ALBERT

Description: Aims We have looked for medication errors involving the use of low-dose methotrexate, by extracting information from Danish sources other than traditional pharmacovigilance databases. We used the data to establish the relative frequencies of different types of errors. Methods We searched four databases for cases involving low-dose methotrexate between 1999 and 2011: the Danish Patient Safety Databases (DPSD), controlled by the Danish National Agency for Patients’ Rights and Complaints, the Patient Compensation Association (PCA), the Danish Poison and Information Centre (DPIC), and the online database of the Department for Patient Complaints (DPC). We categorized the place where the error occurred, the processes and types of error involved, the person responsible, and the clinical outcome. Results We identified 173 errors. In 109 (63 %), either harm resulted or could not be excluded; of these, 26 (15 %) resulted in serious harm, including nine deaths (5 %); 53 (31 %) involved incorrect daily administration; and 107 (62 %) involved a dosing error. Sixteen events (9.2 %) concerned insufficient or faulty monitoring, with four serious outcomes and two deaths. Prescription errors involving daily rather than weekly administration, by hospital physicians, were most likely to result in serious outcomes, including deaths. The error mechanism was evaluated in 129 events. Action-based errors comprised 50 % and knowledge-based errors 34 %. Action-based errors were more likely to result in completed errors, whereas knowledge-based errors more often resulted in near misses. Conclusions The medication errors in this survey were most often action-based (50 %) and knowledge-based (34 %), suggesting that greater attention should be paid to education and surveillance of medical personnel who prescribe and monitor methotrexate, particularly physicians, who accounted for 40 % of the errors.

Description: Purpose To quantify pharmacokinetic (PK) and pharmacodynamic (PD) relationships of various classes of GABA A agonists in healthy volunteers, in order to investigate the sensitivity of the biomarker responses due to differing GABA A -subtype selectivity and to explore the correlation between biomarker responses and side effects of these drugs. Methods A comprehensive search was conducted for published placebo-controlled clinical studies of non- and α 1 -selective GABA A drugs in healthy volunteers. PK/PD models were developed for concentrations and biomarker outcomes (saccadic eye movement (SEM), visual analogue scale (VAS), digit symbol substitution task (DSST), and critical flicker fusion test (CFFT)) extracted from included studies. Predicted responses and equivalent doses for biomarkers (based on predicted response) were used to compare drug effects. And the relationship between biomarkers and safety was explored by linear regression. Results A total of 2237 data from 163 articles were included. Based on PK and placebo effect modeling, linear biomarker-concentration relationships well fit the data. The α 1 -selective compounds had similar equivalent doses for VAS, DSST, and CFFT (4.7–6.7 mg), which were about three to seven times lower than that for SEM (14.4–35.5 mg), while such difference was less evident for non-selective drugs. DSST had the highest correlations with incidences of somnolence and dizziness. Conclusions The integral PK/PD models of GABA A agonists were established in healthy volunteers. SEM was identified as the most sensitive biomarker in differentiating GABA A receptor α 1 subtype selective compounds. The exploratory analysis implied that different relationships existed between the drug effects on biomarkers and the adverse event profiles in healthy volunteers.

Description: Purpose Anticholinergic toxicity can arise as a result of the cumulative burden of multiple medications and metabolites rather than be caused by a single compound. In this sense, prescribing drugs with anticholinergic properties to Parkinson’s disease (PD) patients could contribute to aggravate some frequent problems of the disease, like dementia, urinary retention, falls, or constipation, among others. The main purpose of this article is to measure the total anticholinergic burden in a group of PD inpatients. Method We analyzed information from different administrative Basque Country’s healthcare databases using encrypted unique identifiers in order to detect PD patients admitted to public acute care hospital during 2011–2012. Subsequently, anticholinergic burden was measured using Duran et al.’s list. Secondarily, total anticholinergic load was assessed with the Anticholinergic Drug Scale, the Anticholinergic Risk Score, and the Anticholinergic Burden Scale. A logistic regression model was performed to study association of predictive variables with anticholinergic use. Results A high proportion of PD patients were prescribed anticholinergic drugs, with 53.6 % of admissions receiving at least one drug from Duran et al.’s “low-risk” and 10 % at least “high-risk” drug. Drugs used for non-motor symptoms and other comorbidities other than PD itself contributed significantly to anticholinergic burden, namely antidepressants, antipsychotics, urological drugs, analgesics, and antihistamines, among others. The total number of drugs and cholinesterase inhibitors were independently associated with anticholinergic drug use. Conclusions Anticholinergic burden in PD patients is significant, and is caused mostly by drugs not used for PD motor symptoms. Polypharmacy and cholinesterase inhibitors were independently associated with anticholinergic drug prescriptions.

