Frequent Adverse Drug Reactions Research Articles

Safety of gadoxetate disodium: Results from the clinical phase II–III development program and postmarketing surveillance

To summarize the safety data of gadoxetate disodium, reported in 12 Phase II and III clinical development studies and in the postmarketing surveillance database. Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. Gadoxetate disodium for liver MRI has an excellent safety profile.

Adverse Reactions Associated with Oral and Parenteral Cephalosporin Use: A Retrospective Population-Based Analysis

Population-based, route-specific, data on cephalosporin-associated new drug “allergy” reports and serious adverse drug reaction (ADR) incidence is rare. We determined the incidence of new cephalosporin-associated “allergy” reports and serious ADRs. All cephalosporins administered to Kaiser Permanente Southern California healthplan members between 1-1-2010 and 12-31-2012, new cephalosporin-associated “allergy” reports, and serious ADRs were identified. There were 622,456 healthplan members exposed to 901,908 courses of oral cephalosporins and 326,867 healthplan members exposed to 487,630 courses of parenteral cephalosporins over the 3-year study interval. New cephalosporin “allergy” reports were more frequent in females than males, 0.56% [95% CI, 0.54% to 0.57%] versus 0.43% [95% CI, 0.41% to 0.44%], per course (p < 0.0001). The most frequent serious cephalosporin-associated ADRs were Clostridium difficile (Cdiff) within 90 days (0.91%), nephropathy within 30 days (0.15%), and all cause death within 1 day (0.10%). All were un-correlated to drug “allergy” history. Physician-documented cephalosporin-associated anaphylaxis occurred with 5 oral [95% CI, 1 in 1,428,571 to 1 in 96,154] and 8 parenteral [95% CI, 1 in 200,000 to 1 in 35,971] exposures (p = 0.0761). There were 3 cephalosporin-associated serious cutaneous adverse reactions (SCARs) [95% CI, 0 to 1 in 217,291] documented. All were also associated with another antibiotic used at the same time as the implicated cephalosporin. Cephalosporins are widely and safely used, even in individuals with a history of penicillin “allergy”. Physician-documented cephalosporin-associated anaphylaxis and SCARs are rare compared to Cdiff within 90 days, nephropathy within 30 days, and all cause death within one day.

Development, implementation, and analysis of adverse drug reaction monitoring system in a rural tertiary care teaching hospital in Narketpally, Telangana

Background: Adverse drug reactions (ADR) are the fourth leading cause of mortality and a great concern in therapeutics. Pharmacovigilance is more important in India as the health care system is inadequate with poor doctor-patient ratio, high incidence of self-medication, and presence of counterfeit drugs. The present study was conducted with the aim of analyzing the pattern of ADR occurring in a rural tertiary care hospital with a newly established pharmacovigilance center and to identify the most frequent ADRs, common drugs implicated and severity of reactions.Methods: A non-interventional observational prospective study was conducted over a year. The red boxes for dropping the filled yellow ADR forms were installed in all the wards and outpatient departments. Additional information and missing data were obtained personally by either consulting the physician or through case sheets.Results: The most common class of drugs implicated in the causation of ADRs was antimicrobials (52%), followed by drugs acting on the central nervous system. The most commonly observed ADRs were dermatological Type B reactions. The majority of the reactions belonged to possible or probable category, but no reaction was categorized as definite.Conclusion: Dermatological reactions are the most common ADR occurring in our hospital and antimicrobials are the most common causative drugs. The reporting rate was adequate, and there is still a need for increasing the awareness and knowledge about ADR reporting system and pharmacovigilance for promoting the safe use of drugs.

Systematic analysis of the associations between adverse drug reactions and pathways.

