even if a large proportion of the undesirable events is traceable to falsifications, impurities and lacking quality controls, herbal drugs with controlled quality should not be generally classified as harmless. In the meantime it has been possible to prove the presence of active substances with toxic and cancerogenic properties in various phytopharmaceuticals. Interactions with other drugs have been documented in a number of notes, where phytopharmaceuticals could influence the blood plasma level of various drugs, presumably by activating or inhibiting the cytochrom-P450-system. At present, especially data about adverse effects during long-term administration of herbal remedies are under-represented. Particularly because of their presumed harmlessness they often are prescribed in the case of chronic diseases and then taken over a longer period of time. The frequency of undesirable effects of phytopharmaceuticals is remarkably low, even if the present lack of data about side-effects is considered.
Zurita-Garaicoechea, Ana; Reis-Carvalho, Joana; Ripa-Aisa, Irantzu; Jiménez-Mendoza, Ana; Díaz-Balén, Almudena; Oroviogoicoechea, Cristina
The spontaneous report system, in which suspected adverse drug reaction (ADR) are reported by healthcare workers, is currently one of the primary methods to prevent and discover new and serious ADR to marketed medicinal products. The collaboration of nursing professionals with this task makes it possible to improve patient safety and to reduce ADR costs. Although a total of 781 cases of ADR cases were reported in Navarra in 2011, only 7.33% were reported by nurses. The objectives werw to determine the factors that influence nurses in reporting of ADR, and second, to devise strategies which help to increase reporting. A bibliographic search for articles that included the words: reacciones adversas medicamentosas (adverse drug reactions), notificación (reporting) and enfermería (nursing) was conducted using the PubMed and Cinhal databases. A total of 107 articles were retrieved, of which 27 were selected according to inclusion and exclusion criteria. The conclusion learned by reading and analyzing the selected articles was that the factors that affect the notification depend on the attitude of the notifier, as well as personal and professional factors. The main strategies to encourage notification are education and training, motivation, and the availability of facilitating tools. The main factors that have an influence on under-notification are the lack of knowledge and motivation among professionals. To solve the problem of under-notification, the main actions and strategies to undertake are education, motivation and persistence. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.
Bosak, Magdalena; Porębski, Grzegorz; Słowik, Agnieszka; Turaj, Wojciech
The aim of the study was to establish whether the presence of common allergies increases the risk of drug-related hypersensitivity reactions among patients with epilepsy treated with antiepileptic drugs (AEDs). We studied 753 patients with epilepsy seen in tertiary outpatient epilepsy clinic. We obtained data related to epilepsy type, past and ongoing treatment with AEDs, occurrence of maculopapular exanthema or more serious cutaneous adverse reactions (Stevens-Johnson syndrome - SJS) and their characteristics. We noted an occurrence of allergic reactions unrelated to treatment with AED, including rash unrelated to AED, bronchial asthma, persistent or seasonal allergic rhinitis, atopic dermatitis, rash after specific food and other allergic reactions. There were 61 cases of AED-related cutaneous hypersensitivity reaction (including 3 cases of SJS) noted in association with 2319 exposures to AEDs (2.63%) among 55 out of 753 patients (7.3%). Cutaneous hypersensitivity reaction to AED was most commonly noted after lamotrigine (12.1%), carbamazepine (5.4%) and oxcarbazepine (4.1%). Prevalence of allergic reactions unrelated to AED was similar between patients with and without AED-related cutaneous hypersensitivity reaction (rash unrelated to AED: 16.4% vs. 10.2%; bronchial asthma: 1.8% vs. 0.1%; persistent allergic rhinitis: 7.3% vs. 10.2%; seasonal allergic rhinitis: 7.3% vs. 11.7%; atopic dermatitis: 0 vs. 0.7%; rash after specific food: 5.4% vs. 6.4%; other allergic reactions: 5.4% vs. 5.2%, respectively; P>0.1 for each difference). Presence of common allergies is not a significant risk factor for AED-related cutaneous hypersensitivity reaction among patients with epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.
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
Yan, Ya-Min; Fan, Qiao-Ling; Li, Ai-Qiu; Chen, Jia-Ling; Dong, Fei-Fei; Gong, Mei
Objective: To analyze the effects of hyaluronidase and hirudoid treatment on drug extravasation in neonates. Methods: The medical records of 13 neonates with drug extravasation treated with hyaluronidase and hirudoid between August 1st, 2010 and May 1st, 2012 were analyzed retrospectively. The treatment procedure for drug extravasation adhered to the protocol in neonatal department. The information including age, sex, weight, diagnosis, size of affected area, site of extravasation and treatment was collected. Findings : The extravasation injuries alleviated and the symptoms improved after treatment, no adverse drug effects were reported with use of hyaluronidase and hirudoid. Conclusion: The treatment appeared to be beneficial in the management of extravasations of various medications in neonates and may be useful in reducing the severity of cutaneous toxicosis. However, further studies with large samples are still needed to assess the effectiveness and safety of hyaluronidase and hirudoid. PMID:25755854
Gallelli, Luca; Siniscalchi, Antonio; Palleria, Caterina; Mumoli, Laura; Staltari, Orietta; Squillace, Aida; Maida, Francesca; Russo, Emilio; Gratteri, Santo; De Sarro, Giovambattista
Drug treatment may be related with the development of adverse drug reactions (ADRs). Here, we evaluated the ADRs in patients admitted to Catanzaro Hospital. After we obtained the approval by local Ethical Committee, we performed a retrospective study on clinical records from March 01, 2013 to April30, 2015. The association between drug and ADR or between drug and drug-drug-interactions (DDIs) was evaluated using the Naranjo's probability scale and Drug Interaction Probability Scale (DIPS), respectively. During this time, we analyzed 2870 clinical records and 11,138 prescriptions and we documented the development of 770 ADRs. The time of hospitalization was significantly higher (P<0.05) in women with ADRs (12.6± 1.2 days) respect to men (11.8± 0.83 days). Using the Naranjo score, we documented a probable association in 78% of these reactions, while DIPS revealed that about 22% of ADRs were related to DDIs. Patients with ADRs received 3052 prescription on 11,138 (27.4%), with a mean of 6.1±0.29 drugs that was significantly higher (P<0.01) respect to patients that not experienced ADRs (mean of 3.4±0.13 drugs). About 19% of ADRs were not diagnosed and treated as new disease. In conclusion, we documented that age and gender are risk factors for the development of ADRs, that in some patients are under-diagnosed. Therefore, it is important to motivate healthcare to report the ADRs in order optimize the patient safety. Copyright© Bentham Science Publishers; For any queries, please email at email@example.com.
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.
KARIMZADEH, Parvaneh; BAKRANI, Vahid
Objective According to the basic role of drug side effects in selection of an appropriate drug, patient compliance and the quality of life in epileptic patients, and forasmuch as new drugs with unknown side effect have been introduced, necessity of this research is explained. This study was conducted to evaluate the incidence and clinical characteristics of anti epileptic drug (AED) related adverse reactions in children. Material & Methods In this descriptive study, children less than 14 years old with AED side effects referred to the Children’s Medical Center and Mofid Childeren’s Hospital (Tehran, Iran) were evaluated during 2010-2012. The informations were: sex, age, incriminating drug, type of drug side effect, incubation period, history of drug usage, and patient and family allergy history. Exclusive criterions were age more than 14 years old and reactions due to reasons other than AEDs. Results A total of 70 patients with AED reaction were enrolled in this study. They included 26 (37%) females and 44 (63%) males. The maximum rate of incidence was seen at age less than 5 years old. All the patients had cutaneous eruptions that the most common cutaneous drug eruption was maculopapular rash. The most common culprit was phenobarbital (70%) and the least common was lamotrigine (1.4%). Conclusion In this study, we found higher rates of drug rash in patients treated with aromatic AEDs and lower rates with non-aromatic AEDs. Various endogenous and environmental factors may influence the propensity to develop these reactions. PMID:24665302
Karimzadeh, Parvaneh; Bakrani, Vahid
According to the basic role of drug side effects in selection of an appropriate drug, patient compliance and the quality of life in epileptic patients, and forasmuch as new drugs with unknown side effect have been introduced, necessity of this research is explained. This study was conducted to evaluate the incidence and clinical characteristics of anti epileptic drug (AED) related adverse reactions in children. In this descriptive study, children less than 14 years old with AED side effects referred to the Children's Medical Center and Mofid Childeren's Hospital (Tehran, Iran) were evaluated during 2010-2012. The informations were: sex, age, incriminating drug, type of drug side effect, incubation period, history of drug usage, and patient and family allergy history. Exclusive criterions were age more than 14 years old and reactions due to reasons other than AEDs. A total of 70 patients with AED reaction were enrolled in this study. They included 26 (37%) females and 44 (63%) males. The maximum rate of incidence was seen at age less than 5 years old. All the patients had cutaneous eruptions that the most common cutaneous drug eruption was maculopapular rash. The most common culprit was phenobarbital (70%) and the least common was lamotrigine (1.4%). In this study, we found higher rates of drug rash in patients treated with aromatic AEDs and lower rates with non-aromatic AEDs. Various endogenous and environmental factors may influence the propensity to develop these 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.
Hammann, Felix; Drewe, Juergen
Patients, in particular elderly ones, frequently receive more than one drug at a time. With each drug added to a regime, the number of potential drug-drug interactions (DDIs) increases by a power law. Early prediction of relevant interactions by computerized tools greatly aids clinicians and can guide their prescribing choices. In this article, we discuss different types of DDIs, on which levels they can arise and what efforts have been made in the past to detect and predict them. The emphasis is on data mining technology and network analysis, but overlaps with traditional pharmacovigilance are also discussed. Finally, we discuss strategies to focus and simplify mining efforts to get meaningful results with less effort. The necessary technology for detecting adverse DDIs exists and is quite refined, although it is more often implied in lower risk scenarios (such as syntactic analysis in web searches and online libraries). Data mining for DDIs, on the other hand, still requires a great deal of human intervention, not only to validate the results but also, more importantly, to separate the relevant from the spurious. The fields of network analysis and graph theory show great promise but have not yet shown much beyond descriptive analyses.
Criado, P R; de Oliveira Ramos, R; Vasconcellos, C; Jardim Criado, R F; Valente, N Y S
We report two cases of adverse cutaneous reactions following hepatitis B vaccination. The first case occurred 3 weeks after the first dose of hepatitis B vaccine in a 16-year-old white girl with the onset of lichen planus lesions on her thighs and abdomen. After the second dose a disseminated lichen planus developed within 2 weeks. The second case concerns to the development of papular and patch granuloma annulare in a 58-year-old white woman 2 months after the second dose of hepatitis B vaccine. To the best of our knowledge, only a few paediatric and adult cases of lichen planus as a complication of hepatitis B vaccination have been reported in medical literature so far. This is the second case of granuloma annulare following hepatitis B vaccine. Our report, similar to earlier papers, appears to support the onset of lichen planus and granuloma annulare as a possible rare complication of hepatitis B immunization.
Ramírez-Bellver, Jose Luis; Lopez, Joaquin; Macias, Elena; Fuertes, Laura; Andres, Irene; Alegria, Victoria; Gimeno, Ignacio; Perez, Alejandra; Perez, Yosmar; Requena, Luis
Fixed drug eruption (FDE) consists of recurrent dusky-red to brownish macules or patches at the same sites after the readministration of the causative drug. It usually presents as a solitary lesion, but generalized eruptions have been described. The most frequently implied drugs are antibiotics, anticonvulsants, and analgesics. Only 2 cases due to metformin have been reported. Histopathologic features of FDE include vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphocytic infiltrate. Cutaneous hemophagocytosis in the context of a FDE has not been previously reported. We describe the case of an 86-year-old man who developed a pruritic generalized macular eruption of reddish to violaceous patches. Skin biopsy was performed and the dermal infiltrate was immunohistochemically studied. Histopathology showed interface dermatitis with vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphohistiocytic infiltrate. In deep dermis, histiocytes with engulfed cells inside their cytoplasm were seen. Lymphoid enhancer binding factor 1 immunostain demonstrated that most of these cells were lymphocytes. We present the first case with cutaneous hemophagocytosis in the context of a metformin-induced generalized FDE. In this particular case, hemophagocytosis was just a histopathologic finding with no systemic consequences for the patient.
Vinther, Siri; Klarskov, Pia; Borgeskov, Hanne; Darsø, Perle; Christophersen, Anette Kvindebjerg; Borck, Bille; Christensen, Catrine; Hansen, Melissa Voigt; Halladin, Natalie Monica Løvland; Christensen, Mikkel Bring; Harboe, Kirstine Moll; Lund, Marie; Jimenez-Solem, Espen
Spontaneous reporting of adverse drug reactions (ADRs) is used for continuous risk-benefit evaluation of marketed pharmaceutical products and for signal detection. The Adverse Drug Event Manager (ADEM) is a service offered to clinicians employed at hospitals in the Capital Region of Denmark. The ADEM assists healthcare professionals in reporting suspected ADRs to the Danish Health Authority. The aim of this retrospective observational study was to quantify and describe ADRs reported via the ADEM in 2014. All ADR reports handled by the ADEM in 2014 were recorded anonymously and analysed descriptively. A total of 484 ADRs were reported through the ADEM in 2014 (the median number of reports per month was 37; range: 17-78). The majority of the reports came from departments of internal medicine (61%), psychiatry (14%) and dermatology, ophthalmology or otorhinolaryngology (11%). The drugs most frequently reported were lisdexamphetamine (n = 40), rivaroxaban (n = 16) and warfarin (n = 15) (vaccines excluded). In 13 out of 484 reports, the ADR was associated with a fatal outcome. The findings of this study indicate that an ADEM promotes and facilitates spontaneous ADR reporting and helps raise awareness about ADRs, including how and why they should be reported. Hopefully, this will assist national and European spontaneous reporting systems in their work to increase patient safety nationally and abroad. none. not relevant. .
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.
Berger, Seth I.; Iyengar, Ravi
Systems pharmacology involves the application of systems biology approaches, combining large-scale experimental studies with computational analyses, to the study of drugs, drug targets, and drug effects. Many of these initial studies have focused on identifying new drug targets, new uses of known drugs, and systems-level properties of existing drugs. This review focuses on systems pharmacology studies that aim to better understand drug side effects and adverse events. By studying the drugs in the context of cellular networks, these studies provide insights into adverse events caused by off-targets of drugs as well as adverse events-mediated complex network responses. This allows rapid identification of biomarkers for side effect susceptibility. In this way, systems pharmacology will lead to not only newer and more effective therapies, but safer medications with fewer side effects. PMID:20803507
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
Horcajada-Reales, C; Pulido-Pérez, A; Suárez-Fernández, R
Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are all severe hypersensitivity reactions to medications. While each of these reactions is a well-established entity with specific diagnostic criteria, clinicians see cases that fulfill criteria for more than one form, prompting discussion on the possibility of combined forms. Such overlapping clinical pictures meeting the criteria for 2 conditions have thus become a topic of debate in dermatology in recent years. We describe 2 patients with cutaneous drug reactions having the characteristics of both acute generalized exanthematous pustulosis and Stevens-Johnson syndrome -toxic epidermal necrolysis. We also review previously published cases and current thinking on such overlapping conditions.
Ramanujam, Bhargavi; Ihtisham, Kavish; Kaur, Gurvinder; Srivastava, Shivani; Mehra, Narinder Kumar; Khanna, Neena; Singh, Mahip; Tripathi, Manjari
Background and Purpose Aromatic antiepileptic drugs are frequently implicated for cutaneous adverse drug reactions (cADRs); there are case-reports of even severe reactions like drug reaction eosinophilia and systemic symptoms (DRESS) and Stevens Johnson syndrome (SJS)-toxic epidermal necrolysis with Levetiracetam (LEV). Certain human leukocyte antigen (HLA)-alleles have strong association with cADRs due to specific drugs - HLA-B*15:02 and HLA-A*31:01 in Carbamazepine (CBZ)-related SJS in Han-Chinese and European populations, respectively. Here, the spectrum of cADRs to LEV was studied, and HLA-typing in patients with cADRs due to LEV and some who were LEV-tolerant was performed, in an attempt to find an association between HLA and such reactions. Methods 589 patients taking LEV were screened for skin reactions, and eight patients with LEV-related cADRs and 25 LEV-tolerant controls were recruited - all 33 of North Indian ethnicity, their HLA-A, B, DRB1 genotyping done. Statistical analysis was done to compare carrier-rates and allele-frequencies of HLA-alleles between cases and controls (and healthy population, where necessary) for alleles occurring more than two times in either group. Results Out of 589 patients on LEV screened, there were 8 cases of cADR: 5 with maculopapular exanthema (MPE), 2 of SJS, and 1 with DRESS. Although HLA-A*33:01 was seen to occur more in MPE cases as compared to tolerant controls, the difference was not statistically significant (odds ratio [OR] 6.00, 95% confidence interval [CI] 0.30–116.6; p = 0.31). HLA A*11:01 and 24:02 were found to occur more in LEV-tolerant controls than in cases (OR 0.23 [95% CI 0.02–2.36, p = 0.33] and 1.00 [95% CI 0.09–11.02, p = 1.00] respectively). Conclusions Cutaneous reactions to LEV are very unusual, and their association with HLA in North-Indian population was not statistically significant. PMID:28101480
Hung, Shuen-Iu; Chung, Wen-Hung; Liou, Lieh-Bang; Chu, Chen-Chung; Lin, Marie; Huang, Hsien-Ping; Lin, Yen-Ling; Lan, Joung-Liang; Yang, Li-Cheng; Hong, Hong-Shang; Chen, Ming-Jing; Lai, Ping-Chin; Wu, Mai-Szu; Chu, Chia-Yu; Wang, Kuo-Hsien; Chen, Chien-Hsiun; Fann, Cathy S. J.; Wu, Jer-Yuarn; Chen, Yuan-Tsong
Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens–Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol–SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol–SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol–SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) (P < 10–7). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol–SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4–9780.9); corrected P value = 4.7 × 10–24] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23–6665.26); corrected P value = 8.1 × 10–18]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol–SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition. PMID:15743917
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.
Huang, Hung-Chi; Wang, Cheng-Hua; Chen, Pi-Ching; Lee, Yen-Der
Medication errors and adverse drug events are a key concern of the health-care industry. The objectives of this study were to map the intellectual structure of the studies of medication errors and adverse drug events and to investigate the developing path of this literature and interrelationships among the main topics. The Web of Science database was searched for documentation of medication errors and adverse drug events from 1961 to 2013. The most cited articles and references were profiled and analyzed using HistCite software to draw a historiograph and Ucinet software to draw a sociogram. The database search revealed 3343 medication errors and 3342 adverse drug event documents. The most cited articles on medication errors focused on 3 key themes from 1961 to 2013, namely, medication errors in adult inpatients, computerized physician order entry in medication error studies, and medication errors in pediatric inpatients. The developing path for the most cited articles about adverse drug events from 1987 to 2013 was as follows: detection, analysis, effect, and prevention from adult inpatient to pediatric inpatient settings and from hospitalized care to ambulatory care. In addition, social network analysis based on the most cited references revealed a close relationship between medication errors and adverse drug events. The mapping results provide a valuable tool for researchers to access the literature in this field and can be used to help identify the direction of medication errors and adverse drug events research.
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.
Shio, Marina Temi; Paquet, Marilene; Martel, Caroline; Bosschaerts, Tom; Stienstra, Stef; Olivier, Martin; Fortin, Anny
This study establishes a proof-of-concept that a tattoo device can target intra-dermal drug delivery against cutaneous leishmaniasis (CL). The selected drug is oleylphosphocholine (OlPC) formulated as liposomes, particles known to be prone to macrophage ingestion. We first show that treatment of cultured Leishmania-infected macrophages with OlPC-liposomes results in a direct dose-dependent killing of intracellular parasites. Based on this, in vivo efficacy is demonstrated using a 10 day tattooing-mediated treatment in mice infected with L. major and L. mexicana. In both models this regimen results in rapid clinical recovery with complete regression of skin lesions by Day 28. Parasite counts and histopathology examination confirm high treatment efficacy at the parasitic level. Low amount of drug required for tattooing combined with fast clinical recovery may have a positive impact on CL patient management. This first example of tattoo-mediated drug delivery could open to new therapeutic interventions in the treatment of skin diseases. PMID:24561704
LYRA, Marcelo Rosandiski; PASSOS, Sonia Regina Lambert; PIMENTEL, Maria Inês Fernandes; BEDOYA-PACHECO, Sandro Javier; VALETE-ROSALINO, Cláudia Maria; VASCONCELLOS, Erica Camargo Ferreira; ANTONIO, Liliane Fatima; SAHEKI, Mauricio Naoto; SALGUEIRO, Mariza Mattos; SANTOS, Ginelza Peres Lima; RIBEIRO, Madelon Noato; CONCEIÇÃO-SILVA, Fatima; MADEIRA, Maria Fatima; SILVA, Jorge Luiz Nunes; FAGUNDES, Aline; SCHUBACH, Armando Oliveria
SUMMARY American tegumentary leishmaniasis is an infectious disease caused by a protozoan of the genus Leishmania. Pentavalent antimonials are the first choice drugs for cutaneous leishmaniasis (CL), although doses are controversial. In a clinical trial for CL we investigated the occurrence of pancreatic toxicity with different schedules of treatment with meglumine antimoniate (MA). Seventy-two patients were allocated in two different therapeutic groups: 20 or 5 mg of pentavalent antimony (Sb5+)/kg/day for 20 or 30 days, respectively. Looking for adverse effects, patients were asked about abdominal pain, nausea, vomiting or anorexia in each medical visit. We performed physical examinations and collected blood to evaluate serum amylase and lipase in the pre-treatment period, and every 10 days during treatment and one month post-treatment. Hyperlipasemia occurred in 54.8% and hyperamylasemia in 19.4% patients. Patients treated with MA 20 mg Sb5+ presented a higher risk of hyperlipasemia (p = 0.023). Besides, higher MA doses were associated with a 2.05 higher risk ratio (p = 0.003) of developing more serious (moderate to severe) hyperlipasemia. The attributable fraction was 51% in this group. Thirty-six patients presented abdominal pain, nausea, vomiting or anorexia but only 47.2% of those had hyperlipasemia and/ or hyperamylasemia. These findings suggest the importance of the search for less toxic therapeutic regimens for the treatment of CL. PMID:27680173
Lyra, Marcelo Rosandiski; Passos, Sonia Regina Lambert; Pimentel, Maria Inês Fernandes; Bedoya-Pacheco, Sandro Javier; Valete-Rosalino, Cláudia Maria; Vasconcellos, Erica Camargo Ferreira; Antonio, Liliane Fatima; Saheki, Mauricio Naoto; Salgueiro, Mariza Mattos; Santos, Ginelza Peres Lima; Ribeiro, Madelon Noato; Conceição-Silva, Fatima; Madeira, Maria Fatima; Silva, Jorge Luiz Nunes; Fagundes, Aline; Schubach, Armando Oliveria
American tegumentary leishmaniasis is an infectious disease caused by a protozoan of the genus Leishmania. Pentavalent antimonials are the first choice drugs for cutaneous leishmaniasis (CL), although doses are controversial. In a clinical trial for CL we investigated the occurrence of pancreatic toxicity with different schedules of treatment with meglumine antimoniate (MA). Seventy-two patients were allocated in two different therapeutic groups: 20 or 5 mg of pentavalent antimony (Sb5+)/kg/day for 20 or 30 days, respectively. Looking for adverse effects, patients were asked about abdominal pain, nausea, vomiting or anorexia in each medical visit. We performed physical examinations and collected blood to evaluate serum amylase and lipase in the pre-treatment period, and every 10 days during treatment and one month post-treatment. Hyperlipasemia occurred in 54.8% and hyperamylasemia in 19.4% patients. Patients treated with MA 20 mg Sb5+ presented a higher risk of hyperlipasemia (p = 0.023). Besides, higher MA doses were associated with a 2.05 higher risk ratio (p = 0.003) of developing more serious (moderate to severe) hyperlipasemia. The attributable fraction was 51% in this group. Thirty-six patients presented abdominal pain, nausea, vomiting or anorexia but only 47.2% of those had hyperlipasemia and/ or hyperamylasemia. These findings suggest the importance of the search for less toxic therapeutic regimens for the treatment of CL.
Moore, Douglas E
The interaction of sunlight with drug medication leads to photosensitivity responses in susceptible patients, and has the potential to increase the incidence of skin cancer. Adverse photosensitivity responses to drugs occur predominantly as a phototoxic reaction which is more immediate than photoallergy, and can be reversed by withdrawal or substitution of the drug. The bias and inaccuracy of the reporting procedure for these adverse reactions is a consequence of the difficulty in distinguishing between sunburn and a mild drug photosensitivity reaction, together with the patient being able to control the incidence by taking protective action. The drug classes that currently are eliciting a high level of adverse photosensitivity are the diuretic, antibacterial and nonsteroidal anti-inflammatory drugs (NSAIDs). Photosensitising chemicals usually have a low molecular weight (200 to 500 Daltons) and are planar, tricyclic, or polycyclic configurations, often with heteroatoms in their structures enabling resonance stabilisation. All absorb ultraviolet (UV) and/or visible radiation, a characteristic that is essential for the chemical to be regarded as a photosensitiser. The photochemical and photobiological mechanisms underlying the adverse reactions caused by the more photoactive drugs are mainly free radical in nature, but reactive oxygen species are also involved. Drugs that contain chlorine substituents in their chemical structure, such as hydrochlorthiazide, furosemide and chlorpromazine, exhibit photochemical activity that is traced to the UV-induced dissociation of the chlorine substituent leading to free radical reactions with lipids, proteins and DNA. The photochemical mechanisms for the NSAIDs that contain the 2-aryl propionic acid group involve decarboxylation as the primary step, with subsequent free radical activity. In aerated systems, the reactive excited singlet form of oxygen is produced with high efficiency. This form of oxygen is highly reactive towards
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).
Lorcy, S; Gaudy-Marqueste, C; Botta, D; Portal, I; Quiles, N; Oulies, V; Mancini, J; Grob, J-J; Richard, M-A
Telaprevir, sale of which was suspended, has been approved in combination with pegylated interferon and ribavirin (triple therapy) in the treatment of chronic hepatitis C virus (HCV). Skin eruptions and isolated cases of severe cutaneous adverse reactions (SCAR) have been reported. Our aim was to assess the incidence of skin eruption and the clinical characteristics of mucocutaneous adverse events (AE), and to identify potential risk factors for telaprevir-associated skin eruption. A prospective observational multicenter follow-up cohort study with monthly controls by a dermatologist and additional examinations in case of any undercurrent AE. Among the 48 enrolled patients, the incidence of skin eruption was 58.4%, consisting mainly of maculopapular and eczematous lesions and only one case of SCAR. Telaprevir was discontinued in 6% of patients due to severe rash, whereas peginterferon and ribavirin were continued. The median time to onset of rash following telaprevir initiation was 25 days (range: 3-79 days). The rash was preceded by skin dryness and associated with pruritus in 100% and 90% of patients, respectively. Of those presenting with skin eruption, 37.5% also complained of conjunctival or oral lesions, or of anorectal symptoms. Neither a past history of dermatological conditions nor sociodemographic or viral status was predictive factor for skin rash. Telaprevir-related dermatitis has a high incidence but is mostly of mild intensity. In most cases, tri-therapy was continued under close dermatological follow-up allowing rapid detection of rare instances of severe drug eruptions. Ribavirin and Interferon were thus continued even in the event of diffuse eruptions, enabling confirmation of the causative role of telaprevir in these eruptions. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
Lin, Shih-Fang; Xiao, Ke-Ting; Huang, Yu-Ting; Chiu, Chung-Cheng; Soo, Von-Wun
The purpose of this study was to integrate knowledge about drugs, drug targets, and topological methods. The goals were to build a system facilitating the study of adverse drug events, to make it easier to find possible explanations, and to group similar drug-drug interaction cases in the adverse drug reaction reports from the US Food and Drug Administration (FDA). We developed a system that analyses adverse drug reaction (ADR) cases reported by the FDA. The system contains four modules. First, we integrate drug and drug target databases that provide information related to adverse drug reactions. Second, we classify drug and drug targets according to anatomical therapeutic chemical classification (ATC) and drug target ontology (DTO). Third, we build drug target networks based on drug and drug target databases. Finally, we apply topological analysis to reveal drug interaction complexity for each ADR case reported by the FDA. We picked 1952 ADR cases from the years 2005-2006. Our dataset consisted of 1952 cases, of which 1471 cases involved ADR targets, 845 cases involved absorption, distribution, metabolism, and excretion (ADME) targets, and 507 cases involved some drugs acting on the same targets, namely, common targets (CTs). We then investigated the cases involving ADR targets, ADME targets, and CTs using the ATC system and DTO. In the cases that led to death, the average number of common targets (NCTs) was 0.879 and the average of average clustering coefficient (ACC) was 0.067. In cases that did not lead to death, the average NCTs was 0.551, and the average of ACC was 0.039. We implemented a system that can find possible explanations and cluster similar ADR cases reported by the FDA. We found that the average of ACC and the average NCTs in cases leading to death are higher than in cases not leading to death, suggesting that the interactions in cases leading to death are generally more complicated than in cases not leading to death. This indicates that our system
Pavlos, Rebecca; Mallal, Simon; Ostrov, David; Pompeu, Yuri; Phillips, Elizabeth
Drug hypersensitivity syndromes such as abacavir hypersensitivity and the severe cutaneous adverse drug reactions have been associated with significant short- and long-term morbidity and mortality. More recently, these immunologically mediated and previously unpredictable diseases have been shown to be associated with primarily class I but also class II HLA alleles. The case of the association of HLA-B*57:01 and abacavir hypersensitivity has created a translational roadmap for how this knowledge can be used in the clinic to prevent severe reactions. Although many hurdles exist to the widespread translation of such HLA screening approaches, our understanding of how drugs interact with the major histocompatibility complex has contributed to the discovery of new models that have provided considerable insights into the immunopathogenesis of severe cutaneous adverse drug reactions and other T-cell-mediated drug hypersensitivity syndromes. Future translation of this knowledge will facilitate the development of preclinical toxicity screening to significantly improve efficacy and safety of drug development and design. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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."