Description: Purpose Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine. Methods A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine ( n  = 18) followed by oral vardenafil ( n  = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria. Results Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p  〈 0.001 and p  = 0.026, respectively) and pulmonary vascular resistance ( p  〈 0.001 and p  〉 0.001, respectively), and significantly increased cardiac output ( p  = 0.001 and p  = 0.005, respectively). Vardenafil reduced mPAP more than adenosine ( p  = 0.044), while adenosine resulted in higher responses of cardiac index ( p  = 0.009) and pulmonary arterial oxygen saturation ( p  = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders. Conclusions Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment.

Description: Purpose In Europe, little empirical evidence is available about over-the-counter (OTC) drug consumption and risk perceptions. The objective of this study was to describe consumers’ OTC drug use and perceptions of OTC drug safety in Germany. Methods An online survey based on a quota sample with combined strata for age, gender, and education of 300 adult German participants was conducted in June and July 2013. The survey questionnaire covered the participants’ OTC and prescription drug use, risk perceptions of OTC and prescription drugs, package leaflet reading habits, and OTC drug off-label use. Results Seven day prevalences of OTC drug use were higher in women (52.0 %) than in men (40.8 %). The risk perception of specific OTC drugs was impacted by the route of administration, the indication, and the drugs’ ingredients. Products for dermal application or plant-based products were considered ‘rather not risky’ by 82.7–96.6 % of the participants, depending on the product. Products for oral use or chemically synthesized substances were considered less safe. While 48.0 % of consumers reported always reading the package leaflet of OTC drugs, 44.5 % reported not reading it if they knew the drug or believed the drug was very safe. People, 60 years and older, reported significantly lower levels of OTC drug off-label use (9.3 %) than younger people (22.0 %). Conclusions The 7-day prevalence of OTC drug use in Germany is high, especially among women. Consumers generally have balanced perceptions regarding OTC drug safety. Behaviours and knowledge related to OTC drug use should be considered by health care providers and regulators.

Description: Purpose The study aims to quantify anaphylaxis signal for combined exposure of benzylpenicilin and qingkailing injection (QI) compared with individual exposure of the two drugs and the background risk based on all other exposures in SRS database. Methods Data used in this study were collected during 2003–2014 from China Guangdong Provincial Center of ADR Monitoring. We studied the suspected ADR reports using a case/non-case design. The cases were defined as the reactions coded by WHO-preferred terms of anaphylactic shock or anaphylactoid reaction. Reporting odds ratios (RORs) were used as a measure of disproportionality and were adjusted for age and gender to reduce confounding effects. An observed-to-expected ratio Ω was also used for interaction detection. Results The crude RORs (95 % CIs) for anaphylaxis in patients who used only benzylpenicillin or QI and those who used the two drugs concomitantly compared with patients who used neither of the two drugs were 2.50 (2.34–2.68), 1.59 (1.46–1.73), and 6.22 (3.34–11.58), respectively. The adjusted RORs (95 % CIs) were 2.48 (2.31–2.65), 1.54 (1.41–1.67), and 6.01 (3.22–11.20), respectively, after being adjusted for age and gender. The measured Ω, Ω 0 , Ω 025 , and Ω 975 was 1.03, 1.09, 0.14, and 1.71, respectively. Conclusions Case reports in the database are suggestive of a safety signal which indicates that an interaction between benzylpenicillin and QI resulting in excess risk of anaphylaxis may occur. SRS databases have a potential for signaling unknown drug–herbal interactions. More effort is needed to expand this potential.

