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Purpose: To evaluate the therapeutic effects of TNF-α blockers on ulcerative colitis (UC) and their safety. Methods: Randomized controlled trials (RCTs) of TNF-α blockers for treatment of UC were retrieved from databases. Heterogeneity test was performed on all data to select effects models. Finally, sensitivity analysis was carried out, and a funnel plot was drawn to evaluate publication bias. Results: A total of nine RCTs conformed to the inclusion criteria. Of 1,226 patients with UC, 806 were given a TNF-α blocker, and 420 were given placebo or other drugs as control. Infliximab was used in eight papers and adalimumab in one paper. Placebo was used in seven papers and hormones in two papers. Short-term response, short-term relief, long-term response, and long-term relief were better in the TNF-α blocker group than in the control group ( P < 0.05). TNF-α blockers decreased the colectomy rate ( P < 0.05). There were no significant differences in mucosal healing and quality of life between the two groups ( P > 0.05). The rates of adverse reactions were similar in the two groups ( P > 0.05), but the rate of severe adverse reactions was significantly lower in the TNF-α blocker group than in the control group ( P < 0.05). The funnel plot of each parameter was symmetrical with the lower part broader than the upper. Conclusions: TNF-α blockers have better therapeutic effects on moderate or severe UC, which shows little response to conventional therapy. TNF-α blockers can induce short-term response, maintain long-term clinical response and clinical relief, and decrease the colectomy rate and the severe adverse reaction rate, but they fail to improve quality of life and mucosal healing. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the quality of data reporting and statistical methods performed in drug utilization studies in the pediatric population. Methods: Drug utilization studies evaluating all drug prescriptions to children and adolescents published between January 1994 and December 2011 were retrieved and analyzed. For each study, information on measures of exposure/consumption, the covariates considered, descriptive and inferential analyses, statistical tests, and methods of data reporting was extracted. An overall quality score was created for each study using a 12-item checklist that took into account the presence of outcome measures, covariates of measures, descriptive measures, statistical tests, and graphical representation. Results: A total of 22 studies were reviewed and analyzed. Of these, 20 studies reported at least one descriptive measure. The mean was the most commonly used measure (18 studies), but only five of these also reported the standard deviation. Statistical analyses were performed in 12 studies, with the chi-square test being the most commonly performed test. Graphs were presented in 14 papers. Sixteen papers reported the number of drug prescriptions and/or packages, and ten reported the prevalence of the drug prescription. The mean quality score was 8 (median 9). Only seven of the 22 studies received a score of ≥10, while four studies received a score of <6. Conclusions: Our findings document that only a few of the studies reviewed applied statistical methods and reported data in a satisfactory manner. We therefore conclude that the methodology of drug utilization studies needs to be improved. [ABSTRACT FROM AUTHOR]

Purpose: Only 53% and 63% of studies and clinical trials results presented at congresses are published. Company-sponsored trial results are being posted on publicly accessible Web sites. We analyzed the public availability (publication or posting on a Web site) rate, time to publication, and factors predicting public availability of results of studies sponsored by a pharmaceutical company. Methods: This was a retrospective cohort study analyzing all studies conducted by GlaxoSmithKline in Spain between 2001 and 2006. Initiation and completion were defined as first participant/first visit and last participant/last visit (or their equivalents). Papers published up to 31 March 2009 were considered. Logistic regression models were used to identify factors predicting public availability of results. Results: The cohort comprised 143 studies (94 clinical trials; of these, 87 were included in international products clinical development plans). Public availability rate was 80% (114/143) for all studies and 78% (73/94) for clinical trials; publication rates were 68% and 61%, respectively. The median time to publication for all studies and trials was 27.3 and 28.4 months, respectively. Study associated to a cancelled project was the only significant factor associated with lower publication rate for all studies [odds ratio (OR) 0.069; 95% confidence interval (CI) 0.02-024; p < 0.001) and trials (OR 0.075; 95% CI 0.016-0.343; p = 0.001) and a lower public availability rate (OR 0.052; 95% CI 0.007-0.382; p = 0.004) for trial results. Therapy area, sample size, positive trial results, duration of experimental phase, and being a clinical trial did not predict publication or public availability. Conclusions: Eighty percent of studies included in this analysis are publicly available. Web site posting increases public availability rate of clinical trial results from 61% to 78%. Cancellation of projects is the single factor negatively influencing publication and public availability rates. [ABSTRACT FROM AUTHOR]

Purpose: Statin use has increased in older age groups, although there is little evidence for the benefits of statin therapy in the elderly, especially in low-risk persons. The aim of this paper is to describe recent trends in the prevalence and incidence of statin use among the Finnish older population, according to the person's estimated cardiovascular (CV) event risk. Methods: We conducted a register study covering the whole community-dwelling population of Finland, aged >70 years in 2000-2008 ( N = 883,051). Data on reimbursed purchases of statins, antidiabetic and CV drugs, and pre-existing CV diseases were retrieved from comprehensive national registers. We stratified each person into low, moderate or high CV risk category, and according to age (70-74, 75-79, and >80 years) and sex. Results: Between 2000 and 2008, the age-sex-standardized prevalence of statin use tripled from 12.2 % to 38.7 % (rate ratio 3.0, 95 % CI 3.0-3.1), and the incidence almost doubled (from 3.7 % to 6.8 %; rate ratio 1.8, 95 % CI 1.8-1.9). The prevalence and incidence of statin use were consistently highest among high-risk persons. The greatest relative increases were observed in persons aged >80 years and in those at low risk; however, the proportion of statin users at low CV risk remained the same (∼7 % of all users). Conclusions: Statin prescribing is shifting towards older age groups. A substantial increase in prevalence and incidence was seen across all risk categories, but the channeling of statin use towards high-risk persons remained unchanged. [ABSTRACT FROM AUTHOR]

Objective: Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction. Methods: Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation. Results: Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14±0.11 vs. 0.08±0.50 mg Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism. Conclusions: The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore unlikely that its use would be of clinical importance. [ABSTRACT FROM AUTHOR]

Purpose: The Dutch national guideline for Cardiovascular Risk Management advised in 2006 initiation of statin therapy in new patients with simvastatin. After the introduction of this guideline several measures were taken to increase the prescription of simvastatin in general practice. The aim of this paper is to describe the trend and interpractice variation in the relative share of simvastatin in statin prescription over a 7-year period (2003-2009) in Dutch general practices. Methods: Data were used from the National Registration Network of General Practice (LINH) in the Netherlands. We used multilevel logistic regression analysis with individuals nested within practices. We evaluated the variance at different time points by the intra-class correlation (ICC). Results: The share of simvastatin prescriptions of all statin prescriptions increased from 40% in 2003 to 82% in 2009. While the ICC was above 20% during the periods 2005 to 2007, it decreased rapidly from 25% in 2007 to only 9% in 2009. Conclusion: Our results indicate that a combination of several intervention measures seems to have been successful. While it seems like the implementation of the guidelines alone had some effect, there was an additional effect when reimbursement measures were implemented. Furthermore, the practice seemed to have affected the adoption of the national CVRM guideline as the variation initially increased after the guideline implementation. By including information on both the proportion of simvastatin prescribed and interpractice variation, we achieved a more complete evaluation of how simvastatin prescription developed over time and how it was related to the different measures taken. [ABSTRACT FROM AUTHOR]

Background: The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 has led to an enormous surge of clinical research. So far, the speed and success rate of related drug development projects, especially of vaccines, is unprecedented. For the first time, this situation allowed for the opportunistic evaluation of a translatability score, originally proposed in 2009, in a prospective manner. Methods: Several vaccines and treatments under development in clinical phase III trials were selected for translational scoring with the translatability score. Six prospective and six retrospective case studies were performed. The scores had to be determined for a fictive date before any results of the phase III trial were reported in any media. Spearman correlation analysis and a Kruskal Wallis test were performed for statistical evaluation. Results: A significant correlation between the translatability scores and the clinical outcomes in translation was found, as judged on the basis of positive/intermediate/negative endpoint studies or market approval. The Spearman correlation analysis of all cases (r = 0.91, p < 0.001), the prospective cases alone (r = 0.93, p = 0.008), and the retrospective cases alone (r = 0.93, p = 0.008) showed a strong correlation between the score and outcome; R2 demonstrated a score-derived determination of outcomes by 86%. Conclusions: The score detects strengths and weaknesses of a given project, resulting in the opportunity of selective amelioration of a project, as well as prospective portfolio risk balancing. Its substantial predictive value that has been demonstrated here for the first time could be of particular interest for biomedical industry (pharmaceutical and device manufacturers), funding agencies, venture capitalists, and researchers in the area. Future evaluations will have to address the generalizability of results obtained in an exceptional pandemic situation, and the potential adaptations of weighing factors/items to particular therapeutic areas. [ABSTRACT FROM AUTHOR]