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
Riley, Gerald F; Levy, Jesse M; Montgomery, Melissa A
The Medicare Part D drug benefit created choices for beneficiaries among many prescription drug plans with varying levels of coverage. As a result, Medicare enrollees with high prescription drug costs have strong incentives to enroll in Part D, especially in plans with more comprehensive coverage. To measure this potential problem of "adverse selection," which could threaten plans' finances, we compared baseline characteristics among groups of beneficiaries with various drug coverage arrangements in 2006. We found some significant differences. For example, enrollees in stand-alone prescription drug plans, especially in plans offering benefits in the coverage gap, or "doughnut hole," had higher baseline drug costs and worse health than enrollees in Medicare Advantage prescription drug plans. Although risk-adjusted payments and other measures have been put in place to account for selection, these patterns could adversely affect future Medicare costs and should be watched carefully.
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.
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.
Gupta, A; Waldhauser, L K
Neonates and older infants are a diverse group of children, quite different from their older counterparts. Adverse drug reactions may have profound immediate, delayed, and long-term implications for their neurologic and somatic development. The intrauterine, neonatal, and infancy periods are the only stages in life in which one is exposed to and affected by drugs administered to another person, the mother. In addition, because of the fragility of the neonate and the complexity of their illnesses, their pharmacotherapy is frequently complicated with misadventure and adverse drug reactions that are unavoidable or difficult to assess. Because of their differences in morphology and disease process and treatments, infants and children experience a different range of adverse drug reactions. These reactions are not necessarily predictable from the adult experience. Despite the advances made in the field of pediatric adverse drug reactions and the lessons learned through the misfortunes involving children, children continue to suffer. Sixty years after the Elixir of Sulfanilamide-Massengill disaster, children continue to be given medications with diethylene glycol in developing countries. Pediatricians, pharmacologists, and others must continue to be vigilant and active in preventing, monitoring, and treating adverse drug reactions in children. Learning from mistakes of the past will improve the health of children by preventing mistakes in the future.
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 systems1,2. 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. PMID:22195073
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
Shimakura, Hidekatsu; Uchiyama, Jumpei; Saito, Taku; Miyaji, Kazuki; Fujimura, Masato; Masuda, Kenichi; Okamoto, Noriaki; DeBoer, Douglas J; Sakaguchi, Masahiro
Dogs with cutaneous adverse food reactions (CAFR) often have specific IgE to food allergens. Egg white, which is majorly composed of ovomucoid, ovalbumin, ovotransferrin, and lysozyme, is a food allergen in dogs. Information of the IgE reactivity to purified egg white allergens supports accurate diagnosis and efficiency treatment in humans. However, to the best of our knowledge, there have been no studies on the IgE reactivity to purified egg white allergens in dogs. Here, we investigated the IgE reactivity to crude and purified allergens of hen egg white in dogs with CAFR. First, when we examined serum samples from 82 dogs with CAFR for specific IgE to crude egg white by ELISA, 9.8% (8/82) of the dogs with CAFR showed the IgE reactivity to crude egg white. We then used sera from the eight dogs with positive IgE reactivity to crude egg white to examine the IgE reactivity to four purified allergens, ovomucoid, ovalbumin, ovotransferrin, and lysozyme, by ELISA. We found that 75% (6/8) of the dogs showed IgE reactivity to both ovomucoid and ovalbumin, and that 37.5% (3/8) of the dogs showed IgE reactivity to ovotransferrin. None (0/8) showed IgE reactivity to lysozyme. Moreover, validating these results, the immunoblot analyses were performed using the sera of the three dogs showing the highest IgE reactivity to crude egg white. Both anti-ovomucoid and anti-ovalbumin IgE were detected in the sera of these dogs, while anti-ovotransferrin IgE was not detected. Considering these, ovomucoid and ovalbumin appears to be the major egg white allergens in dogs with CAFR.
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
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.
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
Belloni, Benedetta; Schönewolf, Nicola; Rozati, Sima; Goldinger, Simone M; Dummer, Reinhard
There is a variety of adverse effects and toxicities of newer and older chemotherapeutic agents which emerge in the skin, mucosa and adnexa. Common skin reactions while undergoing chemotherapy include alopecia, changes in skin pigmentation, palmoplantar erythrodysesthesia, nail dystrophies and stomatitis. Extravasation injuries or hypersensitivity reactions may be severe. New oncologic agents have led to the development of different, class-specific cutaneous side effects. Epidermal growth factor receptor (EGFR) inhibitors induce papulopustular rashes in a high percentage of patients as well as, to a smaller degree, xerosis cutis, hair and nail changes, hyper pigmentation and enhancement of radiation dermatitis. Multikinase inhibitors will often cause hand-foot syndrome, but may also induce facial erythema, subungual splinter hemorrhages and other less frequent skin changes. BRAF inhibitors can lead to rash and development of cutaneous keratinocytic neoplasias for which patients should be closely monitored. Finally, MEK/ERK inhibitors induce similar skin toxicities to EGFR inhibitors such as papulopustular rashes, xerosis cutis and paronychia. Our chapter will focus on the clinical picture, histopathology and treatment options of these new class-specific cutaneous side effects. Copyright © 2012 S. Karger AG, Basel.
Maitland, Ronald I
Medline, Embase, Chinese National Knowledge Infrastructure VIP Database for Chinese Technical Periodicals (and Chinese Biomedical Literature Database. Randomised controlled trials (RCTs), non-RCTs, case-control studies, case reports, case series and cross-sectional studies that focused on adverse drug reactions of local anaesthetics were considered. Data abstraction was conducted independently by two reviewers, and summary data and a meta-analysis presented. One hundred and one studies reporting 1645 events were included. Seven of these were deaths. Lidocaine (43.17%) and bupivacaine (16.32%) were the most often involved local anaesthetics. According to the meta-analysis, the risk of using LA alone was lower than when combined with epinephrine. The present study demonstrated that the adverse drug reactions of local anaesthetics could not be ignored, especially in oral and ophthalmologic treatments. Some adverse drug reactions could be avoided by properly evaluating the conditions of patients and correctly applying local anaesthetics.
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.
Tuccori, Marco; Montagnani, Sabrina; Capogrosso-Sansone, Alice; Mantarro, Stefania; Antonioli, Luca; Fornai, Matteo; Blandizzi, Corrado
Oncology is one of the areas of medicine with the most active research being conducted on new drugs. New pharmacological entities frequently enter the clinical arena, and therefore, the safety profile of anticancer products deserves continuous monitoring. However, only very severe and (unusual) suspected adverse drug reactions (ADRs) are usually reported, since cancer patients develop ADRs very frequently and some practical selectivity must be used. Notably, a recent study was able to identify 76 serious ADRs reported in updated drug labels of oncologic drugs and 50% of them (n = 38) were potentially fatal. Of these, 49 and 58%, respectively, were not described in initial drug labels. The aims of this article are to provide an overview about spontaneous reporting of ADRs of oncologic drugs and to discuss the available methods to analyze the safety of anticancer drugs using databases of spontaneous ADR reporting.
Sheik Ali, Shirwa; Goddard, Allison L; Luke, Jason J; Donahue, Hilary; Todd, Derrick J; Werchniak, Andrew; Vleugels, Ruth Ann
Ipilimumab, a human monoclonal antibody targeted against cytotoxic T-lymphocyte antigen 4, has shown promise in the treatment of metastatic melanoma. However, given its mechanism of action, immune-related adverse effects have been reported with this therapy. Despite increasing reports of immune-related adverse effects related to ipilimumab therapy, dermatomyositis associated with this agent has not previously been reported. We describe a woman undergoing treatment with ipilimumab for metastatic melanoma who developed classic cutaneous findings of dermatomyositis along with proximal muscle weakness and elevated muscle enzymes. This case adds to the expanding literature regarding immune-related adverse events associated with ipilimumab. To our knowledge, drug-induced dermatomyositis from ipilimumab has not previously been reported. Physicians should be aware of these potential immune-related adverse events and consider drug-associated dermatomyositis in the differential diagnosis in patients receiving ipilimumab who present with a cutaneous eruption or muscle weakness.
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.
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
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.
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. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
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
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.
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.
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.
Cevc, Gregor; Vierl, Ulrich
We analysed quantitatively blood microvessels distribution in normal skin. We conclude that the segmental area of blood vessels peaks approximately 0.1 mm below the skin surface, where the upper cutaneous blood plexus resides. Total blood vessels area then decreases quasi-exponentially to a depth of approx. -0.75 mm, with a decay length of approximately 0.1 mm, which is site and skin condition dependent, but at greater depths the decrease is approx. 6-times less steep. The corresponding permeability sink exhibits a similar, but superficially steeper, depth-profile. The lateral localisation of superficial blood vessels is such that ensures maximum diffusion from and into the capillaries, which affects transdermal drug delivery: each hairpin-like loop is in the centre of a papilla that corresponds to a cluster of corneocytes surrounded by main diffusion pathways. The aggregate area of blood vessels in the skin is >or=2.5-fold greater than total organ surface area under normal physiological conditions. The molecules diffusing through the skin barrier are thus largely cleared in outermost 20% of the organ, which may create a drug concentration maximum in the dermis, if clearance increases significantly with time. Skin microdialysis data are therefore extremely sensitive to cutaneous blood flow (distribution) and sampling. Skin microvasculature and its distribution must consequently be considered in all topical or transdermal drug transport studies, for example, by including suitably formulated clearance term into generalised diffusion equation.
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
Farrah, Kelly; Mierzwinski-Urban, Monika; Cimon, Karen
Objective The study tested the performance of adverse effects search filters when searching for safety information on medical devices, procedures, and diagnostic tests in MEDLINE and Embase. Methods The sensitivity of 3 filters was determined using a sample of 631 references from 131 rapid reviews related to the safety of health technologies. The references were divided into 2 sets by type of intervention: drugs and nondrug health technologies. Keyword and indexing analysis were performed on references from the nondrug testing set that 1 or more of the filters did not retrieve. Results For all 3 filters, sensitivity was lower for nondrug health technologies (ranging from 53%–87%) than for drugs (88%–93%) in both databases. When tested on the nondrug health technologies set, sensitivity was lower in Embase (ranging from 53%–81%) than in MEDLINE (67%–87%) for all filters. Of the nondrug records that 1 or more of the filters missed, 39% of the missed MEDLINE records and 18% of the missed Embase records did not contain any indexing terms related to adverse events. Analyzing the titles and abstracts of nondrug records that were missed by any 1 filter, the most commonly used keywords related to adverse effects were: risk, complications, mortality, contamination, hemorrhage, and failure. Conclusions In this study, adverse effects filters were less effective at finding information about the safety of medical devices, procedures, and tests compared to information about the safety of drugs. PMID:27366123
Farrah, Kelly; Mierzwinski-Urban, Monika; Cimon, Karen
The study tested the performance of adverse effects search filters when searching for safety information on medical devices, procedures, and diagnostic tests in MEDLINE and Embase. The sensitivity of 3 filters was determined using a sample of 631 references from 131 rapid reviews related to the safety of health technologies. The references were divided into 2 sets by type of intervention: drugs and nondrug health technologies. Keyword and indexing analysis were performed on references from the nondrug testing set that 1 or more of the filters did not retrieve. For all 3 filters, sensitivity was lower for nondrug health technologies (ranging from 53%-87%) than for drugs (88%-93%) in both databases. When tested on the nondrug health technologies set, sensitivity was lower in Embase (ranging from 53%-81%) than in MEDLINE (67%-87%) for all filters. Of the nondrug records that 1 or more of the filters missed, 39% of the missed MEDLINE records and 18% of the missed Embase records did not contain any indexing terms related to adverse events. Analyzing the titles and abstracts of nondrug records that were missed by any 1 filter, the most commonly used keywords related to adverse effects were: risk, complications, mortality, contamination, hemorrhage, and failure. In this study, adverse effects filters were less effective at finding information about the safety of medical devices, procedures, and tests compared to information about the safety of drugs.
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.
Wiley, Laura K; Moretz, Jeremy D; Denny, Joshua C; Peterson, Josh F; Bush, William S
It is unclear the extent to which best practices for phenotyping disease states from electronic medical records (EMRs) translate to phenotyping adverse drug events. Here we use statin-induced myotoxicity as a case study to identify best practices in this area. We compared multiple phenotyping algorithms using administrative codes, laboratory measurements, and full-text keyword matching to identify statin-related myopathy from EMRs. Manual review of 300 deidentified EMRs with exposure to at least one statin, created a gold standard set of 124 cases and 176 controls. We tested algorithms using ICD-9 billing codes, laboratory measurements of creatine kinase (CK) and keyword searches of clinical notes and allergy lists. The combined keyword algorithms produced were the most accurate (PPV=86%, NPV=91%). Unlike in most disease phenotyping algorithms, addition of ICD9 codes or laboratory data did not appreciably increase algorithm accuracy. We conclude that phenotype algorithms for adverse drug events should consider text based approaches.
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.
Bhushan, Bharat; Chander, Ramesh; Kajal, N C; Ranga, Vikrant; Gupta, Ajay; Bharti, Heena
The aim of the study was to elucidate the profile of adverse drug reactions (ADRs) associated with second-line anti-tubercular treatment for drug-resistant tuberculosis. ADR profile of diagnosed drug-resistant tuberculosis cases on supervised second-line anti-tubercular drug regimen under Programmatic Management of Drug-resistant Tuberculosis under Revised National Tuberculosis Control Programme, were studied over two years' period. Adverse reactions were categorised into mild, moderate and severe types with subsequent systematic data-analysis. Out of total 207 patients in the study, 81.16% reported with adverse drug reactions. Out of total 195 adverse events, 63.58%, 18.46% and 17.94% were of mild, moderate and severe types respectively. Gastrointestinal events, hepatitis, hearing impairment, arthralgia, psychosis, hypothyroidism, visual disturbances, giddiness, peripheral neuropathy, skin reactions, swelling or pain at injection site, anorexia and sleep disturbances were important amongst these. High proportion of drug and/or alcohol abuse was an important observation. The offending drug(s) had to be terminated in 12.08% of the patients. Early detection, management and pharmaco-vigilance reporting of ADRs remain key factors in the management of drug-resistant tuberculosis with remarkable relevance of the need for early diagnosis and treatment of 'drug-sensitive tuberculosis', to prevent emergence of drug-resistant tuberculosis.
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
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.
Horvath, Monica M; Cozart, Heidi; Ahmad, Asif; Langman, Matthew K; Ferranti, Jeffrey
Duke University Health System uses computerized adverse drug event surveillance as an integral part of medication safety at 2 community hospitals and an academic medical center. This information must be swiftly communicated to organizational patient safety stakeholders to find opportunities to improve patient care; however, this process is encumbered by highly manual methods of preparing the data. Following the examples of other industries, we deployed a business intelligence tool to provide dynamic safety reports on adverse drug events. Once data were migrated into the health system data warehouse, we developed census-adjusted reports with user-driven prompts. Drill down functionality enables navigation from aggregate trends to event details by clicking report graphics. Reports can be accessed by patient safety leadership either through an existing safety reporting portal or the health system performance improvement Web site. Elaborate prompt screens allow many varieties of reports to be created quickly by patient safety personnel without consultation with the research analyst. The reduction in research analyst workload because of business intelligence implementation made this individual available to additional patient safety projects thereby leveraging their talents more effectively. Dedicated liaisons are essential to ensure clear communication between clinical and technical staff throughout the development life cycle. Design and development of the business intelligence model for adverse drug event data must reflect the eccentricities of the operational system, especially as new areas of emphasis evolve. Future usability studies examining the data presentation and access model are needed.
Dalleur, Olivia; Beeler, Patrick E; Schnipper, Jeffrey L; Donzé, Jacques
To analyze the patterns of potentially avoidable readmissions due to adverse drug events (ADEs) to identify the most appropriate risk reduction interventions. In this observational study, we analyzed a random sample of 534 potentially avoidable 30-day readmissions from 10,275 consecutive discharges from the medical department of an academic hospital. Readmissions due to ADEs were reviewed to identify the causative drugs and the severity and interventions to prevent them. Seventy cases (13.1%) of readmission were partially or predominantly due to ADEs, of which, 58 (82.9%) were serious ADEs. Overall, 65 (92.9%) of the ADEs have been confirmed to be preventable. Inappropriate prescribing was identified as the cause of ADE in 34 cases (48.6%) mainly involving diuretics, analgesics, or antithrombotics: misprescribing n = 19 (27.1%), underprescribing n = 8 (11.4%), and overprescribing n = 7 (10.0%). The remaining half of preventable ADEs (n = 36; 51.4%) were related to suboptimal patient monitoring/education, such as adherence issues (n = 6; 8.6%) or lack of monitoring (n = 31; 44.3%). In 64 cases (91.4%), the readmission could have been potentially prevented by better monitoring for drug efficacy/disease control, or for predictable side effect. Thirty-three (97.1%) of the 34 ADEs due to inappropriate prescribing could have also been prevented by better monitoring. Adverse drug events accounted for approximately 13% of 30-day preventable readmissions. A half were due to prescription errors involving mainly diuretics, analgesics, or antithrombotics, and the other half were due to suboptimal patient monitoring/education, most frequently with antineoplastics. Both these avoidable causes may represent opportunities to reduce the total drug-related adverse events.
Williamson, S; Gossop, M; Powis, B; Griffiths, P; Fountain, J; Strang, J
A sample of drug users (n = 158) were contacted and interviewed in non-clinical community settings about their use of Ecstasy, cocaine powder, and amphetamines and the adverse effects of these drugs. Subjects reported a wide range of adverse effects including anxiety problems, depression, mood swings, feelings of paranoia, and panic attacks. Sleep and appetite disturbances were the most commonly reported problems. About half of all subjects reported depression and paranoid feelings associated with their stimulant use. Many of those reporting problems stated that these were mild. However, for all drugs, a substantial minority of users reported adverse effects which they rated as 'severe'. Between 30 and 55% of the sample reported having had at least one 'severe' adverse effect (30% cocaine, 35% Ecstasy and 55% amphetamine). There were clear differences between the different drugs in the likelihood and reported severity of adverse effects. Amphetamine use was associated with significantly more adverse effects and with more severe adverse effects than Ecstasy or cocaine. Cocaine powder was associated with the least severe adverse effects. A common pattern of drug use involved the use of depressant drugs such as opiates and benzodiazepines in addition to stimulants. The stimulant and depressant users were more likely than the stimulants-only users to use stimulants by injection and more likely to report adverse effects associated with stimulant use. The stimulant and depressant users were also more likely to have been treated for a drug problem. Approximately a quarter of the sample stated that they had stopped using stimulants up to the point of interview as a result of their bad experiences.
Reyes, Hans A; Cativo, Eder H; Sy, Alexander M
Hepatitis C infection and its treatment have been associated with extrahepatic manifestations, including different skin conditions. Over the past decades, a greater number of drugs have been implicated as triggers for drug-induced subacute cutaneous lupus erythematosus. We report a case of a 42-year-old Hispanic man who developed a forehead violaceous rash during treatment with pegylated interferon alpha-2a as part of his therapy against hepatitis C infection that subsequently resulted to be subacute cutaneous lupus erythematosus. The skin lesion improved with discontinuation of medication and some topic therapy.
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.
Xiang, Yang; Albin, Aaron; Ren, Kaiyu; Zhang, Pengyue; Etter, Jonathan P.; Lin, Simon; Li, Lang
Efficiently mining multiple drug interactions and reactions from Adverse Event Reporting System (AERS) is a challenging problem which has not been sufficiently addressed by existing methods. To tackle this challenge, we propose a FCI-fliter approach which leverages the efforts of UMLS mapping, frequent closed itemset mining, and uninformative association identification and removal. By applying our method on AERS, we identified a large number of multiple drug interactions with reactions. By statistical analysis, we found most of the identified associations have very small p-values which suggest that they are statistically significant. Further analysis on the results shows that many multiple drug interactions and reactions are clinically interesting, and suggests that our method may be further improved with the combination of external knowledge. PMID:25717411
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
Zhou, Zhi-Wei; Chen, Xiao-Wu; Sneed, Kevin B; Yang, Yin-Xue; Zhang, Xueji; He, Zhi-Xu; Chow, Kevin; Yang, Tianxin; Duan, Wei; Zhou, Shu-Feng
Adverse drug reactions (ADRs) are a major public health concern and cause significant patient morbidity and mortality. Pharmacogenomics is the study of how genetic polymorphisms affect an individual's response to pharmacotherapy at the level of a whole genome. This article updates our knowledge on how genetic polymorphisms of important genes alter the risk of ADR occurrence after an extensive literature search. To date, at least 244 pharmacogenes identified have been associated with ADRs of 176 clinically used drugs based on PharmGKB. At least 28 genes associated with the risk of ADRs have been listed by the Food and Drug Administration as pharmacogenomic biomarkers. With the availability of affordable and reliable testing tools, pharmacogenomics looks promising to predict, reduce, and minimize ADRs in selected populations.
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.
Smyth, Rebecca Mary Diane; Gargon, Elizabeth; Kirkham, Jamie; Cresswell, Lynne; Golder, Su; Smyth, Rosalind; Williamson, Paula
Background Adverse drug reactions in children are an important public health problem. We have undertaken a systematic review of observational studies in children in three settings: causing admission to hospital, occurring during hospital stay and occurring in the community. We were particularly interested in understanding how ADRs might be better detected, assessed and avoided. Methods and Findings We searched nineteen electronic databases using a comprehensive search strategy. In total, 102 studies were included. The primary outcome was any clinical event described as an adverse drug reaction to one or more drugs. Additional information relating to the ADR was collected: associated drug classification; clinical presentation; associated risk factors; methods used for assessing causality, severity, and avoidability. Seventy one percent (72/102) of studies assessed causality, and thirty four percent (34/102) performed a severity assessment. Only nineteen studies (19%) assessed avoidability. Incidence rates for ADRs causing hospital admission ranged from 0.4% to 10.3% of all children (pooled estimate of 2.9% (2.6%, 3.1%)) and from 0.6% to 16.8% of all children exposed to a drug during hospital stay. Anti-infectives and anti-epileptics were the most frequently reported therapeutic class associated with ADRs in children admitted to hospital (17 studies; 12 studies respectively) and children in hospital (24 studies; 14 studies respectively), while anti-infectives and non-steroidal anti-inflammatory drugs (NSAIDs) were frequently reported as associated with ADRs in outpatient children (13 studies; 6 studies respectively). Fourteen studies reported rates ranging from 7%–98% of ADRs being either definitely/possibly avoidable. Conclusions There is extensive literature which investigates ADRs in children. Although these studies provide estimates of incidence in different settings and some indication of the therapeutic classes most frequently associated with ADRs, further
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
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.
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.
Amann, Jonna; Wessels, Anne-Marie; Breitenfeldt, Friederike; Huscher, Dörte; Bijlsma, Johannes W J; Jacobs, Johannes W G; Buttgereit, Frank
EULAR guidelines state that adverse effects (AEs) of glucocorticoid (GC) therapy should be considered and discussed with the patient before treatment is initiated. However, reliable quantitative data, especially on cutaneous AEs of low-to-medium dose GCs are lacking. We performed a study assessing the occurrence of cutaneous AEs of GCs and its association with current and cumulative GC doses in patients with rheumatoid arthritis (RA). In a cross-sectional study performed in 2 outpatient rheumatology centres, 381 RA patients were enrolled. They were classed into 4 groups, according their mean daily dose during the past 12 months: 0 mg (n=87), <5mg (n=108), 5-7.5 mg (n=130), and >7.5 mg (n=56) of prednisone equivalent. AEs of GC on the skin were assessed by physical examination using a predefined scoring system, and by patients' self-assessments. Data were analysed according GC dose categories and cumulative doses. Cushingoid habitus, easy bruising, skin atrophy, and impaired wound healing as reported by patients occurred significantly more frequently in those using a GC the past 12 months, compared to those not using a GC. At physicians' assessments, only Cushingoid habitus and ecchymosis were more prevalent in GC users. The prevalence of these AEs was statistically significantly positively associated with current and cumulative GC dose. There was low occurrence of abnormal stretch marks, acne, perioral dermatitis, alopecia and hirsutism, which were not correlated with GC use. Certain GC-associated cutaneous AEs are common in RA, but other AEs of GC occur infrequently at the low-to-medium GC doses used in RA.
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
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
Alsbou, Mohammed; Alzubiedi, Sameh; Alzobi, Hamed; Samhadanah, Nawal Abu; Alsaraireh, Yousef; Alrawashdeh, Omar; Aqel, Amin; Al-Salem, Khalil
Adverse drug reactions (ADRs) represent a major health care problem. To identify the most common ADRs, drugs implicated in ADRs, and to assess their causality, severity, preventability and risk factors predisposing to reported ADRs in Jordan. Al-Karak teaching hospital, southern of Jordan. Method A cross sectional observational study was carried out for 11 months from January to November 2013. Suspected ADRs were recorded in ADRs report forms and analyzed for causality, severity, and preventability. Most common ADRs, drugs involved in these ADRs, causality, severity, and preventability of suspected ADRs. A total of 64 reports were received. Some patients suffered more than one ADR. The total number of ADRs identified was 108. Forty one drugs were involved in causing these ADRs. About 2/3 of adverse reactions (73.4 %) did not cause admission to the hospital, whereas 26.6 % of the ADRs resulted in admission. Majority of the ADRs were type A (62.5 %). Most of ADRs (92.2 %) were assessed as probable. Nearly, 65.6 % of ADRs were categorized as mild. Majority of ADRs were assessed as "not preventable" (75 %). The most common classes of drugs involved in ADRs were antibiotics, analgesics, vaccines and antiepileptics. The most commonly identified ADRs were abdominal pain, skin rash, shortness of breath, fever, upper gastrointestinal bleeding and vomiting. Risk factors contributed to ADRs were age and polypharmacy. Jordanian healthcare providers should be aware of the importance of detecting and reporting ADRs, in order to prevent and reduce the incidence of ADRs. Awareness of risk factors predisposing to ADRs may help in identifying patients with higher risk and therefore reducing the risk of these ADRs and improving patient outcome.
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
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
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.
Franconi, Flavia; Campesi, Ilaria; Occhioni, Stefano; Antonini, Paola; Murphy, Michael F
Sex-gender-based differences in response to pharmaceutical treatments are still under evaluation but evidence already exists regarding the impact of sex-gender-related differences on drug safety profile, drug abuse/addiction, and placebo effects. For a number of drugs it is well recognized that a sex-gender dimorphic profile in terms of drug adverse effects exists and appears to be more frequent and severe in women than in men. However, it is not well known whether this is due to pharmacodynamic or pharmacokinetic differences. Indeed the optimization of therapy requires that attention is paid to single sex-gender. Numerous pharmacokinetic, pharmacodynamic, and sociocultural differences between women and men in drug abuse have been described. Here we focus on sex-gender differences in alcoholism and nicotine addiction. The relevance of sex and gender differences in addiction appear to be relevant. Specific programs aimed to address addicted women's specific needs (child care, pregnancy, housing, and violence and others) are recommended. Finally, this article discusses the possible effect of sex-gender on placebo response in the light of the more significant recent literature evidencing that studies are urgently required in order to better understand the role of sex-gender on placebo mechanism and its impact on randomized clinical trials outcomes.
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
Leroy, Nicolas; Chazard, Emmanuel; Beuscart, Régis; Beuscart-Zephir, Marie Catherine
Adverse Drug Events (ADE) due to medication errors and human factors are a major public health issue. They endanger patient safety and cause considerable extra healthcare costs. The European project PSIP (Patient Safety through Intelligent Procedures in medication) aims to identify and prevent ADE. Data mining of the structured hospital data bases will give a list of observed ADE with frequencies and probabilities, thereby giving a better understanding of potential risks. The main objective of the project is to develop innovative knowledge based on the mining results and to deliver to professionals and patients, in the form of alerts and decision support functions, a contextualized knowledge fitting the local risk parameters.
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.
Eaglstein, William H; Kirsner, Robert S; Robson, Martin C
The rising costs of caring for chronic cutaneous ulcers (CCUs) and recent appreciation of the mortality of CCUs have led to consideration of the reasons for the failure to have new drug therapies. No new chemical entities to heal CCUs have been approved by the Food and Drug Administration (FDA) in over a decade, in part due to an inability to reach the FDA accepted end point of "complete wound closure." The frequent failure to reach the complete closure end point brings forward the question of the relevance of other healing end points such as improved quality of life, or partial healing. Because CCUs carry a prognosis and mortality rate worse than many cancers, it is reasonable to compare the FDA trial end points for cancer drug approval with those for CCUs. And the difference is quite striking. While there is only one end point for CCUs, there are five surrogate and three direct end points for cancers. In contrast to cancer, surrogate end points and partial healing are not acceptable for therapies aimed at CCUs. For example, making tumors smaller is an acceptable end point, but making CCUs smaller is not and improvement in the signs and symptoms of cancer is an acceptable end point for cancers but not CCUs. As CCUs carry a prognosis and mortality rate worse than many cancers, we believe a reconsideration of end points for CCUs is highly warranted.
Maeda, Hideki; Kurokawa, Tatsuo
The compensation scheme for adverse drug reactions in Japan was implemented more than three decades ago as relief system by regulatory agencies. Because of the high frequency of adverse drug reactions, anticancer drugs have been excluded from coverage by the relief system since its implementation. Requests have recently been made by some patient advocates for the expansion of relief coverage to include anticancer drugs. In response to these requests, the Ministry of Health, Labor and Welfare of Japan established a committee to discuss relief from anticancer drug-induced health damages in June 2011. We conducted comprehensive research into the compensation scheme for adverse drug reactions in the world. We also investigated the situation of compensation and the committee for discussing inclusion of anticancer drugs into the relief system in Japan. Many countries including the United States and UK do not have relief or compensation schemes for no-fault compensation. We investigated whether a no-fault compensation system exists in Nordic countries (Sweden, Denmark, Norway and Finland), France, Germany, New Zealand and Taiwan in the world, although they offer different services from Japan. We also reviewed current situation and the fundamental difficulties associated with including anticancer drugs in the systems in Japan. The present study investigated the current situation and the fundamental difficulties associated with including anticancer drugs in the systems in Japan and pointed out part of the reason why the committee could not conclude involvement of anticancer drugs in the relief system.