Description: ᅟ Medical students should be better prepared for their future role as prescribers. A new educational concept to achieve this is learning by doing. This encompasses legitimate, context-based training and gives students responsibility as early as possible in their medical education. Student-run clinics (SRCs) are an example of this concept. Aim Describe the development of a new SRC for insured patients, primarily focused on medical (pharmacotherapy) education, the learner-centered student-run clinic (LC-SRC), and its feasibility. Methods Teams each comprising of three students (first, third, and fifth year) performed consultations including proposing management plans, all under the supervision of an internist. Patients were voluntary selected from the internal medicine outpatient clinic for follow-up in the LC-SRC. Feasibility was evaluated using a set of questionnaires for patients, supervisors, and students. Results In total, 31 consultations were conducted; 31 students and 4 clinical specialists participated. A pharmacotherapeutic treatment plan was drawn up in 33 % of the consultations. Patients were content with the care provided and rated the consultation with a 7.9 (SD 1.21) (1(min)-10(max)). Supervisors regarded LC-SRC safe for patients with guaranteed quality of care. They found the LC-SRC a valuable tool in medical education although it was time-consuming. Students appreciated their (new) responsibility for patient care and considered the LC-SRC a very valuable extracurricular activity. Discussion The LC-SRC is feasible, and all participants considered it to be a valuable educational activity. It offers students the opportunity to learn in a real interprofessional and longitudinal setting for their future role as prescriber in clinical practice. The benefits and learner effects need to be investigated in a larger study with a longer follow-up.

Description: Purpose STOPP and START criteria identify potential inappropriate prescribing and potential prescribing omissions. It is unknown whether STOPP/START criteria identify all drug-related problems. This study aims to determine to what extent STOPP/START correspond to drug-related problems (DRPs) identified during a full clinical medication review. Methods In 13 Dutch community pharmacies, 457 community-dwelling patients aged ≥65 years and using ≥5 drugs, received a full clinical medication review. Community pharmacists identified potential DRPs and recommendations by implicit criteria. After completion, all identified DRPs and recommendations were compared with STOPP and START criteria by investigators. Results The total number of potential DRPs identified by community pharmacists was 1656 in 457 patients (mean 3.6 per patient). Eighty-one percent of DRPs were not associated with STOPP/START criteria. The percentage of START criteria present in identified DRPs was higher than the percentage of STOPP criteria (13 vs. 5.7 %, p  〈 0.01). The implementation rate for recommendations associated with STOPP criteria was higher compared to recommendations associated with START criteria (56 vs. 39 %, p  〈 0.01). Both implementation rates of STOPP and START recommendations were lower compared to recommendations not associated with STOPP/START criteria (66 %, p  = 0.047 and p  〈 0.001, respectively). Conclusions This study shows that the majority of drug-related problems of community-dwelling older patients was not associated with STOPP/START criteria. These findings suggest that application of STOPP/START criteria in full clinical medication review should preferably be combined with implicit criteria.

Description: Purpose Quality of care is strongly influenced by evidence-based medicine, a large part of which is based on results obtained from clinical trials. If trials are conducted in secret, patient safety is at risk. Several mandates—legal, editorial, financial, and ethical—have tried to influence the disclosure of clinical trials, first by encouraging registration in publicly accessible registers and, second, by calling for the publication of results. Not all these initiatives have reached high rates of compliance, but the succession of national and international events over a few years gave an important boost to information disclosure. This article provides a chronicle of the succession of the events, from the historical calls to the recent EMA policy and WHO statement, and public consultations requested by the NIH, and the HHS, which will inevitably change the international panorama. The path of these new policies is moving towards more supervised clinical research. Individual scientific institutions can also contribute, at the local level, to such an ethical endeavor as is improving research transparency, by disclosing information on the trials coordinated by their own researchers. Results The way is long and complex, but, if everyone contributes there could be a prompt, worldwide diffusion of the findings of clinical trials, and therefore a more possible evidenced-based medicine.