Background: To date, no study has identified a clear relationship between drug and a specific clinical presentation of DRESS. Objectives: To investigate the particularities of DRESS and analyze the variation of DRESS pattern according to culprit drugs. Methods: We analyzed cases of DRESS notified to the Department of Clinical Pharmacology at the University Hospital of Monastir over a 15-year period. The statistical study was performed using the comparative and multivariate analysis. Results: DRESS was mostly induced by anticonvulsive agents (27%) followed by allopurinol (26.3%) and antibiotics (24%): For anticonvulsive agents, the occurrence of lymphadenopathy was higher, renal involvement was rare and mild, and positive skin tests were more frequent. The allopurinol group was associated with the patient's older age and a lower incidence of lymphadenopathy and kidney injury. For antibiotics, eosinophilia rate was lower, time to recovery was shorter, and RegiSCAR score was low. The multivariate analysis showed a link of allopurinol with severe renal impairment, antibiotics with short latency period and low RegiSCAR score, and anticonvulsants with high propensity of positive skin test. Conclusion: We report the largest African and south Mediterranean cohort of DRESS and evaluated the usefulness of skin tests in identifying the culprit drug. The prominent finding was that latency period and renal involvement may independently differ according to culprit drugs. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to explore the relationship between proton pump inhibitors use and the risk of dementia. Methods: A comprehensive literature search was conducted in English and Chinese databases from origination to December 2018. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with a random-effects model. Subgroup analyses and sensitivity analyses were also conducted. Cochran's Q test and the I2 statistic were used to evaluate the heterogeneity. Publication bias was assessed by Begg's test and Egger's test. Results: Six studies were included, which contained a total of 166,146 participants. The overall result demonstrated a significant increase in dementia risk with proton pump inhibitors use (HR = 1.29, 95% CI = 1.12–1.49). In subgroup analyses, a significant association was detected between proton pump inhibitors use and the risk of dementia in Europe (HR = 1.46, 95% CI = 1.23–1.73) and among participants aged ≥ 65 years (HR = 1.39, 95% CI = 1.17–1.65). For the factor follow-up time ≥ 5 years, the pooled HR was 1.28 (95% CI = 1.12–1.46), demonstrating a 1.28-fold increase in the risk of dementia among proton pump inhibitors users. In the case of regional impact, participants from Europe showed an overall pooled HR estimate of 1.46 (95% CI = 1.23–1.73). There was no evidence of publication bias. Conclusions: The overall result of this meta-analysis supports the hypothesis that proton pump inhibitors increase the risk of dementia. Furthermore, high-quality cohort studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Non-medical use of benzodiazepines and Z-drugs is common; however, there is limited information available on the extent of harm related to this in Europe, as well as the relationship between misuse and availability.Aim: To describe presentations to the emergency department in Europe related to the recreational use of benzodiazepines and Z-drugs and compare regional differences in these presentations with legal drug sales of benzodiazepines and Z-drugs within each country.Methods: Emergency department presentations with recreational misuse of benzodiazepines and Z-drugs were obtained from the Euro-DEN dataset for the period from October 2013 to September 2015; data extracted included demographics, clinical features, reported coused drugs, and outcome data. Sales figures obtained by QuintilesIMS™ (Atlanta, Georgia) were used to compare regional differences in the proportion of benzodiazepines and Z-drugs in the emergency department presentations and legal drug sales across Europe.Results: Over the 2 years, there were 2119 presentations to the Euro-DEN project associated with recreational use of benzodiazepines and/or Z-drugs (19.3% of all Euro-DEN presentations). Presentations with 25 different benzodiazepines and Z-drugs were registered in all countries, most (1809/2340 registered benzodiazepines and Z-drugs, 77.3%) of which were prescription drugs. In 24.9%, the benzodiazepine was not specified. Where the benzodiazepine/Z-drug was known, the most frequently used benzodiazepines and Z-drugs were respectively clonazepam (29.5% of presentations), diazepam (19.9%), alprazolam (11.7%), and zopiclone (9.4%). The proportions of types of benzodiazepines/Z-drugs related to ED-presentations varied between countries. There was a moderate (Spain, UK, Switzerland) to high (France, Ireland, Norway) positive correlation between ED presentations and sales data (Spearman Row's correlation 0.66-0.80, p < 0.005), with higher correlation in countries with higher ED presentation rates.Conclusion: Presentations to the emergency department associated with the non-medical use of benzodiazepines and/or Z-drugs are common, with variation in the benzodiazepines and/or Z-drugs between countries. There was a moderate to high correlation with sales data, with higher correlation in countries with higher ED presentation rates. However, this is not the only explanation for the variation in non-medical use and in the harm associated with the non-medical use of benzodiazepines/Z-drugs. [ABSTRACT FROM AUTHOR]

Purpose: Unclear labeling has been recognized as an important cause of look-alike medication errors. The aim of this literature review is to systematically evaluate the current evidence on strategies to minimize medication errors due to look-alike labels.Methods: A literature search of PubMed and EMBASE for all available years was performed independently by two reviewers. Original studies assessing strategies to minimize medication errors due to look-alike labels focusing on readability of labels by health professionals or consumers were included. Data were analyzed descriptively due to the variability of study methods.Results: Sixteen studies were included. Thirteen studies were performed in a laboratory and three in a healthcare setting. Eleven studies evaluated Tall Man lettering, i.e., capitalizing parts of the drug name, two color-coding, and three studies other strategies. In six studies, lower error rates were found for the Tall Man letter strategy; one showed significantly higher error rates. Effects of Tall Man lettering on response time were more varied. A study in the hospital setting did not show an effect on the potential look-alike sound-alike error rate by introducing Tall Man lettering. Color-coding had no effect on the prevention of syringe-swaps in one study.Conclusions: Studies performed in laboratory settings showed that Tall Man lettering contributed to a better readability of medication labels. Only few studies evaluated other strategies such as color-coding. More evidence, especially from real-life setting is needed to support safe labeling strategies. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the prevalence and quality of medication schedules of elderly ambulatory patients and assessed factors associated with the availability of a medication schedule. In particular, we evaluated whether sending out a blank medication schedule template would increase the chances to use such a document. Methods: Data originate from the ESTHER study, a cohort study conducted in Saarland, Germany, in which trained study physicians performed home visits. They scanned all medication schedules, recorded the participants' medication, and performed thorough geriatric assessments. As part of the intervention, a blank medication schedule template along with a brochure was mailed to half of the participants (intervention group) 4 weeks prior to the home visits. Results: In total, 553 of 2470 participants (22.4 %) had a medication schedule. Almost two thirds of the schedules were issued by health care professionals ( n = 353, 63.8 %). These schedules offered a higher quality, although important information such as over-the-counter (OTC) medication was regularly missing. Self-reported adherence was higher in participants who used self-issued medication schedules; however, self-reported medication adherence in patients with any medication schedule was poorer compared to those patients not using a schedule. Factors associated with the availability of a medication schedule were male sex, a higher number of medicines to take, and a more complex drug regimen. The intervention did not increase the number of patients having a medication schedule. Conclusion: Only a minority of elderly ambulatory patients had a medication schedule at home. Sending out a brochure along with a blank medication schedule template did not increase the prevalence of medication schedules. [ABSTRACT FROM AUTHOR]

Background: Anti-tumor necrosis factor-alpha (TNF-α) agents have considerable advances in treating inflammatory bowel disease (IBD). These drugs carry possible risk of adverse symptoms, and no meta-analysis has examined this issue and the potential duration-response relationship. Purpose: The purpose of this study was to assess duration-response relationship between anti-TNF-α agents and risk of adverse symptoms from all available randomized control trials (RCTs) with placebo arms in IBD. Methods: PubMed, OVID, and Cochrane Library were searched to January 2015. The RCTs comparing anti-TNF-α therapy with placebo in adults with IBD were eligible. We estimated pooled relative risks (RRs) of adverse symptoms for anti-TNF-α therapy and examined both non-linear and linear duration-response relations between therapy duration and significant related adverse symptoms. Results: Twenty-three RCTs with 7325 patients were included. Adverse symptoms of headache, nausea/vomit, abdominal pain, fever, and arthralgia showed no significant relationship with anti-TNF-α therapy, respectively. Fatigue was significantly associated with anti-TNF-α therapy (RR 1.35, 95 % confidence interval (CI) 1.01-1.81), and subgroup analysis indicated that long therapy duration (>30 weeks) and combination without azathioprine (AZA) were two risk factors for the occurrence of fatigue (RR 1.74, 95 % CI 1.03-2.93; RR 1.65, 95 % CI 1.13-2.40). In the trials without AZA combination, there was a linear duration-response relationship between therapy duration and risk of fatigue ( P = 0.0217), and duration of 35 weeks increased the risk of fatigue by 50 %. Conclusion: This meta-analysis suggested a promotive effect of anti-TNF-α therapy to the occurrence of fatigue, and for the anti-TNF-α therapy without AZA combination, a linear duration-response relationship existed between therapy duration and risk of fatigue. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to develop a clinically applicable limited sampling strategy for ambulatory Caucasian kidney transplant patients to estimate area under the curve in a 24-h period (AUC) of prolonged-release tacrolimus. Methods: Twenty six kidney recipients, at least 6 months after transplantation, receiving prolonged-release tacrolimus, were enrolled. In each patient, seven blood samples were collected during a period of 24 h by use of the validated dried blood spot method. Best subset selection multiple linear regression was performed to derive limited sampling strategy (LSS). The equations were constrained to include a maximum of three samples collected within 4 h after the intake to maintain clinical applicability. To assess the predictive performance of LSS, residuals for each patient were calculated based on models fitted to a dataset where that patient was omitted. Results: The prediction formula for the AUC using the time points 0, 2, and 4 h after ingestion (C-C-C) provided the highest correlation with the AUC ( r = 0.95): AUC = 44.9 + 8.9 × C + 2.1 × C + 7.6 × C. Measures for bias and precision, i.e., median percentage prediction error (MPPE) and median absolute prediction error (MAPE), were 0.4 and 4.8 %, respectively. For the same patients, the correlation between C and AUC was worse ( r = 0.77) while MPPE and MAPE were 6.2 and 7.2 %, respectively. Conclusion: In the outpatient department, a LSS using C-C-C can be used for reliable estimation of the AUC of prolonged-release tacrolimus [ABSTRACT FROM AUTHOR]