Adverse drug reactions (ADRs) are responsible for drug candidate failure during clinical trials. It is crucial to investigate biological pathways contributing to ADRs. Here, we applied a large-scale analysis to identify overrepresented ADR-pathway combinations through merging clinical phenotypic data, biological pathway data, and drug-target relations. Evaluation was performed by scientific literature review and defining a pathway-based ADR-ADR similarity measure. The results showed that our method is efficient for finding the associations between ADRs and pathways. To more systematically understand the mechanisms of ADRs, we constructed an ADR-pathway network and an ADR-ADR network. Through network analysis on biology and pharmacology, it was found that frequent ADRs were associated with more pathways than infrequent and rare ADRs. Moreover, environmental information processing pathways contributed most to the observed ADRs. Integrating the system organ class of ADRs, we found that most classes tended to interact with other classes instead of themselves. ADR classes were distributed promiscuously in all the ADR cliques. These results reflected that drug perturbation to a certain pathway can cause changes in multiple organs, rather than in one specific organ. Our work not only provides a global view of the associations between ADRs and pathways, but also is helpful to understand the mechanisms of ADRs.

Safety issues of current analgesics: an update.

Pain represents a complex experience which can be approached by various medicines. Non-opioid and opioid analgesics are the most common drugs used to manage different types of pain. The increased attention nowadays to pain management entailed concomitantly more frequent adverse drug reactions (ADRs) related to analgesic use. Drug-drug interactions can be sometimes responsible for the adverse effects. However, a significant proportion of analgesic ADRs are preventable, which would avoid patient suffering. In order to draw the attention to analgesics risks and to minimize the negative consequences related to their use, the present review comprises a synthesis of the most important safety issues described in the scientific literature. It highlights the potential risks of the most frequently used analgesic medicines: non-opioid (paracetamol, metamizole, non-steroidal anti-inflammatory drugs) and opioid analgesics. Even if there is a wide experience in their use, they continue to capture attention with safety concerns and with potential risks recently revealed. Acknowledging potential safety problems represents the first step for health professionals in assuring a safe and efficient analgesic treatment with minimum risks to patients. Taking into consideration all medical and environmental factors and carefully monitoring the patients are also essential in preventing and early detecting analgesic ADRs.

Hepatotoxicity and Changes in Liver Enzymes Due to Use of Non-Steroidal Anti Inflammatory Drugs (NSAIDs) in Non-Traumatic Musculoskeletal Painful Disorders

The present study aims at critical analysis and investigation of liver function test and hepatotoxity with use of NSAIDs in patients of Non- Traumatic musculoskeletal painful disorders. NSAIDs are most commonly used by medical fraternity worldwide for relief from acute, recurring or chronic pain conditions and are easily available in India in many forms over-the-counter analgesic, sometimes resulting in adverse drug reactions (ADR). The use of NSAIDs and gastrointestinal and renal disturbance is well known. The most frequent ADR due to NSAIDs use was gastrointestinal effects leading to discontinuation of treatment The liver plays a central role in drug metabolism. However, little is known about the cause and effect of NSAIDs on liver and liver enzymes. Most NSAIDs induce hepatic toxicity are due to individual patient susceptibility (idiosyncrasy), and intrinsic associated with mainly hepatocellular tissue. Hepatic toxicity response ranges from asymptomatic or transient derangement in liver function test to fulminant liver damage. The hepatotoxicity due to risk factors associated with NSAID toxicity must be kept in mind by physicians whenever prescribing NSAIDs, because much of underreporting is usually due to transient and asymptomatic effects on liver.

Gastrointestinal Adverse Effects due to Use of Non-Steroidal Anti- Inflammatory Drugs (NSAIDs) in Non-Traumatic Painful Musculoskeletal Disorders

Background: The present study aims at investigation of the gastrointestinal adverse drug reactions (ADRs) with use of NSAIDs in patients of Non-Traumatic musculoskeletal painful disorders. Our study is unique in terms that it aims at investigations and evaluations of the gastrointestinal adverse drug reactions (ADRs) with use of NSAIDs in patients of non-traumatic musculoskeletal painful disorders, where most of the concurrent and concomitant risk factors like hepatobiliary system, renal system are mostly excluded, along with a dedicated follow up of large population included in our study. Non-Steroidal anti-inflammatory drugs (NSAIDs) such as Diclofenac sodium, Ibuprofen and others are effective for non-traumatic musculoskeletal painful disorders ranging from acute to chronic conditions. NSAIDs are probably most commonly used medications by medical fraternity worldwide for relief from acute, recurring or chronic pain conditions and are easily available in India in many forms as over-the-counter analgesic. Prolonged unsupervised use of these medications leads to disturbance in achieving pain relief and risk of gastrointestinal symptoms ranging from dyspepsia to acute and chronic gastrointestinal ulcer. The most frequent ADRs due to NSAIDs use was gastrointestinal effects leading to discontinuation of treatment. The other ADRs for which NSAIDs are blamed widely are alteration of renal or cardiac parameters in a small subset of patients. Renal and cardiac side effects are well documented and evaluated by clinicians prior to administration of NSAIDs, but the gastrointestinal adverse reactions are overlooked by medical fraternity while