Description: Purpose The present open single-centre, descriptive and comparative pharmacokinetic study aimed to investigate the efficacy of iontophoresis to enhance transdermal delivery by measuring concentration vs. time profiles of diclofenac in local tissue and in plasma in two separate study periods. Methods Period 1 determined diclofenac concentrations in both calf muscles simultaneously by using microdialysis after applying diclofenac gel topically as a single dose of 5 g with or without iontophoresis in eight healthy volunteers. In period 2, the same dose was applied to another 8 volunteers to determine plasma concentrations of diclofenac either with or without iontophoresis in a cross over design. Results In period 1, tissue concentrations were found to be under the limit of detection of 0.5 ng/ml both with and without iontophoresis in all subjects. In period 2, after iontophoresis in 75 % of study participants, plasma concentrations of diclofenac could be determined, but only in 25 % without iontophoresis. Although area under the concentration-time-curve (AUC, 187.97 ± 315.92 vs. 22.92 ± 42.44 ng*min/ml) and maximum concentration (C max , 2.06 ± 3.79 vs. 0.22 ± 0.41 ng/ml) values showed a numerically clear trend for higher values with iontophoresis compared to passive diffusion, no significant difference could be found due to high inter-individual variability. In total, 18.75 % of all subjects presented adverse events. Conclusions Despite a higher percentage of subjects showed detectable plasma levels of diclofenac after iontophoresis, iontophoresis failed to achieve potentially more effective topical concentrations. The typical mechanism of iontophoresis like electromigration, electroosmosis and increased subcutaneous circulation could be responsible for the results of the present observation. Additional clinical studies are needed to justify the transdermal delivery of diclofenac by using iontophoresis.

Description: Purpose NAD(P)H dehydrogenase, encoded by NAD(P)H quinone oxidoreductase 1 (NQO1), is an enzyme that catalyzes the reduction of quinones, including vitamin K. Given its potential role in vitamin K metabolism, this study aimed to investigate the effects of NQO1 polymorphisms on stable warfarin doses. Methods We tested a possible effect of gene polymorphisms on variability in warfarin response using 206 Korean patients with mechanical cardiac valves. Single nucleotide polymorphisms (SNPs) of NQO1 with a minor allele frequency of at least 15 % were included. Also, genotypes of vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 (CYP) 2C9, CYP4F2, gamma-glutamyl carboxylase (GGCX), and GATA4 were determined. Results NQO1 rs1800566 (C〉T) and rs10517 (C〉T) were significantly associated with stable warfarin doses. Variant homozygote carriers required lower stable warfarin doses than those with wild-type C allele in rs1800566 (4.85 ± 1.61 vs. 5.61 ± 1.94 mg; p  = 0.033), whereas patients with wild homozygote required lower doses than those with T allele in rs10517 (5.11 ± 1.73 vs. 5.75 ± 1.98 mg; p  = 0.017). Similar results were obtained from stratified analysis using VKORC1 variant homozygote carriers in both SNPs. Multivariate analysis showed that rs10517 (C〉T) increased contribution of gene variations to the overall warfarin dose variability from 42.5 to 43.8 %. Conclusion Our results demonstrate that NQO1 gene polymorphisms influence stable warfarin doses in Korean patients.

Description: Purpose Interferon beta (IFN-β) is the drug of choice for treatment of relapsing forms of multiple sclerosis and is known to reduce the frequency and severity of relapses. This systematic review determines the occurrence of neutralising antibodies (NAbs) against different formulations of IFN-β: IFN-β-1a Avonex™, IFN-β-1a Rebif™ and IFN-β-1b Betaferon/Betaseron™. Methods The databases used in the review included MEDLINE Ovid (from 1950 to March 2015), Embase Ovid (from 1980 to March 2015), CENTRAL on The Cochrane Library (2011, Issue 4) and ClinicalTrials.gov (from 1997 to March 2015). All studies that compared the efficacy of the different formulations of IFN-β in patients with relapsing forms of multiple sclerosis including IFN-β-1a Avonex™, IFN-β-1a Rebif™, IFN-β-1b Betaferon/Betaseron™ and IFN-β-1b Extavia™ were included. Results Assessment of randomised controlled trials demonstrated that Avonex™ was 76 % less likely than Rebif™ to lead to the formation of NAbs. Avonex™ was 88 % less likely than Betaferon/Betaseron™ to lead to the formation of NAbs. Similar findings were also observed in the non-randomised controlled studies, with Avonex™ having the lowest risk. The formation of NAbs was dose dependent: Avonex™ at 30 μg was 64 % less risky than Avonex™ at 60 μg. Conclusions Our data show that 2.0–18.9 % of patients developed NAbs to Avonex™, 16.5–35.4 % of patients developed NAbs to Rebif™ and 27.3–53.3 % of patients developed NAbs to Betaferon/Betaseron™.