Purpose: This is the first study that connects pharmacokinetics of tolperisone with genetic polymorphism of the enzymes involved in its metabolism in human. We aimed to identify the influence of polymorphism of two main enzymes (CYP2D6 and CYP2C19) on pharmacokinetic profile of parent drug. Methods: In a single-dose study, 28 healthy Caucasian male volunteers received an oral dose of 150 mg of tolperisone. The subjects were genotyped with respect to CYP2D6 and CYP2C19 enzymes. Plasma was sampled for up to 12 h post dose, followed by quantification of tolperisone by a fully validated HPLC-tandem mass spectrometry (MS/MS) method. The pharmacokinetic parameters were estimated using a non-compartmental method and compared statistically at level p < 0.05 across the genotyped groups. Results: High variability (exceeded 100 %) of main bioavailability parameters (AUC, AUC, C) was observed in the whole group of subjects. An essential difference in the pharmacokinetics of tolperisone of quick metabolizers whose genotype expressed wild homozygote CYP2D6 *1/*1 with respect to heterozygous *1/*4 and *1/*5 subjects was demonstrated. The mean AUC was 2.1- and 3.4-fold higher in *1/*4 and *1/*5, respectively, than in *1/*1 subjects. In case of C, the differences were greater and reached maximally 3.8 times (mean values 54.00, 98.85, and 205.20 ng/mL for CYP2D6 *1/*1, *1/*4, and *1/*5, respectively). Values of the parameters for the one subject that expressed *4/*4 genotype were even 8.5 times higher than in subjects with extensive or intermediate phenotype. Although CYP2C19 *1/*2 subjects had higher AUC, AUC and C values than *1/*1, no statistically significant differences were observed. Oral clearance (CL/F) significantly decreased by 65.7 % in heterozygous *1/*2 relative to homozygous *1/*1 extensive metabolizers. Conclusion: In this study, we first demonstrated the effect of CYP2D6 polymorphism on pharmacokinetics of tolperisone in Caucasian subjects. The contribution of CYP2C19 enzyme seems to be less important. [ABSTRACT FROM AUTHOR]

Background: Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor). Methods: We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods. Results: Terbinafine increased the area under plasma concentration-time curve (AUC) of tramadol by 115 % and decreased the AUC of M1 by 64 % ( P < 0.001). Terbinafine increased the peak concentration ( C) of tramadol by 53 % ( P < 0.001) and decreased the C of M1 by 79 % ( P < 0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively ( P < 0.001). Terbinafine reduced subjective drug effect of tramadol ( P < 0.001). Itraconazole had minor effects on tramadol pharmacokinetics. Conclusions: Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to assess the current status of non-fixed sample size designs in bioequivalence trials with a focus on two-stage adaptive approaches. Methods: We searched PubMed and Google Scholar from inception to October 2014. Regulatory guidelines were obtained from the public domain. Different methods were compared by Monte Carlo simulations for their impact on the patient's and producer's risks. Results: Add-on designs, group sequential designs and adaptive two-stage sequential designs are currently accepted to demonstrate bioequivalence in various regulations. All three approaches may inflate the patient's risk if applied inconsiderately. Direct transfer of methods developed for superiority testing to bioequivalence is not warranted. Published two-stage frameworks maintain the type I error and generally the desired power. Adaptation based on the observed T/R ratio observed in the first stage should be applied with caution. Monte Carlo simulations are an efficient tool to explore the operating characteristics of methods. Conclusions: Validated two-stage frameworks can be applied without requiring the sponsor to perform own simulations-which could further improve power based on additional assumptions. Two-stage designs are both ethical and economical alternatives to fixed sample designs. [ABSTRACT FROM AUTHOR]

Purpose: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI > 40 kg/m) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. Methods: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. Results: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL = 23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1 = 7.0 L × (LBW/60)). Conclusions: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to evaluate the association between variants in prostaglandin-endoperoxide synthase 1 ( PTGS1), prostaglandin F (2α) receptor ( PTGFR), and multidrug resistance protein 4 ( MRP4) genes and intraocular pressure (IOP) response to latanoprost in Chinese patients with primary open-angle glaucoma (POAG). Methods: The IOP response to latanoprost was evaluated by percent IOP reduction (%ΔIOP) in the treated eye with the formula %ΔIOP = (Baseline IOP values − IOP values posttreatment) / Baseline IOP values × 100 %. Polymorphisms in PTGS1 (rs3842787 and rs10306114), PTGFR (rs3753380 and rs3766355), and MRP4 (rs11568658 and rs11568668) genes were detected by direct DNA sequencing. The differences among %ΔIOP of genotypes or haplotypes were obtained by use of the Mann-Whitney U test. Association analyses were performed by multiple linear regression analysis. Results: Latanoprost were prescribed to 63 subjects, 60 of which met the inclusion/exclusion criteria for the current study. Notably, the %ΔIOP in the rs11568658 GT heterozygous genotype was 10.4 %ΔIOP lower than that of GG homozygous wild-type on day 7 (15.7 ± 2.52 vs. 26.1 ± 2.88, P = 0.003), and the corresponding results in the rs10306114 AG heterozygous genotype and AT haplotype constructed by rs3753380 and rs3766355 on day 7 were 7.2 and 10.3 %ΔIOP ( P < 0.05). Interestingly, similar results were also observed on day 30 ( P = 0.008, P = 0.006, and P = 0.002, respectively). Multiple regression analysis showed that heterozygous genotypes of rs10306114, rs11568658, and carrier of AT haplotype were significantly correlated with the lower %ΔIOP. On day 30, the above variations explained 9.9, 10.7, and 17.7 % of the total variability of %ΔIOP in the Chinese POAG patients, respectively. Conclusion: rs10306114, rs3753380, rs3766355, and rs11568658 single-nucleotide polymorphisms (SNPs) correlate with a response to latanoprost treatment in patients with POAG. These SNPs may be important determinants of variability in response to latanoprost. [ABSTRACT FROM AUTHOR]