Interventions pharmaceutiques émises par les pharmaciens sur les médicaments psychotropes

The French Society of Clinical Pharmacy (SFPC) through the special interest group "standardization and optimization of clinical pharmacy activities" stated that the study of pharmacists' interventions (PIs) conducted during prescription analysis was a priority. The SFPC developed an internet website named Act-IP(®) (http://www.sfpc.eu/fr/) where French speaking pharmacists were able to document PIs using a normalized codification. The objective of this study was to analyze medication-related problems linked to psychotropic drugs in hospital and to investigate PIs performed during prescription analysis. This is a multicenter, retrospective, observational study using PIs involving psychotropic medications recorded between September 2006 and February 2009 on the Act-IP(®) website. Four thousand six hundred and twenty PIs recorded by 165 pharmacists in 57 hospitals were related to psychotropic drugs. Patients concerned by these drug-related problems were 64 years old on average. Seven categories of medication-related problems represented more than 69% of PIs (1.1-Non Conformity of the drug choice compared to the formulary; 4.1 Supratherapeutic dose; 5.3 Therapeutic redundancy; 6.2 Drug interaction (all levels of severity); 7.0 Adverse drug reaction; 8.3 Inappropriate drug form; 8.5 Inappropriate timing of administration). The PIs related to 9.2 Patient's non compliance, 2.0 Untreated indication and 3.2 Length of the treatment too short were infrequent (less than 1%). The most common type of intervention was the dose adjustment. Almost 45% of these PIs involved Zopiclone or Zolpidem prescription in elderly patients. Seven hundred and nine drug interactions were identified by pharmacists. The most common type of drug interaction considered the risk of cardiac arrhythmias due to antipsychotic medications. One hundred and thirty-three PIs concerned adverse drug reaction. The most frequent adverse drug reactions were a fall (36 PIs), hemorrhage/bleeding (32 PIs), drowsiness (12 PIs) and extrapyramidal syndrome (12 PIs). Antidepressant drugs were the greatest pharmacological class concerning adverse drug reaction. The overall acceptance rate was 57%. Eight hundred and seventy-four PIs (19%) were refused and 1111 (24%) were non-assessable. PIs avoids drug-related problems, such as the polyprescription of benzodiazepine or supratherapeutic dose. However, few PIs concern compliance to therapy or polyprescription of antipsychotic drugs. These two categories of medication-related problems are known to be an issue in mental health therapy. The lack of guidelines describing mental health pathology (such as the HAS guideline) is an obstacle for performing evidence-based PIs. The lack of information describing the context of the prescription is a limitation of this study. In order to improve their practice, pharmacists have to focus more on the context in which patients are evolving, and to take into account its entire situation based on Anglo-Saxon approaches. A second way is to identify clinical settings where PIs are useful and to describe PIs needed. Doctors and pharmacists should get together and talk about these clinical situations and PIs, because some may be misunderstood or disapproved by prescribers. This collaboration could take the form of a thesaurus combining clinical situation and PIs. It appears important for pharmacists to show their daily involvement in the quality of medical care. This feedback on medication problems encountered and PIs proposed should help prescribers to identify clinical situations at risk. Nevertheless, this study also suggests that progress is possible. Dialogue must allow pharmacists and physicians to delete misunderstandings about their practices.

The sociodemographic, clinical and pharmacotherapy characteristics influencing quality of life in patients with epilepsy: A cross-sectional study.