Description: Background The ARCTIC study randomized 2440 patients scheduled for stent implantation to a strategy of platelet function monitoring with drug adjustment in patients who had a poor response to antiplatelet therapy or to a conventional strategy without monitoring and drug adjustment. No significant improvement in clinical outcomes with platelet function monitoring was observed. Objective The purpose of this study is to assess the relationships between CYP2C19 genotypes, clopidogrel pharmacodynamic response, and clinical outcome. Methods and results In the ARCTIC-GENE study, 1394 patients were genotyped for loss- and gain-of-function CYP2C19 alleles. Randomization of treatment strategy was well balanced. Slow metabolizers identified as carriers of at least one loss-of-function allele CYP2C19*2 ( n  = 459) were more likely poor responders at randomization (41.6 vs. 31.6 %, p  = 0.0112) and 14 days later (23.8 vs. 10.4 %, p  〈 0.0001) and more frequently on prasugrel (11.5 vs. 8.1 %, p  = 0.039) as compared with rapid metabolizers ( n  = 935). Intensification of antiplatelet treatment did not differ between slow and rapid metabolizers according to the study algorithm based on platelet function only. The primary study outcome defined as the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation did not differ between slow and rapid metabolizers (HR 0.988, 95 % CI [0.812;1.202], p  = 0.90). Likewise, the primary safety outcome did not differ between rapid and slow metabolizer phenotype. Conclusions The genetic clopidogrel profile was a good marker of platelet function response on clopidogrel but was not related to clinical outcome suggesting that the genetic added little to the pharmacodynamic information used in the study to adjust antiplatelet therapy. ClinicalTrials.gov : NCT00827411.

Description: Background Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. Methods Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage. Results Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3 % reduction) by PH-797804 compared to placebo in studies 1 and 2 ( p  = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0 % reduction, p  = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. Conclusions PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

Description: Purpose It is well documented that drug-drug interaction databases (DIDs) differ substantially with respect to classification of drug-drug interactions (DDIs). The aim of this study was to study online available transparency of ownership, funding, information, classifications, staff training, and underlying documentation of the five most commonly used open access English language-based online DIDs and the three most commonly used subscription English language-based online DIDs in the literature. Methods We conducted a systematic literature search to identify the five most commonly used open access and the three most commonly used subscription DIDs in the medical literature. The following parameters were assessed for each of the databases: Ownership, classification of interactions, primary information sources, and staff qualification. We compared the overall proportion of yes/no answers from open access databases and subscription databases by Fisher’s exact test—both prior to and after requesting missing information. Results Among open access DIDs, 20/60 items could be verified from the webpage directly compared to 24/36 for the subscription DIDs ( p  = 0.0028). Following personal request, these numbers rose to 22/60 and 30/36, respectively ( p  〈 0.0001). For items within the “classification of interaction” domain, proportions were 3/25 versus 11/15 available from the webpage ( P  = 0.0001) and 3/25 versus 15/15 ( p  〈 0.0001) available upon personal request. Conclusion Available information on online available transparency of ownership, funding, information, classifications, staff training, and underlying documentation varies substantially among various DIDs. Open access DIDs had a statistically lower score on parameters assessed.