Purpose: Clobazam (CLB) is metabolized by cytochrome P450 (CYP) 3A4 to yield N-desmethylclobazam ( N-CLB), which is further inactivated by CYP2C19. The aim of this study was to retrospectively evaluate the relationship between CYP2C19 polymorphisms and the efficacy of low-dose, add-on CLB therapy in Japanese patients with epilepsy. Methods: Fifty patients were divided into three groups according to their CYP2C19 polymorphism. CLB and N-CLB serum concentrations and seizure frequency before and after starting CLB were analyzed. Results: Extensive metabolizers (EMs, n = 11), intermediate metabolizers (IMs, n = 22), and poor metabolizers (PMs, n = 17) were included. Although the dose-normalized CLB serum concentrations were not significantly different, the dose-normalized N-CLB serum concentrations were significantly higher in PMs than in EMs or IMs. Seizure frequency was significantly decreased by the CLB therapy in PMs ( p < 0.01), but not in EMs or IMs. CLB serum concentrations did not correlate with seizure reduction rate, but median N-CLB serum concentrations were significantly higher in patients with excellent seizure control (≧90 % seizure reduction) compared to those with ≧50 % seizure reduction or with <50 % seizure reduction (1103, 341, and 570 ng/mL, respectively). Conclusions: The efficacy of low-dose CLB therapy was significantly influenced by CYP2C19 polymorphisms. Ideally, CLB therapy should be started with a low dose (2.5 mg/day) and dosage increased until N-CLB serum concentration reaches 1100 ng/mL or until the desired effect is acquired, a recommendation that is particularly important for PMs. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to investigate possible associations of the single-nucleotide variants in six genes encoding the key molecules mediating the metformin pharmacodynamic effect with the response to treatment with metformin in patients with type 2 diabetes. Methods: One hundred forty-eight drug-naïve patients with type 2 diabetes were included in the study. PRKAA1 rs249429, STK11 rs741765, PCK1 rs4810083, PPARGC1A rs10213440, HNF1A rs11086926, and CAPN10 rs3792269 variants were genotyped. The outcomes of the study were treatment success defined by achieving HbA1c <7 % and absolute reduction in HbAlc after 6-month metformin therapy. The relationships between genotypes and outcomes were evaluated in multivariate logistic and linear models. The level of statistical significance after Bonferroni correction was predefined as p < 0.0083. Results: The minor G-allele of CAPN10 rs3792269 A > G polymorphism was significantly associated with less treatment success with an odds ratio of 0.27 (95 % CI 0.12-0.62, p = 0.002) per variant allele. When the reduction in HbA1c was analyzed as a quantitative trait, G-allele was nominally associated with a smaller reduction in HbA1c (per allele β = −0.26, 95 % CI −0.50 to −0.02, p = 0.032). The reduction in HbA1c in minor allele carriers (24 % of study population) was smaller by 0.3 % in comparison with the major allele homozygotes. Conclusions: The present study provides the first observation of an association between a variant in CAPN10 gene and the response to metformin therapy in patients with type 2 diabetes. This observation needs to be replicated in further studies in different populations. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate reported ingested dose of paracetamol as a risk assessment tool in acute paracetamol overdose. Methods: Data was retrospectively obtained from a clinical toxicology database linked to one Australian and two United Kingdom hospitals. Plasma paracetamol concentrations (PPCs) of adult patients presenting with acute single ingestion, non-staggered paracetamol deliberate self-poisoning between 2006 and 2012 were recorded and plotted on a treatment nomogram to determine accuracy of reported dose ingested as an indicator for antidotal treatment. PPC plotted on a treatment nomogram with a line intersecting a 4-h concentration of 100 mg/L [667 μmol/L] was considered an indication for antidotal treatment in the UK; the corresponding Australasian population utilised a line intersecting 150 mg/L [1000 μmol/L]. Results: Of 1246 patients, 65.7 % were female and 88 % were from the UK. Fifty-two percent of patients reporting ingestion of ≥8 g paracetamol had a PPC above the 100 mg/L treatment line; PPV 52 % [95 % confidence interval (CI) 49 %, 55 %], sensitivity 81 % [95 %CI 78 %, 85 %]. Forty-four of patients reporting percent ingestion of ≥10 g had a PPC above the 150 mg/L treatment line; PPV 44 % [95 % CI 41 %, 49 %], sensitivity 85 % [95 % CI 78 %, 89 %], 72 % of patients reporting ingestion of ≥16 g had a PPC above the 100 mg/L treatment line; PPV 72 % [95% CI 67 %, 77 %], sensitivity 50 % [95 % CI 45 %, 54 %]. Overall, there was moderate correlation ( R = 0.58) between reported paracetamol dose ingested and extrapolated 4-h PPC. Conclusions: There is a positive correlation between reported ingested dose of paracetamol and subsequent chance of a PPC being above a defined treatment line; however, ingested dose of paracetamol alone is a poor risk assessment tool in accurately determining need for treatment with an antidote. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the effect of cytochrome P450 (CYP) inducers/inhibitors on the pharmacokinetics of clobazam (CLB) in patients receiving antiepileptic polypharmacy. Methods: A total of 2,504 samples obtained from 1,280 patients for routine therapeutic drug monitoring were retrospectively reviewed. These samples were grouped according to the antiepileptic drug regimens or age, and then the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB was calculated for comparison. Results: The mean CD ratio of CLB in adult patients using enzyme inducers (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) alone or in combination) was 60.8 % lower than the ratio in patients without inducers. Among the inducers, patients using PHT had a significantly lower CD ratio than patients using PB or CBZ ( p < 0.001). When PHT was combined with CBZ and/or PB, no additive or synergetic interactions was observed. The CD ratio of CLB in pediatric patients using inducers was 44.3 % lower than in patients without inducers. The influence of inducers was unchanged regardless of the child's age, and the effect was stronger in adults than in pediatric patients. Other than inducers, valproic acid (VPA) additively reduced the CD ratio, whereas concomitant use of stiripentol significantly elevated the CD ratio in patients receiving VPA. In contrast, CYP3A4 substrates, such as zonisamide and topiramate, had little influence on the CD ratio of CLB. Conclusion: We identified an impact of CYP inducers/inhibitors on the CLB concentration. Our findings demonstrated that clinically relevant interactions occur between CLB and concomitant antiepileptic drugs. [ABSTRACT FROM AUTHOR]

Purpose: The feasibility of applying the Fit fOR The Aged (FORTA) list, a drug classification combining positive and negative labeling of drugs, should be studied in geriatric patients and medication quality and clinical endpoints measured. FORTA labels range from A (indispensable), B (beneficial), C (questionable) to D (avoid). Methods: A prospective randomized controlled pilot trial was performed in hospitalized geriatric patients in whom the FORTA instrument or standard care was applied. Patients were randomly admitted to an intervention and a control ward. Changes of FORTA label distributions between admission and discharge, over- and under-prescription rates, clinical endpoints including the number of falls during the hospitalization, and Barthel Index (BI) at admission and discharge were measured. Results: Polypharmacy persisted in both groups. At discharge, a higher rate of A drugs was prescribed in the intervention group (58 patients, median age 84 years) vs. standard care (56 patients, median age 83 years, p < 0.02), and both over- and under-prescriptions were significantly lower in the FORTA than in the control group ( p < 0.03). Two (3.4 %) intervention, but 12 (21.4 %) control, patients fell at least once ( p < 0.001). The fall rate per 1,000 patient years was 1.5 ± 8.3 in the intervention and 10.6 ± 25.4 in the control group ( p < 0.004). Conclusions: This pilot study shows that the application of the FORTA list is feasible in geriatric patients. In this small study, the medication quality improved in the intervention group, but polypharmacy persisted in both groups. The fall rate was significantly lower in the intervention group. These encouraging results must be interpreted carefully. [ABSTRACT FROM AUTHOR]

Purpose: Guidelines discourage chronic benzodiazepines and related Z drugs (BZD/Zs) for sleep problems. However, prevalence among nursing home residents remains high. Discontinuing these drugs is widely recommended but seems difficult to implement. The aim of our study was to evaluate the overall feasibility in the nursing home, in terms of willingness towards discontinuation and success rate at 8 months, together with the impact on withdrawal symptoms, change in sleep quality, quality of life and medication use. Methods: In a convenience sample of five nursing homes (823 residents), we included cognitively competent residents with chronic BZD/Z use for insomnia. We investigated sleep quality [with Pittsburgh Sleep Quality Index (PSQI)], quality of life (EQ-5D) and withdrawal symptoms [Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)]. Success rate was analysed with survival analysis. Results: Of the 135 eligible residents, both general physician (GP) and resident were willing to initiate discontinuation in 38 residents. Reasons for refusing to initiate discontinuation among GPs was the unmotivated patient and among residents the reluctance towards change. At 8 months, 66.0 % were successful discontinuers, with the subjective PSQI component evolving favourably ( p = 0.013) and a decreasing number of midnight awakenings ( p = 0.041). In the relapse group ( n = 13), the quality of life decreased ( p = 0.012), with mainly an increase of problems with activities and pain/discomfort. In both groups, the withdrawal symptoms, functionality and medication use did not change. Conclusion: Discontinuation of chronic BZD/Z use is feasible in the nursing home setting without noticeable withdrawal symptoms, without a switch in medication use, without detrimental effect on quality of life and with a positive effect on the self-perceived sleep quality. [ABSTRACT FROM AUTHOR]

Purpose: We examined the effect of a single apple juice intake on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese subjects. Methods: In a randomized two phase, open-label crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or apple juice. For the uptake studies, oocytes expressing organic anion-transporting polypeptide 2B1 (OATP2B1) were incubated with 100 μM ( R)- and ( S)-fexofenadine in the presence or absence of 10 % apple juice. Results: One-time ingestion of apple juice significantly decreased the area under the plasma concentration-time curve (AUC) for ( R)- and ( S)-fexofenadine by 49 and 59 %, respectively, and prolonged the time to reach the maximum plasma concentration ( t) of both enantiomers ( P < 0.001). Although apple juice greatly reduced the amount of ( R)- and ( S)-fexofenadine excretion into urine (Ae) by 54 and 58 %, respectively, the renal clearances of both enantiomers were unchanged between the control and apple juice phases. For in vitro uptake studies, the uptake of both fexofenadine enantiomers into OATP2B1 complementary RNA (cRNA)-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for ( R)-fexofenadine. In addition, apple juice significantly decreased the uptake of both enantiomers into OATP2B1 cRNA-injected oocytes. Conclusions: These results suggest that OATP2B1 plays an important role in the stereoselective pharmacokinetics of fexofenadine and that one-time apple juice ingestion probably inhibits intestinal OATP2B1-mediated transport of both enantiomers. In addition, this study demonstrates that the OATP2B1 inhibition effect does not require repeated ingestion or a large volume of apple juice. [ABSTRACT FROM AUTHOR]