Context:Quality of life (QOL) assessment in patients with epilepsy (PWE) is increasingly recognized as an important component in the management of epilepsy.Aims:The objective of the present study was to assess influence of sociodemographic, clinical and pharmacotherapy characteristics collectively on QOL in adult PWE.Settings and Design:This was a cross-sectional, observational study in patients with confirmed diagnosis of epilepsy.Materials and Methods:QOL was assessed using modified QOLIE-10 questionnaire for epilepsy. Univariate and multiple regression analysis were done to determine factors associated with poor QOL, respectively.Results:There were 451 PWE, with a mean age 27.3 ± 8.15 years, 251 (56%) males and 191 (42%) had monthly income < 5000 Indian national rupees (INR)/month. The QOLIE score was 64.1 ± 15.97 (Mean ± SD). The univariate analysis showed factors such as lower monthly income, focal epilepsy, seizure frequency, antiepileptic drug (AED) polytherapy, conventional AEDs and frequent adverse drug reactions (ADRs) had significant negative influence on various domains of QOLIE-10 questionnaire. Multiple regression analysis showed seizure frequency as a significant predictor of most QOL domains and overall score, while ADRs as a significant predictor of all the domains. Seizure type was a predictive factor for domains like emotional well-being and overall score.Conclusion:Present findings showed patients on monotherapy had better QOL while those having lower monthly income, having focal epilepsy and who received conventional AEDs had negative influence on QOL scores. Further, higher seizure frequency and occurrence of ADRs were significant predictors of all the domains of QOL in PWE.

Arthritis and benznidazole: more closely related than we thought.

Chagas disease is a parasitic infection that leads to a significant public health problem in countries where the disease is endemic and where it is nonendemic. Benznidazole is the most commonly used drug for the etiological treatment of Chagas disease. Patients treated with benznidazole suffer frequent adverse drug reactions. Although arthralgia is common, arthritis has been reported as a very rare side effect. The objective of this study was to describe arthritis in a cohort of Trypanosoma cruzi-infected patients treated with benznidazole.

Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010.

Background:Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations.Methods:Of 169 278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed.Results:Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%), TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure.Conclusions:Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings.

Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital

The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database "Programme de Médicalisation des Systèmes d'Information" (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre. The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture-recapture method was applied to estimate the incidence of ADRs. During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of "serious" ADRs was higher in PMSI reports (74.6% vs 38.9%, p < 0.0001). The most frequent ADRs reported were musculoskeletal (12.4%) and central (11.3%) ADRs in PMSI database versus cutaneous (22.4%) and general (17.5%) ADRs in FPVDB. The most frequently suspected drugs were antineoplastic drugs (31.1%) in PMSI database versus anti-infectives (38.2%) in FPVDB. The estimated number of ADRs was 717 [95% confidence interval (CI) 513, 921], and the incidence of ADRs among admissions was 0.6% (95% CI 0.4, 0.8). Use of PMSI database improves from around 30% detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.

Understanding adverse drug reactions in older adults through drug–drug interactions

AimsThe aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug–drug interactions (DDIs) in older adults. MethodsAll ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate. ResultsAmongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%). ConclusionDDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly.

Adverse drug reactions in elderly patients following discharge from an internal medicine clinic.

The aim of this study was to evaluate the incidence and type of adverse drug reactions (ADRs) and identify risk factors for ADRs in elderly patients within 30 days following discharge from an internal medicine clinic. A prospective observational study was conducted at the Internal Medicine Clinic of University Hospital Dubrava, Zagreb, Croatia, between September 1(st) and November 30(th) 2012. Patients aged ≥ 65 years discharged from the clinic during the study period were eligible for inclusion in the study. The follow-up visit was scheduled ~ 30 days after discharge. During the visit, the patients were assessed for the occurrence of ADRs. Two independent physicians evaluated each possible ADR by using the Naranjo ADR probability scale. Multivariate logistic regression analysis was used to identify predisposing factors for ADRs. There were 209 patients included in this study. A total of 72 ADRs were detected in 63 (30.1%) patients. The most frequent ADRs were bleeding disorders associated with warfarin therapy, followed by hypoglycemia associated with antidiabetics. Five (6.9%) ADRs, which resulted in hospital admission, were classified as serious. Multivariate logistic regression analysis indicated number of prescribed drugs ≥4 and prescription of furosemide and warfarin to be associated with increased risk of ADRs. Our study showed that ADRs are an important cause of morbidity in elderly patients after hospital discharge. Judicious prescription of drugs and careful and frequent monitoring of drug therapy are necessary to reduce the risk of ADRs.