Description: Purpose The purpose of the present study was to examine the relationship between the incidence of hyperammonemia and changes in the prescribing of concomitant antiepileptic drugs (AEDs) in patients receiving valproic acid. Methods We evaluated 40,363 plasma samples from 6009 epilepsy patients obtained from 2006 to 2013. Hyperammonemia was defined as a plasma ammonia level exceeding 100 μg/dL. Results In 2006, 32.6 % of the plasma samples were from patients with concomitant use of phenytoin but this decreased to 16.0 % in 2013. Lamotrigine and levetiracetam were approved in 2008 and 2010, respectively, and were prescribed for patients who provided 27.8 and 14.9 % of the plasma samples in 2013. The incidence rate of hyperammonemia (per 100 person years) decreased markedly from 40.8 (95 % confidence interval (CI), 37.7–43.9) in 2006 to 14.2 (95 % CI, 12.5–15.9) in 2013. In any year reviewed, concomitant use of phenytoin, phenobarbital, carbamazepine, or carbonic anhydrase inhibitors was a risk factor for hyperammonemia. Among enzyme-inducing AEDs, concomitant use of phenytoin was associated with the highest risk of hyperammonemia. Conclusion Drug interactions caused by enzyme-inducing AEDs, especially phenytoin, are closely related to the development of hyperammonemia. This study demonstrated that introduction of new AEDs changed the co-prescribing pattern in patients receiving valproic acid, resulting in a marked decrease of hyperammonemia. Although their higher cost may be problematic, new AEDs are beneficial for reducing the risk of drug interactions.

Description: Purpose It is established that omeprazole increases (R)+ warfarin levels with around 10 %. Whether (es)omeprazole also increase the plasma levels of acenocoumarol or phenprocoumon is still uncertain. We analyzed whether addition of (es)omeprazole to acenocoumarol or phenprocoumon increases the international normalized ratio (INR) levels and the risk of overanticoagulation. Methods We analyzed all hospital admissions in four teaching hospitals. Patients who used coumarins and pantoprazole or (es)omeprazole simultaneously for at least four consecutive days were included in the study. We analyzed the highest INR level and whether patients had an INR level above six. We compared patients using omeprazole or esomeprazole with patients using pantoprazole, because for pantoprazole, no interaction has been reported. Results We analyzed 5747 admissions with 4540 patients using one of the drug combinations. For acenocoumarol (4578 admissions), no significant differences were found between users of esomeprazole, omeprazole, and pantoprazole. For phenprocoumon (1169 admissions), the highest INR measured was significantly higher in users of esomeprazole than in users of pantoprazole (4.7 versus 4.3; p  = 0.035). No significant difference was found with omeprazole versus pantoprazole (4.3 versus 4.3; p  = 0.66). A non-significant association was found between the esomeprazole dose and the highest INR level ( p  = 0.055). The risk of an INR above six did not differ significantly between esomeprazole and pantoprazole (27.7 % versus 22.9 %; p  = 0.34). Conclusions The use of esomeprazole simultaneously with phenprocoumon during hospital admissions might increase the anticoagulant effect. The clinical relevance seems to be limited, because no statistically significant increased risk of overanticoagulation was found.

Description: Purpose Potentially inappropriate prescriptions (PIPs) criteria are widely used for evaluating the quality of prescribing in elderly. However, there is limited evidence on their association with adverse drug reactions (ADRs) across healthcare settings. The study aimed to determine the prevalence of PIPs, defined by the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP) criteria, in the Swedish elderly general population and to investigate the association between PIPs and occurrence of ADRs. Method Persons ≥65 years old were identified from a random sample of 5025 adults drawn from the Swedish Total Population Register. A retrospective cohort study was conducted among 813 elderly with healthcare encounters in primary and specialised healthcare settings during a 3-month period in 2008. PIPs were identified from the Swedish Prescribed Drug Register, medical records and health administrative data. ADRs were independently identified by expert reviewers in a stepwise manner using the Howard criteria. Multivariable logistic regression examined the association between PIPs and ADRs. Results Overall, 374 (46.0 %) persons had ≥1 PIPs and 159 (19.5 %) experienced ≥1 ADRs during the study period. In total, 29.8 % of all ADRs was considered caused by PIPs. Persons prescribed with PIPs had more than twofold increased odds of experiencing ADRs (OR 2.47; 95 % CI 1.65–3.69). PIPs were considered the cause of 60 % of ADRs affecting the vascular system, 50 % of ADRs affecting the nervous system and 62.5 % of ADRs resulting in falls. Conclusion PIPs are common among the Swedish elderly and are associated with increased odds of experiencing ADRs. Thus, interventions to decrease PIPs may contribute to preventing ADRs, in particular ADRs associated with nervous and vascular disorders and falls.