Aims: For market approval, new drug formulations (test) must demonstrate bioequivalence (BE) to at least one approved formulation (reference). If several formulations of a drug are already on the market, one might have to show BE to more than one reference formulation. Similarly, if several test formulations have shown BE to a reference formulation, it will be of interest whether the test formulations are bioequivalent to each other. Methods: An enhanced statistical model to assess BE indirectly through a network meta-analysis is provided. Statistical properties of a parallel and a bridging approach are derived, in particular the relative statistical efficiency of the two approaches. The analysis is illustrated using individual subject data from two 3×3 crossover trials of metformin formulations, which have one of the formulations in common. Results: The parallel estimate of relative bioavailability is confounded with between-trial differences, while the bridging estimate is not. The standard errors of the formulation differences using the bridging approach are smaller than the standard errors using the parallel approach if the within-subject correlation in each trial of the network is larger than 0.5. This is the condition for a crossover trial to be more efficient than a parallel trial, and thus is usually fulfilled in pharmacokinetic crossover trials. Conclusions: Indirect BE assessment offers the opportunity to efficiently determine the relative bioavailability of drug formulations that have not been studied in the same randomized BE trial. The methodology developed here allows estimating formulation differences across a larger network. [ABSTRACT FROM AUTHOR]

Purpose: Network meta-analysis (NMA) is a new technique that allows multiple treatment comparisons and provides estimates of effect sizes for all possible pair-wise comparisons. Several NMAs of antiepileptic drug (AED) efficacy and tolerability in individuals with refractory focal epilepsy, however, came to non-specific and, in some cases, divergent conclusions. We review some clinical factors that may be responsible for these inconsistent findings. Results: A major issue is the small number of individuals included in the meta-analyses with consequent wide confidence intervals and lack of ability to achieve significant results. Further issues are lack of robustness of the measured efficacy outcome-the responder ratio (the percentage of individuals with a >50 % improvement in seizure frequency); the selection of randomized studies (RCTs) included, i.e., the inclusion of studies with heterogeneous populations (children and adults); and inclusion of people treated with different doses of the experimental drug. Some methods of analysing data from RCTs, such as the last observation carried forward (LOCF) analysis, the choice of different phases of the study to compare to baseline, and the year in which the trial was conducted, selectively affect measurement of efficacy outcomes. Titration speed and other methodological aspects selectively affect tolerability. Conclusion: Several factors restrict the analysis of clinically useful estimates of the comparative efficacy of AEDs, while analysis of tolerability may be easier to accomplish. [ABSTRACT FROM AUTHOR]

Purpose: Data mining in spontaneous reporting databases generates large numbers of signals of disproportionate reporting (SDRs) that need to be prioritised for assessment. The pharmacological relevance of drug-event associations is not considered in SDR prioritisation algorithms. This aimed to propose and test a pharmacological score for SDR prioritisation. Methods: The Pharmacological Score for SDRs Prioritisation (PS-SP) was developed using a Delphi approach. An expert group agreed that PS-SP should include general criteria concerning SDRs and criteria concerning pharmacological relevance, and that criteria should be weighted for their risk representation. Once defined, the PS-SP was tested for prioritisation of SDRs for extrapyramidal syndrome in the French Pharmacovigilance database; the SDR classification was compared to that obtained using a traditional disproportionality approach. Results: For a given drug, the general criteria retained were the reporting rate of the adverse drug reaction (ADR) and value of the 95% confidence interval (CI) lower boundary of the Reporting Odds Ratio (ROR). Pharmacological criteria consisted of the ADR reporting rate without concomitant at-risk drugs or those indicated for ADR treatment, and the value of the ROR 95% CI lower boundary as estimated in the subset of reports concerning drugs from the same therapeutic and then pharmacological class. Compared with traditional disproportionality, PS-SP prioritised specific drugs within congeners: metoclopramide, indoramin, and trimetazidine appeared as outliers within their classes; conventional antipsychotics had higher prioritisation than atypical antipsychotics. Conclusion: The pilot evaluation of PS-SP performed in extrapyramidal syndrome advocates for the use of pharmacological criteria in SDR prioritisation algorithms. [ABSTRACT FROM AUTHOR]

Purpose: We sought to estimate the prevalence of potentially inappropriate prescriptions (PIP) and potential prescribing omissions (PPOs) using a subset of the STOPP/START criteria in a population based sample of Irish adults aged ≥65 years using data from The Irish Longitu Dinal Study on Ageing (TILDA). Methods: A subset of 26 PIP indicators and 10 PPO indicators from the STOPP/START criteria were applied to the TILDA dataset. PIP/PPO prevalence according to individual STOPP/START criteria and the overall prevalence of PIP/PPO were estimated. The relationship between PIP and PPOs and polypharmacy, age, gender and multimorbidity was examined using logistic regression. Results: The overall prevalence of PIP in the study population ( n = 3,454) was 14.6 %. The most common examples of PIP identified were NSAID with moderate-severe hypertension (200 participants; 5.8 %) and aspirin with no history of coronary, cerebral, or peripheral vascular symptoms or occlusive event (112 participants; 3.2 %). The overall prevalence of PPOs was 30 % ( n = 1,035). The most frequent PPO was antihypertensive therapy where systolic blood pressure consistently >160 mmHg ( n = 341, 9.9 %), There was a significant association between PIP and PPO and polypharmacy when adjusting for age, sex and multimorbidity (adjusted OR 2.62, 95 % CI 2.05-3.33 for PIP and adjusted OR 1.46, 95 % CI 1.23-1.75 for prescribing omissions). Conclusion: Our findings indicate prescribing omissions are twice as prevalent as PIP in the elderly using a subset of the STOPP/START criteria as an explicit process measure of potentially inappropriate prescribing and prescribing omissions. Polypharmacy was independently associated with both PPO and PIP. Application of such screening tools to prescribing decisions may reduce unnecessary medication, related adverse events, healthcare utilisation and cost. [ABSTRACT FROM AUTHOR]

Purpose: In previous studies from the Swedish Medical Birth Register, a possible association between erythromycin therapy and an increased risk for cardiovascular defects was found. Other studies using different methodology have not verified this observation. The finding resulted in a warning for the use of erythromycin in early pregnancy, followed by a marked decline in such use. The present study was conducted to follow up on the previous observations and to find methodological explanations for the variation in results in these different published studies. Methods: Data on Swedish women who gave birth during the period 1996-2011 were studied using the drug information in the Medical Birth Registry, obtained from midwife interviews conducted toward the end of the first trimester. Data on the presence of congenital malformations were ascertained from national health registers. Odds ratios were then determined using the Mantel-Haenszel methodology. Results: A persistent association was seen between erythromycin use and the occurrence of cardiovascular defects, with a risk estimate of 1.70 (95 % confidence interval (CI): 1.26-2.39), of similar strength during the first and last 8 years of observation. We discussed the contradictory findings of the other published studies and pointed out possible methodological problems that may explain the absence of an effect in studies based on prescription registers. Conclusions: Our study verified an association between early pregnancy erythromycin use and infant cardiovascular defects; most defects were mild. The cause of this association is unclear. [ABSTRACT FROM AUTHOR]

Purpose: To analyse the prevalence rate of antibiotics and anti-asthmatics in children and adolescents at the healthcare district level. Methods: Data sources were three regional prescription databases. A total of 175 healthcare districts (3.3 million children/adolescents) participated in the study, providing data for the year 2008. Prevalence rate was standardised by age. The ANOVA test was used to compare prevalence rates of districts in the three regions. The standardised prevalence ratio (SPR) was calculated for each district and a map of the index was elaborated. The correlation among latitude, average annual income per inhabitant, hospitalisation rate, number of paediatricians per 1,000 resident children and prevalence rate was evaluated by district (Spearman's test). Results: The antibiotic prevalence rate was, on average, 47.9 % (34.0 to 67.9 % between districts), while the anti-asthmatic prevalence was 21.4 % (11.7−35.6 %). The prevalence was higher in districts from the southern regions (antibiotics F = 92.1, anti-asthmatics F = 107.5; p < 0.001). There was a significant correlation between the prevalence of antibiotics and anti-asthmatics (r = 0.77 p < 0.001), and the prevalence of both was inversely related to latitude (respectively r = −0.71, −0.72; p < 0.001) and average income (r = −0.77, −0.73; p < 0.001). Children/adolescents living in districts in the lower quintile of average income were more exposed to antibiotic (OR = 1.75; 1.74-1.77) and anti-asthmatic (OR 1.56, 1.55-1.57) prescriptions. Conclusions: A lower income at the district level is related to higher antibiotic and anti-asthmatic drug prescription rates. Local socio-economic inequities can concur in prescribing distribution and must be considered when planning educational interventions to reduce over-prescription. [ABSTRACT FROM AUTHOR]