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
Hosford, David A; Lai, Eric H; Riley, John H; Xu, Chun-Fang; Danoff, Theodore M; Roses, Allen D
Identification of reliable markers to predict drug-related adverse events (DRAEs) is an important goal of the pharmaceutical industry and others within the healthcare community. We have used genetic polymorphisms, including the most frequent source of variation (single nucleotide polymorphisms, SNPs) in the human genome, in pharmacogenetic approaches designed to predict DRAEs. Three studies exemplify the principles of using polymorphisms to identify associations in progressively larger genomic regions: polymorphic repeats within the UDP-glucuronysltransferase I (UGT1A1) gene in patients experiencing hyperbilirubinemia after administration of tranilast, an experimental drug to prevent re-stenosis following coronary revascularization; high linkage disequilibrium within the Apolipoprotein E (ApoE) gene in patients with Alzheimer Disease (AD); and the polymorphic variant HLA-B57 in patients with hypersensitivity reaction after administration of abacavir, a nucleoside reverse transcriptase inhibitor for the treatment of HIV. Together, these studies demonstrate in a stepwise manner the feasibility of using pharmacogenetic approaches to predict DRAEs.
Usui, Toru; Naisbitt, Dean J
A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well-established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavir-induced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose response is restricted by specific HLA risk alleles have been detected from IADR patients, also suggesting an adaptive immune pathogenesis. T-cells from carbamazepine SJS/TEN patients are activated by direct pharmacological interaction between carbamazepine and HLA-B*15:02 expressed on antigen presenting cells (APCs). Abacavir-specific, HLA-B*57:01-restricted T-cells are activated by APCs presenting peptides which are only displayed by the HLA molecule when abacavir is bound during peptide loading. Finally, HLA-B*57:01-restricted activation of T-cells from patients with flucloxacillin-induced liver injury is dependent on processing of drug protein adducts. Based on these observations, it is now possible to utilize blood from healthy drug-naïve volunteers to study the priming of naïve T-cells to drugs. Future development of these methodologies may lead to the development of assays that predict intrinsic immunogenicity of drugs and chemicals at the preclinical stage of drug development. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Iadanza, E; Pettenati, M C; Bianchi, L; Turchi, S; Ciofi, L; Pirri, F; Biffi Gentili, G; Giuli, D
In this paper we present PHARMA 2.0 a telematics integrated system aimed at reducing Adverse Drug Events (ADEs) in the phases of drug prescription, transcription, distribution and administration. The proposed system is grounded on three sub-systems: a CPOE (Computerized Prescription Order Entry), an RFID-based drug container and dispenser and a middleware system. The visualization and management of prescription and administration data are handled through a web application designed to comply with international usability regulation.
Glucksberg, H; Singer, J
An analysis of the types and costs of drugs imported by seven multinational pharmaceutical companies in Zaire, an underdeveloped country in Africa, reveals that three-fourths of the drugs consisted of expensive and nonessential items. The prices of essential drugs (24 percent of their total imports) were much higher than those of available generic sources (average difference of 300 percent). The importation of nonessential drugs and high prices paid for essential drugs exacerbate the scarcity of needed items because of Zaire's limited supply of hard currency. In addition, two drug firms imported and promoted the sale of aminopyrone-dipyrone analgesic-antipyretics, drugs now rarely used in Western industrialized countries because of potentially fatal complications. Thus, in Zaire, the multinational pharmaceutical industry has an adverse effect on the availability and cost of drugs, as well as on the pattern of drug usage.
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
Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment.
Bardin, Thomas; Chalès, Gérard; Pascart, Tristan; Flipo, René-Marc; Korng Ea, Hang; Roujeau, Jean-Claude; Delayen, Aurélie; Clerson, Pierre
To investigate the cutaneous tolerance of febuxostat in gouty patients with skin intolerance to allopurinol. We identified all gouty patients who had sequentially received allopurinol and febuxostat in the rheumatology departments of 4 university hospitals in France and collected data from hospital files using a predefined protocol. Patients who had not visited the prescribing physician during at least 2 months after febuxostat prescription were excluded. The odds ratio (OR) for skin reaction to febuxostat in patients with a cutaneous reaction to allopurinol versus no reaction was calculated. For estimating the 95% confidence interval (95% CI), we used the usual Wald method and a bootstrap method. In total, 113 gouty patients had sequentially received allopurinol and febuxostat; 12 did not visit the prescribing physician after febuxostat prescription and were excluded. Among 101 patients (86 males, mean age 61±13.9 years), 2/22 (9.1%) with a history of cutaneous reactions to allopurinol showed skin reactions to febuxostat. Two of 79 patients (2.5%) without a skin reaction to allopurinol showed skin intolerance to febuxostat. The ORs were not statistically significant with the usual Wald method (3.85 [95% CI 0.51-29.04]) or bootstrap method (3.86 [95% CI 0.80-18.74]). The risk of skin reaction with febuxostat seems moderately increased in patients with a history of cutaneous adverse events with allopurinol. This moderate increase does not support the cross-reactivity of the two drugs. Copyright © 2015. Published by Elsevier SAS.
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
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
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.
Talat, Bilal; Mayers, Andrew; Baldwin, David S
Case reports of adverse reactions with psychotropic drugs can be useful in raising hypotheses, to be tested with more rigorous study designs. However such reports have significant methodological drawbacks, making it hard to determine causality. We undertook a systematic assessment of the quality of case reports and small case series published within Human Psychopharmacology over 25 years. For reports of adverse drug reactions, modified Bradford Hill criteria for causality (for consistency, strength, specificity, temporal relationship and plausibility) were used to ascertain the quality of the account. Reports which had been cited at least 10 times by December 2010 were examined in detail, to assess their overall contribution in extending understanding and influencing clinical practice. Of 40 reports of adverse drug reactions, only seven were sufficiently robust for confidence in probable or possible causality. Nine reports had been cited more than 10 times: the five most frequently cited reports of adverse drug reactions described movement disorders, suicidal thoughts and discontinuation symptoms with SSRIs: clinical relevance was high, but their quality was not markedly greater than less frequently cited reports. Nearly all reports of adverse drug reactions, published in a single journal over 25 years, were insufficiently robust to demonstrate probable causality. Reports that are cited frequently become influential because of their potential clinical relevance, rather than due to their methodological quality. Copyright © 2013 John Wiley & Sons, Ltd.
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
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
Egger, Sabin S; Krähenbühl, Stephan; Schlienger, Raymond G
Dentists may be confronted with adverse drug reactions (ADRs) in their dental practice, and are--like other health professionals--obliged to report certain ADRs. The aim of this article is to sensitise dentists for this topic, to show how to proceed in case of a supposed ADR, and to emphasise the importance of spontaneous reporting of ADRs. ADRs may not always be clearly distinguished from symptoms of underlying diseases, and in cases of polypharmacy multiple drugs may be responsible for the reaction. It is therefore important to get a detailed medical history, and to establish a temporal relationship between start of a therapy and appearance of the symptom. Information from the medical literature, exclusion of other possible causes, and identification of risk factors help to confirm a causal relationship between a suspected drug and an observed reaction. In Switzerland severe and unexpected ADRs have to be reported to one of the regional Pharmacovigilance centres with the yellow ADR reporting form from Swissmedic. The spontaneous reports of ADRs help to early identify new problems of a drug therapy, and permit to take measures to minimise the risk.
Sevene, Esperança; Mariano, Alda; Mehta, Ushma; Machai, Maria; Dodoo, Alexander; Vilardell, David; Patel, Sam; Barnes, Karen; Carné, Xavier
The roll out of various public health programmes involving mass administration of medicines calls for the deployment of responsive pharmacovigilance systems to permit identification of signals of rare or even common adverse reactions. In developing countries in Africa, these systems are mostly absent and their performance under any circumstance is difficult to predict given the known shortage of human, financial and technical resources. Nevertheless, the importance of such systems in all countries is not in doubt, and research to identify problems, with the aim of offering pragmatic solutions, is urgently needed. To examine the impact of training and monitoring of healthcare workers, making supervisory visits and the availability of telecommunication and transport facilities on the implementation of a pharmacovigilance system in Mozambique. This was a descriptive study enumerating the lessons learnt and challenges faced in implementing a spontaneous reporting system in two rural districts of Mozambique - Namaacha and Matutuíne - where remote location, poor telecommunication services and a low level of education of health professionals are ongoing challenges. A 'yellow card' system for spontaneous reporting of adverse drug reactions (ADRs) was instituted following training of health workers in the selected districts. Thirty-five health professionals (3 medical doctors, 2 technicians, 24 nurses, 4 basic healthcare agents and 2 pharmacy agents) in these districts were trained to diagnose, treat and report ADRs to all medicines using a standardized yellow card system. There were routine site visits to identify and clarify any problems in filling in and sending the forms. One focal person was identified in each district to facilitate communication between the health professionals and the National Pharmacovigilance Unit (NPU). The report form was assessed for quality and causality. The availability of telecommunications and transport was assessed. Fourteen months after
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
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. © 2015 The British Pharmacological Society.
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
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.
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.
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
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.
Esfandiarpour, Iraj; Farajzadeh, Saeedeh; Rahnama, Zahra; Fathabadi, Elahe Arabpoor; Heshmatkhah, Amireh
Intralesional injection of pentavalent antimoniate is recommended by the World Health Organization for the treatment of cutaneous leishmaniasis (CL). This study aimed to evaluate the adverse effects of intralesional injection of meglumine antimoniate (Glucantime(®) ) and its influence on clinical laboratory parameters. A total of 105 patients with suspected lesions and therapeutic features of CL diagnosed by direct smear or skin biopsy were included in this study. Intralesional injection of Glucantime(®) was administered to treat CL. Fifty-five of the 105 patients were checked for hematological features, liver and kidney function, and fasting blood sugar levels before and after treatment. The observed side effects included pain (89.5%), burning sensation (81.9%), erythema (45.7%), pruritus (28.6%), secondary infection (17.1%), nausea (11.4%), vomiting (7.6%), urticaria (5.7%), necrosis (2.9%), sporotrichoid lesions (2.9%), dizziness (1.9%), dyspnea (1.9%), and anaphylactic shock (0.9%). No statistically significant differences were found in occurrences of adverse effects according to the part of the body affected, patient sex or age group, except for pruritus, which appeared more frequently in extremities than in other parts of the body (P < 0.001), and secondary infection, which was observed more frequently in people aged >45 years (P < 0.042). All clinical parameters remained normal after treatment. The occurrence of severe adverse reactions, particularly of anaphylactic shock, should be considered before treatment with Glucantime(®) is initiated. Thus, it is important that intralesional Glucantime(®) injections are administered in centers that are well equipped with appropriate resuscitation and support apparatus. © 2012 The International Society of Dermatology.
Pavlos, Rebecca; Mallal, Simon; Ostrov, David; Pompeu, Yuri; Phillips, Elizabeth
Drug hypersensitivity syndromes such as abacavir hypersensitivity and the severe cutaneous adverse drug reactions (SCAR) have been associated with significant short and long-term morbidity and mortality. More recently these immunologically mediated and previously unpredictable diseases have been shown to be associated with primarily Class I and also Class II HLA alleles. The case of the association of HLA-B*57:01 and abacavir hypersensitivity has created a translational roadmap for how this knowledge can be utilized in the clinic to prevent severe reactions. Although many hurdles exist to the widespread translation of such HLA screening approaches, our understanding of how drugs interact with the MHC has contributed to the discovery of new models that have provided considerable insights into the immunopathogenesis of SCAR and other T-cell mediated drug hypersensitivity syndromes. Future translation of this knowledge will facilitate the development of pre-clinical toxicity screening to significantly improve efficacy and safety of drug development and design. PMID:24565765
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
Bailey, Clifford J.
Detection and interpretation of adverse signals during preclinical and clinical stages of drug development inform the benefit-risk assessment that determines suitability for use in real-world situations. This review considers some recent signals associated with diabetes therapies, illustrating the difficulties in ascribing causality and evaluating absolute risk, predictability, prevention, and containment. Individual clinical trials are necessarily restricted for patient selection, number, and duration; they can introduce allocation and ascertainment bias and they often rely on biomarkers to estimate long-term clinical outcomes. In diabetes, the risk perspective is inevitably confounded by emergent comorbid conditions and potential interactions that limit therapeutic choice, hence the need for new therapies and better use of existing therapies to address the consequences of protracted glucotoxicity. However, for some therapies, the adverse effects may take several years to emerge, and it is evident that faint initial signals under trial conditions cannot be expected to foretell all eventualities. Thus, as information and experience accumulate with time, it should be accepted that benefit-risk deliberations will be refined, and adjustments to prescribing indications may become appropriate. PMID:23695817
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.
Iyer, Srinivasan V; Harpaz, Rave; LePendu, Paea; Bauer-Mehren, Anna; Shah, Nigam H
Background and objective Electronic health records (EHRs) are increasingly being used to complement the FDA Adverse Event Reporting System (FAERS) and to enable active pharmacovigilance. Over 30% of all adverse drug reactions are caused by drug–drug interactions (DDIs) and result in significant morbidity every year, making their early identification vital. We present an approach for identifying DDI signals directly from the textual portion of EHRs. Methods We recognize mentions of drug and event concepts from over 50 million clinical notes from two sites to create a timeline of concept mentions for each patient. We then use adjusted disproportionality ratios to identify significant drug–drug–event associations among 1165 drugs and 14 adverse events. To validate our results, we evaluate our performance on a gold standard of 1698 DDIs curated from existing knowledge bases, as well as with signaling DDI associations directly from FAERS using established methods. Results Our method achieves good performance, as measured by our gold standard (area under the receiver operator characteristic (ROC) curve >80%), on two independent EHR datasets and the performance is comparable to that of signaling DDIs from FAERS. We demonstrate the utility of our method for early detection of DDIs and for identifying alternatives for risky drug combinations. Finally, we publish a first of its kind database of population event rates among patients on drug combinations based on an EHR corpus. Conclusions It is feasible to identify DDI signals and estimate the rate of adverse events among patients on drug combinations, directly from clinical text; this could have utility in prioritizing drug interaction surveillance as well as in clinical decision support. PMID:24158091
Jiang, Guoqian; Liu, Hongfang; Solbrig, Harold R; Chute, Christopher G
Drug-drug interactions (DDIs) are a major contributing factor for unexpected adverse drug events (ADEs). However, few of knowledge resources cover the severity information of ADEs that is critical for prioritizing the medical need. The objective of the study is to develop and evaluate a Semantic Web-based approach for mining severe DDI-induced ADEs. We utilized a normalized FDA Adverse Event Report System (AERS) dataset and performed a case study of three frequently prescribed cardiovascular drugs: Warfarin, Clopidogrel and Simvastatin. We extracted putative DDI-ADE pairs and their associated outcome codes. We developed a pipeline to filter the associations using ADE datasets from SIDER and PharmGKB. We also performed a signal enrichment using electronic medical records (EMR) data. We leveraged the Common Terminology Criteria for Adverse Event (CTCAE) grading system and classified the DDI-induced ADEs into the CTCAE in the Web Ontology Language (OWL). We identified 601 DDI-ADE pairs for the three drugs using the filtering pipeline, of which 61 pairs are in Grade 5, 56 pairs in Grade 4 and 484 pairs in Grade 3. Among 601 pairs, the signals of 59 DDI-ADE pairs were identified from the EMR data. The approach developed could be generalized to detect the signals of putative severe ADEs induced by DDIs in other drug domains and would be useful for supporting translational and pharmacovigilance study of severe ADEs.
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
Krahn, Tobias; Eichelberg, Marco; Müller, Frerk; Gönül, Suat; Laleci Erturkmen, Gokce B; Sinaci, A Anil; Appelrath, H-Jürgen
Adverse drug events (ADEs) are common, costly and one of the most important issues in contemporary pharmacotherapy. Current drug safety surveillance methods are largely based on spontaneous reports. However, this is known to be rather ineffective. There is a lack of automated systems checking potential ADEs on routine data captured in electronic health records (EHRs); present systems are usually built directly on top of specific clinical information systems through proprietary interfaces. In the context of the European project "SALUS", we aim to provide an infrastructure as well as a tool-set for accessing and analyzing clinical patient data of heterogeneous clinical information systems utilizing standard methods. This paper focuses on two components of the SALUS architecture: The "Semantic Interoperability Layer" (SIL) enables an access to disparate EHR sources in order to provide the patient data in a common data model for ADE detection within the "ADE Detection and Notification Tool" (ANT). The SIL in combination with the ANT can be used in different clinical environments to increase ADE detection and reporting rates. Thus, our approach promises a profound impact in the domain of pharmacovigilance.
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.
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
Olivry, Thierry; Mueller, Ralf S
The prevalence of cutaneous adverse food reactions (CAFRs) in dogs and cats is not precisely known. This imprecision is likely due to the various populations that had been studied. Our objectives were to systematically review the literature to determine the prevalence of CAFRs among dogs and cats with pruritus and skin diseases. We searched two databases for pertinent references on August 18, 2016. Among 490 and 220 articles respectively found in the Web of Science (Science Citation Index Expanded) and CAB Abstract databases, we selected 22 and nine articles that reported data usable for CAFR prevalence determination in dogs and cats, respectively. The prevalence of CAFR in dogs and cats was found to vary depending upon the type of diagnoses made. Among dogs presented to their veterinarian for any diagnosis, the prevalence was 1 to 2% and among those with skin diseases, it ranged between 0 and 24%. The range of CAFR prevalence was similar in dogs with pruritus (9 to 40%), those with any type of allergic skin disease (8 to 62%) and in dogs diagnosed with atopic dermatitis (9 to 50%). In cats presented to a university hospital, the prevalence of CAFR was less than 1% (0.2%), while it was fairly homogeneous in cats with skin diseases (range: 3 to 6%), but higher in cats with pruritus (12 to 21%) than in cats with allergic skin disease (5 to 13%). Among dogs and cats with pruritus and those suspected of allergic skin disease, the prevalence of CAFR is high enough to justify this syndrome to be ruled-out with a restriction (elimination)-provocation dietary trial. This must especially be considered in companion animals with nonseasonal pruritus or signs of allergic dermatitis.
Zhou, T; Duan, J J; Zhou, G P; Cai, J Y; Huang, Z H; Zeng, Y T; Xu, F
The aim of this study was to explore the impact of depression mood disorder on the incidence of adverse drug reactions of anticancer drugs in cancer patients. The Hamilton Depression Scale 17 was used to evaluate the depression mood disorder level in 73 cancer patients before chemotherapy. Pharmacists monitored adverse drug reactions during the chemotherapy period. The relationship between depression mood disorder level and the incidence of adverse drug reactions was analysed. The frequency and extent of total adverse drug reactions were not related to depression mood disorder level. The frequency and extent of subjectively experienced adverse drug reactions such as anorexia, nausea and fatigue were related to depression mood disorder level. In conclusion, psychological support and intervention should be provided to cancer patients in order to improve patient adherence and cancer chemotherapy effectiveness, and to decrease the incidence of adverse drug reactions.
Staines, Anthony; Mattia, Costanza; Schaad, Nicolas; Lécureux, Estelle; Bonnabry, Pascal
The Hospital Federation of Vaud (Switzerland) used a Breakthrough Collaborative with the aim of reducing adverse drug events (ADEs) by 20% in 10 participating hospitals. A set of interventions (covering patient identification, high-alert medication and medication preparation in the ward) was deployed over 18 months starting in October 2010. All hospitals monitored discrepancies between drugs prescribed and those prepared for administration, as well as the occurrence of ADEs using the ADE Trigger Tool for 18 months (cohort 1). A subset of five hospitals continued this monitoring for 12 additional months (cohort 2). In cohort 1, pill box discrepancies were present in 5.9% of doses (n = 9772) in 2011 and in 5.8% (n = 2251) in the first 3 months of 2012 (no statistical significance). There were no significant differences in the rate of ADEs/1000 doses across time (1.2 in 2010, 1.0 in 2011 and 1.0 in 2012). In cohort 2, pill box discrepancies were reduced from 6.5% (n = 4846 doses) in 2011 to 4.4% (n = 7355) in 2012 (P < 0.001) to 3.0% for the first 3 months of 2013 (n = 2251; P = 0.004). The rate of ADEs/1000 doses decreased (1.8 in 2010, 1.1 in 2011 and 0.6 in 2012/13 (P = 0.008 for 2010-2011, and P < 0.001 for 2011-2012/2013). Reductions in drug discrepancies and ADEs occurred in the cohort with the longer monitoring duration. Factors contributing to success may include the strategic status of the project, executive support, perseverance in post-intervention measurement, and institution-wide rather than partial deployment. © 2015 John Wiley & Sons, Ltd.
Gonzalez-Guerrero, Miriam; Martínez-Camblor, Pablo; Vivanco, Blanca; Fernández-Vega, Ivan; Munguía-Calzada, Pablo; Gonzalez-Gutierrez, Maria Paz; Rodrigo, Juan Pablo; Galache, Cristina; Santos-Juanes, Jorge
Tumor budding is a readily detectable histopathologic feature that has been recognized as an adverse prognostic factor in several human cancers. We sought to assess the correlation of tumor budding with the clinicopathologic features and the prognostic value of tumor budding in cutaneous squamous cell carcinoma (cSCC). Forty-nine primary nonmetastatic and 49 primary metastatic cSCCs to regional lymph nodes were retrospectively studied. Statistical analyses were carried out to assess the relationship between tumor budding, clinicopathologic parameters, and patient survival. Tumor budding was observed in 45 cases of 98 (46%). High-intensity budding (≥5 tumor buds) was observed in 20 tumors. Presence of tumor buds was a significant risk factor for nodal metastasis with crude and adjusted hazard ratios (HRs) of 8.92 (95% CI, 4.39-18.1) and 6.93 (95% CI, 3.30-14.5), respectively, and for reduced overall survival time (crude and adjusted HRs of 2.03 [95% CI, 1.26-3.28] and 1.72 [95% CI, 1.05-2.83], respectively). This was a retrospective study limited to cSCCs of the head and neck. Examined tumors were >2 mm thick, and all were from a primary excision. These results indicate an increased frequency of nodal metastasis and risk of death in patients with tumor buds. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Background Adverse drug events are a frequent cause of emergency department presentations. Administrative data could be used to identify patients presenting with adverse drug events for post-market surveillance, and to conduct research in patient safety and in drug safety and effectiveness. However, such data sources have not been evaluated for their completeness with regard to adverse drug event reporting. Our objective was to determine the proportion of adverse drug events to outpatient medications diagnosed at the point-of-care in emergency departments that were documented in administrative data. Methods We linked the records of patients enrolled in a prospective observational cohort study on adverse drug events conducted in two Canadian tertiary care emergency departments to their administrative data. We compared the number of adverse drug events diagnosed and recorded at the point-of-care in the prospective study with the number of adverse drug events recorded in the administrative data. Results Among 1574 emergency department visits, 221 were identified as adverse drug event-related in the prospective database. We found 15 adverse drug events documented in administrative records with ICD-10 codes clearly indicating an adverse drug event, indicating a sensitivity of 6.8% (95% CI 4.0–11.2%) of this code set. When the ICD-10 code categories were broadened to include codes indicating a very likely, likely or possible adverse event to a medication, 62 of 221 events were identifiable in administrative data, corresponding to a sensitivity of 28.1% (95% CI 22.3-34.6%). Conclusions Adverse drug events to outpatient medications were underreported in emergency department administrative data compared to the number of adverse drug events diagnosed and recorded at the point-of-care. PMID:24219303
Singh, Harpreet; Tanwar, Vikram; Arora, Sameer; Bhutani, Jaikrit
Leflunomide is an immunomodulatory drug exhibiting anti-inflammatory, anti-proliferative and immunosuppressive effects. It has been widely used for treatment of active rheumatoid arthritis. Despite its good safety profile cutaneous side effects like alopecia, eczema, pruritis and dry skin have been reported with Leflunomide use. Skin ucleration, vasculitis, lichenoid drug rash and Subacute Cutaneous Lupus Erythematosus (SCLE) have been rarely reported with its use. A rare case of Leflunomide induced SCLE is being reported in a female patient with rheumatoid arthritis. The clinical features, histopathological and immunological characteristics were consistent with drug induced SCLE. Withdrawal of Leflunomide along with short course of topical steroids resulted in resolution of symptoms suggesting the drug to be the culprit. As this drug comes into widespread use, it remains to be seen whether more cases of DI-SCLE will occur/be reported. Fortunately, such a condition till times appears rare and is reversible once the drug is discontinued thus avoiding over evaluation and over treatment if the triggering drug is recognized. PMID:27891379
Singh, Harpreet; Sukhija, Gagandeep; Tanwar, Vikram; Arora, Sameer; Bhutani, Jaikrit
Leflunomide is an immunomodulatory drug exhibiting anti-inflammatory, anti-proliferative and immunosuppressive effects. It has been widely used for treatment of active rheumatoid arthritis. Despite its good safety profile cutaneous side effects like alopecia, eczema, pruritis and dry skin have been reported with Leflunomide use. Skin ucleration, vasculitis, lichenoid drug rash and Subacute Cutaneous Lupus Erythematosus (SCLE) have been rarely reported with its use. A rare case of Leflunomide induced SCLE is being reported in a female patient with rheumatoid arthritis. The clinical features, histopathological and immunological characteristics were consistent with drug induced SCLE. Withdrawal of Leflunomide along with short course of topical steroids resulted in resolution of symptoms suggesting the drug to be the culprit. As this drug comes into widespread use, it remains to be seen whether more cases of DI-SCLE will occur/be reported. Fortunately, such a condition till times appears rare and is reversible once the drug is discontinued thus avoiding over evaluation and over treatment if the triggering drug is recognized.
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.
Vural, Fisun; Ciftci, Seval; Vural, Birol
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. 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. 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. 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.
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
Varallo, Fabiana Rossi; Planeta, Cleopatra S; Herdeiro, Maria Teresa; Mastroianni, Patricia de Carvalho
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. 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. 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). 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.
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
Schoretsanitis, Georgios; Stegmann, Benedikt; Hiemke, Christoph; Gründer, Gerhard; Schruers, Koen R J; Walther, Sebastian; Lammertz, Sarah E; Haen, Ekkehard; Paulzen, Michael
The aim of the study was to investigate a correlation between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety (AM) (RIS + 9-OH-RIS), and adverse drug reactions (ADRs) in a naturalistic sample. Plasma concentrations of RIS, 9-OH-RIS, and AM in patients out of a therapeutic drug monitoring (TDM) database complaining ADRs were categorized according to the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 97) and compared to patients without ADRs (n = 398). Patients in the ADR group received a significantly lower daily dosage of risperidone (trimmed mean 3.64 mg/day) than patients without ADRs (4.40 mg/day). No differences were found for active moiety plasma concentrations between the groups (p = 0.454). Differences were detected only in the case of dose-adjusted plasma concentration values (concentration-by-dose, C/D) for 9-OH-RIS, being higher in patients reporting ADRs (4.78 ng/mL/mg) than in patients without ADRs (4.3 ng/mL/mg) (p = 0.037 for Mann-Whitney U test). Note that differences for non-adjusted 9-OH-RIS plasma levels between groups failed to reach significance (p = 0.697). Our findings are consistent with previous data supporting a prominent role of 9-hydroxyrisperidone, but not of risperidone with regard to ADRs. When studying the various subgroups of reported ADRs separately, the size of these subsamples offers some plausible limitations by reducing the power of the analysis.
Bansal, Dipika; Azad, Chandrika; Kaur, Manpreet; Rudroju, Neelima; Vepa, Pravallika; Guglani, Vishal
The present study investigates the pattern and predictors of treatment-emergent adverse drug reactions (ADRs) in children diagnosed with epilepsy. We conducted prospective observational study in a tertiary care teaching hospital on 277 epileptic children. Antiepileptic drug (AED)-associated ADRs, demographic and clinical characteristics, AED regimen, and so on were recorded. Causality, severity, and preventability were performed by World Health Organization-Uppsala Monitoring Center scale, Hartwig's severity scale, and Schumock and Thornton questionnaire, respectively. Of the enrolled population, 53% children had symptomatic epilepsy, and 51% were in 5- to 10-year age group. More than two-thirds of children were on monotherapy, with phenytoin (n = 176, 63.5%) being the most common AED. Three hundred fifty-three AED-related ADRs were recorded in 175 children (63.2%). Poor scholastic performance (19%) was the most common ADR, followed by gum hypertrophy (13.3%), headache (10.2%), behavioral problems (5.7%), drowsiness (5.7%), and others. Two hundred sixteen ADRs were probable, and 126 ADRs were possible. Severe ADRs were noted in 6 children. Girls (odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.07-3.45; P = 0.03), children with secondary epilepsy (OR, 3.31; 95% CI, 1.76-6.23; P ≤ 0.001), children older than 5 years (5-10 years; OR, 6.28; 95% CI, 2.79-14.12; P ≤ 0.001), and those older than 10 years (OR, 9.04; 95% CI, 3.69-22.17; P ≤ 0.001) were found to be at higher risk of experiencing ADRs. Monotherapy was the preferred treatment. Phenytoin was the most common ADR causative agent. Female sex, symptomatic epilepsy, and older age (> 5 years) were found to be associated with higher probability of ADR development.
de Figueiredo, Tácita Pires; de Souza Groia, Ronara Camila; Barroso, Soraya Coelho Costa; do Nascimento, Mariana Martins Gonzaga; Reis, Adriano Max Moreira
Background Adverse drug reactions (ADRs) occur frequently during hospital stays and are an important public health problem, particularly in the care of the older. Objectives This study aimed to determine the prevalence of ADRs among older inpatients and the factors associated with their occurrence. Setting Brazilian teaching hospital. Methods This was a cross-sectional study with older inpatients in the internal medicine ward of a teaching hospital. The dependent variable was the occurrence of an ADR during hospitalization. The independent variables were gender, age, length of hospitalization, number of health problems, medications, and potentially inappropriate medications for the older. Logistic regression was performed to analyze the association between an ADR and the independent variables. Main outcome measure Factors associated with ADR in older inpatients. Results Among the 237 inpatients investigated, 50 (21.1%) developed at least one ADR. The total number of ADRs observed was 62 and the most frequent were acute kidney injury, hypotension, and cutaneous adverse reactions A multivariate analysis demonstrated a positive and independent association between the occurrence of an ADR and the presence of heart failure [odds ratio (OR) 2.4; 95% confidence interval (CI) 1.2-4.6], and with hospitalization time exceeding 12 days (OR 2.3; 95% CI 1.2-4.4). Conclusions The study showed a high prevalence of ADRs among the older and a positive association with hospitalization time and heart failure. Understanding the factors associated with the occurrence of ADRs among older inpatients provides elements for improving the safety of care and optimization of pharmacotherapy.