Description: Purpose The purpose of this study was to compare longitudinal data on drug utilization between 10-year-old children and 15-year-old adolescents and to analyse the association of drug use at the age of 15 years with drug use at the age of 10 years. Methods Based on the German GINIplus (German infant study on the Influence of Nutrition Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influence of lifestyle factors on the immune system and allergies in East and West Germany plus the influence of traffic emissions and genetics) birth cohorts, data on drug utilization (past 4 weeks) were collected using a self-administered questionnaire for 3642 children (10-year follow-up) and 4677 adolescents (15-year follow-up). The drugs were classified by therapeutic categories (conventional drugs, homeopathic drugs, etc.) and by codes according to the anatomical therapeutic chemical (ATC) classification system. Associations of adolescents’ drug use with gender, study area, maternal education, parental income, presence of chronic conditions, and prior drug use at the age of 10 years were analysed using a logistic regression model. Results The 4-week prevalence rates of overall drug use were similar for adolescents (41.1 %) and children (42.3 %). However, adolescents used noticeably more anti-inflammatory drugs, analgesics, and systemic antihistamines. Exactly 3194 children/adolescents participated in both follow-ups. Adolescents’ use of anti-inflammatory drugs was predicted (OR = 3.37) by use of anti-inflammatory drugs as a child. In summary, the strongest predictor of adolescents’ use of specific therapeutic categories or ATC groups was the previous use of the same therapeutic drug category or ATC group as a 10-year-old child. Conclusions Despite similar prevalence rates of overall drug utilization among both age groups, there is a noticeable difference concerning the use of drugs from specific ATC groups. Drug use as a child may partly determine what they use as an adolescent.

Description: Purpose The existence of gender differences in the management of statin therapy among patients with chronic heart failure (HF) is still poorly investigated. We aimed at exploring the effect of gender on statin prescription rates and adequacy of dosing and on the association between statin therapy and all-cause 1-year mortality, after HF hospitalization in a community setting. Methods Statin prescription rates, adequacy of dosing (estimated as a PDD/DDD ratio 〉0.80), and 1-year mortality were retrospectively assessed in 2088 consecutive patients discharged from 5 local community hospitals with a definite diagnosis of HF after a mean length of stay of 7.6 days. The effect of gender was explored using multivariable logistic and Cox analyses adjusting to confounders. Results Women showed a lower statin prescription rate (25.7 vs 35.3 %, P  〈 0.0001) and a lower prevalence of adequate statin dose (32.6 vs 42.3 %, P  〈 0.0001) than men. Female gender was independently associated with a 24 % lower probability of statin prescription and a 48 % higher probability of inadequate statin dose. Statin prescription and adequacy of dosing were associated with 35 and 44 % decreases in the risk of 1-year mortality, respectively, irrespective of gender. A nested case/control analysis confirmed that adequate statin dose was associated with 48 % lower 1-year mortality, again without interaction with gender. Conclusions In patients with chronic HF, female gender is independently associated with lower statin prescription rates and higher probability of inadequate dose. Statin therapy in these subjects is associated with improved 1-year survival in both men and women. This prognostic benefit is not affected by gender.