Purpose: Concerns have been raised about the abuse potential of pregabalin. Therefore, the aim of our study was to characterize patients dispensed pregabalin at higher than the maximum allowed dose in a cohort study based on data extracted from Swedish national registers. Methods: All patients dispensed at least three prescriptions of pregabalin between July 2006 and December 2009 were included ( n = 48,550). The daily dose was defined as the amount of pregabalin dispensed divided by the number of days between the second and third dispensings. Associations between sociodemographic and clinical variables and dispensing pregabalin at a dose exceeding the maximum daily allowed dose (600 mg) were investigated in multivariate regression models. Results: Of the patients dispensed pregabalin during the study period, 8.5 % were dispensed a dose that exceeded the maximum daily allowed dose. A previous addictive disorder drug treatment or diagnosis was present in 20 and 31 % of patients dispensed pregabalin within and exceeding the recommended dose range, respectively. Our analysis revealed that those patients at increased risk of being dispensed pregabalin at higher than the maximum allowed dose were male [adjusted odds ratio (aOR) 1.40, 95 % confidence interval (CI) 1.31-1.49], were between 18 and 29 years of age compared with those aged ≥65 years (aOR 1.62, 95 % CI 1.45-1.82), had a low income (aOR 1.24, 95 % CI 1.10-1.40), had epilepsy compared with no diagnosis (aOR 1.41, 95 % CI 1.10-1.81), had a previous substance use disorder treatment or diagnosis (aOR 1.41, 95 % CI 1.31-1.52) or had previously been dispensed high doses of drugs with abuse potential (aOR 1.77, 95 % CI 1.62-1.94). Conclusion: Based on our results we conclude that patients at a high risk of addiction and patients with epilepsy are more likely to be dispensed pregabalin at higher than the maximum approved daily dose. [ABSTRACT FROM AUTHOR]

Purpose: To reveal and evaluate the efficacy and safety of intensive statin therapy in older patients (age ≥ 65 years) with coronary heart disease (CHD). Methods: Electronic databases were searched for randomized controlled trials (RCTs) that involved intensive statin therapy use in older patients with CHD. Data was extracted and used to calculate risk ratios (RR) by software Revman 5.1. Results: Five RCTs and 11,132 patients were included in. Compared with non-intensive statin therapy, intensive statin therapy had significant effect on reducing low density lipoprotein cholesterol (LDL-C) levels (55.4 %) and total cholesterol (TC) and triglyceride (Tg). Although the results showed that intensive statin therapy had no superior effect on reduction of mortality (both all-cause mortality [RR = 0.97, p = 0.65] and cardiac death [RR = 0.95, p = 0.57]) and cardiac arrest (RR = 1.09, p = 0.81), it possessed significant effects on prevention of nonfatal myocardial infarction (MI) (RR = 0.78, p = 0.008), stroke (RR = 0.72, p = 0.02) and coronary revascularization (RR = 0.69, p = 0.007). In terms of side effects, intensive statin therapy was associated with small absolute increase in incidence of drug discontinuation, due to adverse events (3.9 %) and liver enzymes abnormalities (1.7 %). And the occurrence rates of myopathy, rhabdomyolysis and creatine kinase (CK) elevation were very low. Conclusions: This results show that intensive statin therapy has excellent effects on reduction of serum lipid level including LDL-C, TC, Tg, and also on prevention of nonfatal MI, stroke and coronary revascularization with small absolute increased risk of side effects. Our analysis supports the use of intensive statin therapy in patients ≥ 65 years old with CHD. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the association of PON1 genetic variants with the susceptibility to coronary artery disease (CAD) and with the clinical endpoints in aspirin and clopidogrel (dual antiplatelet therapy)-treated Han Chinese patients with CAD after percutaneous coronary intervention (PCI). Methods: A total of 538 Han Chinese patients undergoing PCI and receiving dual-antiplatelet therapy were sequentially recruited to the study and followed for up to 1 year. Healthy controls ( n = 539) were enrolled during the same period. All study participants were genotyped for five genetic variants in PON1 and the cytochrome P450 2C19*2 mutation ( CYP2C19*2). The effect of genetic variants on disease risk and clinical outcome of major adverse cardiac events (MACE) within 1 year or bleeding within 6 months was assessed. Results: CYP2C19*2 was associated with a higher risk of MACE (adjusted P = 0.0098), but a lower risk of bleeding events (adjusted P = 0.0016). The PON1 Q192R polymorphism was significantly associated with a lower risk of bleeding events [odds ratio (OR) 0.61, 95% confidence interval (CI) 0.43-0.87, adjusted P = 0.0066). The haplotype bearing the PON1 -126C allele was associated with a higher risk to CAD (OR 1.48, 95% CI 1.04-2.09, P = 0.029) and a higher risk of bleeding events (OR 1.68, 95% CI 1.10-2.56, P = 0.017) compared to the most frequent haplotype. The transcription activity of haplotype p-162A-126C-108C in the PON1 promoter was 2.6-fold higher than that of the most frequent haplotype (p-162G-126G-108T). Conclusions: Based on these results, we suggest that the haplotype-bearing PON1 -126C allele contributes to the disease risk and the risk of bleeding events in dual antiplatelet-treated CAD patients after PCI. [ABSTRACT FROM AUTHOR]

Objective: Few studies have investigated potentially inappropriate medication (PIM) use in patients with Alzheimer's disease (AD). The aim of our study was to assess the prevalence of PIM in community-dwelling patients diagnosed with mild-to-moderate AD and identify the clinical factors associated with PIM prescriptions. Methods: REAL.FR is a 4-year, prospective, multicenter French cohort of AD patients recruited in centers of expertise. We analyzed patient baseline data at entry into the study. PIMs were assessed using the Laroche list. A multivariate logistic regression was conducted to assess factors associated with PIMs. Results: A total of 684 AD patients were enrolled in the study [mean age 77.9 ± 6.8 years, 486 (71.0 %) females]. According to the Laroche list, 46.8 % [95 % confidence interval (CI) 43.0-50.5 %] of the patients had at least one PIM. 'Cerebral vasodilators' were the most widely used class of PIM, accounting for 24.0 % (95 % CI 20.9-27.3 %) of all prescriptions, followed by atropinic drugs (17.0 %, 95 % CI 14.1-19.8 %) and long half-life benzodiazepines (8.5 %, 95 % CI 6.4-10.6 %). Atropinic drugs were associated with cholinesterase inhibitors in 16 % of patients. In the multivariate analysis, only two factors, namely, female gender [odds ratio (OR) 1.5, 95 % CI 1.1-2.2] and polypharmacy (≥5 drugs; OR 3.6, 95 % CI 2.6-4.5) were associated with prescriptions for PIMs. Conclusions: These results reveal that approximately one out of two community-dwelling patients with mild-to-moderate AD treated by AD specialists use PIMs. They also indicate that the characteristics of the disease and the pharmacodynamic/pharmacokinetic profile of the drugs prescribed are not sufficiently taken into account by physicians when prescribing for AD patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to analyse non-warfarin-associated bleeding adverse drug events reported to the Norwegian spontaneous reporting system, with characterisation of the bleeding locations, outcome and drug interactions. In addition, concordance in assessments between reporters and evaluators, trend shifts in reporting, and detection of potentially new adverse drug interaction signals were studied. Methods: Data on bleeding events reported between 1 January 2003 and 31 December 2005 were retrieved from the Norwegian spontaneous reporting system database. Results: Of 327 case reports of non-warfarin-associated bleeding events, 270 reports (82.6 %) were characterised as serious and 69 (21.1 %) had a fatal outcome. One hundred and eighty-seven bleeds (57.5 %) were gastrointestinal, 57 (17.4 %) were cerebral, and 81 (24.8 %) were from other bleeding sites. The bleeding sites differed with respect to the patient's age, drug use, diagnoses and outcomes. Of drugs associated with bleeding, nonsteroidal anti-inflammatory drugs (NSAIDs)/COX-2 inhibitors (145 reports) and acetylsalicylic acid (128 reports) were most frequently used. Only fibrinolytics were associated with increased mortality. There was a 67.4 % correlation between reporters and evaluators in assessment of drugs associated with bleeding ( P < 0.001), with considerable variation in concordance between drug groups. Conclusion: Non-warfarin-associated bleeding events are associated with substantial mortality. Old age, cerebral bleeds, number of drugs used, and use of fibrinolytics are all independently associated with increased mortality. The recognition of the bleeding risk of commonly used drugs such as acetylsalicylic acid and heparins may be insufficient among prescribers. [ABSTRACT FROM AUTHOR]