Ilyina, Rosa Yu; Pasynkova, Olga O; Ziganshina, Lilia E
Neuroleptic induced extrapyramidal disorders are often presented in a form of orofacial hyperkinesias and dystonia. Rational use of neuroleptic drugs requires individualised approach to a patient, however simple criteria for determining individual, "personalised" dosage regimen have not been fully developed for routine practice in resource-limited hospital settings. To study the tonus of tongue muscles as a measure of orofacial dystonia and the total hepatic oxidative capacity as a potential predictor of excessive vulnerability to neuroleptic-induced dystonia in psychiatric patients. We measured the maximal force of the tongue manoeuvre (F, g/cm2), the total (integral) hepatic oxidative capacity by the antipyrine-test and used chlorpromazine equivalent to calculate the total daily neuroleptic load in 283 psychiatric patients and 30 healthy volunteers. The tonus of tongue muscles depends on the total daily neuroleptic dose and the length of antipsychotic treatment. The higher the total daily neuroleptic dose and the longer the treatment history, the greater the tongue muscles' tonus is. The tongue muscles' tonus was greater in patients with low rate of oxidative antipyrine metabolism. Antidepressants contributed to the increased tonus of the tongue muscles in "slow metabolisers" of antipyrine. The simple and cheap measurements of total hepatic oxidative capacity and of muscle tonus of the tongue could be used to predict and manage neuroleptic-induced adverse reactions.
Phansalkar, Shobha; Hoffman, Jennifer M; Hurdle, John F; Patel, Vimla L
Manual chart review is an effective but expensive method for adverse drug event (ADE) detection. Building an expert system capable of mimicking the human expert's decision pathway, to deduce the occurrence of an ADE, can improve efficiency and lower cost. As a first step to build such an expert system, this study explores pharmacist's decision-making processes for ADE detection. Think-aloud procedures were used to elicit verbalizations as pharmacists read through ADE case scenarios. Two types of information were extracted, firstly pharmacists' decision-making strategies regarding ADEs and secondly information regarding pharmacists' unmet information needs for ADE detection. Verbal protocols were recorded and analysed qualitatively to extract ADE information signals. Inter-reviewer agreement for classification of ADE information signals was calculated using Cohen's kappa. We extracted a total of 110 information signals, of which 73% consisted of information that was interpreted by the pharmacists from the case scenario and only about half (53%, n = 32) of the information signals were considered relevant for the detection of the ADEs. Excellent reliability was demonstrated between the reviewers for classifying signals. Fifty information signals regarding unmet information needs were extracted and grouped into themes based on the type of missing information. Pharmacists used a forward reasoning approach to make implicit deductions and validate hypotheses about possible ADEs. Verbal protocols also indicated that pharmacists' unmet information needs occurred frequently. Developing alerting systems that meet pharmacists' needs adequately will enhance their ability to reduce preventable ADEs, thus improving patient safety.
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.
Abubakar, Abdullahi Rabiu; Chedi, Bashir A Z; Mohammed, Khalid Garba; Haque, Mainul
Spontaneous reporting (SPR) and intensive monitoring are the conventional systems used for detecting, recording, and reporting adverse drug reactions (ADRs). Using spontaneous reporting a lot of successes has been made as existing ADRs were identified and new ones prevented through this methods. The aim of this appraisal was to evaluate the knowledge, attitude, and the practice of medical students with regards to ADRs reporting and to see if differences exist between the level of study and genders. The questionnaire was adopted, modified, and validated from previous studies. It comprised of 25 questions. It was administered year-IV and V medical students of Bayero University Kano, Nigeria. The data collected were coded and analyzed using the Statistical Package for the Social Sciences (SPSS) version 20, currently known as IBM SPSS Statistics. The response rate was 74%. Among the 108 participants, 80% got the definition of ADRs correct; 63% of them knew the precise functions of pharmacovigilance (PV). In addition, 82% strongly agreed that ADR reporting is health care workers responsibility; 82% also said PV should be taught in detail. Meanwhile, 99% have noticed patient experiencing ADRs; 67% said even mild ADRs should be reported. The outcome of this study showed good knowledge and attitude with respect to ADRs and PV among the medical students surveyed. Unfortunately, the practice of medical students was found to be unsatisfactory. There is a need to upgrade the students teaching the curriculum with respect to ADRs monitoring.
Davies, Emma C; Green, Christophe F; Mottram, David R; Pirmohamed, Munir
The serious nature of adverse drug reactions (ADRs) has been highlighted in a number of instances over the last forty years, the most recent of these being the occurrence of serious thrombotic events with the use of COX-2 inhibitors. ADRs are estimated to be between the 4(th) and 6(th) leading cause of death in the USA, with fatal ADRs occurring in 0.32% of patients. A recent UK study showed that 6.5% of hospital admissions were related to ADRs. ADRs can therefore be regarded as a significant public health and economic problem. There is an urgent need to develop better preventive strategies to reduce the burden of ADRs. Because ADRs can affect any bodily system, can have many different clinical presentations, and are of widely variable severity, prevention will not be easy and will have to be multifactorial in its approach. This paper reviews the epidemiology of ADRs in hospitals and evaluates the research that has been undertaken to date to prevent ADRs.
Ko, Tai-Ming; Tsai, Chang-Youh; Chen, Shih-Yang; Chen, Kuo-Shu; Yu, Kuang-Hui; Chu, Chih-Sheng; Huang, Chung-Ming; Wang, Chrong-Reen; Weng, Chia-Tse; Yu, Chia-Li; Hsieh, Song-Chou; Tsai, Jer-Chia; Lai, Wen-Ter; Tsai, Wen-Chan; Yin, Guang-Dar; Ou, Tsan-Teng; Cheng, Kai-Hung; Yen, Jeng-Hsien; Liou, Teh-Ling; Lin, Tsung-Hsien; Chen, Der-Yuan; Hsiao, Pi-Jung; Weng, Meng-Yu; Chen, Yi-Ming; Chen, Chen-Hung; Liu, Ming-Fei; Yen, Hsueh-Wei; Lee, Jia-Jung; Kuo, Mei-Chuan; Wu, Chen-Ching; Hung, Shih-Yuan; Luo, Shue-Fen; Yang, Ya-Hui; Chuang, Hui-Ping; Chou, Yi-Chun; Liao, Hung-Ting; Wang, Chia-Wen; Huang, Chun-Lin; Chang, Chia-Shuo; Lee, Ming-Ta Michael; Chen, Pei; Wong, Chih-Shung; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Chen, Yuan-Tsong
Objective To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. Design National prospective cohort study. Setting 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. Participants 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants’ peripheral blood was used to assess the presence of HLA-B*58:01. Main outcome measures Incidence of allopurinol induced SCARs with and without screening. Results Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). Conclusions Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence
Loo, Tenneille T; Ross, Colin J D; Sistonen, Johanna; Visscher, Henk; Madadi, Parvaz; Koren, Gideon; Hayden, Michael R; Carleton, Bruce C
Juxtaposing clinical pharmacology with human genetics, pharmacogenomics utilizes a patient's genetic information to identify genetic variants that have the potential to provide clinically relevant predictions of toxicity and efficacy. The goal is to develop personalized and genetic-based predictions of an individual's drug response and likelihood of experiencing an adverse drug reaction. The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) has implemented active adverse drug reaction surveillance to monitor and discover genetic markers related to serious adverse drug reactions in the pediatric population. Evidence-based pharmacogenomics research will inform public policy and influence drug benefit-risk decision-making. Regulatory processes and future challenges in pharmacogenomics research will be discussed.
Plichta, Danuta; Doryńska, Agnieszka; Spiewak, Radosław
The research of drug consumption is focused mainly upon the elderly, while the knowledge of drug consumption patterns among young people remains insufficient. Public health students (PHS) seem of particular interest as future opinion leaders and drug policy makers. The aim of the study was to analyze opinions and patterns of drug consumption, and adverse drug reactions (ADR) in this group. 130 PHS took part in the anonymous questionnaire survey. All students admitted to using some drug at least once in their lives. While purchasing over-the-counter (OTC) drugs, 51.6% students trusted their own knowledge and experience. Women more often relied on a pharmacist's recommendation (47.2% vs 21.7% men; p = 0.045), while men were more influenced by advertising (34.8% vs 12.3% women, p = 0.008). Strict adherence to recommended dosage of OTC and prescription drugs (Rx) was declared by 41.1% and 71.9% students, respectively. Every fourth student (24.8%) admitted to having purchased a Rx drug at least once without having the prescription. Past episodes of ADR to OTC were reported by 7.8% students and to Rx by 38.4% (p < 0.001). Respectively 27.2% and 34.4% students were never, or hardly ever asked about past ADR by prescribing physicians. According to 89.2% students, drug advertising should be subject to regulation and policing, and 66.1% considered it inaccurate and unreliable. Forty-five percent of students had an OTC drug on them while responding the questionnaire, 20.0% had a prescription drug. Students of public health seem to be notorious consumers of drugs and their attitude seems not fully rational.
Bartal, Alexandra; Mátrai, Zoltán; Szucs, Attila; Belinszkaja, Galina; Langmár, Zoltán; Rosta, András
Each aspect of oncological care is widely affected by the spread of oral anticancer agents, which raises several questions in terms of safe medication use and patient adherence. Over the past decade targeted therapies have appeared in clinical practice and revolutionized the pharmacological treatment of malignancies. Regular patient - doctor visits and proper patient education is crucial in order to comply with the therapy previously agreed upon with the oncologist, to increase patient adherence, to detect and to treat adverse effects in early stages. Since the information on the new medicines in Hungarian language is sparse it is the intention of the authors to give an overview of the basic knowledge, patient safety issues, adverse effects and interactions. Official drug information summaries and data on pharmacokinetics, interactions and adverse effects from the literature are reviewed as the basis for this overview.
Uhara, H; Kiyohara, Y; Tsuda, A; Takata, M; Yamazaki, N
Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients.
Ekman, Elisabet; Petersson, Göran; Tågerud, Sven; Bäckström, Martin
Background The purpose of this study was to investigate awareness among nurses regarding their new role as reporters of adverse drug reactions in Sweden and factors that may influence reporting by nurses. Methods In 2007, all nurses were included in the adverse drug reaction reporting scheme in Sweden. A questionnaire was sent to 753 randomly selected nurses in September 2010. Results Of the 453 (60%) responding nurses, 265 (58%) were aware that nurses were included in the reporting of adverse drug reactions. Sixty-one nurses (14%) stated that they had reported an adverse drug reaction. Fifteen percent (n = 70) of the respondents had received training about reporting of adverse drug reactions. Almost one third of these (n = 21, 30%) had reported an adverse drug reaction on at least one occasion. Among nurses without training, a smaller proportion (n = 40, 11%, P < 0.05) had reported an adverse drug reaction on at least one occasion. The two factors considered most important by nurses for reporting were the severity of the adverse drug reaction and if the reaction was to a newly approved drug. A majority of the nurses (n = 397, 88%) were interested in a training course in pharmacology as part of their ongoing professional development. One third (32%) of all nurses stated that one reason for not reporting a suspected adverse drug reaction was that the physician responsible did not regard the reaction necessary to report. Conclusion We found that more than half of the study population of nurses in Sweden were aware of their new role as reporters of adverse drug reactions, but few of the responding nurses had reported an adverse drug reaction. Given that training seems to be associated with high reporting frequency, we suggest more training in pharmacovigilance for nurses. PMID:22826643
(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
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
Trombetta, Luis; Oliva, Adriana; Galache, Viviana; Bava, Javier; Troncoso, Alcides
Myiasis is the condition resulting from the invasion of tissues or organs of man or animals by dipterous larvae. The blowflies (Calliphoridae) of Argentina comprise several species that may cause myiasis by colonizing wounds or infected body orifices, and one specific parasite: Cochliomyia hominivorax. This species often causes traumatic myiasis in cattle, dogs and cats, and it is not rare in humans. The larvae consume living tissues, so they are dangerous unless speedily removed. Immediate operative exploration along with the removal of larvae and primary defect closure is recommended in every case. Here we report a case of myiasis in a scalp wound caused by blunt force trauma to the area, in a male patient with a case history of alcohol and drug abuse. Seventy-one living larvae were extracted from the wound and determined as C. hominivorax in the Forensic Entomology Laboratory. Given the aggressiveness of these larvae, specific and quick diagnosis as well as the application of appropriate treatment is crucial.
Imaura, Masaharu; Yamaya, Takeshi; Uehara, Nozomi; Mano, Narutoshi; Nagase, Satoshi; Kimura, Koji; Kanno, Hiroshi; Yamada, Yasuhiko
We evaluated the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, as well as the severity and outcome of reactions based on analyses of pharmacist involvement in a collaborative approach to medicine. Of 5436 cases with pharmacist involvement, adverse drug reaction prevention was seen in 440, accounting for 8.1%, and exacerbation avoidance in 213, accounting for 3.9%. We concluded that pharmacist involvement contributes to detect adverse drug reactions and avoid exacerbation, and improves pharmacotherapy safety. We also analyzed 131 cases in which the course after intervention was followed. When categorized by adverse drug reaction severity, Grade 1 and 2 were the same at 45.8%, Grade 3 at 8.4%, respectively. Those findings suggested that pharmacist intervention contributes to early detection of an adverse drug reaction. Also, the relationship between clues for detecting adverse drug reactions by a pharmacist and their severity showed that objective evaluations such as clinical laboratory test results, physical assessments and medication history were important for detecting reactions that became more serious. Patients recovered or recovering from an adverse reaction comprised 76.4%, indicating that pharmacist intervention contributed to exacerbation avoidance and improvement. Our findings revealed the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, and for safety improvement of pharmacotherapy. Additionally, we considered it necessary for the future pharmacist intervention to improve skills of assessing an adverse drug reaction objectively.
Kumaran, Muthu S; Narang, Tarun; Jitendriya, Madhukara; Tirumale, Rajalakshmi; Manjunath, Suraj; Savio, Jayanthi
Tuberculosis (TB) is still a major public health problem in the world, with many factors contributing to this burden, including poor living conditions, overcrowding, poverty, malnutrition, illiteracy, and rapid spread of human immunodeficiency virus infection. Cutaneous tuberculosis is a less common form of extrapulmonary tuberculosis, and in this paucibacillary form the diagnosis depends on histopathology, tuberculin positivity, and response to treatment. The diagnosis is even more difficult in cases with drug resistant Mycobacterium tuberculosis due to lack of awareness and lack of facilities to diagnose drug resistant tuberculosis. In this article, we describe an unusual case of multidrug resistant lupus vulgaris (LV), in a 34-year-old male who responded to anti-tubercular treatment (ATT) initially, but developed recurrent disease which failed to respond to standard four-drug ATT; subsequently, tissue culture showed growth of multidrug resistant M. tuberculosis. Subsequently, he also developed cutaneous squamous cell carcinoma. This article aims to exemplify a grave complication that can occur in long-standing case of LV, the limitations faced by clinicians in developing countries where tuberculosis is endemic, and classical methods of proving drug resistance are generally unavailable or fail.
Kumaran, Muthu S.; Narang, Tarun; Jitendriya, Madhukara; Tirumale, Rajalakshmi; Manjunath, Suraj; Savio, Jayanthi
Tuberculosis (TB) is still a major public health problem in the world, with many factors contributing to this burden, including poor living conditions, overcrowding, poverty, malnutrition, illiteracy, and rapid spread of human immunodeficiency virus infection. Cutaneous tuberculosis is a less common form of extrapulmonary tuberculosis, and in this paucibacillary form the diagnosis depends on histopathology, tuberculin positivity, and response to treatment. The diagnosis is even more difficult in cases with drug resistant Mycobacterium tuberculosis due to lack of awareness and lack of facilities to diagnose drug resistant tuberculosis. In this article, we describe an unusual case of multidrug resistant lupus vulgaris (LV), in a 34-year-old male who responded to anti-tubercular treatment (ATT) initially, but developed recurrent disease which failed to respond to standard four-drug ATT; subsequently, tissue culture showed growth of multidrug resistant M. tuberculosis. Subsequently, he also developed cutaneous squamous cell carcinoma. This article aims to exemplify a grave complication that can occur in long-standing case of LV, the limitations faced by clinicians in developing countries where tuberculosis is endemic, and classical methods of proving drug resistance are generally unavailable or fail. PMID:28761842
Rodrigues, Maria Cristina Soares; Oliveira, Cesar de
to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. 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. 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. 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. identificar e sintetizar estudos que examinam as interações medicamentosas (IM) e reações adversas a medicamentos (RAM) em idosos polimedicados. revisão integrativa de estudos publicados de janeiro de 2008 a dezembro de 2013, de acordo com critérios de inclusão e exclusão, nas bases de dados eletrônicas MEDLINE e EMBASE. foram analisados 47 estudos de texto completo, incluindo 14,624,492 idosos (≥ 60 anos): 24 (51,1%) sobre RAM, 14 (29,8%) sobre IM e 9 estudos (19,1%) que investigaram tanto IM como RAM. Encontramos uma variedade de desenhos metodológicos. Os estudos revisados reforçaram que a polifarmácia é um processo multifatorial, e os preditores e a prescrição inadequada estão associados a
Zhichkin, P E; Athey, B D; Avigan, M I; Abernethy, D R
The growing significance of bioinformatics and systems biology in drug safety research requires a system of adverse-event classification that goes beyond a simple vocabulary. This opinion piece outlines the need for development of an ontology-based framework of describing adverse drug reactions (ADRs) and describes the potential applications for such a framework.
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.
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
Ortiz-Sanjuán, Francisco; Blanco, Ricardo; Hernández, José L; Pina, Trinitario; González-Vela, María C; Fernández-Llaca, Héctor; Calvo-Río, Vanesa; Loricera, Javier; Armesto, Susana; González-López, Marcos A; Rueda-Gotor, Javier; González-Gay, Miguel A
The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides defined drug-associated immune complex vasculitis as a distinct entity included within the category of vasculitis associated with probable etiology. In the present study we assessed the clinical spectrum of patients with drug-associated cutaneous vasculitis (DACV). Case records were reviewed of patients with DACV treated at a tertiary referral hospital over a 36-year period. A diagnosis of DACV was considered if the drug was taken within a week before the onset of the disease. From a series of 773 unselected cutaneous vasculitis cases, 239 patients (30.9%; 133 men and 106 women; mean age 36 yrs) were diagnosed with DACV. Antibiotics (n=149; 62.3%), mainly β-lactams and nonsteroidal antiinflammatory drugs (NSAID; n=24; 10%) were the most common drugs. Besides skin lesions (100%), the most common clinical features were joint (51%) and gastrointestinal (38.1%) manifestations, nephropathy (34.7%), and fever (23.8%). The most remarkable laboratory data were increased erythrocyte sedimentation rate (40.2%), presence of serum cryoglobulins (26%), leukocytosis (24.7%), positive antinuclear antibodies (21.1%), anemia (18.8%), and positive rheumatoid factor (17.5%). Despite drug discontinuation and bed rest, 108 patients (45.2%) required medical treatment, mainly corticosteroids (n=71) or immunosuppressive drugs (n=7). After a median followup of 5 months, relapses occurred in 18.4% of patients, and persistent microhematuria or renal insufficiency in 3.3% and 5%, respectively. DACV is generally associated with antibiotics and NSAID. In most cases it has a favorable prognosis, although a small percentage of patients may develop residual renal damage.
Subacute cutaneous lupus erythematosus (SCLE) is an autoimmune disease that may be induced by proton pump inhibitors (PPIs) in at-risk populations. The US FDA does not recognize SCLE as an adverse event associated with PPIs. We queried the FDA Adverse Event Reporting System database, which contains adverse event case reports submitted by the public as well as by industry, and analyzed the data to quantify passive pharmacovigilance signals for SCLE associated with PPIs. A disproportionality analysis of the signals yielded a significant association between SCLE and PPIs. Discontinuation of PPI resulted in remission, with PPI re-challenge causing SCLE to reoccur. A follow-up analysis also yielded a significant association between SCLE and H2 receptor antagonists. We conducted a brief literature survey of published case reports and studies to discern the validity of PPI-induced SCLE signals. Healthcare prescribers and patients should be made aware that SCLE can be induced by PPIs. In such cases, PPIs should be discontinued and alternative clinical treatment sought. Regulatory bodies such as the FDA should incorporate the adverse reaction in PPI prescription labels.
de Boer, Monica; Boeker, Eveline B; Ramrattan, Maya A; Kiewiet, Jordy J S; Dijkgraaf, Marcel G W; Boermeester, Marja A; Lie-A-Huen, Loraine
Errors occurring during different steps of the medication process can lead to adverse drug events (ADEs). Surgical patients are expected to have an increased risk for ADEs during hospitalization. However, detailed information about ADEs in the surgical patient is lacking. In this study, we aim to measure the incidence and nature of (preventable) ADEs, potential risk factors for and outcome parameters of (preventable) ADEs in surgical patients. Observational multicentre cohort study in which eight surgical wards participated from three Dutch hospitals, all using computerized physician order entry (CPOE) systems with clinical decision support. Electively admitted surgical patients of the participating wards were included from March until June 2009. ADEs were measured using a standardized method with expert judgment. Incidence, severity, preventability and accountable medication were assessed. Poisson regression analysis was applied to determine the associations between possible risk factors and the occurrence of ADEs, expressed as incidence rate ratio (IRR). Also outcomes of ADEs in surgical patients were measured. The incidence and nature of (preventable) ADEs in surgical patients. A total of 567 surgical patients were included. We found an incidence of 27.5 ADEs and 4.2 preventable ADEs (pADEs) per 100 admissions (15.4 %). A quarter of the pADEs were severe or life-threatening. Opioids and anti-coagulation medication play a major role in the occurrence of ADEs and pADEs respectively. Univariate analysis revealed an American Society of Anesthesiologists classification of III or more as a risk factor for ADEs. Patients older than 65 years [IRR 2.77 (1.14-6.72)], with cardiovascular comorbidity [IRR 2.87 (1.13-7.28)], or undergoing vascular surgery [IRR 2.32 (1.01-5.32)] were at risk for pADEs. Patients experiencing an ADE had a significant longer duration of admission than patients without an ADE. Surgical patients are at considerable risk of experiencing one or more
Liu, Jun; Zhou, Zhongliang; Yang, Shimin; Feng, Bianling; Zhao, Jun; Liu, Hua; Huang, Haiyan; Fang, Yu
Hospital pharmacists can make a considerable contribution to the spontaneous reporting system of adverse drug reactions. The factors that influence adverse drug reaction reporting among hospital pharmacists remain largely unknown in China. This study aims to identify factors that affect hospital pharmacist-led adverse drug reaction reporting in Xi'an, and to obtain suggestions from pharmacists about how to improve the current adverse drug reaction reporting system. Hospital settings throughout Xi'an, a region of Western China. A matched case-control study was conducted on a population of 2,814 hospital pharmacists in Xi'an during 2011. Cases included all pharmacists who had reported at least one adverse drug reaction between 2008 and 2010 and agreed to participate in the study (186/204; 91.2 %); controls (n = 372) were pharmacists who had not reported any adverse drug reaction during the same period. A self-administered questionnaire was distributed to the participants. Logistic regression was performed to evaluate the association between indicator variables and the outcome of having reported at least one adverse drug reaction. Pharmacists' knowledge, attitude and practice towards adverse drug reaction reporting and factors affecting reporting. Higher professional title (adjusted OR 1.44; 95 % CI 1.07-1.94; p = 0.018), having received training about adverse drug reaction reporting (1.64; 1.04-2.57; p = 0.032), better knowledge about reporting (1.53; 1.12-2.08; p = 0.007), "lack of access to adverse drug reaction reporting form" (0.29; 0.12-0.72; p = 0.008) was independently associated with adverse drug reaction reporting. Clinical pharmacists were more likely to report an adverse drug reaction than dispensary pharmacists (1/adjusted OR 5.26; p < 0.001), pharmacy administrators (5.00; p = 0.003), and other technicians (5.56; p = 0.001). Higher professional title, having received training, mastering knowledge about reporting, and being a clinical pharmacist were
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
Background The "Put Prevention into Practice" campaign of the US Public Health Service (USPHS) was launched with the dissemination of the Clinician's Handbook of Preventive Services that recommended standards of clinical care for various prevention activities, including preventive clinical strategies to reduce the risk of adverse drug events. We explored whether nonprescribing clinicians such as chiropractors may contribute to advancing drug safety initiatives by identifying potential adverse drug events in their chiropractic patients, and by bringing suspected adverse drug events to the attention of the prescribing clinicians. Methods Mail survey of US chiropractors about their detection of potential adverse drug events in their chiropractic patients. Results Over half of responding chiropractors (62%) reported having identified a suspected adverse drug event occurring in one of their chiropractic patients. The severity of suspected drug-related events detected ranged from mild to severe. Conclusions Chiropractors or other nonprescribing clinicians may be in a position to detect potential adverse drug events in the community. These detection and reporting mechanisms should be standardized and policies related to clinical case management of suspected adverse drug events occurring in their patients should be developed. PMID:21083911
Lamond, N W D; Younis, T; Purdy, K; Dorreen, M S
Drug-induced lupus erythematosus (dile) syndromes are documented complications of chemotherapeutic agents, including paclitaxel. Subacute cutaneous lupus erythematosus (scle) is a distinct dile syndrome presenting with characteristic annular or papulosquamous skin lesions in a photosensitive distribution with associated high anti-ssa titres. Previously, dile syndromes complicating paclitaxel therapy have been attributed to polyethoxylated castor oil (Kolliphor EL: BASF, Ludwigshafen, Germany), the biologic solvent included in the drug's original formulation (Taxol: Bristol-Myers Squibb, Montreal, QC), rather than the parent chemotherapy molecule. Here, we report a characteristic case of drug-induced scle complicating treatment with nanoparticle albumin bound (nab)-paclitaxel (Abraxane: Celgene, Summit, NJ, U.S.A.), a solvent-free taxane formulation. The pertinent English-language literature is also discussed. This case report is the first to link solvent-free paclitaxel with scle, and it suggests that the parent molecule is responsible for the reaction.
Fernandes-Silva, Gabriel; Ivani de Paula, Mayara; Rangel, Érika B
Patient and pancreas allograft survival improved following reductions in surgical complications, tighter donor selection and optimization in immunosuppressive protocols. However, long-term survival of pancreas allografts is adversely affected by rejection and immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of mammalian target of rapamycin inhibitors (mTORi). Some clinically relevant drug-drug interactions are highlighted. We summarize the nephrotoxic and diabetogenic mechanisms of mTORi after pancreas transplant, the alternatives to minimize these effects, and report on other adverse events. Expert opinion: Calcineurin inhibitor (CNI)-based regimens remain the mainstay treatment after pancreas-kidney transplant. However, long-term use of CNIs may be associated with nephrotoxicity. Switching from CNIs to mTORi (sirolimus/SRL and everolimus/EVR) may preserve kidney function, mainly EVR conversion. However, mTORi promote an imbalance of mTOR signaling during long-term follow-up and may ultimately contribute to proteinuria and hyperglycemia. These drugs disrupt autophagy, inhibit cell proliferation, and downregulate VEGF. Therefore, it is important to comprehend and interpret the experimental data. It is equally important to critically analyze clinical studies. Of importance, minimization of side effects, based on safe approaches, can prolong kidney allograft survival. Additional randomized-controlled studies are required to assess the impact of mTORi on pancreas allograft survival.
Bertin, P; Gillet, P; Treves, R; Netter, P
The potential chondrotoxicity of drugs is very difficult to appreciate because of the difficulties involved in evaluating the evolution of cartilage in human beings. This article attempts to summarize the data from the literature concerning the hypothetical chondrotoxicity of non steroidal anti-inflammatory drugs, fluoroquinolones, intra-articular injections of corticosteroids, and other drugs.