Adverse reactions associated with oral and parenteral use of cephalosporins: A retrospective population-based analysis

Few studies have provided population-based, route-specific data on allergy to cephalosporin or incidence of serious adverse drug reactions (ADRs). We investigated the incidence of new reports of cephalosporin-associated "allergy" and serious ADRs. We identified all members of the Kaiser Permanente Southern California health plan given cephalosporins (from January 1, 2010, through December 31, 2012), all new reports of cephalosporin-associated allergy, and all serious ADRs. There were 622,456 health plan members exposed to 901,908 courses of oral cephalosporins and 326,867 members exposed to 487,630 courses of parenteral cephalosporins over the 3-year study period. New reports of allergy to cephalosporin were more frequent among women (0.56%; 95% CI, 0.54% to 0.57%) than among men (0.43%; 95% CI, 0.41% to 0.44%) per course (P < .0001). The most frequent serious cephalosporin-associated ADRs were Clostridium difficile infection within 90 days (0.91%), nephropathy within 30 days (0.15%), and all-cause death within 1 day (0.10%). None correlated with history of drug allergy. Physician-documented cephalosporin-associated anaphylaxis occurred with 5 oral exposures (95% CI, 1/1,428,571-1/96,154) and 8 parenteral exposures (95% CI, 1/200,000-1/35,971) (P = .0761). There were 3 documented cephalosporin-associated serious cutaneous adverse reactions (95% CI, 0-1 in 217,291). All were associated with the use of another antibiotic at the same time as cephalosporin. Cephalosporins are widely and safely used, even in individuals with a history of penicillin allergy. Physician-documented cephalosporin-associated anaphylaxis and serious cutaneous adverse reactions are rare compared with C difficile infection within 90 days, nephropathy within 30 days, and all-cause death within 1 day.

Adherence in the treatment of patients with extensively drug-resistant tuberculosis and HIV in South Africa: a prospective cohort study.

Extensively drug-resistant tuberculosis (XDR-TB)/HIV coinfection is difficult to treat with frequent adverse drug reactions and associated with high mortality. Adherence to antiretroviral therapy (ARV) and second-line TB medications may reduce mortality, prevent amplification of drug resistance, and improve outcomes. Prospective cohort study of XDR-TB patients on treatment in KwaZulu-Natal, South Africa. Adherence to ARV and TB medications was assessed separately at baseline and monthly. Knowledge, attitudes, and beliefs were assessed at baseline. Optimal adherence was defined as self-report of taking all pills in the previous 7 days; missing any pills was defined as suboptimal adherence. Primary outcome was optimal adherence 6 months after initiation of XDR-TB treatment to TB medications, ARV, and both ("dual adherence"). One hundred four XDR-TB patients (79.8% HIV coinfected, 84.3% on ARV at enrollment) were enrolled and followed monthly (median 8 visits; interquartile range: 4-12). Six-month optimal adherence was higher for ARV (88.2%) than TB medications (67.7%) (P < 0.001). Low educational attainment, male gender, and year of enrollment were independently associated with dual suboptimal adherence. At baseline, participants indicated that XDR-TB was curable (76.0%), HIV and TB were linked (81.7%), and ARV improves TB outcomes (72.1%). Baseline knowledge, attitudes, and beliefs did not predict subsequent adherence. Medication adherence was significantly higher for ARV than for TB medications in this cohort. Short-course treatment regimens for drug-resistant TB with lower pill burden may increase adherence and improve outcomes in XDR-TB/HIV. Programmatic support for dual adherence is critical in the treatment of drug-resistant TB and HIV.