Aim: The rising prevalence of bronchial asthma has led to world-wide efforts to understand and stem this development. Cross-sectional studies appear to show that early childhood use of antibiotics may be an important contributory factor, with paracetamol as an additional suspected cause. However, mounting evidence, which is reviewed here, points to various confounding factors as the major reasons for these reported associations. Methods: PubMed and EMBASE were systematically searched for studies on associations between antibiotics and/or paracetamol with asthma and/or wheezing, published up to November 2012. A total of 64 pertinent studies were identified, 35 focusing on antibiotics, 19 on paracetamol, and ten addressing both antibiotics and paracetamol, bringing the number of relevant datasets to 74. Results: Numerous studies were cross-sectional and made no adjustment for the indication of antibiotics or paracetamol; consequently, they were unable to dismiss possible confounding by indication. Where such adjustments could be performed (mostly in longitudinal studies), they substantially weakened or entirely eliminated the association with asthma or asthma surrogates present in the unadjusted data. Conclusion: The weight of evidence of the collected studies in our review strongly suggests that the association of antibiotics with childhood asthma reflects various forms of bias, the most prominent of which is confounding by indication. Recent studies and meta-analyses support the same conclusion for paracetamol. Truly indicated antibiotics should not be withheld from infants or young children for fears they might develop asthma. Likewise, there is no sound reason to replace paracetamol as the preferred pain relief and fever medication in this age group. [ABSTRACT FROM AUTHOR]

Purpose: To describe the pattern of drug consumption among patients with dementia in a geographically defined general population in Catalonia (Spain), and to determine its association with age, gender, type of dementia and severity indicators. Methods: Cross-sectional study that included 1,894 cases of dementia registered by the Registry of Dementias of Girona from 2007 to 2009. Prescribed drugs were categorized according to the Anatomical Therapeutic Chemical (ATC) classification. A descriptive analysis of drug consumption was stratified according to age, gender, dementia subtypes and dementia severity. Binary logistic regression models were adjusted to detect the association of these variables with drug consumption according to the ATC groups. Results: The most commonly prescribed drugs were for the central nervous system (CNS) (96.4 %), cardiovascular system (79.4 %) and digestive and metabolic system categories (77.7 %). No significant differences were found between the use of nervous system drugs and age, gender, dementia subtypes or dementia severity. The use of alimentary tract and metabolism related drugs, as well as cardiovascular and blood system drugs, were positively correlated with age and secondary dementia. The prevalence of use of cardiovascular and musculoskeletal drugs was higher in women than in men (OR: 1.34; OR: 1.26 respectively). A negative association was found between the severity of dementia and the use of musculoskeletal drugs (OR: 0.71), while its use was significantly higher in the youngest patients (OR: 1.71). Conclusions: Almost all patients with dementia received a CNS drug, being at risk of inappropriate treatment. Treatment for comorbidities in patients with dementia should not be withheld on the basis of age or dementia severity, but rather on the benefit/risk ratio of its prescription. Further studies are needed to evaluate potentially inappropriate drug use and possible untreated conditions in this population. [ABSTRACT FROM AUTHOR]

Aim: To test the ability a new Spanish primary care research database (BIFAP) to capture the association between upper gastrointestinal bleeding (UGIB) and NSAIDs and other drugs and compare the results with previous studies. Methods: We performed a nested case-control study in persons aged 40-90 years old included in the period 2001-2005. Potential cases were selected through a computer search followed by an individual blinded review. Controls matched for age, sex and calendar year were randomly selected. The exposure window was defined as 0-30 days before the index date. Adjusted odds ratios were obtained through unconditional logistic regression models. Results: In a study cohort of 669,115 subjects (1,576,442 person-years) we retrieved 1,193 valid incident cases. Increased risks were found with current use of NSAIDs (RR = 1.72; 95 %CI: 1.41-2.09), metamizole (1.52; 1.09-2.13), low-dose aspirin (1.74; 1.37-2.21), other antiplatelet drugs (1.73; 1.27-2.36), and oral anticoagulants (2.00; 1.44-2.77). We did not find an increased risk with current use of oral corticosteroids (1.11; 0.66-1.86), SSRIs (1.05; 0.77-1.42), or paracetamol (1.00; 0.82-1.23). Acid-suppressing drugs reduced the risk among users of NSAIDs (0.58; 0.39-0.85), particularly in users with antecedents of peptic ulcer (0.16; 0.05-0.58). We detected a decreasing time-trend in the relative risk and the population attributable proportion associated with NSAIDs over the study period. Conclusions: The increased risk of UGIB associated with NSAIDs was lower than previously reported, which could partly be explained by methodological differences, but a decreasing burden over time of this drug safety problem is suggested. BIFAP has shown to be a valuable tool for pharmacoepidemiological research. [ABSTRACT FROM AUTHOR]

Purpose: The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case-population study, named SALT (Study of Acute Liver Transplant), is documented here. Methods: This was a multicentre, multinational retrospective case-population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005-31 December 2007). Cases were patients ≥18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals. Results: The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy. Conclusion: The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF. [ABSTRACT FROM AUTHOR]

Purpose: To re-evaluate the cardiovascular risk of lumiracoxib compared with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo in patients with osteoarthritis. Methods: We conducted a meta-analysis of randomised controlled trials of lumiracoxib versus placebo or other NSAIDs in patients with osteoarthritis reported up to January 2010. Both published and unpublished trials were included. PubMed searches using predefined search criteria (lumiracoxib AND osteoarthritis, limits: none; COX-189 AND osteoarthritis, limits: none) were used to obtain the relevant published trials. Novartis granted explicit access to their company studies and the right to use these study reports for the purposes of publication in peer reviewed journals. Endpoints were the Antiplatelet Trialists' Collaboration (APTC) endpoint and individual cardiovascular endpoints. Results: Meta-analysis of 6 trials of lumiracoxib versus placebo revealed no difference in cardiovascular outcomes. Meta-analysis of 12 trials of lumiracoxib versus other NSAIDs also revealed no difference. The pooled odds ratios were: 1.16 (95% CI 0.82, 1.63); 1.66 (95% CI 0.84, 3.29); 0.95 (95% CI 0.52, 1.76) and 1.04 (95% CI 0.60, 1.80) for the APTC endpoint, myocardial infarction, stroke and cardiovascular death respectively. Conclusions: The results suggest that there were no significant differences in cardiovascular outcomes between lumiracoxib and placebo or between lumiracoxib and other NSAIDs in patients with osteoarthritis. Wide confidence intervals mean that further research is needed in this area to confirm these findings. [ABSTRACT FROM AUTHOR]

Purpose: We sought to estimate the prevalence of potentially inappropriate prescribing (PIP) in the Northern Ireland (NI) population aged ≥70 years, to investigate factors associated with PIP and to calculate total gross cost of PIP. Methods: A retrospective cross-sectional population study was carried out in those aged ≥70 years in 2009/2010 who were in primary care in NI. Data were extracted from the Enhanced Prescribing Database, which provides details of prescribed and dispensed medications for each individual registered with a general practitioner. Twenty-eight PIP indicators from the Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) criteria were applied to these data. PIP prevalence according to individual STOPP criteria and the overall prevalence of PIP were estimated. The relationship between PIP and polypharmacy, age and gender was examined using logistic regression. Gross cost of PIP was ascertained. Results: The overall prevalence of PIP in the study population ( n = 166,108) was 34 %. The most common examples of PIP identified were proton pump inhibitors at maximum therapeutic dose for >8 weeks (17,931 patients, 11 %), non-steroidal anti-inflammatory drugs >3 months (14,545 patients, 9 %) and long-term long-acting benzodiazepines (10,147 patients, 6 %). PIP was strongly associated with polypharmacy, with those receiving seven different medications being fivefold more likely to be exposed to PIP than those on zero to three medications (odds ratio 5.04, 95 % confidence interval 4.84-5.25) The gross cost of PIP was estimated to be €6,098,419 Conclusions: Consistent with other research, the prevalence of PIP was high among the study cohort, increased with polypharmacy and was associated with significant cost. [ABSTRACT FROM AUTHOR]

Introduction: Bayesian forecasting has been shown to improve the accuracy of pharmacokinetic/pharmacodynamic (PK/PD) models by adding measured values to a population model. It could be done in real time for neuromuscular blockers (NMB) using measured values of effect. This study was designed to assess feasibility and benefit of Bayesian forecasting during a rocuronium target-controlled infusion (TCI). Methods: After internal review board (IRB) approval and informed consent, 21 women scheduled for breast plastic surgery were included. Anesthesia was maintained with propofol, alfentanil, and controlled ventilation through a laryngeal mask. Rocuronium was delivered in TCI with Stanpump software and the Plaud population model. The target effect was 50% blockade until insertion of breast prosthesis; thereafter it was set to 0%. Response to train of four (TOF) at adductor pollicis was recorded using a force transducer. In ten patients, drug delivery was based on the population model. In the others, repeated measures values were entered in the software, and the PK model was adjusted to minimize the error in predicted effect. Model precision was compared between groups using mean prediction error and mean absolute prediction error. Results: At target 50%, model accuracy was not improved with Bayesian adjustments; conversely, post-infusion errors were significantly decreased. The first two measures had the most influence on the model changes. Discussion: Below clinical utility, such adjustments may be used to explore cofactors influencing interindividual and intraindividual variability in NMB dose-response relationship. Similar tools may also be developed for drugs in which a quantitative effect is available, such as electroencephalography (EEG) for hypnotics. Implication: Real-time Bayesian forecasting combining measured values of effect with a population model is suitable to guide NMB-agent delivery using Stanpump software. [ABSTRACT FROM AUTHOR]