Winnenburg, Rainer; Shah, Nigam H
Identification of associations between marketed drugs and adverse events from the biomedical literature assists drug safety monitoring efforts. Assessing the significance of such literature-derived associations and determining the granularity at which they should be captured remains a challenge. Here, we assess how defining a selection of adverse event terms from MeSH, based on information content, can improve the detection of adverse events for drugs and drug classes. We analyze a set of 105,354 candidate drug adverse event pairs extracted from article indexes in MEDLINE. First, we harmonize extracted adverse event terms by aggregating them into higher-level MeSH terms based on the terms' information content. Then, we determine statistical enrichment of adverse events associated with drug and drug classes using a conditional hypergeometric test that adjusts for dependencies among associated terms. We compare our results with methods based on disproportionality analysis (proportional reporting ratio, PRR) and quantify the improvement in signal detection with our generalized enrichment analysis (GEA) approach using a gold standard of drug-adverse event associations spanning 174 drugs and four events. For single drugs, the best GEA method (Precision: .92/Recall: .71/F1-measure: .80) outperforms the best PRR based method (.69/.69/.69) on all four adverse event outcomes in our gold standard. For drug classes, our GEA performs similarly (.85/.69/.74) when increasing the level of abstraction for adverse event terms. Finally, on examining the 1609 individual drugs in our MEDLINE set, which map to chemical substances in ATC, we find signals for 1379 drugs (10,122 unique adverse event associations) on applying GEA with p < 0.005. We present an approach based on generalized enrichment analysis that can be used to detect associations between drugs, drug classes and adverse events at a given level of granularity, at the same time correcting for known dependencies among
Mori, Jinichi; Tanimoto, Tetsuya; Miura, Yuji; Kami, Masahiro
All-case post-marketing surveillance of newly approved anticancer drugs is usually conducted on all patients in Japan. The present study investigates whether all-case post-marketing surveillance identifies fatal adverse drug reactions undetected before market entry. We examined fatal adverse drug reactions identified via all-case post-marketing surveillance by reviewing the disclosed post-marketing surveillance results, and determined the time points in which the fatal adverse drug reactions were initially reported by reviewing drug labels. We additionally scanned emergency alerts on the Japanese regulatory authority website to assess the relationship between all-case post-marketing surveillance and regulatory action. Twenty-five all-case post-marketing surveillances were performed between January 1999 and December 2009. Eight all-case post-marketing surveillances with final results included information on all fatal cases. Of these, the median number of patients was 1287 (range: 106-4998), the median number of fatal adverse drug reactions was 14.5 (range: 4-23). Of the 111 fatal adverse drug reactions detected in the eight post-marketing surveillances, only 28 (25.0%) and 22 (19.6%) were described on the initial global and the initial Japanese drug label, respectively, and 58 (52.3%) fatal adverse drug reactions were first described in the all-case post-marketing surveillance reports. Despite this, the regulatory authority issued only four warning letters, and two of these were prompted by case reports from the all-case post-marketing surveillance. All-case post-marketing surveillance of newly approved anticancer drugs in Japan was useful for the rigorous compilation of non-specific adverse drug reactions, but it rarely detected clinically significant fatal adverse drug reactions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Blumenthal, Kimberly G.; Kuhlen, James L.; Weil, Ana A.; Varughese, Christy A.; Kubiak, David W.; Banerji, Aleena; Shenoy, Erica S.
Background Ceftaroline fosamil is a cephalosporin approved for treating skin and soft tissue infections (SSTIs), including those caused by methicillin-resistant Staphylococcus aureus (MRSA) and community acquired pneumonia (CAP). Objective We aimed to study ceftaroline use and associated adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs), among inpatients. Methods We performed a retrospective electronic health record review of inpatients from Massachusetts General Hospital and Brigham and Women’s Hospital who received ceftaroline between May 2012 and February 2015. ADRs diagnosed by clinical providers during the course of clinical care were subsequently verified and classified. Risk factors for ADRs were identified. Results Among 96 patients (median age 57 years, 54% female) who received a median of 28 [IQR 6, 63] ceftaroline doses, 54% were being treated for MRSA and treatment indications other than SSTI and CAP comprised 59% of care. There were 31 ADRs observed in 20 (21%) of patients; hematologic (n=15) and cutaneous (n=9) findings were most common. Observed HSRs included rash with mucosal lesions (n=1), rash with skin desquamation (n=1) and possible organ specific HSRs (n=2). Patients who suffered an ADR received more doses of ceftaroline (median 46 vs. 21, p=0.013). There was no increased risk of ceftaroline ADR among patients with prior reported beta-lactam allergy (p >0.5). Conclusions Ceftaroline is used to treat a range of infections beyond SSTI and CAP. We observed a high rate of ADRs from ceftaroline, including signs of severe HSRs. More data are needed to understand the frequency and predictors of ceftaroline ADRs and HSRs. PMID:27130709
Gurulingappa, Harsha; Toldo, Luca; Rajput, Abdul Mateen; Kors, Jan A; Taweel, Adel; Tayrouz, Yorki
The aim of this study was to assess the impact of automatically detected adverse event signals from text and open-source data on the prediction of drug label changes. Open-source adverse effect data were collected from FAERS, Yellow Cards and SIDER databases. A shallow linguistic relation extraction system (JSRE) was applied for extraction of adverse effects from MEDLINE case reports. Statistical approach was applied on the extracted datasets for signal detection and subsequent prediction of label changes issued for 29 drugs by the UK Regulatory Authority in 2009. 76% of drug label changes were automatically predicted. Out of these, 6% of drug label changes were detected only by text mining. JSRE enabled precise identification of four adverse drug events from MEDLINE that were undetectable otherwise. Changes in drug labels can be predicted automatically using data and text mining techniques. Text mining technology is mature and well-placed to support the pharmacovigilance tasks. Copyright © 2013 John Wiley & Sons, Ltd.
Edlinger, D; Sauter, S K; Rinner, C; Neuhofer, L M; Wolzt, M; Grossmann, W; Endel, G; Gall, W
The objective of our project was to create a tool for physicians to explore health claims data with regard to adverse drug reactions. The Java Adverse Drug Event (JADE) tool should enable the analysis of prescribed drugs in connection with diagnoses from hospital stays. We calculated the number of days drugs were taken by using the defined daily doses and estimated possible interactions between dispensed drugs using the Austria Codex, a database including drug-drug interactions. The JADE tool was implemented using Java, R and a PostgreSQL database. Beside an overview of the study cohort which includes selection of gender and age groups, selected statistical methods like association rule learning, logistic regression model and the number needed to harm have been implemented. The JADE tool can support physicians during their planning of clinical trials by showing the occurrences of adverse drug events with population based information.
Sauter, S.K.; Rinner, C.; Neuhofer, L.M.; Wolzt, M.; Grossmann, W.; Endel, G.; Gall, W.
Summary Objective The objective of our project was to create a tool for physicians to explore health claims data with regard to adverse drug reactions. The Java Adverse Drug Event (JADE) tool should enable the analysis of prescribed drugs in connection with diagnoses from hospital stays. Methods We calculated the number of days drugs were taken by using the defined daily doses and estimated possible interactions between dispensed drugs using the Austria Codex, a database including drug-drug interactions. The JADE tool was implemented using Java, R and a PostgreSQL database. Results Beside an overview of the study cohort which includes selection of gender and age groups, selected statistical methods like association rule learning, logistic regression model and the number needed to harm have been implemented. Conclusion The JADE tool can support physicians during their planning of clinical trials by showing the occurrences of adverse drug events with population based information. PMID:25298803
Background Postmarket drug safety surveillance largely depends on spontaneous reports by patients and health care providers; hence, less common adverse drug reactions—especially those caused by long-term exposure, multidrug treatments, or those specific to special populations—often elude discovery. Objective Here we propose a low cost, fully automated method for continuous monitoring of adverse drug reactions in single drugs and in combinations thereof, and demonstrate the discovery of heretofore-unknown ones. Methods We used aggregated search data of large populations of Internet users to extract information related to drugs and adverse reactions to them, and correlated these data over time. We further extended our method to identify adverse reactions to combinations of drugs. Results We validated our method by showing high correlations of our findings with known adverse drug reactions (ADRs). However, although acute early-onset drug reactions are more likely to be reported to regulatory agencies, we show that less acute later-onset ones are better captured in Web search queries. Conclusions Our method is advantageous in identifying previously unknown adverse drug reactions. These ADRs should be considered as candidates for further scrutiny by medical regulatory authorities, for example, through phase 4 trials. PMID:23778053
Elbe, Dean; Savage, Robert
Objective: To review the background and mechanisms behind how certain psychotropic medications cause adverse drug reactions. Methods: A literature review pertaining to several interesting and unusual adverse drug reactions attributed to selected psychotropic medications was conducted. These include: 1) QTc interval prolongation secondary to ziprasidone, pimozide, and other antipsychotic agents. 2) Nephrogenic diabetes insipidus and hypernatremia secondary to lithium. 3) Hypothyroidism secondary to lithium. 4) Erectile dysfunction secondary to selective serotonin and serotonin/norepinephrine reuptake inhibitors (SSRIs/SNRIs). Results: Biochemical mechanisms of how certain psychotropic medications cause adverse drug reactions were reviewed. Specific interventions and monitoring recommendations to prevent or reduce the impact of these adverse reactions are discussed briefly. Conclusion: Knowledge of risk factors and mechanisms of adverse drug reactions with psychotropic medications can help to guide medication prescribing, monitoring and interventions to prevent or mitigate these reactions. PMID:20119566
Tassaneeyakul, Wichittra; Prabmeechai, Napat; Sukasem, Chonlaphat; Kongpan, Thachanan; Konyoung, Parinya; Chumworathayi, Pansu; Tiamkao, Somsak; Khunarkornsiri, Usanee; Kulkantrakorn, Kongkiat; Saksit, Niwat; Nakkam, Nontaya; Satapornpong, Patompong; Vannaprasaht, Suda; Sangviroon, Alisara; Mahasirimongkol, Surakameth; Wichukchinda, Nuanjun; Rerkpattanapipat, Ticha; Tassaneeyakul, Wongwiwat
Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population. Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined. Six HLA alleles including HLA-A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA-B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41-13.09, P<0.05). Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA-B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population.
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
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).
Chattopadhyay, C; Chakrabarti, N
Cutaneous drug reactions are a common impediment in therapy, the incidence ranging from 2% to 8%. This cross-sectional study was designed to compare different trends of cutaneous drug reaction in two different socio-economic groups of patients in the same region. The aim was to evaluate common drugs implicated in causing reactions, describe the adverse cutaneous drug reactions, study the characteristics of patients presenting with the reactions. This is an observational study of cross-sectional type. The study was carried out in the department of Oral and Maxillofacial surgery in a Private dental College and department of General Medicine in a Medical College only on outdoor basis for 3 years. Out of 2000 patients observed in each college for their necessary treatment 75 patients in the dental College and 200 patients in the Medical College were reported to have various types of cutaneous drug reactions. Diagnosis was based on detailed history including temporal correlation between drug intake and onset of rash and thorough clinical examination Apart from history of drug intake, information regarding associated other allergy, comorbidity and severity (whether hospitalization was required or not) was recorded. Rechallenge with the drug was not possible due to ethical problem. Out of 2000 patients observed in each college 75 patients in dental College and 200 patients in Medical College were documented to have different kinds of cutaneous drug reactions. A total of 30 were male and 45 female in dental college whereas 90 male and 110 female patients were enrolled in Medical College. The age group of the patients in both the colleges ranged from 18 to 75 years. Common culprits observed in this study were antibiotics and NSAIDs. They had contributed 53% and 40% of the total skin reactions respectively in dental college and 47.5% and 45% in Medical College. We encountered 6 patients of systemic lupus erythematosus (SLE), 20 patients with allergic rhinitis and 12 patients
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.
Sabblah, George Tsey; Darko, Delese Mimi; Mogtari, Hudu; Härmark, Linda; van Puijenbroek, Eugène
Recent efforts to introduce direct patient reporting into pharmacovigilance systems have proved that patient reports contribute significantly to medicine safety, but there is a paucity of information relating to patients' perspectives regarding adverse drug reaction reporting in developing countries. The objective of this study was to explore patients' knowledge, attitudes, behaviours and opinions on spontaneous adverse drug reaction reporting in Ghana. A cross-sectional study using questionnaires administered through face-to-face interviews was carried out from 25 August, 2016 to 20 September, 2016 with 442 patients aged 18 years and above selected by convenience sampling from two community pharmacies in urban and rural Ghana. Reasons and opinions on patients' reporting on adverse drug reactions were surveyed using a 5-point Likert scale. The Pearson chi-square test was used to determine associations between background variables and responses on knowledge of adverse drug reaction reporting. Responses from 434 patients (86.7%) were included in the analysis. Among those interviewed, there was a high level of awareness regarding the existence of the National Pharmacovigilance Centre (81.6%). Approximately half of the respondents (49.5%) were aware that patients were able to report adverse drug reactions associated with medicinal products directly to the National Pharmacovigilance Centre. Of the respondents, 46.3% stated that they had an adverse drug reaction to their medicines in the past; of these, 53.2% reported to healthcare professionals and 36.9% failed to report because they stopped their medication. The three main reasons for patients' reporting were desire for extra information (92.4%), desire to share experiences with other people (91.7%) and expectation for the National Pharmacovigilance Centre to inform others about the possible adverse drug reactions (88.0%). Patients' opinions were to contribute to research/knowledge (96.5%) and improvements in drug
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.
Planchamp, F; Nguyen, K-A; Vial, T; Nasri, S; Javouhey, E; Gillet, Y; Ranchin, B; Villard, F; Floret, D; Cochat, P; Gueyffier, F; Kassaï, B
The aim of this study was to systematically evaluate adverse drug reactions (ADRs) in children consulting at the pediatric emergency unit during a 6-month period. The regional pharmacovigilance center (CRPV) and the department of clinical pharmacology prospectively and systematically recorded all potential ADRs among patients younger than 18 years of age in the pediatric emergency unit reported at the daily staff meetings. All cases were then screened and validated by the CRPV. For validated cases, preventability, seriousness, and off-label use were evaluated. During the study period, from 1 March to 1 September 2005, 90 children presented potential adverse drug events. ADRs were confirmed in 43 patients, 19 females and 24 males. Thirty-four patients (79%) were under the age of 5. According to the European definition, 14 patients (33%) had serious ADRs. One anaphylactic shock after amoxicillin injection; antimalarial prophylaxis misuse leading to convulsive status epilepticus, convulsion, and coma after hepatitis B and MMR vaccines were deemed life-threatening. Three ADRs were considered avoidable. Antibiotics and vaccines were the most common possible cause of ADRs (76%). Skin reactions (n=27), fever (n=8), and gastric disorders (n=5) were the most common clinical manifestations. Because ADRs were reported by clinicians on a voluntary basis, serious ADRs were probably reported more systematically. Compared to a similar period without active monitoring, active drug monitoring of ADRs doubled the number of confirmed cases 43 vs 17, p<0.001. Close collaboration between the pharmacovigilance center, pharmacologists, and clinicians is necessary and seems feasible for improving the monitoring of ADRs in children.
Pinzón, José Fernando; Maldonado, Carlos; Díaz, Jorge A; Segura, Omar
Implementing pharmacovigilance activities consists of monitoring and assessment of activities related to medical attention. However, additional data are necessary to identify conditions where care quality can be improved. Therefore, a focus on adverse drug events analysis from a prevention and economic perspective is needed, with emphasis on its local impact. Preventable adverse drug events were summarized to establishing their impact on morbidity and mortality, as well as to estimate the ensuing economic burden. The data were gathered from a level 3 hospital (high complexity), located in Bogotá, Colombia, where specific pharmacovigilance activities were recorded in 2007. Patient charts were reviewed to characterize adverse drug events according to their causality, severity and preventability. Direct costs were estimated by grouping diagnostic tests, length of hospitalization, procedures and additional drugs required. The charts of 283 patients and 448 reports were analyzed. These data indicated that 24.8% of adverse drug events were preventable and that an associated mortality of 1.1% had occurred. The associated direct costs were between USD $16,687 and $18,739. Factors more commonly associated with preventability were drug-drug interactions, as well as inappropriate doses and unsuitable frequencies at which the drugs were administrated. The data recommended that actions be taken to decrease preventable adverse drug events, because of negative impact on patient´s health, and unnecessary consumption of healthcare resources.
Lebrun-Vignes, B; Kreft-Jais, C; Castot, A; Chosidow, O
The question of quantitative and qualitative differences between adverse drug reactions (ADRs) to tetracyclines was raised many years ago, especially for minocycline and doxycycline. To assess and compare ADRs related to tetracyclines according to sales figures in France through a national survey. ADR data were collected from the French Pharmacovigilance Database (FPD), marketing authorization holders (MAH) and the literature. Sales analyses were based on MAH data provided annually to the French Drugs Agency. Among the tetracyclines available in France, doxycycline and minocycline are the most frequently used. However, their sales decreased between 1995 and 2007, more sharply for minocycline than doxycycline. According to the FPD, based on MAH data and published reports, minocycline-associated ADRs were more serious and were reported more frequently than for the other tetracyclines. Minocycline and doxycycline ADR patterns differed: gastrointestinal disorders (especially oesophageal lesions) predominated with doxycycline, while intracranial hypertension and hepatic disorders were primarily reported with minocycline. Autoimmune disorders, drug reaction with eosinophilia and systemic symptoms (DRESS) and other hypersensitivity reactions were also more frequent with minocycline. ADRs reported with lymecycline and metacycline were essentially cutaneous and gastrointestinal disorders. In the absence of markedly better efficacy against the various indications for tetracyclines, the minocycline benefit/risk ratio was clearly lower than that of doxycycline, and possibly those of lymecycline and metacycline. In light of these findings, minocycline should no longer be considered first-line therapy for inflammatory skin disorders, especially acne. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.
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
Manohar, Hasitha Diana; Adiga, Shalini; Thomas, Joseph; Sharma, Ajitha
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. 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. 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. 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.
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.
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
Ramachandran, Sarika M; Leventhal, Jonathan S; Franco, Loren G; Mir, Adnan; Walters, Ruth F; Franks, Andrew G
Subacute cutaneous lupus erythematosus (SCLE) is a well-defined subtype of lupus erythematosus, characterised by photosensitivity, annular and/or psoriasiform lesions, variable systemic involvement and presence of circulating SSA/anti-Ro antibodies. SCLE may be idiopathic or drug-induced. Both the idiopathic and drug-induced forms of SCLE are analogous in their clinical, serological and histological features. Drug-induced SCLE has been reported with various oral agents, but to our knowledge this is the first reported case due to a topical medication. A 34-year-old female foot masseuse presented with a 2-month history of scaly, erythematous lesions isolated to the dorsal hands and interdigital spaces. She had used topical terbinafine, a topical antifungal cream, to her clients’ feet for a number of years. ANA and anti-SSA/Ro antibodies were positive. Physical examination, serology and histopathology were consistent with SCLE. We propose that our patient's unique presentation of SCLE may be explained by a prolonged occupational exposure to topical terbinafine as a foot masseuse. While oral terbinafine is a drug known to cause drug-induced SCLE, to our knowledge, this is the first topically induced form of the disease. PMID:28331627
Wei, Xu; Xie, Yan-Ming
Adverse drug reaction (ADR) is the key contents in traditional Chinese medicine (TCM) injection safety research. However, influencing factors of ADR is not clearly, mechanism research is relatively rare, which are to be found in the literature to date. Qualified drugs and normal usage and dosage are the premise condition of ADR judgment. Age, sex, basic diseases, allergic constitution or drug allergy history are common factors. Kinds of solvent, drug concentration, storage time after liquid drug preparation, dripping speed, incompatibility of TCM injection and clinical commonly used medicine are the major ADR research factors. Adverse events mechanism should be synthetically judged by pre-clinical research, clinical manifestation, drug epidemiological trials results. In order to judge and study ADR correctly, It should be acquainted with TCM injection adverse events or ADR influencing factors,improve injection specification, and pay attention to the ADR mechanism, promote post-marketed reevaluation of safety in TCM injection.
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.
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
de Vries, Tjalling W; van Roon, Eric N
Randomised controlled trials (RCT) offer an opportunity to learn about frequency and character of adverse drug reactions. To improve the quality of reporting adverse effects, the Consort group published recommendations. The authors studied the application of these recommendations in RCTs performed in children. Literature search. The authors found 107 articles on paediatric RCTs written in English and published between 1 January 2006 and 1 April 2009. 83 articles (78%) mentioned adverse drug reactions, 36 articles (34%) used standardised methods for the disclosure of adverse drug reactions, 33 articles (31%) tabulated the reactions, and 27 (25%) stated numbers of and reasons for withdrawal. Registration of the RCT did not influence reporting. Sponsoring did lead to better reporting. According to the Consort guidelines, 19 (18%) reported safety data adequately. Reporting of adverse drug reactions in RCTs is often inadequate. Authors should anticipate and define adverse drug reactions. During research all adverse events should be monitored and assessed actively. Monitoring and assessment should be described in articles in accordance with the extended Consort recommendations. Both authors and editors share the responsibility for the improvement of reporting safety data.
Rosebraugh, Curtis J; Tsong, Yi; Zhou, Feng; Chen, Min; Mackey, Ann Corken; Flowers, Charlene; Toyer, Denise; Flockhart, David A; Honig, Peter K
Evaluate whether a 15-minute lecture intervention will improve adverse drug reaction reporting quality on standard MedWatch forms. Seventy-eight 4th-year medical students were randomized to intervention 'Group-A' or non-intervention 'Group-B' on the first day of a required five-day clinical pharmacology rotation. Group-A participants attended a 15-minute lecture on completing a MedWatch form with quality information considered by the Food and Drug Administration as critical to adequate adverse drug reaction reporting. Group-B participants did not attend this lecture. Both groups then watched a standardized patient interview of a recognizable adverse drug reaction and completed MedWatch forms. Four Safety Evaluators from the Food and Drug Administration (FDA) rated student responses in a blinded fashion for the primary efficacy variable of Overall Impression and six informational domins using a standardized data quality analysis form that was developed within the Office of Postmarketing Drug Risk Assessment of the FDA. Seventy-eight MedWatch forms were evaluated (Group-A = 40, Group B = 38). Overall MedWatch information quality scores for the intervention group were significantly higher than the non-intervention group (p < 0.004). As little as a 15-minute intervention can significantly improve the quality of adverse drug reaction reporting by 4th-year medical students. Academic medical centers should consider incorporating adverse drug reaction reporting curriculum into the clinical training of medical students.
Sampathkumar, Hariprasad; Chen, Xue-wen; Luo, Bo
Adverse Drug Reactions are one of the leading causes of injury or death among patients undergoing medical treatments. Not all Adverse Drug Reactions are identified before a drug is made available in the market. Current post-marketing drug surveillance methods, which are based purely on voluntary spontaneous reports, are unable to provide the early indications necessary to prevent the occurrence of such injuries or fatalities. The objective of this research is to extract reports of adverse drug side-effects from messages in online healthcare forums and use them as early indicators to assist in post-marketing drug surveillance. We treat the task of extracting adverse side-effects of drugs from healthcare forum messages as a sequence labeling problem and present a Hidden Markov Model(HMM) based Text Mining system that can be used to classify a message as containing drug side-effect information and then extract the adverse side-effect mentions from it. A manually annotated dataset from http://www.medications.com is used in the training and validation of the HMM based Text Mining system. A 10-fold cross-validation on the manually annotated dataset yielded on average an F-Score of 0.76 from the HMM Classifier, in comparison to 0.575 from the Baseline classifier. Without the Plain Text Filter component as a part of the Text Processing module, the F-Score of the HMM Classifier was reduced to 0.378 on average, while absence of the HTML Filter component was found to have no impact. Reducing the Drug names dictionary size by half, on average reduced the F-Score of the HMM Classifier to 0.359, while a similar reduction to the side-effects dictionary yielded an F-Score of 0.651 on average. Adverse side-effects mined from http://www.medications.com and http://www.steadyhealth.com were found to match the Adverse Drug Reactions on the Drug Package Labels of several drugs. In addition, some novel adverse side-effects, which can be potential Adverse Drug Reactions, were also
Bandekar, M S; Anwikar, S R; Kshirsagar, N A
Adverse drug reactions (ADRs) are considered as one of the leading causes of death among hospitalized patients. Thus reporting of adverse drug reactions become an important phenomenon. Spontaneous adverse drug reaction reporting form is an essential component and a major tool of the pharmacovigilance system of any country. This form is a tool to collect information of ADRs which helps in establishing the causal relationship between the suspected drug and the reaction. As different countries have different forms, our aim was to study, analyze the suspected adverse drug reaction reporting form of different countries, and assess if these forms can capture all the data regarding the adverse drug reaction. For this analysis we identified 18 points which are essential to make a good adverse drug reaction report, enabling proper causality assessment of adverse reaction to generate a safety signal. Adverse drug reaction reporting forms of 10 different countries were collected from the internet and compared for 18 points like patient information, information about dechallenge-rechallenge, adequacy of space and columns to capture necessary information required for its causality assessment, etc. Of the ADR forms that we analyzed, Malaysia was the highest scorer with 16 out of 18 points. This study reveals that there is a need to harmonize the ADR reporting forms of all the countries because there is a lot of discrepancy in data captured by the existing ADR reporting forms as the design of these forms is different for different countries. These incomplete data obtained result in inappropriate causality assessment. Copyright © 2010 John Wiley & Sons, Ltd.
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.
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.
Lattuada, Emanuela; Zorzi, Antonella; Lanzafame, Massimiliano; Antolini, Dario; Fontana, Roberta; Vento, Sandro; Concia, Ercole
We described the first case, to the best of our knowledge, of cutaneous abscess due to Eubacterium lentum in a parenteral drug user, after complete fracture of the right femor. The case underlines the importance of carefully performed microbiological tests, due to the peculiar cultural needs of the micro-organism.
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
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.
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)
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
Tian, Feng; Xie, Yanming
Following more and more new drugs are authorized into market, new, serious or unexpected adverse drug reactions appear frequently, which is a serious threat to people health and life. Through making laws and guidelines, governments of various countries aim to strengthen and standardize the surveillance and reporting of postmarketing drugs. The drugs management department of our country are doing related jobs positively, but there are some problems, such as drug risk-menagement is not emphasized well, and the management department lacks clarity on operating related regulations. This article tries to explore foreign countries' laws and regulations on the surveillance and reporting of postmarketing drugs, aiming to provide reference for our courtry.
Gupta, Mrinal; Gupta, Heena; Gupta, Anish
Cutaneous adverse reactions are a common complication of anti-retroviral therapy. Tenofovir is a newer anti-retroviral drug belonging to the nucleotide reverse transcriptase inhibitor group. Systemic adverse effects like nausea, vomiting, diarrhea, hepatotoxicity and renal toxicity are common with tenofovir but cutaneous adverse effects are rare. Lichenoid drug eruptions are a common adverse effect seen with a large variety of drugs including antimalarials, antihypertensives, nonsteroidal anti-inflammatory drugs and diuretics. Lichenoid drug eruption is a rare cutaneous adverse effect of tenofovir with only a single case reported till date. Here, we report a case of tenofovir induced lichenoid drug eruption in a 54-year-old human immunodeficiency virus affected male who presented with generalized lichenoid eruption after 6 weeks of initiation of tenofovir and complete clearance on cessation of the drug.
Wang, Kejian; Wan, Mei; Wang, Rui-Sheng; Weng, Zuquan
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. 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. 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. 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. 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.
Xue, Yun; Cohen, Jeffrey M; Wright, Natalie A; Merola, Joseph F
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that primarily affects the joints, but may exhibit extra-articular, including cutaneous, manifestations such as rheumatoid nodules, rheumatoid vasculitis, granulomatous skin disorders, and neutrophilic dermatoses. A large burden of cutaneous disease may be an indication of RA disease activity and the need for more aggressive treatment. Many of the therapeutic agents used to treat RA can also result in cutaneous adverse effects, which pose their own diagnostic and therapeutic challenges. Anti-TNFα agents, in particular, have a wide variety of adverse effects including psoraisiform eruptions, granulomatous conditions, and cutaneous connective tissue disorders. Herein we provide an update on the clinical presentations and management of RA-associated cutaneous findings as well as drug-induced cutaneous effects, with particular attention to the adverse effects of biologic disease-modifying agents.
Saheb Sharif-Askari, Fatemeh; Saheb Sharif-Askari, Narjes; Javadi, Mohammadreza; Gholami, Kheirollah
Burden of adverse drug reactions (ADRs), in home-environment and domestic settings, is unknown. To discuss the epidemiology of reported ADRs to 13-Aban drug and poison information center (DPIC) and to discuss the burden of hospitalization caused by these ADRs from commonly implicated therapeutic groups. A retrospective analysis of the yellow card schemes of suspected ADRs reported to the 13-Aban DPIC was conducted from 21 March 2013 to 21 November 2016 inclusive. Characteristics of the ADRs, such as the sex and age of the patient, the therapeutic group involved, and the medical outcome of the exposure, were examined. ADR Hospitalization (ADRH) index was calculated for each drug group by dividing the number of ADR-related hospitalizations with total number of reported ADR cases (n = 748), and then multiplying by 100. ADRs were reported for 748 patients representing 5 cases per 1000 enquiries to the 13-Aban DPIC over almost 4-years of the study period. Public were responsible for reporting every 4 out of 5 ADR cases (n = 651, 87%) and the remaining 1 out of 5 ADR cases was reported by the health care professionals (n = 97, 13%). Most of the ADRs had a medical outcome documented as having a minor effect or were minimally bothersome to the patients (n = 509, 68%), and less than 4.9% (n = 37) were documented as having a major effect or were life-threatening. Overall, 7.4% (n = 55) of ADRs were resulted in hospitalization. Antibacterials for systemic use represented the therapeutic group with the highest hospitalization index (1.7%). The study concluded that ADRs to antibiotics are common and some of them resulted in hospitalization.
De Angelis, Alessia; Colaceci, Sofia; Giusti, Angela; Vellone, Ercole; Alvaro, Rosaria
To describe and synthesise previous research on factors conditioning the spontaneous reporting of adverse drug reactions among nurses. Spontaneous reports of adverse drug reactions by health-care providers, are a main instrument for the continuous evaluation of the risk-benefit ratio of every drug. Under-reporting of adverse drug reactions by all health-care providers, in particular by nurses, is a major limitation to this system. An integrated review of the literature was conducted using MEDLINE, CINAHL, Embase, Scopus databases and Google Scholar. After evaluation for appropriateness related to inclusion/exclusion criteria, 16 studies were included in the final analysis and synthesis. Two factors emerged from the study: (1) intrinsic factors related to nurses' knowledge and attitudes; (2) extrinsic factors related to nurses' interaction with health-care organisations and to the relationship between nurses and physicians. Nurses' attitudes that hinder reporting include ignorance, insecurity, fear and lethargy. Nurses are not fully aware of their role in adverse drug reaction reporting. Nurses must acquire greater knowledge to implement specific skills into their daily clinical practice. To improve nurses' reporting of adverse drug reactions, it is necessary to develop management approaches that modify both intrinsic and extrinsic factors. © 2015 John Wiley & Sons Ltd.