A multivariate approach linking reported side effects of clinical antidepressant and antipsychotic trials to in vitro binding affinities

The vast majority of approved antidepressants and antipsychotics exhibit a complex pharmacology. The mechanistic understanding of how these psychotropic medications are related to adverse drug reactions (ADRs) is crucial for the development of novel drug candidates and patient adherence. This study aims to associate in vitro assessed binding affinity profiles (39 compounds, 24 molecular drug targets) and ADRs (n=22) reported in clinical trials of antidepressants and antipsychotics (n>59.000 patients) by the use of robust multivariate statistics. Orthogonal projection to latent structures (O-PLS) regression models with reasonable predictability were found for several frequent ADRs such as nausea, diarrhea, hypotension, dizziness, headache, insomnia, sedation, sleepiness, increased sweating, and weight gain. Results of the present study support many well-known pharmacological principles such as the association of hypotension and dizziness with α1-receptor or sedation with H1-receptor antagonism. Moreover, the analyses revealed novel or hardly investigated mechanisms for common ADRs including the potential involvement of 5-HT6-antagonism in weight gain, muscarinic receptor antagonism in dizziness, or 5-HT7-antagonism in sedation. To summarize, the presented study underlines the feasibility and value of a multivariate data mining approach in psychopharmacological development of antidepressants and antipsychotics.

Identification of genetic variants associated with capecitabine-induced hand–foot syndrome through integration of patient and cell line genomic analyses

A primary challenge in identifying replicable pharmacogenomic markers from clinical genomewide association study (GWAS) trials in oncology is the difficulty in performing a second large clinical trial with the same drugs and dosage regimen. We sought to overcome this challenge by incorporating GWAS results from cell-based studies using the same chemotherapy as a clinical cohort. In this study, we test whether the overlap between genetic variants identified in a preclinical study and a clinical study on capecitabine is more than expected by chance. A GWAS of capecitabine-induced cytotoxicity was performed in 164 lymphoblastoid cell lines derived from the CEU HapMap population and compared with a GWAS of hand-foot syndrome (HFS), the most frequent capecitabine-induced adverse drug reaction, in Spanish breast and colorectal cancer patients (n=160) treated with capecitabine. We observed an overlap of 16 single nucleotide polymorphisms associated with capecitabine-induced cytotoxicity (P<0.001) in lymphoblastoid cell lines and HFS (P<0.05) in patients, which is a greater overlap than expected by chance (genotype-phenotype permutation empirical P=0.015). Ten tag single nucleotide polymorphisms, which cover the overlap loci, were genotyped in a second patient cohort (n=85) and one of them, rs9936750, was associated with capecitabine-induced HFS (P=0.0076). The enrichment results imply that cellular models of capecitabine-induced cytotoxicity may capture components of the underlying polygenic architecture of related toxicities in patients.

DI-093 Asymmetry of adverse drug reactions distribution between male and female patients with multiple myeloma treated with lenalidomide

BackgroundLenalidomide has a complex mechanism of action which can result in a wide range of adverse reactions, due to its effects on the cytokine network.PurposeTo check the possibility of asymmetric...

Adverse Drug Reaction Reporting Related to the Administration of Antibiotics in Hospitalized Pediatric Patients in Greece

Pharmacosurveillance during the administration of antibiotics is of extreme importance in paediatric patients given their different physiology and adverse drug reaction (ADR) profile compared to the adult population. Systematic reviews show that one in ten hospitalised children will experience ADRs. Administration of antibiotics is among the leading causes of such ADRs. The aim of this study was to assess ADRs reporting related to the administration of antibiotics in hospitalized paediatric patients in Greece. A cross-sectional study was conducted over a seven month period (January to July 2012) in paediatric departments in Greece. A self-administered questionnaire was distributed to a total of 750 health professionals providing paediatric care in 3 specialized paediatric hospitals and 33 paediatric departments in general and university hospitals. Descriptive and multivariate statistical analyses were performed. Levels of significance were two-tailed and statistical significance was set at P =0.05. Overall, 576 out of 750 questionnaires were returned completed, at a response rate of 76.8%. ADRs related to antibiotics were reported by 44.8% of nurses and 23.7% of doctors as occurring often/very often during their practice. 45% of doctors reported amoxicillin/clavulanic acid as the drug with the most frequent ADRs. Overall, 63% of nurses and 32.7% of doctors stated they had never reported ADRs. Doctors used yellow cards more often than nurses (65.2% vs 33.9%). Only 48.4% of doctors and 35.9% of nurses knew that ADR reporting constitutes part of their professional duties. ADRs following antibiotic administration are common in paediatric practice in Greece; however, underreporting remains a significant problem.