Purpose: To compare drug treatment changes in older hip fracture patients with and without multi-dose drug dispensing (MDD) after discharge from hospital. Methods: Hip fracture patients (aged 65 years or older) for whom the same prescribing procedure was used at discharge and at the 6-month follow-up were extracted from two patient cohorts consecutively recruited in 2008 ( n = 100) and 2009 ( n = 99), respectively. Of these hip fracture patients, 107 patients used MDD and 47 used ordinary prescriptions (OP) throughout the study period. Drug treatment was registered at discharge and at the 6-month follow-up. Each drug was classified as changed (withdrawn, dosage adjusted or added) or unchanged. The association between MDD and changes in drug treatment was analysed with generalised estimating equations (GEE). Age, sex, cognition, year of study and type of drug (fall-risk-increasing, fracture-preventing or other) were included in the model. Results: A total of 1,980 drugs were prescribed at discharge and at the 6-month follow-up to the 154 patients. Of the 1,413 drugs prescribed via MDD, 597 (43%) drugs were unchanged. The corresponding figure for drugs prescribed via OP was 166 out of 567 (29%) prescribed drugs. Analysis with GEE revealed an odds ratio (95% confidence interval) of 1.66 (1.20-2.31) to 1.77 (1.38-2.27) for a drug to be classified as unchanged when prescribed via the MDD system. Conclusions: MDD is associated with fewer changes in drug treatment compared with OP. Further studies of risks and benefits from this prescribing procedure are urged. [ABSTRACT FROM AUTHOR]

Purpose: We examined the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral S-ketamine. Methods: A randomized crossover open-label study design with two phases at an interval of 4 weeks was conducted in 12 healthy volunteers. Grapefruit juice or water was ingested 200 ml t.i.d. for 5 days. An oral dose of 0.2 mg/kg of S-ketamine was ingested on day 5 with 150 ml grapefruit juice or water. Plasma concentrations of ketamine and norketamine were determined for 24 h, and pharmacodynamic variables were recorded for 12 h. Noncompartmental methods were used to calculate pharmacokinetic parameters. Results: Grapefruit juice increased the geometric mean value of the area under the plasma ketamine concentration-time curve (AUC) by 3.0-fold (range 2.4- to 3.6-fold; P < 0.001), the peak plasma concentration (C) by 2.1-fold (range 1.8- to 2.6-fold; P < 0.001), and the elimination half-life by 24% ( P < 0.05) as compared to the water phase. The ratio of main metabolite norketamine to ketamine (AUC/AUC) was decreased by 57% ( P < 0.001) during the grapefruit phase. Self-rated relaxation was decreased ( P < 0.05) and the performance in the digit symbol substitution test was increased ( P < 0.05) after grapefruit juice, but other behavioral or analgesic effects were not affected. Conclusions: Grapefruit juice significantly increased the plasma concentrations of oral ketamine in healthy volunteers. Dose reductions of ketamine should be considered when using oral ketamine concomitantly with grapefruit juice. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to investigate the antisecretory activity of rabeprazole administered once daily in doses of 5, 10, 20, and 40 mg and different cytochrome P450 2C19 (CYP2C19) genotypes on gastric pH in healthy individuals. Additional objectives were delineating the nighttime from the daytime effect and determining the relationships between the pharmacokinetics and pharmacodynamics of rabeprazole. Methods: Eight individuals of each of the three genotypes of CYP2C19-homozygous extensive metabolizers (homo-EMs), heterozygous EMs (hetero-EMs), and poor metabolizers (PMs)-were recruited. Twenty-four individuals received a once-daily dose, with dosing interval 24 h of 5, 10, 20, or 40 mg rabeprazole for 5 days in a 4-period crossover fashion. Twenty-four-hour intragastric pH and plasma rabeprazole concentrations were determined on day 5. Results: A dose-dependent increase in median pH and in pH 4 holding time was observed across all CYP2C19 genotypes. When rabeprazole was increased from 20 mg to 40 mg, the differences and 95% confidence intervals (CIs) of nighttime pH 4 holding time between 40 mg and 20 mg in homo-EMs, hetero-EMs, and PMs were 8.0% (−5.0% − 21.0%), 28.7% (15.7% − 41.6%), and 16.9% (3.9% − 29.9%), respectively. The relationship between the area under the plasma concentration-time curve up to the last time point at which rabeprazole was quantifiable (AUC) and the pH 4 holding time could be described using a sigmoid maximum effect (E) model. Conclusions: Our data demonstrate that increasing rabeprazole dose up to 40 mg once daily results in an increasing pharmacodynamic effect, which is most apparent for the control of nocturnal gastric acid secretion. [ABSTRACT FROM AUTHOR]

Purpose: Statins have potential anti-inflammatory effects, but the association between statin use and lower incidence of pneumonia is unclear. We have therefore performed a systematic review on the risk of pneumonia in statin users versus non-users. Methods: MEDLINE and EMBASE were searched in December 2010 for controlled observational studies that reported on the risk of pneumonia in statin users. We performed a random effects meta-analysis and assessed heterogeneity using the I statistic. Results: A total of 451 citations were screened, and ultimately nine studies (4 case-control, 4 retrospective cohort, 1 prospective cohort) with more than 3 million participants were included in the meta-analysis. Pooled analysis of seven studies that reported unadjusted data failed to show a significantly reduced risk of pneumonia [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.84-1.06, p = 0.33, I = 79%] in statin users as compared to non-users. However, a significant reduction in the likelihood of pneumonia associated with statin use ( n = 8 studies, OR 0.85, 95% CI 0.75-0.97, p = 0.02, I = 81%) was found in the meta-analysis of adjusted data. Both analyses were limited by substantial statistical heterogeneity. Sensitivity analysis failed to fully clarify the source of heterogeneity, but cohort studies seemed to be less heterogenous ( n = 5 studies, OR 0.92, 95% CI 0.84-1.01, I = 43%). Conclusion: Our findings indicate that the purported benefit of statins in preventing pneumonia is inconsistent, and of low magnitude, with upper bounds of the confidence interval being close to null. In view of the substantial statistical and clinical heterogeneity in the dataset, there is no convincing evidence to support the therapeutic application of statins for reducing the risk of pneumonia. [ABSTRACT FROM AUTHOR]

Purpose: Current evidence suggests that erythropoiesis-stimulating agents (ESAs), including erythropoietin and darbepoetin, may have a direct cardio-protective effect. However, randomized controlled trials (RCTs) assessing the efficacy and safety of ESAs in patients with acute ST-segment elevation myocardial infarction (STEMI) have yielded heterogeneous results. Here, we performed a meta-analysis of RCTs to assess whether the administration of ESAs can improve cardiac functional parameters, such as left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV), and attenuate infarct size in patients with acute STEMI. Methods and results: The PubMed, EBSCO, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched for relevant RCT studies on ESAs published before May 13, 2011. A total of nine RCTs involving 1,244 participants were identified. The original data of these studies were aggregated using fixed effect models. Compared with controls, the administration of ESAs showed a slight but significant improvement in LVEF (1.38%; 95% confidence interval 0.38-2.37%; p = 0.007). However, no significant improvement in LVEDV, LVESV, and infarct size was observed, and no increase in all-cause severe adverse effect was indicated. Conclusions: Our meta-analysis indicates that the superiority of ESAs over conventional therapy in patients with acute STEMI is limited using current procedures. However, there is evidence to suggest that the timing and dosing of ESA administration may be optimized. Moreover, the long-term cardio-protective effect of ESAs in this patient population may be beneficial and worth exploring. [ABSTRACT FROM AUTHOR]

Background: Understanding the epidemiology and risk factors of adverse drug reactions (ADRs) is important in order to develop appropriate prevention strategies. This study aimed to identify risk factors associated with ADRs in hospitalised children and recommend strategies to minimise ADRs. Methods: A prospective multicentre cohort study was conducted on paediatric general medical wards in five European and non-European hospitals. ADRs were identified by intensive chart review. Multivariable logistic regression was used to investigate risk factors associated with ADRs. For the risk factor analysis, prescribed drugs were divided into high-risk and low-risk drug groups. Analgesics, anti-epileptics, antibacterials and antimycotics for systemic use, corticosteroids for systemic use and immunosuppressant agents were considered as high-risk groups whereas the remaining drug classes were defined as low-risk drug groups. Results: A total of 1,253 paediatric patients were identified [Australia ( n = 145), Germany ( n = 372), Hong Kong ( n = 138), Malaysia ( n = 291), UK ( n = 307)]. A total of 328 ADRs were observed in 16.7% of patients (186/1,115). Use of five or more low-risk drugs per patient or three or more high-risk drugs was a strong predictor for ADRs (OR 4.7, 95% CI 2.4-9.3; OR 6.5, 95% CI 2.7-16.0 respectively; p < 0.001). Older children were more likely to experience ADRs; gender was not significantly associated. Conclusion: To reduce the risk of ADRs in children, clinicians and pharmacists should aim to minimise polypharmacy and be aware of higher ADR risks associated with some drug groups. [ABSTRACT FROM AUTHOR]