Sutter, Raoul; Rüegg, Stephan; Tschudin-Sutter, Sarah
Antibiotic drugs are commonly associated with seizures. Tailoring antibiotics to the individual risk for seizures is challenged as avoidance of certain antibiotic classes may no longer be possible due to the emergence of resistant bacteria. We performed a systematic review regarding the current evidence for seizures associated with all antibiotic classes, their underlying mechanisms, and predisposing factors. The medical search engine PubMed was systematically screened to identify articles in English published between 1960 and 2013. All study designs were considered and evidence was assessed. We included 143 articles involving 25,712 patients and 25 different antibiotics. Evidence for antibiotic-related symptomatic seizures is low to very low, mainly deriving from studies regarding β-lactams, especially unsubstituted penicillins and fourth-generation cephalosporins, as well as carbapenems, mainly imipenem, all administered in high doses or in patients with renal dysfunction, brain lesions, or known epilepsy. Evidence regarding symptomatic seizures from fluoroquinolones only relies on case reports and case series with most reports for ciprofloxacin in patients with renal dysfunction, mental disorders, prior seizures, or coadministered theophylline. Evidence for an association between antibiotic drugs and symptomatic seizures is low to very low (evidence Class III-IV). Despite this, numerous reports point to an increased risk for symptomatic seizures especially of unsubstituted penicillins, fourth-generation cephalosporins, imipenem, and ciprofloxacin in combination with renal dysfunction, brain lesions, and epilepsy. During administration of such antibiotics in patients with particular predispositions, close monitoring of serum levels is advocated. As most seizures associated with cephalosporins are nonconvulsive, continuous EEG should be considered in patients with altered levels of consciousness. © 2015 American Academy of Neurology.
Avanesian, Agnesa; Semnani, Sahar; Jafari, Mahtab
Once a molecule is identified as a potential drug, the detection of adverse drug reactions is one of the key components of its development and the FDA approval process. We propose using Drosophila melanogaster to screen for reproductive adverse drug reactions in the early stages of drug development. Compared with other non-mammalian models, D. melanogaster has many similarities to the mammalian reproductive system, including putative sex hormones and conserved proteins involved in genitourinary development. Furthermore, the D. melanogaster model would present significant advantages in time efficiency and cost-effectiveness compared with mammalian models. We present data on methotrexate (MTX) reproductive adverse events in multiple animal models, including fruit flies, as proof-of-concept for the use of the D. melanogaster model.
Härkänen, Marja; Kervinen, Marjo; Ahonen, Jouni; Voutilainen, Ari; Turunen, Hannele; Vehviläinen-Julkunen, Katri
To identify the prevalence, preventability, and severity of adverse drug events in randomly selected adult hospital inpatients, and to study the association between adverse drug events and patient-specific factors. Adverse drug events represent one of the major concerns in patient safety. A retrospective record review. The study was conducted in an 800-bed university hospital in Finland within a 12-month period. Retrospective reviews of randomly selected discharged patients' (n = 463) records using the Global Trigger Tool method were undertaken. The prevalence, preventability, and severity of adverse drug events were studied, and the association between patient-specific factors and adverse drug events were examined using a binary logistic regression model and Pearson's chi-squared tests. A total of 180 adverse drug events were detected in 125 (27%) patients, of which 74 (41·1%) were preventable, and 94·4% caused temporary harm. An abnormal level of potassium in the blood was the most frequent adverse drug event (n = 37). The risk of adverse drug events increased with the length of hospital stay and the increased number of drugs patients used. The patients with coronary diseases (n = 130) had a 2·5 times higher risk of experiencing adverse drug events. In addition, the risk of adverse drug events during hospitalisation increased together with the co-morbidity of patients. Adverse drug events were experienced by a quarter of inpatients, while severe adverse drug events were rare. The risk of adverse drug events increased with patients' prolonged hospital stay, polypharmacy, and morbidity. In addition, information of the usefulness of the Global Trigger tool can be used for future development of the method. Patient-specific risk factors were identified using the Global Trigger Tool method revealing that more efficient monitoring of inpatients with these risk factors may be profitable for decreasing adverse drug events. © 2014 John Wiley & Sons Ltd.
In Colombia, aging of the population is a reality and elders consume more drugs than the young do. Consequently, they are more exposed to adverse drug reactions. To characterize suspected adverse drug reactions in adults over 44 years of age in Bogota in 2012. We conducted a pharmacological surveillance study that included 470 reports of adverse drug events and associated problems with the use of drugs in adults over 44 years old included in the database of Bogotá´s pharmacosurveillance program. We evaluated 470 reports of adverse drug events and associated problems with the use of drugs in adults over 44 years of age. From these, 432 reports (91.9%) were classified as suspected adverse drug reactions and 28 (6%), as associated problems with the use of drugs. The incidence rate for adverse drug events reported in Bogotá was 22.5 for every 100,000 elders, which increased in direct proportion to patients´ age. The most frequently reported drug was antibacterials with 94 notifications (20%). The organ system with the highest number of alterations was the skin and annexes with 21.2% of cases. Regarding severity assessment, 69.5% of adverse drug reactions were moderate, and as for causality, most adverse drug reactions were classified as possible, with 45.8% of the reports. The characterization of adverse drug reactions in older adults in Bogotá is similar to that reported in the literature for this population age group.
Yagiela, J A
Adrenergic vasoconstrictors are commonly used by dentists to enhance the pain-relieving action of local anesthetics and to control local bleeding. Although normally considered safe for these applications, vasoconstrictors can participate in drug interactions that potentially are harmful to patients. The faculty of a March 1998 symposium entitled "Adverse Drug Interactions in Dentistry: Separating the Myths From the Facts" extensively reviewed the literature on drug interactions. They then established a significance rating of alleged adverse drug interactions pertaining to dentistry, based on the quality of documentation and severity of effect. The author of this article focused on the adrenergic vasoconstrictors epinephrine and levonordefrin. Vasoconstrictor drug interactions involving tricyclic antidepressants, nonselective beta-adrenergic blocking drugs, certain general anesthetics and cocaine are well-documented in both humans and animals as having the potential for causing serious morbidity or death. Evidence for adverse interactions involving adrenergic neuronal blocking drugs, drugs with alpha-adrenergic blocking activity, local anesthetics and thyroid hormones is much less compelling, suggesting for the most part that clinically significant reactions may occur only when both the vasoconstrictor and the interacting drug are used in excessive doses. In the case of monoamine oxidase inhibitors, there is no credible evidence of a significant interaction with epinephrine or levonordefrin. Potentially serious adverse drug interactions involving adrenergic vasoconstrictors can occur in dental practice. In most circumstances, careful administration of small doses of vasoconstrictors and avoidance of gingival retraction cord containing epinephrine, coupled with monitoring of vita signs, will permit these drugs to be used with no risk or only minimally increased risk. Only in the case of cocaine intoxication must adrenergic vasoconstrictors be avoided completely. For
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
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.
Oshima, Shinji; Enjuji, Takako; Negishi, Akio; Akimoto, Hayato; Ohara, Kousuke; Okita, Mitsuyoshi; Numajiri, Sachihiko; Inoue, Naoko; Ohshima, Shigeru; Terao, Akira; Kobayashi, Daisuke
In order to avoid adverse drug reactions (ADRs), pharmacists are reconstructing ADR-related information based on various types of data gathered from patients, and then providing this information to patients. Among the data provided to patients is the time-to-onset of ADRs after starting the medication (i.e., ADR onset timing information). However, a quantitative evaluation of the effect of onset timing information offered by pharmacists on the probability of ADRs occurring in patients receiving this information has not been reported to date. In this study, we extracted 40 ADR-drug combinations from the data in the Japanese Adverse Drug Event Report database. By applying Bayes' theorem to these combinations, we quantitatively evaluated the usefulness of onset timing information as an ADR detection predictor. As a result, when information on days after taking medication was added, 54 ADR-drug combinations showed a likelihood ratio (LR) in excess of 2. In particular, when considering the ADR-drug combination of anaphylactic shock with levofloxacin or loxoprofen, the number of days elapsed between start of medication and the onset of the ADR was 0, which corresponded to increased likelihood ratios (LRs) of 138.7301 or 58.4516, respectively. When information from 1-7 d after starting medication was added to the combination of liver disorder and acetaminophen, the LR was 11.1775. The results of this study indicate the clinical usefulness of offering information on ADR onset timing.
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
Park, Kyounghoon; Soukavong, Mick; Kim, Jungmee; Kwon, Kyoung Eun; Jin, Xue Mei; Lee, Joongyub; Yang, Bo Ram; Park, Byung Joo
To detect signals of adverse drug events after imipenem treatment using the Korea Institute of Drug Safety & Risk Management-Korea adverse event reporting system database (KIDS-KD). We performed data mining using KIDS-KD, which was constructed using spontaneously reported adverse event (AE) reports between December 1988 and June 2014. We detected signals calculated the proportional reporting ratio, reporting odds ratio, and information component of imipenem. We defined a signal as any AE that satisfied all three indices. The signals were compared with drug labels of nine countries. There were 807582 spontaneous AEs reports in the KIDS-KD. Among those, the number of antibiotics related AEs was 192510; 3382 reports were associated with imipenem. The most common imipenem-associated AE was the drug eruption; 353 times. We calculated the signal by comparing with all other antibiotics and drugs; 58 and 53 signals satisfied the three methods. We compared the drug labelling information of nine countries, including the USA, the UK, Japan, Italy, Switzerland, Germany, France, Canada, and South Korea, and discovered that the following signals were currently not included in drug labels: hypokalemia, cardiac arrest, cardiac failure, Parkinson's syndrome, myocardial infarction, and prostate enlargement. Hypokalemia was an additional signal compared with all other antibiotics, and the other signals were not different compared with all other antibiotics and all other drugs. We detected new signals that were not listed on the drug labels of nine countries. However, further pharmacoepidemiologic research is needed to evaluate the causality of these signals.
Kim, Siin; Suh, Hae Sun
The aim of the study was to explore the current status of drug-induced parkinsonism and drugs possibly related to drug-induced parkinsonism in Korea. We conducted a cross-sectional study using the Korea Adverse Event Reporting System database between July 1, 2010, and June 30, 2015. We identified all adverse event reports associated with parkinsonism. There were 1402 adverse event reports associated with parkinsonism. The number of adverse event reports has increased annually. Among the 1499 drugs associated with parkinsonism, the most common were metoclopramide (49.77%) and paliperidone (16.14%). The major therapeutic groups (the third level of the Anatomical Therapeutic Chemical code) were propulsives (53.87%) and antipsychotics (35.58%). The mean time of onset of parkinsonism was 34.9 days. However, the time of onset of parkinsonism varied by drug, for example, it was 4.6 days for metoclopramide and 37.2 days for paliperidone. Metoclopramide and antipsychotics were reported in most adverse event reports associated with parkinsonism in Korea.
Because the drug-induced severe adverse reaction (SAR) is rare and often occur in the unexpected organs, the physician could be unfamiliar to SAR. In that case the early stage of the SAR is easy to overlook. So the Ministry of the Health and Welfare of Japan (MHLW) started the "Comprehensive project to deal with the disorders due to adverse drug reactions" as a four years plan since 2005. In this project, the MHLW published "the manual for handling disorders due to adverse drug reactions" in corporation with the academia. This manual is constituted by two parts, one is intended for the parents, and the other is for the general healthcare providers. In this article, the aim and the progress of the manuals and the brief summary of the SAR induced by the antibiotics will be explained. By the end of the June 2008, 29 manuals have been released, and 16 of them are antibiotics-related. It is needless to say that antibiotics are essential in the modern medical care, close monitoring of the symptom of SAR in untargeted organ is required in use of the antibiotics.
Loke, Yoon K; Golder, Su P; Vandenbroucke, Jan P
While systematic reviews and meta-analyses are at the top of the evidence hierarchy, most of the methodology has focused on assessing treatment benefit. Hence, we propose a structured framework for the initial steps of searching and identifying relevant data sources so that adverse effects can be evaluated in a comprehensive, unbiased manner. The unique methodological challenges stem from the difficulties of addressing diverse outcomes encompassing common, mild symptoms to rare, fatal events. Retrieval of the most appropriate studies should be specifically tailored to fit the nature of the adverse effects, according to the primary objective and study question. In our framework, the structure of the review takes different forms depending on whether the main aim is on scoping/hypothesis generation, or evaluating statistically the magnitude of risk (hypothesis testing), or clarifying characteristics and risk factors of the adverse effect. The wide range of data sources covering adverse effects all have distinct strengths and limitations, and selection of appropriate sources depends on characteristics of the adverse effect (e.g. background incidence and effect size of the drug, clinical presentation, time of onset after drug exposure). Reviewers need to retrieve particular study designs that are most likely to yield robust data on the adverse effects of interest, rather than rely on studies that cannot reliably detect adverse effects, and may yield 'false negatives'. Type II errors (a particular problem when evaluating rare adverse effects) can lull us into a false sense of security (e.g. wrongly concluding that there was no significant difference in harm between drug and control, with the drug erroneously judged as safe). Given the rapid rate at which methodological improvements occur, this proposed framework is by no means definitive, but aims to stimulate further debate and discussion amongst the pharmacoepidemiological and systematic review communities to reach a
Su, Eric Wen; 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).
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
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.
Takarabe, Masataka; Kotera, Masaaki; Nishimura, Yosuke; Goto, Susumu; Yamanishi, Yoshihiro
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. 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. Softwares are available upon request. email@example.com Datasets and all results are available at http://cbio.ensmp.fr/~yyamanishi/aers/.
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
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.
Dohle, Simone; Dawson, Ian G J
Adverse drug events relating to drug-drug interactions are a common cause of patient harm. Central to avoiding this harm is the patients' understanding that certain drug combinations present a synergistic risk. Two studies tested whether providing individuals with information about a drug combination that presents a synergistic (cf. additive) risk would elicit higher perceived risk and, therefore, would result in greater precaution in terms of dosing behaviour. Both studies employed an experimental design. Participants were presented with a scenario describing how two symptoms of an infection could each be treated by a different drug. In Experiment 1, information about the effects of combining the two drugs was varied: (1) no information, (2) combination elicits an additive risk, or (3) combination elicits a synergistic risk. In Experiment 2, the size of the risk (small or large) and the participant's role (patient or doctor) was also varied. In both experiments, perceived risk and negative affect increased in response to information about the increased probability of side effects from the drug-drug interaction. Despite these increases, participants did not adjust their drug dosing behaviour in either experiment: Dosing was similar when these interactions were large or small, or when they were due to synergistic or additive effects. People may struggle to transfer their knowledge of drug-drug interaction risks into decision-making behaviours. Care should be taken not to assume that holding accurate risk perceptions of a drug's side effect will result in decisions that help avoid adverse drug events. Statement of contribution What is already known on this subject? Adverse effects of drug-drug interactions are a cause of hospital admissions and increase morbidity and mortality. Patients' understanding that certain drug combinations present a synergistic risk is crucial to avoid harm. It is not clear whether synergistic drug interactions increase risk perception and
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.
Hillesheim, Paul B; Bahrami, Soon; Jeffy, Brooke G; Callen, Jeffrey P
To investigate whether tissue eosinophilia is a differentiating histopathologic feature of drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) compared with non-DI-SCLE. Retrospective medical record review with prospective blinded histopathologic analysis. University-affiliated dermatology and dermatopathology practice. Fifty-nine patients with SCLE were divided into DI (n = 15) and non-DI (n = 44) groups. A dermatopathologist masked to the etiologic associations reviewed corresponding histopathologic specimens. For each patient, an eosinophil ratio was calculated as the mean eosinophil score (averaging eosinophil counts from 10 high-power histologic fields) divided by the intensity of inflammation. Eosinophil ratios for both groups were compared using the Mann-Whitney test. No significant difference was found in mean eosinophil ratios in the DI vs non-DI groups (0.11 vs 0.004; P = .34). Mucin deposition was present in both populations and was not significantly different (P = .18). The inflammatory infiltrate was superficial and deep in 10 patients (67%) in the DI group vs 24 (55%) in the non-DI group. Periadnexal inflammation was observed in 12 patients (80%) in the DI group vs 37 (84%) in the non-DI group, and basal layer liquefaction with dyskeratosis was seen in 15 patients (100%) in the DI group and in 37 (84%) in the non-DI group. Tissue eosinophilia is not a differentiating histopathologic feature of DI-SCLE. Careful review of a patient's drug history in correlation with clinical findings remains the standard for identifying a drug as an etiologic or exacerbating factor in patients with SCLE.
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.
Just, Katja Susanne; Schneider, Katharina Luise; Schurig, Marlen; Stingl, Julia Carolin; Brockmöller, Jürgen
Falls is a frequent type of adverse drug reactions causing significant morbidity and mortality in the elderly. We reviewed, with which drugs the risk of falls is relevant and might depend on genomic variation. Pharmacogenetic variability may contribute to drug-induced falls for instance mediated by impaired drug elimination due to inherited deficiency in enzymes like CYP2C9, CYP2C19 and CYP2D6. The relative role of specific genes and polymorphisms in old age may differ from younger people. Biomarkers for frailty, but also genomic biomarkers might help identifying patients at high risk for drug-induced falls. Many other factors including disease and drug-drug interactions also contribute to risk of falls. Further studies analyzing the impact of genomic variation on the medication-related fall risk in the older adult are urgently needed.
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.
Fabiano, Valentina; Mameli, Chiara; Zuccotti, Gian Vincenzo
The detection, assessment, understanding and prevention of adverse drug reactions (ADRs) are the primary aims of pharmacovigilance activities. Pediatric patients, especially all newborns and infants, are particularly at risk for experiencing drug-related adverse events. This review briefly analyzes the physiological peculiarities of pharmacodynamic and pharmacokinetic aspects of drugs in newborns, infants and toddlers and children. It also deals with specific pediatric pharmacovigilance aspects, such as the frequent use of unlicensed and/or off-label drugs in neonatal intensive care units in European countries and in Australia. This review reports on European, American and Canadian data about the incidence and type of pediatric ADRs, particularly focusing on neonates, infants and toddlers. The awareness of pediatricians about the importance of reporting ADRs should be stimulated, new reporting systems should be encouraged and pediatric pharmacovigilance activities should be improved, first, by intensifying active post-marketing surveillance methods.
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
Soleimanifard, Simindokht; Arjmand, Reza; Saberi, Sedighe; Salehi, Mansoor; Hejazi, Seyed Hossain
Background: Resistance of Leishmania species to antimonial drugs has increased. Hence, in the present study Leishmania major isolates were collected from patients with resistance phenotype and the presence/absence of resistance to Glucantime was investigated. Materials and Methods: Samples were taken from 10 cutaneous leishmaniasis (CL) patients who had not responded to chemotherapy with Glucantime. Nested polymerase chain reaction (PCR) was performed to identify the isolated species. Stationary phase promastigotes were added to the grown, adhesive J774 macrophages. Values obtained from standard strain were compared with the test cultures after exposure to the medicine. In vivo, the effects of Glucantime were assessed by comparing the sizes and the parasite burden of the lesions on mouse model. Results: The results of amplified band on agarose gel demonstrated all samples were L. major. After exposure to medicine, a reduction of intracellular amastigotes to half was detected. In vivo, the parasite was eliminated in 90% of mice with lesions caused by both isolates of patients and standard L. major, and their lesions became smaller significantly. Conclusion: Pentavalent antimonial (SbV) salts are the main component of chemotherapy against leishmaniasis. However, the medicine has been found ineffective. In the present study, isolates from patients with no response to treatment had no significant difference from the standard L. major strain (as the sensitive strain). Therefore, in patients with resistance phenotype to Glucantime, the parasites did not actually have intrinsic resistance, i.e., environmental and host factors prevented the successful treatment of the disease. PMID:28349020
Rahman, Md Motiur; Alatawi, Yasser; Cheng, Ning; Qian, Jingjing; Plotkina, Annya V; Peissig, Peggy L; Berg, Richard L; Page, David; Hansen, Richard A
Despite the cost saving role of generic anti-epileptic drugs (AEDs), debate exists as to whether generic substitution of branded AEDs may lead to therapeutic failure and increased toxicity. This study compared adverse event (AE) reporting rates for brand vs. authorized generic (AG) vs. generic AEDs. Since AGs are pharmaceutically identical to brand but perceived as generics, the generic vs. AG comparison minimized potential bias against generics. Events reported to the U.S. Food and Drug Administration Adverse Event Reporting System between January 2004 to March 2015 with lamotrigine, carbamazepine, and oxcarbazepine listed as primary or secondary suspect were classified as brand, generic, or AG based on the manufacturer. Disproportionality analyses using the reporting odds ratio (ROR) assessed the relative rate of reporting of labeled AEs compared to reporting these events with all other drugs. The Breslow-Day statistic compared RORs across brand, AG, and other generics using a Bonferroni-corrected P<0.01. A total of 27,150 events with lamotrigine, 13,950 events with carbamazepine, and 5077 events with oxcarbazepine were reported, with generics accounting for 27%, 41%, and 32% of reports, respectively. Although RORs for the majority of known AEs were different between brand and generics for all three drugs of interest (Breslow-Day P<0.001), RORs generally were similar for AG and generic comparisons. Generic lamotrigine and carbamazepine were more commonly involved in reports of suicide or suicidal ideation compared with the respective AGs based on a multiple comparison-adjusted P<0.01. Similar AED reporting rates were observed for the AG and generic comparisons for most outcomes and drugs, suggesting that brands and generics have similar reporting rates after accounting for generic perception biases. Disproportional suicide reporting was observed for generics compared with AGs and brand, although this finding needs further study. Copyright © 2017 Elsevier B
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.
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
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
van Amsterdam, J G C; Best, W; Opperhuizen, A; de Wolff, F A
The assessment procedure of new synthetic illicit drugs that are not documented in the UN treaty on psychotropic drugs was evaluated using a modified Electre model. Drugs were evaluated by an expert panel via the open Delphi approach, where the written score was discussed on 16 items, covering medical, health, legal, and criminalistic issues of the drugs. After this face-to-face discussion the drugs were scored again. Taking the assessment of ketamine as an example, it appeared that each expert used its own scale to score, and that policymakers do not score deviant from experts trained in the medical-biological field. Of the five drugs evaluated by the panel, p-methoxy-metamphetamine (PMMA), gamma-hydroxybutyric acid (GHB), and 4-methylthio-amphetamine (MTA) were assessed as more adverse than ketamine and psilocine and psilocybine-containing mushrooms. Whereas some experts slightly adjusted during the assessment procedure their opinion on ketamine and PMMA, the opinion on mushrooms was not affected by the discussion held between the two scoring rounds. All experts rank the five drugs in a similar way on the adverse effect scale i.e., concordance scale of the Electre model, indicating unanimity in the expert panel with respect to the risk classification of these abused drugs.
Vingerhoets, R W; van Marum, R J; Jansen, P A F
Elderly patients are highly susceptible for developing adverse drug reactions (ADR) that can lead to hospitalisation or death. Most of these ADR can be prevented if doctors adjust their prescriptions. Beers et al. have developed a list of drugs that should not be prescribed to elderly patients since they are known for their association with serious ADR. In The Netherlands, 20% of elderly patients receive drugs that are in the so-called Beers list. Although the Beers list has not been adjusted to the Dutch situation, avoidance of these drugs may reduce drug-related hospital admittance. Development of an improved list of drugs that should not be prescribed to elderly patients is needed that is applicable to The Netherlands.
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
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.
Machado-Alba, Jorge Enrique; Londoño-Builes, Manuel José; Echeverri-Cataño, Luis Felipe; Ochoa-Orozco, Sergio Andrés
Recognizing adverse drug reactions (ADRs) is becoming more important in clinical practice. To determine the frequency of adverse drug reactions and ADR suspicions among the population affiliated to the Colombian health system and to describe the drugs, reactions and associated variables. We revised ADRs and ADRs suspicion databases from drugs dispensed by Audifarma, S.A., both for inpatient and outpatient care from 2007 to 2013. Variables included ADR report date, city, drug, drug's Anatomical Therapeutic Classification (ATC), ADR severity, ADR type, ADR classification and ADR probability according to the World Health Organization's definitions. We obtained 5,342 reports for 468 different drugs. The ATC groups with the most reports were anti-infectives for systemic use (25.5%), nervous system agents (17.1%) and cardiovascular system drugs (15.0%). The drugs with the highest number of reports were metamizole (4.2%), enalapril (3.8%), clarithromycin (2.8%), warfarin (2.5%) and ciprofloxacin (2.4%). The most common ADR, classified following the World Health Organization adverse reaction terminology, were: skin and appendages disorders (35.3%), general disorders (14.2%) and gastrointestinal system disorders (11.8%). Overall, 49.4% of the ADRs were classified as "moderate" and 45.1% as "mild". An increasing number of ADR reports were found coinciding with a worldwide tendency. Differences between inpatient and outpatient ADR reports were found when compared to scientific publications. The information on ADR reports, mainly gathered by the Instituto Nacional de Vigilancia de Medicamentos y Alimentos - Invima, should be made public for academic and institutional use.
Aderemi-Williams, R I; Awodele, O; Boyle, C A
Adverse drug reaction (ADR) is a global drug therapy problem. It has been rated as one of the top leading causes of morbidity and mortality. In Nigeria, not much is known about ADRs especially with the existing weak post marketing surveillance for monitoring drug use, and its effect on the population. The study is aimed at determining the incidence of ADRs, presentations of ADRs, classes of drugs that frequently cause ADRs and predictors of ADRs in adult medical in-patients in LASUTH. A retrospective study of six hundred and twenty four (624) case notes of all patients admitted to the medical wards in LASUTH between January 1, 2009 and December 31, 2009 was carried out. Information obtained included age, gender, and adverse drug reaction and drug details. The results obtained were analyzed using SPSS version 16 statistical software. Level of significance was set at p ≤ 0.05. A total of 624 case notes consisting of 358 males and 266 females were assessed. The number of patients who experienced adverse drug reactions was 67 (n = 624, 10.7%). The incidence rate of ADRs in LASUTH from the study was 10.7 per 100 patients' population. Most of the ADRs observed were type A reactions (97.8%). Mostly implicated classes of drugs were antidiabetics (26.7%) and NSAIDs (29.3%). The incidence rate of ADRs was 10.7%. ADRs which are predictable and preventable occur in hospitalized patients, such may be prevented or minimized by implementing measures to target specific drugs that are commonly suspected.
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
Muringazuva, Caroline; Chirundu, Daniel; Mungati, More; Shambira, Gerald; Gombe, Notion; Bangure, Donewell; Juru, Tsitsi; Tshimanga, Mufuta
Medicines have the potential to cause adverse drug reactions and because of this Zimbabwe monitor reactions to medicines through the Adverse Drug Reaction Surveillance System. The Medicines Control Authority of Zimbabwe monitors reactions to medicines through the Adverse Drugs Reactions Surveillance System. The system relies on health professionals to report adverse drug reactions to maximize patient safety. We report results of an evaluation of the Adverse Drugs Reactions Surveillance System in Kadoma District. A descriptive cross-sectional study was conducted using the updated CDC guidelines in six health facilities in Kadoma City. Data were collected using a pretested interviewer administered questionnaire, checklists and records review. Data was analyzed using Epi Info(TM) to calculate frequencies and means. Qualitative data were analyzed manually. Written informed consent was obtained from all study participants. The surveillance system did not meet up to its objectives as it failed to detect the adverse drug reactions and there was no monitoring of increases in known events. Fewer than half (43%) of the participants were aware of at least 2 objectives of the surveillance system but 83% of health workers willing to participate. However the system was not acceptable, 79% did not perceive the system to be necessary with the majority saying ''why should we fill in the forms when the reactions were already known or minor''. Though the system was supposed to identify potential patient risk factors for particular types of events health workers were reluctant to participate as evidenced by only one form filled out of 20 reactions experienced in the district. The system was simple as the notification form has 16 fields which require easily obtainable information from the patient records. The surveillance system was not useful and was not acceptable to health workers but was simple and stable. Health workers lacked knowledge. Sharing of results with the Medicines
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.
Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumor necrosis factor antagonists: study using the Spanish registry of adverse events of biological therapies in rheumatic diseases.
Hernández, M Victoria; Sanmartí, Raimon; Cañete, Juan D; Descalzo, Miguel A; Alsina, Mercè; Carmona, Loreto; Gomez-Reino, Juan J
To analyze the incidence rate (IR) and risk factors of cutaneous adverse events (CAE) in patients with chronic inflammatory rheumatic diseases treated with tumor necrosis factor (TNF) antagonists. We analyzed all patients from the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) registry treated with a TNF antagonist (infliximab, etanercept, or adalimumab). Data collected included age, sex, diagnosis and duration of rheumatic disease, type of TNF antagonist, and concomitant treatment. Type of CAE was classified as local or systemic cutaneous manifestation related to treatment administration (infusion reaction), infection, malignancy, or autoimmune skin disease. Time of onset of CAE and outcome were also recorded. The IRs of CAE per 1,000 patient-years of exposure with 95% confidence intervals (95% CIs) were estimated. Multivariable analysis was performed to identify potential risk factors for CAE. A total of 5,437 patients were included, representing 17,330 patient-years of exposure. A total of 920 CAE were reported; the IRs per 1,000 patient-years were 53 (95% CI 50-57) for CAE, 28 (95% CI 25-30) for infection, 15 (95% CI 13-17) for infusion reactions, 5 (95% CI 4-6) for autoimmune skin diseases, and 3 (95% CI 2-4) for skin malignancy. The mean time between starting TNF antagonist treatment and CAE was 1.78 years. In 32% of patients, CAE required TNF antagonist withdrawal. The main risk factors for CAE were female sex and treatment with infliximab, leflunomide, and glucocorticoids. The IR of CAE in patients treated with TNF antagonists is significant and should be addressed carefully, and withdrawal of therapy is required in some cases. Copyright © 2013 by the American College of Rheumatology.
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.
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
De Las Salas, Roxana; Díaz-Agudelo, Daniela
The appearance of adverse drug reactions in neonates is an important issue due to the lack of drug safety data. To identify the behavior of adverse drug reactions (ADR) in hospitalized neonates at two intensive care units in Barranquilla, Colombia. We conducted a cross-sectional prospective descriptive study based on patientcentered intensive pharmacosurveillance. We followed up and monitored the appearance of ADRs for six months. We used Naranjo's algorithm to assess causality, modified Hartwig and Siegel assessment scale to establish severity and Schumock and Thornton criteria to determine ADR preventability. We detected 123 adverse drug reactions in 78 neonates of the 284 monitored. The cumulative incidence of ADRs was 27.4% (78/284); incidence density was 30.60 ADRs per 1,000 patients/day (78/2,549). The most affected organ system was the digestive (33.6%). Systemic anti-infective drugs were the most involved pharmacological group. Most of the ADRs were mild (58.5%), 83% were classified as probable, 16.2% as possible and 0.8% as definite. ADR incidence was high in newborns, and it increased in preterm infants (less than 38 weeks of age).
Huybrechts, Krista F; Desai, Rishi J; Park, Moa; Gagne, Joshua J; Najafzadeh, Mehdi; Avorn, Jerry
Many countries lack fully functional pharmacovigilance programs, and public budgets allocated to pharmacovigilance in industrialized countries remain low due to resource constraints and competing priorities. Using 3 case examples, we sought to estimate the public health and economic benefits resulting from public investment in active pharmacovigilance programs to detect adverse drug effects. We assessed 3 examples in which early signals of safety hazards were not adequately recognized, resulting in continued exposure of a large number of patients to these drugs when safer and effective alternative treatments were available. The drug examples studied were rofecoxib, cerivastatin, and troglitazone. Using an individual patient simulation model and the health care system perspective, we estimated the potential costs that could have been averted by early systematic detection of safety hazards through the implementation of active surveillance programs. We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773-$884 million for rofecoxib, $3-$10 million for cerivastatin, and $38-$63 million for troglitazone in the United States through the prevention of adverse events. By contrast, the yearly public investment in Food and Drug Administration initiated population-based pharmacovigilance activities in the United States is about $42.5 million at present. These examples illustrate a critical and economically justifiable role for active adverse effect surveillance in protecting the health of the public.
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.
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.
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
Evans, Elizabeth A; Grella, Christine E; Upchurch, Dawn M
To examine gender differences in the associations between childhood adversity and different types of substance use disorders and whether gender moderates these relationships. We analyzed data from 19,209 women and 13,898 men as provided by Wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to examine whether gender moderates the associations between childhood adversity and DSM-IV defined lifetime occurrence of alcohol, drug, and polysubstance-related disorders. We used multinomial logistic regression, weighted to be representative of the US adult civilian, noninstitutionalized population, and we calculated predicted probabilities by gender, controlling for covariates. To test which specific moderation contrasts were statistically significant, we conducted pair-wise comparisons corrected for multiple comparisons using Bonferroni's method. For each type of substance use disorder, risk was increased by more exposure to childhood adversity, and women had a lower risk than men. However, moderation effects revealed that with more experiences of childhood adversity, the gender gap in predicted probability for a disorder narrowed in relation to alcohol, it converged in relation to drugs such that risk among women surpassed that among men, and it widened in relation to polysubstances. Knowledge regarding substance-specific gender differences associated with childhood adversity exposure can inform evidence-based treatments. It may also be useful for shaping other types of gender-sensitive public health initiatives to ameliorate or prevent different types of substance use disorders.
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
Giacone, Daniela V; Carvalho, Vanessa F M; Costa, Soraia K P; Lopes, Luciana B
Because P-glycoprotein (P-gp) plays an absorptive role in the skin, its pharmacological inhibition represents a strategy to promote cutaneous localization of anticancer agents that serve as its substrates, improving local efficacy while reducing systemic exposure. Here, we evaluated the ability of a nanoemulsion (NE) co-encapsulating a P-gp inhibitor (elacridar) with the antitumor drug paclitaxel to promote epidermal targeting. Loaded NE displayed a nanometric size (45.2±4.0 nm) and negative zeta potential (-4.2±0.8 mV). Elacridar improved NE ability to inhibit verapamil-induced ATPase activity of P-gp; unloaded NE inhibited P-gp when used at a concentration of 1500 μM, while elacridar encapsulation decreased this concentration by 3-fold (p<0.05). Elacridar-loaded NE reduced paclitaxel penetration into the dermis of freshly excised mice skin and its percutaneous permeation by 1.5 and 1.7-fold (p<0.05), respectively at 6h, whilst larger drug amounts (1.4-fold, p<0.05) were obtained in viable epidermis. Assessment of cutaneous distribution of a fluorescent paclitaxel derivative confirmed the smaller delivery into the dermis at elacridar presence. In conclusion, we have provided novel evidence that NE containing elacridar exhibited a clear potential for P-gp inhibition, and enabled epidermal targeting of paclitaxel, which in turn, can potentially reduce adverse effects associated with systemic exposure to anticancer therapy. Copyright © 2017. Published by Elsevier Inc.
Einbinder, J. S.; Scully, K.
As a result of increased attention to medical errors, many institutions are contemplating increased use of information technology and clinical decision support. We conducted a retrospective analysis to estimate the frequency and cost of adverse drug events (ADEs) for inpatients at the University of Virginia. Applying published criteria for the detection of potential adverse events, we used a clinical data warehouse to identify patients and cases with potential ADEs. Again using published criteria, we then estimated the actual number of adverse drug events and preventable adverse drug events, as well as their attributable costs and excess length of stay. Our results showed a higher estimate (10.4-11.5 events per 100 admissions) for ADEs than seen in the ADE Prevention Study, highlighting the importance of considering the generalizability of published ADE studies to other settings. Our analysis demonstrates that retrospective analysis can be an efficient and powerful technique to evaluate rules and criteria used to detect ADEs and to assess their impact. PMID:11833476
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
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
Carlson, J Andrew; Cavaliere, L Frank; Grant-Kels, Jane M
Vasculitis is histologically defined as inflammatory cell infiltration and destruction of blood vessels. Vasculitis is classified as primary (idiopathic, eg, cutaneous leukocytoclastic angiitis, Wegener's granulomatosis) or secondary, a manifestation of connective tissue diseases, infections, adverse drug eruptions, or a paraneoplastic phenomenon. Cutaneous vasculitis, manifested as urticaria, purpura, hemorrhagic vesicles, ulcers, nodules, livedo, infarcts, or digital gangrene, is a frequent and often significant component of many systemic vasculitic syndromes such as lupus or rheumatoid vasculitis and antineutrophil cytoplasmic antibody-associated primary vasculitic syndromes such as Churg-Strauss syndrome. In most instances, cutaneous vasculitis represents a self-limited, single-episode phenomenon, the treatment of which consists of general measures such as leg elevation, warming, avoidance of standing, cold temperatures and tight fitting clothing, and therapy with antihistamines, aspirin, or nonsteroidal anti-inflammatory drugs. More extensive therapy is indicated for symptomatic, recurrent, extensive, and persistent skin disease or coexistence of systemic disease. For mild recurrent or persistent disease, colchicine and dapsone are first-choice agents. Severe cutaneous and systemic disease requires more potent immunosuppression (prednisone plus azathioprine, methotrexate, cyclophosphamide, cyclosporine, or mycophenolate mofetil). In cases of refractory vasculitis, plasmapheresis and intravenous immunoglobulin are viable considerations. The new biologic therapies that work via cytokine blockade or lymphocyte depletion such as tumor alpha inhibitor infliximab and the anti-B-cell antibody rituximab, respectively, are showing benefit in certain settings such as Wegener's granulomatosis, antineutrophil cytoplasmic antibody-associated vasculitis, Behçet's disease, and cryoglobulinemic vasculitis.
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. PMID:14728261
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.
Smithburger, Pamela L; Buckley, Mitchell S; Culver, Mark A; Sokol, Sarah; Lat, Ishaq; Handler, Steven M; Kirisci, Levent; Kane-Gill, Sandra L
Prior research indicates that off-label use is common in the ICU; however, the safety of off-label use has not been assessed. The study objective was to determine the prevalence of adverse drug reactions associated with off-label use and evaluate off-label use as a risk factor for the development of adverse drug reactions in an adult ICU population. Multicenter, observational study : Medical ICUs at three academic medical centers. Adult patients (age ≥ 18 yr old) receiving medication therapy. All administered medications were evaluated for Food and Drug Administration-approved or off-label use. Patients were assessed daily for the development of an adverse drug reaction through active surveillance. Three adverse drug reaction assessment instruments were used to determine the probability of an adverse drug reaction resulting from drug therapy. Severity and harm of the adverse drug reaction were also assessed. Cox proportional hazard regression was used to identify a set of covariates that influenced the rate of adverse drug reactions. Overall, 1,654 patient-days (327 patients) and 16,391 medications were evaluated, with 43% of medications being used off-label. One hundred and sixteen adverse drug reactions were categorized dichotomously (Food and Drug Administration or off-label), with 56% and 44% being associated with Food and Drug Administration-approved and off-label use, respectively. The number of adverse drug reactions for medications administered and the number of harmful and severe adverse drug reactions did not differ for medications used for Food and Drug Administration-approved or off-label use (0.74% vs 0.67%; p = 0.336; 33 vs 31 events, p = 0.567; 24 vs 24 events, p = 0.276). Age, sex, number of high-risk medications, number of off-label medications, and severity of illness score were included in the Cox proportional hazard regression. It was found that the rate of adverse drug reactions increases by 8% for every one additional off-label medication
Background Constipation and diarrhoea are common complaints and often reported as adverse drug reactions. This study aimed at finding associations between drugs and constipation and diarrhoea in a general population. Methods A selection of inhabitants in Oppland County, Norway participated in a cross-sectional survey. Information about demographics, diseases including gastrointestinal complaints classified according to the Rome II criteria and use of drugs were collected on questionnaires. Constipation was defined as functional constipation and constipation predominant Irritable Bowel Syndrome (IBS), and diarrhoea as functional diarrhoea and diarrhoea predominant IBS. Associations between drugs and constipation and diarrhoea were examined with multivariable logistic regression models. Based on the multivariable model, the changes in prevalence (risk difference) of the abdominal complaints for non-users and users of drugs were calculated. Results In total 11078 subjects were invited, 4622 completed the questionnaires, 640 (13.8%) had constipation and 407 (8.8%) had diarrhoea. To start using drugs increased the prevalence of constipation and diarrhoea with 2.5% and 2.3% respectively. Polypharmacy was an additional risk factor for diarrhoea. Use of furosemide, levothyroxine sodium and ibuprofen was associated with constipation, and lithium and carbamazepine with diarrhoea. The excess drug related prevalence varied from 5.3% for the association between ibuprofen and constipation to 27.5% for the association between lithium and diarrhoea. Conclusions Use of drugs was associated with constipation and diarrhoea in the general population. The associations are most likely adverse drug reactions and show that drug-induced symptoms need to be considered in subjects with these complaints. PMID:21332973
[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.
Golder, Su; Wright, Kath; Loke, Yoon K
Authors and indexers are increasingly including terms for adverse drug effects in the titles, abstracts or indexing of records in MEDLINE and Embase. However, it is not clear if this is the same for studies with non-drug adverse effects data. We therefore assessed the feasibility of using adverse effects terms when searching MEDLINE or Emabse to retrieve papers of non-drug adverse effects. A collection of papers that reported data on non-drug adverse effects was sought from included studies of systematic reviews. Each included study was analysed to ascertain whether the corresponding record in MEDLINE and Embase included adverse effects terms in the title, abstract or indexing. From 9,129 records screened from DARE (Database of Abstracts of Reviews of Effects), 30 reviews evaluating non-drug adverse effects met our inclusion criteria. From these, 635 unique papers were included in our analysis. Sensitive searches for adverse effects required generic and specific named adverse effects terms using the title, abstract and indexing. Records relating to surgical interventions were more likely to contain adverse effects terms than records relating to non-surgical interventions. Using any adverse effects terms in the title, abstract or indexing in MEDLINE and Embase would have identified an average of 94% of papers on surgical adverse effect interventions per systematic review and 72% of papers on non-surgical adverse effects per systematic review. Hence, while a generic non-drug adverse effect search filter may not yet be feasible, a filter for the adverse effects of surgical interventions may be within reach. This article is protected by copyright. All rights reserved.
Sandreva, Tatjana; Voss, Anne; Bygum, Anette
Cutaneous lupus erythematosus (LE) is an autoimmune disease. The most common clinical forms are acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE) and discoid LE (DLE). Cutaneous LE, mainly ACLE, can be the first sign of systemic LE (SLE). DLE and SCLE are less associated with development of SLE, however, up to 85% of patients with SLE have cutaneous manifestations. The aetiology is multifactorial. Drugs such as proton pump inhibitors can induce SCLE, while UV-light and smoking can worsen the lesions. Treatment includes preventive strategies in addition to topical steroids and systemic hydroxychloroquine.
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
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. 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. 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. 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.
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
Adrover, Cosme; Bodnar, Todd; Huang, Zhuojie
Background Social media platforms are increasingly seen as a source of data on a wide range of health issues. Twitter is of particular interest for public health surveillance because of its public nature. However, the very public nature of social media platforms such as Twitter may act as a barrier to public health surveillance, as people may be reluctant to publicly disclose information about their health. This is of particular concern in the context of diseases that are associated with a certain degree of stigma, such as HIV/AIDS. Objective The objective of the study is to assess whether adverse effects of HIV drug treatment and associated sentiments can be determined using publicly available data from social media. Methods We describe a combined approach of machine learning and crowdsourced human assessment to identify adverse effects of HIV drug treatment solely on individual reports posted publicly on Twitter. Starting from a large dataset of 40 million tweets collected over three years, we identify a very small subset (1642; 0.004%) of individual reports describing personal experiences with HIV drug treatment. Results Despite the small size of the extracted final dataset, the summary representation of adverse effects attributed to specific drugs, or drug combinations, accurately captures well-recognized toxicities. In addition, the data allowed us to discriminate across specific drug compounds, to identify preferred drugs over time, and to capture novel events such as the availability of preexposure prophylaxis. Conclusions The effect of limited data sharing due to the public nature of the data can be partially offset by the large number of people sharing data in the first place, an observation that may play a key role in digital epidemiology in general. PMID:27227141
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.
Hasegawa, Shiori; Matsui, Toshinobu; Hane, Yuuki; Abe, Junko; Hatahira, Haruna; Motooka, Yumi; Sasaoka, Sayaka; Fukuda, Akiho; Naganuma, Misa; Hirade, Kouseki; Takahashi, Yukiko; Kinosada, Yasutomi; Nakamura, Mitsuhiro
Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3-71.4), 29.1 (23.5-35.9), 42.9 (32.3-57.0), 44.7 (32.7-61.1), and 38.6 (26.3-56.7), respectively. The medians (25%-75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3-314.0), 128.0 (27.0-279.0), 204.0 (44.0-660.0), 142.0 (41.3-344.0), and 16.5 (8.8-32.0) days, respectively. The 95% CIs of the WSP-β for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning.
Nitya, Selvaraj; Deepa, Kameswari; Mangaiarkkarasi, Adhimoolam; Karthikeyan, Kaliaperumal
Adverse drug reactions are a major hazard of modern medicine. Fixed drug eruption, which is a cutaneous adverse drug reaction, is commonly seen with antimicrobials and analgesics. Here we report 37-year-old female with bullous fixed drug eruptions due to doxycycline administration.
Parekh, Ameeta; Fadiran, Emmanuel O; Uhl, Kathleen; Throckmorton, Douglas C
The requirement to establish safety of drugs prior to marketing has been in place since 1938 by the US Food, Drug and Cosmetic Act and is by no means a new concept. The efficacy regulations were enacted in 1962 via the Kefauver-Harris Amendment and the drug approval process has evolved thereafter. The assessment of safety and efficacy of drug products is made by pharmaceutical companies during drug development, which then goes through a regulatory review by the US FDA for the determination of market approval or nonapproval. The drug development and regulatory approval processes have endured close ongoing scrutiny by regulatory bodies, the public, US Congress and academic and private organizations and, as a result, have ensured continual refinement. Over the years, evidence has been emerging on varied drug responses in subgroup populations, and the underlying biology associated with age, race and sex as demographic variables have been examined. The resulting growing knowledge of disease burden, treatment response and disparate outcomes has generated opportunities to streamline and improve treatment outcomes in these populations. This article discusses the historical context of women's participation in clinical drug trials submitted to the FDA for regulatory review and approval purposes. The inadvertent consequences of women's exclusion or inadequate representation in past clinical trials and the evidentiary basis for understanding sex differences are also evaluated. Advances in the US regulatory processes to address treatment outcomes that are tied to the topic of this paper, specifically, adverse drug effects in women, are also discussed.
Clavenna, A; Bonati, M
To assess the incidence of adverse drug reactions (ADRs) in the paediatric population and the safety alerts concerning children and adolescents issued by international drug regulatory agencies since 2001. A bibliographic search was performed in the Medline and Embase databases for prospective studies published between January 2001 and December 2007 evaluating the ADR incidence in the paediatric population. Data were analysed by a random effect model. Moreover, the websites of nine international drug regulatory agencies were searched to collect information on safety alerts concerning the paediatric population. A total of eight prospective studies were evaluated, six of which concerned the ADR incidence in hospitalised children. The overall incidence of ADRs was 10.9% (95% CI 4.8 to 17.0) in hospitalised children and 1.0% (95% CI 0.3 to 1.7) in outpatient children. The rate of hospital admission due to ADRs was 1.8% (95% CI 0.4 to 3.2). The skin and gastrointestinal system were the organs most commonly affected and antibiotics were the drugs most commonly associated with ADRs. Safety alerts in the paediatric population were retrieved for 28 drugs, five of which were for psychotropic drugs and most of which were issued by the Food and Drug Administration (20 drugs). For 12 drugs, warnings were published in the 2006-2007 period. Antidepressants were the only drugs for which alerts were issued by all the drug regulatory agencies. To ensure safe and effective medicines for children, efforts are needed at different levels (governments, drug regulatory agencies, pharmaceutical industries, health care professionals, and parents). Collaborative regulatory initiatives, such as the use of common warnings, can also contribute to a more rational use of drugs for children.
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
Singhal, Mayank; Del Río-Sancho, Sergio; Sonaje, Kiran; Kalia, Yogeshvar N
The efficacy of some dermatological therapies might be improved by the use of "high dose" intraepidermal drug reservoir systems that enable sustained and targeted local drug delivery, e.g., in the treatment of keloids and hypertrophic scars. Here, a fractionally ablative erbium:YAG laser was used to enable "needle-less" cutaneous deposition of polymeric microparticles containing triamcinolone acetonide (TA). The microparticles were prepared using a freeze-fracture technique employing cryomilling that resulted in drug loading efficiencies of ∼100%. They were characterized by several different techniques, including scanning electron microscopy, powder X-ray diffraction and differential scanning calorimetry. TA was quantified by validated HPLC-UV and UHPLC-MS/MS analytical methods. In vitro release studies demonstrated the effect of polymer properties on TA release kinetics. Confocal laser scanning microscopy enabled visualization of cryomilled microparticles containing fluorescein and Nile Red in the cutaneous micropores and the subsequent release of fluorescein into the micropores and its diffusion throughout the epidermis and upper dermis. The biodistribution of TA, i.e. the amount of drug as a function of depth in skin, following microparticle application was much more uniform than with a TA suspension and delivery was selective for deposition with less transdermal permeation. These findings suggest that this approach may provide an effective, targeted and minimally invasive alternative to painful intralesional injections for the treatment of keloid scars.
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
Luo, Heng; Chen, Jian; Shi, Leming; Mikailov, Mike; Zhu, Huang; Wang, Kejian; He, Lin; Yang, Lun
Identifying new indications for existing drugs (drug repositioning) is an efficient way of maximizing their potential. Adverse drug reaction (ADR) is one of the leading causes of death among hospitalized patients. As both new indications and ADRs are caused by unexpected chemical–protein interactions on off-targets, it is reasonable to predict these interactions by mining the chemical–protein interactome (CPI). Making such predictions has recently been facilitated by a web server named DRAR-CPI. This server has a representative collection of drug molecules and targetable human proteins built up from our work in drug repositioning and ADR. When a user submits a molecule, the server will give the positive or negative association scores between the user’s molecule and our library drugs based on their interaction profiles towards the targets. Users can thus predict the indications or ADRs of their molecule based on the association scores towards our library drugs. We have matched our predictions of drug–drug associations with those predicted via gene-expression profiles, achieving a matching rate as high as 74%. We have also successfully predicted the connections between anti-psychotics and anti-infectives, indicating the underlying relevance of anti-psychotics in the potential treatment of infections, vice versa. This server is freely available at http://cpi.bio-x.cn/drar/. PMID:21558322
Berhe, Derbew Fikadu; Juhlin, Kristina; Star, Kristina; Beyene, Kidanemariam G M; Dheda, Mukesh; Haaijer-Ruskamp, Flora M; Taxis, Katja; Mol, Peter G M
Identifying key features in individual case safety reports (ICSR) of suspected adverse drug reactions (ADRs) with cardiometabolic drugs from sub-Saharan Africa (SSA) compared with reports from the rest of the world (RoW). Reports on suspected ADRs of cardiometabolic drugs (ATC: A10[antidiabetic], B01[antithrombotics] and C[cardiovascular]) were extracted from WHO Global database, VigiBase(®) (1992-2013). We used vigiPoint, a logarithmic odds ratios (log2 OR)-based method to study disproportional reporting between SSA and RoW. Case-defining features were considered relevant if the lower limit of the 99% CI > 0.5. In SSA, 3773 (9%) of reported ADRs were for cardiometabolic drugs, in RoW for 18%. Of these, 79% originated from South Africa and 81% were received after 2007. Most reports were for drugs acting on the renin-angiotensin system (36% SSA & 14% RoW). Compared with RoW, reports were more often sent for patients 18-44 years old (log2 OR 0.95 [99 CI 0.80; 1.09]) or with non-fatal outcome (log2 OR 1.16 [99 CI 1.10; 1.22]). Eight ADRs (cough, angioedema, lip swelling, face oedema, swollen tongue, throat irritation, drug ineffective and blood glucose abnormal) and seven drugs (enalapril, rosuvastatin, perindopril, vildagliptin, insulin glulisine, nifedipine and insulin lispro) were disproportionally more reported in SSA than in the RoW. 'In recent years, the number of adverse drug reactions (ADRs) reported in Sub-Saharan Africa (SSA) has sharply increased. The data showed the well-known population-based differential ADR profile of ACE inhibitors in the SSA population.' © 2015 John Wiley & Sons Ltd.
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
Summary Adverse outcome pathways (AOPs) are novel tools in toxicology and human risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of key events connected by key event relationships and an adverse outcome. Development and evaluation of AOPs ideally complies with OECD guidelines. AOP frameworks have yet been proposed for major types of drug-induced injury, especially in the liver, including steatosis, fibrosis and cholestasis. These newly postulated AOPs can serve a number of purposes pertinent to safety assessment of drugs, in particular the establishment of quantitative structure-activity relationships, the development of novel in vitro toxicity screening tests and the elaboration of prioritization strategies. PMID:27311472
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
Star, Kristina; Norén, G Niklas; Nordin, Karin; Edwards, I Ralph
As a first step towards implementing routine screening of safety issues specifically related to children at the Uppsala Monitoring Centre, this study was performed to explore reporting patterns of adverse reactions in children. The first aim of this study was to characterize and contrast child reports against adult reports in an overall drug and adverse reaction review. The second aim was to highlight increases in reporting of specific adverse reactions during recent years subdivided by age group. This was an exploratory study of internationally compiled individual case safety reports (ICSRs). Reports were extracted from the WHO global ICSR database, VigiBase, up until 5 February 2010. The reports in VigiBase originate from 97 countries and the likelihood that a medicine caused the adverse effect may vary from case to case. Suspected duplicate and vaccine reports were excluded from the analysis, as were reports with age not specified. The Medical Dictionary for Regulatory Activities (MedDRA®) and the WHO Anatomical Therapeutic Chemical (ATC) classification were used to group adverse reactions and drugs. In the general review, reports from 1968 to 5 February 2010 were divided into child (aged 0-17 years) and adult (≥ 18 years) age groups. To highlight increases in reporting rates of specific adverse reactions during recent years, reports from 2005 to February 2010 were compared with reports from 1995 to 1999. The ten adverse reactions with the greatest difference in the proportion of reports between the two time periods were reviewed. In the latter analysis, the reports were subdivided into age groups: neonates ≤ 27 days; infants 28 days-23 months; children 2-11 years; and adolescents 12-17 years. A total of 3,472,183 reports were included in the study, of which 7.7% (268,145) were reports for children (0-17 years). Fifty-three percent of the child reports were for males, whilst 39% of reports in the adult group were for males. The proportion of reports
Paveliu, Marian Sorin; Bengea-Luculescu, Simona; Toma, Mihai; Paveliu, Silvia Fraga
The purpose of our study was to investigate and to assess the perceptions of Romanian doctors towards adverse drug reactions (ADRs) reporting. A questionnaire with 20 items accompanied by a letter presenting the study was circulated using Internet and face to face interviews to 532 doctors in Bucharest and two neighboring regions from Romania (Muntenia and Oltenia). 204 (56.2%) of the total number of responders expressed their opinion that the daily number of ADRs observed to be under 5 309 (58%) of responders were never informed about ADRs reporting, 439 (82.52%) did not know that the Romanian College of Physicians is scoring this activity under the "Continuous medical education program". Factors that might encourage voluntary reporting of adverse reactions were identified to be: the easiness of reporting, their periodic information and the training about all adverse reactions reported by doctors and the measures taken. Factors discouraging voluntary reporting of an adverse drug reaction were: the lack of information on where, when and how to report ADRs, the uncertain causality. Currently, the pharmacovigilance activities including reporting of ADRs in Romania are more of an accidental nature, doctors are less or not at all informed about this activity. Doctors have a favorable attitude towards reporting ADRs - as the majority believes that the reporting should be either voluntary or mandatory as opposed to a small number that would expect to be paid for this activity.
PAVELIU, Marian Sorin; BENGEA-LUCULESCU, Simona; TOMA, Mihai; PAVELIU, Silvia Fraga
ABSTRACT Aim: The purpose of our study was to investigate and to assess the perceptions of Romanian doctors towards adverse drug reactions (ADRs) reporting. Method: A questionnaire with 20 items accompanied by a letter presenting the study was circulated using Internet and face to face interviews to 532 doctors in Bucharest and two neighboring regions from Romania (Muntenia and Oltenia). Results: 204 (56.2%) of the total number of responders expressed their opinion that the daily number of ADRs observed to be under 5 309 (58%) of responders were never informed about ADRs reporting, 439 (82.52%) did not know that the Romanian College of Physicians is scoring this activity under the "Continuous medical education program". Factors that might encourage voluntary reporting of adverse reactions were identified to be: the easiness of reporting, their periodic information and the training about all adverse reactions reported by doctors and the measures taken. Factors discouraging voluntary reporting of an adverse drug reaction were: the lack of information on where, when and how to report ADRs, the uncertain causality. Conclusion: Currently, the pharmacovigilance activities including reporting of ADRs in Romania are more of an accidental nature, doctors are less or not at all informed about this activity. Doctors have a favorable attitude towards reporting ADRs – as the majority believes that the reporting should be either voluntary or mandatory as opposed to a small number that would expect to be paid for this activity. PMID:24023593
Holdiness, Mack R
Corynebacterium minutissimum is the bacteria that leads to cutaneous eruptions of erythrasma and is the most common cause of interdigital foot infections. It is found mostly in occluded intertriginous areas such as the axillae, inframammary areas, interspaces of the toes, intergluteal and crural folds, and is more common in individuals with diabetes mellitus than other clinical patients. This organism can be isolated from a cutaneous site along with a concurrent dermatophyte or Candida albicans infection. The differential diagnosis of erythrasma includes psoriasis, dermatophytosis, candidiasis and intertrigo, and methods for differentiating include Wood's light examination and bacterial and mycological cultures. Erythromycin 250mg four times daily for 14 days is the treatment of choice and other antibacterials include tetracycline and chloramphenicol; however, the use of chloramphenicol is limited by bone marrow suppression potentially leading to neutropenia, agranulocytosis and aplastic anaemia. Further studies are needed but clarithromycin may be an additional drug for use in the future. Where there is therapeutic failure or intertriginous involvement, topical solutions such as clindamycin, Whitfield's ointment, sodium fusidate ointment and antibacterial soaps may be required for both treatment and prophylaxis. Limited studies on the efficacy of these medications exist, however, systemic erythromycin demonstrates cure rates as high as 100%. Compared with tetracyclines, systemic erythromycin has greater efficacy in patients with involvement of the axillae and groin, and similar efficacy for interdigital infections. Whitfield's ointment has equal efficacy to systemic erythromycin in the axillae and groin, but shows greater efficacy in the interdigital areas and is comparable with 2% sodium fusidate ointment for treatment of all areas. Adverse drug effects and potential drug interactions need to be considered. No cost-effectiveness data are available but there are
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.
Chen, Yong; Zahui, Tiphaine; Alberti, Ingo; Kalia, Yogeshvar N
The objective was to determine the cutaneous biodistribution of aciclovir (ACV), that is, the amount of drug as a function of depth within the skin following topical iontophoretic administration of amino acid ester prodrugs of ACV (ACV-X, where X=Arg, Ile or Val). The results were compared to those obtained with marketed formulations of aciclovir and penciclovir (PCV), and following topical iontophoresis of ACV. Quantification of molecules as a function of position in the skin was achieved by snap-freezing and cryotoming skin samples to obtain coarse or fine lamellae with a thickness of either 100 μm or 20 μm. The molecules--ACV, ACV-X or PCV--were extracted and quantified by validated UHPLC-MS/MS analytical methods. Passive delivery of ACV or PCV from marketed cream and ointment formulations after application for 60 min resulted in modest cutaneous deposition (QDEP,ACV and QDEP,PCV<2 nmol/cm(2)). Moreover, ACV and PCV were found mainly in the stratum corneum or superficial viable epidermis. The levels in the deeper skin layers (100-200 μm), corresponding to the basal epidermis and adjacent area, where the virus would be found, were negligible. In contrast, iontophoresis of ACV-Ile or ACV-Arg for only 10 min at 0.25 mA/cm(2) resulted in much greater deposition of ACV species at the same skin depths (100-200 μm): for ACV-Ile - QDEP,ACV and QDEP,ACV-Ile were 17.2 ± 6.9 nmol/cm(2) and 8.2 ± 1.3 nmol/cm(2), respectively; in the case of ACV-Arg there was complete bioconversion and only ACV was recovered (QDEP,ACV was 41.2 ± 9.2 nmol/cm(2)). In the higher resolution biodistribution studies, with 20 μm lamellae, short duration iontophoresis at 0.25 mA/cm(2) for only 5 min of ACV-Arg or ACV-Ile still enabled considerable amounts of ACV species to be delivered to the basal epidermis and neighboring layers (QDEP,ACV was 4.0 ± 1.6 nmol/cm(2) and 6.1 ± 1.7 nmol/cm(2), respectively). Iontophoresis of ACV under the same conditions resulted in negligible ACV deposition
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
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
Morimoto, Takeshi; Gandhi, Tejal K; Fiskio, Julie M; Seger, Andrew C; So, Joseph W; Cook, E Francis; Fukui, Tsuguya; Bates, David W
To identify potential factors leading to discontinuation of angiotensin-converting enzyme (ACE) inhibitors because of adverse drug events. Retrospective cohort study was conducted at outpatient clinics affiliated with an urban tertiary care hospital. ACE inhibitors were administered to 2225 consecutive outpatients. In 19% of the total cohort, ACE inhibitors were discontinued because of adverse drug events. Cox proportional hazard model identified the following independent risk factors for discontinuation because of adverse drug events: age, female gender, ethnicity other than African American or Latino, no history of previous ACE inhibitor use, history of cough caused by another ACE inhibitor, hypertension, anxiety or depression, no hemodialysis, and elevated creatinine. History of smoking was shown to be a risk factor for cough [hazard ratio (HR): 2.5; 95% confidence interval (CI): 1.1-5.7], angioedema (HR: 2.7; 95% CI: 1.1-7.0), and hyperkalaemia (HR: 5.4; 95% CI: 1.3-23.2). History of ACE inhibitor-induced cough was not only a risk factor for cough (HR: 12.9; 95% CI: 7.5-22.3) but also for angioedema (HR: 9.1; 95% CI: 2.1-39.9). Patients with creatinine > or = 1.6 mg dL(-1) were likely to discontinue ACE inhibitors because of renal dysfunction (HR: 4.7; 95% CI: 1.5-12.7) and hyperkalaemia (HR: 10.9; 95% CI: 3.1-39.0). East Asians were more likely to develop cough (HR: 2.5; 95% CI: 1.1-5.7) and hyperkalaemia (HR: 80.3; 95% CI: 5.4-1190) and African Americans to develop angioedema (HR: 3.5; 95% CI: 1.3-8.9). Although further validation is necessary, these risk factors should help doctors identify patients with elevated risk for adverse drug events because of ACE inhibitors.
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.
Marbac, Matthieu; Tubert-Bitter, Pascale; Sedki, Mohammed
Spontaneous adverse event reports have a high potential for detecting adverse drug reactions. However, due to their dimension, the analysis of such databases requires statistical methods. In this context, disproportionality measures can be used. Their main idea is to project the data onto contingency tables in order to measure the strength of associations between drugs and adverse events. However, due to the data projection, these methods are sensitive to the problem of coprescriptions and masking effects. Recently, logistic regressions have been used with a Lasso type penalty to perform the detection of associations between drugs and adverse events. On different examples, this approach limits the drawbacks of the disproportionality methods, but the choice of the penalty value is open to criticism while it strongly influences the results. In this paper, we propose to use a logistic regression whose sparsity is viewed as a model selection challenge. Since the model space is huge, a Metropolis-Hastings algorithm carries out the model selection by maximizing the BIC criterion. Thus, we avoid the calibration of penalty or threshold. During our application on the French pharmacovigilance database, the proposed method is compared to well-established approaches on a reference dataset, and obtains better rates of positive and negative controls. However, many signals (i.e., specific drug-event associations) are not detected by the proposed method. So, we conclude that this method should be used in parallel to existing measures in pharmacovigilance. Code implementing the proposed method is available at the following url: https://github.com/masedki/MHTrajectoryR.
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.
Mangoni, Arduino A
Increased, often inappropriate, drug exposure, pharmacokinetic and pharmacodynamic changes, reduced homeostatic reserve and frailty increase the risk of adverse drug reactions (ADRs) in the older population, thereby imposing a significant public health burden. Predicting and diagnosing ADRs in old age presents significant challenges for the clinician, even when specific risk scoring systems are available. The picture is further compounded by the potential adverse impact of several drugs on more 'global' health indicators, for example, physical function and independence, and the fragmentation of care (e.g., increased number of treating doctors and care transitions) experienced by older patients during their clinical journey. The current knowledge of drug safety in old age is also curtailed by the lack of efficacy and safety data from pre-marketing studies. Moreover, little consideration is given to individual patients' experiences and reporting of specific ADRs, particularly in the presence of cognitive impairment. Pending additional data on these issues, the close review and monitoring of individual patients' drug prescribing, clinical status and biochemical parameters remain essential to predict and detect ADRs in old age. Recently developed strategies, for example, medication reconciliation and trigger tool methodology, have the potential for ADRs risk mitigation in this population. However, more information is required on their efficacy and applicability in different healthcare settings.
Arnott, Janine; Hesselgreaves, Hannah; Nunn, Anthony J.; Peak, Matthew; Pirmohamed, Munir; Smyth, Rosalind L.
Background There is little research on parents' experiences of suspected adverse drug reactions in their children and hence little evidence to guide clinicians when communicating with families about problems associated with medicines. Objective To identify any unmet information and communication needs described by parents whose child had a suspected adverse drug reaction. Methods Semi-structured qualitative interviews with parents of 44 children who had a suspected adverse drug reaction identified on hospital admission, during in-patient treatment or reported by parents using the Yellow Card Scheme (the UK system for collecting spontaneous reports of adverse drug reactions). Interviews were conducted face-to-face or by telephone; most interviews were audiorecorded and transcribed. Analysis was informed by the principles of the constant comparative method. Results Many parents described being dissatisfied with how clinicians communicated about adverse drug reactions and unclear about the implications for their child's future use of medicines. A few parents felt that clinicians had abandoned their child and reported refusing the use of further medicines because they feared a repeated adverse drug reaction. The accounts of parents of children with cancer were different. They emphasised their confidence in clinicians' management of adverse drug reactions and described how clinicians prospectively explained the risks associated with medicines. Parents linked symptoms to medicines in ways that resembled the established reasoning that clinicians use to evaluate the possibility that a medicine has caused an adverse drug reaction. Conclusion Clinicians' communication about adverse drug reactions was poor from the perspective of parents, indicating that improvements are needed. The accounts of parents of children with cancer indicate that prospective explanation about adverse drug reactions at the time of prescription can be effective. Convergence between parents and
Arnott, Janine; Hesselgreaves, Hannah; Nunn, Anthony J; Peak, Matthew; Pirmohamed, Munir; Smyth, Rosalind L; Turner, Mark A; Young, Bridget
There is little research on parents' experiences of suspected adverse drug reactions in their children and hence little evidence to guide clinicians when communicating with families about problems associated with medicines. To identify any unmet information and communication needs described by parents whose child had a suspected adverse drug reaction. Semi-structured qualitative interviews with parents of 44 children who had a suspected adverse drug reaction identified on hospital admission, during in-patient treatment or reported by parents using the Yellow Card Scheme (the UK system for collecting spontaneous reports of adverse drug reactions). Interviews were conducted face-to-face or by telephone; most interviews were audiorecorded and transcribed. Analysis was informed by the principles of the constant comparative method. Many parents described being dissatisfied with how clinicians communicated about adverse drug reactions and unclear about the implications for their child's future use of medicines. A few parents felt that clinicians had abandoned their child and reported refusing the use of further medicines because they feared a repeated adverse drug reaction. The accounts of parents of children with cancer were different. They emphasised their confidence in clinicians' management of adverse drug reactions and described how clinicians prospectively explained the risks associated with medicines. Parents linked symptoms to medicines in ways that resembled the established reasoning that clinicians use to evaluate the possibility that a medicine has caused an adverse drug reaction. Clinicians' communication about adverse drug reactions was poor from the perspective of parents, indicating that improvements are needed. The accounts of parents of children with cancer indicate that prospective explanation about adverse drug reactions at the time of prescription can be effective. Convergence between parents and clinicians in their reasoning for linking children
Hoffman, Keith B; Dimbil, Mo; Kyle, Robert F; Tatonetti, Nicholas P; Erdman, Colin B; Demakas, Andrea; Chen, Dingguo; Overstreet, Brian M
Given the multiple limitations associated with relatively homogeneous preapproval clinical trials, inadequate data disclosures, slow reaction times from regulatory bodies, and deep-rooted bias against disclosing and publishing negative results, there is an acute need for the development of analytics that reflect drug safety in heterogeneous, real-world populations. To develop a drug safety statistic that estimates downstream medical costs associated with serious adverse events (AEs) and unfavorable patient outcomes associated with the use of 706 FDA-approved drugs. All primary suspect case reports for each drug were collected from the FDA's Adverse Event Reporting System database (FAERS) from 2010-2014. The Medical Dictionary for Regulatory Activities (MedDRA) was used to code serious AEs and outcomes, which were tallied for each case report. Medical costs associated with AEs and poor patient outcomes were derived from Agency for Healthcare Research and Quality (AHRQ) survey data, and their corresponding ICD-9-CM codes were mapped to MedDRA terms. Nonserious AEs and outcomes were not included. For each case report, either the highest AE cost or, if no eligible AE was listed, the highest outcome cost was used. All costed cases were aggregated for each drug and divided by the number of patients exposed to obtain a downstream estimated direct medical cost burden per exposure. Each drug was assigned a corresponding 1-100 point total. The 706 drugs showed an exponential distribution of downstream costs, and the data were transformed using the natural log to approximate a normal distribution. The minimum score was 8.29, and the maximum score was 99.25, with a mean of 44.32. Drugs with the highest individual scores tended to be kinase inhibitors, thalidomide analogs, and endothelin receptor antagonists. When scores were analyzed across Established Pharmacologic Class (EPC), the kinase inhibitor and endothelin receptor antagonist classes had the highest total. However
Scheifes, Arlette; Walraven, Sanne; Stolker, Joost Jan; Nijman, Henk L I; Egberts, Toine C G; Heerdink, Eibert R
Psychotropic drugs are prescribed to approximately 30-40% of adults with intellectual disability (ID) and challenging behaviour, despite the limited evidence of effectiveness and the potential of adverse events. To assess the prevalence of adverse events in association with psychotropic drug use in adults with ID and challenging behaviour and to examine the relation of these adverse events with the person's quality of life. The presence of adverse events was measured with a questionnaire that had to be filled in by the physicians of the participants. Movement disorders were measured separately with a standardised protocol. The strength of the association between adverse events and Intellectual Disability Quality of Life-16 (IDQOL-16), and daily functioning was investigated using linear regression analyses, taking into account the severity of disease (CGI-S) as potential confounder. Virtually all of 103 adults with ID and challenging behaviour had at least one adverse event (84.4%) and almost half had ≥3 adverse events (45.6%) across different subclasses. Using psychotropic drugs increased the prevalence of adverse events significantly. Respectively 13% of the patients without psychotropic drugs and 61% of the patients with ≥2 psychotropic drugs had ≥3 adverse events. Having adverse events had a significantly negative influence on the quality of life. A large majority of all patients had at least one adverse event associated with psychotropic drug use. More attention is needed for these adverse events and their negative influence on the quality of life of these patients, taking into account the lack of evidence of effectiveness of psychotropic drugs for challenging behaviour. Copyright © 2015. Published by Elsevier Ltd.
Pearce, Alison; Haas, Marion; Viney, Rosalie
Antineoplastic drugs for cancer are often associated with adverse events, which influence patients' physical health, quality of life and survival. However, the modelling of adverse events in cost-effectiveness analyses of antineoplastic drugs has not been examined. This article reviews published economic evaluations that include a calculated cost for adverse events of antineoplastic drugs. The aim is to identify how existing models manage four issues specific to antineoplastic drug adverse events: the selection of adverse events for inclusion in models, the influence of dose modifications on drug quantity and survival outcomes, the influence of adverse events on quality of life and the consideration of multiple simultaneous or recurring adverse events. A systematic literature search was conducted using MESH headings and key words in multiple electronic databases, covering the years 1999-2009. Inclusion criteria for eligibility were papers covering a population of adults with solid tumour cancers, the inclusion of at least one adverse event and the resource use and/or costs of adverse event treatment. From 4,985 citations, 26 eligible articles were identified. Studies were generally of moderate quality and addressed a range of cancers and treatment types. While the four issues specific to antineoplastic drug adverse events were addressed by some studies, no study addressed all of the issues in the same model. This review indicates that current modelling assumptions may restrict our understanding of the true impact of adverse events on cost effectiveness of antineoplastic drugs. This understanding could be improved through consideration of the selection of adverse events, dose modifications, multiple events and quality of life in cost-effectiveness studies.
Jamal, Salma; Goyal, Sukriti; Shanker, Asheesh; Grover, Abhinav
Adverse drug reactions (ADRs) have become one of the primary reasons for the failure of drugs and a leading cause of deaths. Owing to the severe effects of ADRs, there is an urgent need for the generation of effective models which can accurately predict ADRs during early stages of drug development based on integration of various features of drugs. In the current study, we have focused on neurological ADRs and have used various properties of drugs that include biological properties (targets, transporters and enzymes), chemical properties (substructure fingerprints), phenotypic properties (side effects (SE) and therapeutic indications) and a combinations of the two and three levels of features. We employed relief-based feature selection technique to identify relevant properties and used machine learning approach to generated learned model systems which would predict neurological ADRs prior to preclinical testing. Additionally, in order to explain the efficiency and applicability of the models, we tested them to predict the ADRs for already existing anti-Alzheimer drugs and uncharacterized drugs, respectively in side effect resource (SIDER) database. The generated models were highly accurate and our results showed that the models based on chemical (accuracy 93.20%), phenotypic (accuracy 92.41%) and combination of three properties (accuracy 94.18%) were highly accurate while the models based on biological properties (accuracy 82.11%) were highly informative.
Li, Wei; Zeng, Su; Yu, Lu-Shan; Zhou, Quan
Background Omeprazole, a proton pump inhibitor (PPI), is widely used for the treatment of dyspepsia, peptic ulcer, gastroesophageal reflux disease, and functional dyspepsia. Polypharmacy is common in patients receiving omeprazole. Drug toxicity and treatment failure resulting from inappropriate combination therapy with omeprazole have been reported sporadically. Systematic review has not been available to address the pharmacokinetic drug-drug interaction (DDI) profile of omeprazole with adverse consequences, the factors determining the degree of DDI between omeprazole and comedication, and the corresponding clinical risk management. Methods Literature was identified by performing a PubMed search covering the period from January 1988 to March 2013. The full text of each article was critically reviewed, and data interpretation was performed. Results Omeprazole has actual adverse influences on the pharmacokinetics of medications such as diazepam, carbamazepine, clozapine, indinavir, nelfinavir, atazanavir, rilpivirine, methotrexate, tacrolimus, mycophenolate mofetil, clopidogrel, digoxin, itraconazole, posaconazole, and oral iron supplementation. Meanwhile, low efficacy of omeprazole treatment would be anticipated, as omeprazole elimination could be significantly induced by comedicated efavirenz and herb medicines such as St John’s wort, Ginkgo biloba, and yin zhi huang. The mechanism for DDI involves induction or inhibition of cytochrome P450, inhibition of P-glycoprotein or breast cancer resistance protein-mediated drug transport, and inhibition of oral absorption by gastric acid suppression. Sometimes, DDIs of omeprazole do not exhibit a PPI class effect. Other suitable PPIs or histamine 2 antagonists may be therapeutic alternatives that can be used to avoid adverse consequences. The degree of DDIs associated with omeprazole and clinical outcomes depend on factors such as genotype status of CYP2C19 and CYP1A2, ethnicity, dose and treatment course of precipitant
Vilar, Santiago; Hripcsak, George
Drug-target identification is crucial to discover novel applications for existing drugs and provide more insights about mechanisms of biological actions, such as adverse drug effects (ADEs). Computational methods along with the integration of current big data sources provide a useful framework for drug-target and drug-adverse effect discovery. In this article, we propose a method based on the integration of 3D chemical similarity, target and adverse effect data to generate a drug-target-adverse effect predictor along with a simple leveraging system to improve identification of drug-targets and drug-adverse effects. In the first step, we generated a system for multiple drug-target identification based on the application of 3D drug similarity into a large target dataset extracted from the ChEMBL. Next, we developed a target-adverse effect predictor combining targets from ChEMBL with phenotypic information provided by SIDER data source. Both modules were linked to generate a final predictor that establishes hypothesis about new drug-target-adverse effect candidates. Additionally, we showed that leveraging drug-target candidates with phenotypic data is very useful to improve the identification of drug-targets. The integration of phenotypic data into drug-target candidates yielded up to twofold precision improvement. In the opposite direction, leveraging drug-phenotype candidates with target data also yielded a significant enhancement in the performance. The modeling described in the current study is simple and efficient and has applications at large scale in drug repurposing and drug safety through the identification of mechanism of action of biological effects.
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.
Iyer, Geetha; Marimuthu, Sathiya Priya; Segal, Jodi B; Singh, Sonal
Although generic drugs constitute approximately 88% of drugs prescribed in the US, there are no reliable methods to identify generic drugs in the US FDA Adverse Event Reporting System (FAERS). The aim of this study was to develop an algorithm for identifying generic drugs in the FAERS. We used 1237 adverse event reports for tamsulosin, levothyroxine, and amphetamine/dextroamphetamine from the publicly available FAERS from 2011-2013, and 277 source case narratives obtained from the FDA. Two reviewers independently and in duplicate used a three-item algorithm including the following criteria: manufacturer name, New Drug Application (NDA) number/abbreviated NDA (ANDA), and specific use of the term 'generic' or 'brand' to classify the focal drug of each case report as definitely generic (two of three criteria), probably generic (one of three criteria), brand, and cannot be assessed. Inter-rater reliability was estimated using kappa coefficients, and internal consistency was estimated using Cronbach's alpha. We compared the classification of the drugs as generic versus non-generic in publicly available FAERS compared with the original case reports (reference). The focal drug was classified as generic (definite or probable) in 15.8% (39/234), 9% (67/742), and 16.7% (42/261) of tamsulosin, levothyroxine and amphetamine/dextroamphetamine cases, respectively (overall kappa 0.89, 95% confidence interval 0.85-0.93), while 37% of reports could not be classified due to incomplete information. Among the drugs classified as generics using the publicly available FAERS, we categorized 95.3% as generic drugs using the original case reports. Among those drugs that did not meet the algorithm-based definition of generic in the publicly available data, 20.9% were reclassified as generics using the original case reports. The algorithm demonstrated high inter-rater reliability with moderate internal consistency for identifying generic drugs in the FAERS, in our sample. Future efforts
Keating, Christopher; Martinez, Vicente; Ewart, Lorna; Gibbons, Stephen; Grundy, Luke; Valentin, Jean-Pierre; Grundy, David
Motility-related gastrointestinal adverse drug reactions (GADRs), such as constipation and diarrhea, are some of the most frequently reported adverse events associated with the clinical development of new chemical entities, and for marketed drugs. However, biomarkers capable of detecting such GADRs are lacking. Here, we describe an in vitro assay developed to detect and quantify changes in intestinal motility as a surrogate biomarker for constipation/diarrhea-type GADRs. In vitro recordings of intraluminal pressure were used to monitor the presence of colonic peristaltic motor complexes (CPMCs) in mouse colonic segments. CPMC frequency, contractile and total mechanical activity were assessed. To validate the assay, two experimental protocols were conducted. Initially, five drugs with known gastrointestinal effects were tested to determine optimal parameters describing excitation and inhibition as markers for disturbances in colonic motility. This was followed by a 'blinded' evaluation of nine drugs associated with or without clinically identified constipation/diarrhea-type GADRs. Concentration-response relationships were determined for these drugs and the effects were compared with their maximal free therapeutic plasma concentration in humans. The assay detected stimulatory and inhibitory responses, likely correlating to the occurrence of diarrhea or constipation. Concentration-related effects were identified and potential mechanisms of action were inferred for several drugs. Based on the results from the fourteen drugs assessed, the sensitivity of the assay was calculated at 90%, with a specificity of 75% and predictive capacity of 86%. These results support the potential use of this assay in screening for motility-related GADRs during early discovery phase, safety pharmacology assessment.
Shin, Yoo Seob; Lee, Yong-Won; Choi, Young Hwa; Park, Byungjoo; Jee, Young Koo; Choi, Sung-Kyu; Kim, Eung-Gyu; Park, Jung-Won; Hong, Chein-Soo
Patterns of prescriptions are markedly influenced by regional disease entities, medical education, culture, economic status, and available pharmaceutical companies. Features of adverse drug reactions (ADRs) may vary in different countries. In this study, we analyzed the causative drugs and clinical manifestations of spontaneously reported ADRs in Korea. Six Korean Regional Pharmacovigilance Centers collected 1418 cases of spontaneously reported adverse drug events (ADEs) by doctors, pharmacists, and nurses, and the clinical features and causative drugs were evaluated. The data were collected from general hospitals (76.5%), primary clinics, and pharmacies (23.5%). Based upon the World Health Organization (WHO)-Uppsala Monitoring Center criteria (certain-13.7%, probable-46.1%, possible-32.1%), 91.9% of the collected events were suspected to be ADRs and 15.8% of patients experienced serious ADRs. The most prevalent causative drugs were antibiotics (31.6%), followed by contrast dyes (14.0%), non-steroidal anti-inflammatory drugs (NSAIDs) (11.1%), anti-psychotics (5.4%), anti-convulsants (5.2%), cardiovascular agents (4.8%), anti-neoplastics (4.6%), and opiates and non-opiate pain killers (3.5%). Among the antibiotics, cephalosporins (8.1%) were the most common, followed by anti-tuberculosis agents (5.7%), quinolones (4.0%), vancomycin (3.1%), and penicillin (2.8%). The most common side effect was skin manifestations, which were seen in 42% of the patients, followed by neurologic manifestations (14%), gastrointestinal involvements (12.9%), generalized reactions (9.4%), and respiratory involvements (4.5%). Antibiotics, contrast dyes, and NSAIDs were the most common causative drugs for ADRs, which reflects the prescription pattern and the prevalence of diseases in Korea. These data may be useful in establishing a Korean pharmacovigilance system. 2009 John Wiley & Sons, Ltd.
Ohashi, Wataru; Tanaka, Hiroshi
Currently, pharmaceutical companies are reluctant to introduce pharmacogenomics (PGx) in their practice, since cost-benefit of PGx is obscure and methodology to use PGx in drug development has not been fully established yet. The purpose of this study is to investigate advantages obtained by introducing PGx in clinical trials. Particularly, taking Warfarin as an example, we investigate benefits of Enrichment effect that raises response rate of the drug by PGx. When response rate is raised by only 5%, cost of a clinical trial can be reduced to about 40% of a conventional clinical trial. Furthermore, since period necessary for a trial also can be reduced, development period can be shortened by about 750 days. In summary, PGx enables earlier launch of a drug with less cost, representing benefit to pharmaceutical companies, patients and public as a whole.
Bagal, Sharan; Bungay, Peter
Some drug discovery approaches can benefit from restricting the access of compounds to the central nervous system (CNS) to minimise the risk of side-effects. Designing compounds that act as substrates for efflux transporters in the blood–brain barrier can achieve CNS restriction without significantly impairing absorption in the intestine. In vitro assays can be deployed to optimise a balance between passive permeability and active efflux via the ABC family transporters P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2) whilst in vivo estimates of distribution of unbound concentrations of drug are needed to understand pharmacologically relevant exposure in peripheral and central compartments. This strategy can deliver significant CNS restriction whilst retaining good oral bioavailability, cell penetration and pharmacological activity. The possible risks of targeting P-gp and BCRP in orally delivered drugs are discussed.
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
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.
YOSHIMASU, T; NISHIDE, T; SEO, N; HIROI, A; OHTANI, T; UEDE, K; FURUKAWA, F
The anticancer agent 5-fluorouracil (FU) frequently induces cutaneous lupus erythematosus (LE) lesions on sun exposed sites. Based on this observation, we have tried to establish a cutaneous LE model of C57BL/6 J (B6) mice, B6 T cell receptor (TCR)-α–/– mice and B6 TCR-δ–/– mice treated with FU and/or ultraviolet B light (UVBL) in order to clarify the role of T cells and the cytokine profile of cutaneous lupus lesions. Cutaneous LE-like skin lesions could be induced in TCR-α–/– mice with low FU (0·2 mg) plus UVBL, and in B6 mice treated with a high dose of FU (2·0 mg) plus UVBL. In contrast, low FU plus UVBL induced such skin lesions in TCR-δ–/– mice at a very low incidence. Specifically, the skin lesions of TCR-α–/– mice with low FU plus UVBL appeared more rapidly and were more severe than lesions in B6 mice. The former had the common characteristic features of human chronic cutaneous LE such as typical histology, positive IgG at the dermoepidermal junction, low antinuclear antibody and low mortality. Furthermore, a Th1 response was induced in the development of drug-induced cutaneous LE. FU and UVBL-induced cutaneous LE-like eruption is an excellent model for better understanding the pathomechanisms of skin lesion development in LE. PMID:15086387
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
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.
Wang, Chen; Zimmermann, Michael T.; Chute, Christopher G.; Jiang, Guoqian
The underlying molecular mechanisms of adverse drug events (ADEs) associated with cancer therapy drugs may overlap with their antineoplastic mechanisms. In a previous study, we developed an ADE-based tumor stratification framework (known as ADEStrata) with a case study of breast cancer patients receiving aromatase inhibitors, and demonstrated that the prediction of per-patient ADE propensity simultaneously identifies high-risk patients experiencing poor outcomes. In this study, we aim to evaluate the ADEStrata framework with a different tumor type and chemotherapy class – ovarian cancer treated with platinum chemotherapeutic drugs. We identified a cohort of ovarian cancer patients receiving cisplatin (a standard platinum therapy) from The Cancer Genome Atlas (TCGA) (n=156). We demonstrated that somatic variant prioritization guided by known ADEs associated with cisplatin could be used to stratify patients treated with cisplatin and uncover tumor subtypes with different clinical outcomes. PMID:26306234
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
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
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
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.
Liu, Mei; Cai, Ruichu; Hu, Yong; Matheny, Michael E; Sun, Jingchun; Hu, Jun; Xu, Hua
Adverse drug reaction (ADR) can have dire consequences. However, our current understanding of the causes of drug-induced toxicity is still limited. Hence it is of paramount importance to determine molecular factors of adverse drug responses so that safer therapies can be designed. We propose a causality analysis model based on structure learning (CASTLE) for identifying factors that contribute significantly to ADRs from an integration of chemical and biological properties of drugs. This study aims to address two major limitations of the existing ADR prediction studies. First, ADR prediction is mostly performed by assessing the correlations between the input features and ADRs, and the identified associations may not indicate causal relations. Second, most predictive models lack biological interpretability. CASTLE was evaluated in terms of prediction accuracy on 12 organ-specific ADRs using 830 approved drugs. The prediction was carried out by first extracting causal features with structure learning and then applying them to a support vector machine (SVM) for classification. Through rigorous experimental analyses, we observed significant increases in both macro and micro F1 scores compared with the traditional SVM classifier, from 0.88 to 0.89 and 0.74 to 0.81, respectively. Most importantly, identified links between the biological factors and organ-specific drug toxicities were partially supported by evidence in Online Mendelian Inheritance in Man. The proposed CASTLE model not only performed better in prediction than the baseline SVM but also produced more interpretable results (ie, biological factors responsible for ADRs), which is critical to discovering molecular activators of ADRs.
Teixeira, Marcus Zulian
Supported in the Hippocratic aphorism primum non nocere, the bioethical principle of non-maleficence pray that the medical act cause the least damage or injury to the health of the patient, leaving it to the doctor to assess the risks of a particular therapy through knowledge of possible adverse events of drugs. Among these, the rebound effect represents a common side effect to numerous classes of modern drugs, may cause serious and fatal disorders in patients. This review aims to clarify the health professionals on clinical and epidemiological aspects of rebound phenomenon. A qualitative, exploratory and bibliographic review was held in the PubMed database using the keywords 'rebound', 'withdrawal', 'paradoxical', 'acetylsalicylic acid', 'anti-inflammatory', 'bronchodilator', 'antidepressant', 'statin', 'proton pump inhibitor' and 'bisphosphonate'. The rebound effect occurs after discontinuation of numerous classes of drugs that act contrary to the disease disorders, exacerbating them at levels above those prior to treatment. Regardless of the disease, the drug and duration of treatment, the phenomenon manifests itself in a small proportion of susceptible individuals. However, it may cause serious and fatal adverse events should be considered a public health problem in view of the enormous consumption of drugs by population. Bringing together a growing and unquestionable body of evidence, the physician needs to have knowledge of the consequences of the rebound effect and how to minimize it, increasing safety in the management of modern drugs. On the other hand, this rebound can be used in a curative way, broadening the spectrum of the modern therapeutics. Copyright © 2012 Elsevier Editora Ltda. All rights reserved.
Liu, Mei; Cai, Ruichu; Hu, Yong; Matheny, Michael E; Sun, Jingchun; Hu, Jun; Xu, Hua
Objective Adverse drug reaction (ADR) can have dire consequences. However, our current understanding of the causes of drug-induced toxicity is still limited. Hence it is of paramount importance to determine molecular factors of adverse drug responses so that safer therapies can be designed. Methods We propose a causality analysis model based on structure learning (CASTLE) for identifying factors that contribute significantly to ADRs from an integration of chemical and biological properties of drugs. This study aims to address two major limitations of the existing ADR prediction studies. First, ADR prediction is mostly performed by assessing the correlations between the input features and ADRs, and the identified associations may not indicate causal relations. Second, most predictive models lack biological interpretability. Results CASTLE was evaluated in terms of prediction accuracy on 12 organ-specific ADRs using 830 approved drugs. The prediction was carrie