Description: Purpose Self-medication is common worldwide. However, the prevalence of sale of prescription medications without prescription and the quality of assessment and counselling provided by community pharmacists to cardiac patients is unknown. We sought to determine the prevalence of prescription medication sales and explore how pharmacists assess and counsel patients with acute cardiac conditions. Methods Six hundred community pharmacies in the two largest cities in Saudi Arabia were selected. Two simulated clients presented either an acute coronary syndrome (ACS) scenario or an acute heart failure (AHF) scenario to the pharmacists. Descriptive statistics and regression models were used to analyse and present the collected data. Results Of 600 pharmacies, 379 (63.2 %) sold various prescription medications to simulated patients without prescription. Assessment and counselling provided by pharmacists were inadequate. Almost a quarter of pharmacists did not ask simulated patients any questions; 52 % asked one or two questions; and only 24 % asked three or more questions. Only 28 pharmacists (4.7 %) inquired about drug allergies; 48.5 % instructed simulated patients on the dosage and frequency of the sold medications; 21.6 % provided instruction on treatment duration; and 19.4 % gave instructions on dose, frequency, and duration of treatment. Compared to AHF, ACS simulated patients were more likely to be asked about other symptoms and comorbidities (59.7 % vs. 48.7 %, p  = 0.007 and 46.3 % vs. 37.3 %, p  = 0.005, respectively) and were more likely to be advised to go to hospital (70.3 % vs. 56.3 %, p  〈 0.001). Conclusions The sale of prescription medications by community pharmacists to simulated cardiac patients without prescription is very common; assessment and counselling qualities are suboptimal.

Description: 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.

Description: Purpose Oncological patients are at increasing risk of QT prolongation, a risk factor for ventricular arrhythmia. We assessed impact and risk factors for corrected QT (QTc) prolongation during multiple-cycle chemotherapy. Methods We enrolled 100 outpatients initiating chemotherapy in a university center specializing in female cancer. Clinical, drug, laboratory, and 12-lead ECG data collection at baseline and at each chemotherapy cycle was performed. Results Enrolled patients were followed for 992 chemotherapy cycles (median 7; interquartile range 6–13); 2438 ECGs were recorded (20; 18–31) 36.8 % pre-therapy, 36.8 % following chemotherapy, and 22.5 % 7–10 days after chemotherapy. Maximum QTc (Max-QTc) was recorded after 4 chemotherapy administrations in 〉50 % of the entire cohort and also within every subset of patients with prolonged QTc (57 % 471–480 ms; 54 % 481–500 ms; 66 % 〉500 ms). No cumulative effect on QTc was shown. QTc prolongation was comparable among the various protocols. Prophylactic/supportive drugs were not associated with additional QTc prolongation. Variables independently associated with QTc prolongation 〉470 ms were age (OR 1.056 95 % CI 1.006–1.108, p  = 0.028) and the baseline-first chemotherapy averaged QTc (BC-QTc) (OR 1.092 95 % CI 1.051–1.136), a novel parameter devised for this study. Only BC-QTc maintained significance for QTc 〉480 ms. BC-QTc 〉435 ms identified 100 % of patients with Max-QTc 〉500 ms, 96 % with Max-QTc 481–500 ms, and 66 % with Max-QTc 471–480 ms. Only 29 % of patients with Max-QTc ≤470 ms presented a BC-QTc 〉435 ms. Conclusions Our results confirm the high prevalence of QTc prolongation after chemotherapy. Most of the patients reached Max-QTc after several cycles. BC-QTc may help in stratifying arrhythmic risk in real-world clinical practice.

Description: Purpose Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that affects blood pressure by promoting vasodilation mediated by nitric oxide. Angiotensin-converting enzyme inhibitors (ACEi) up-regulate the VEGF expression; thus, genetic polymorphisms in the VEGFA gene could affect the antihypertensive responses to these drugs. Methods Hypertensive patients ( n  = 102) were prospectively treated only with the ACEi enalapril for 60 days. We compared the effect of VEGFA polymorphisms on changes in blood pressure after enalapril treatment. In addition, multiple linear regression analysis was carried out to assess the effect of covariates on blood pressure. Genotypes for g.-2578C〉A (rs699947), g.-1154G〉A (rs1570360), and g.-634G〉C (rs2010963) VEGFA polymorphisms were determined, and haplotype frequencies were estimated. Results Individuals carrying the CA and AA genotypes for the g.-2578C〉A polymorphism and the AGG haplotype showed more intense decrease in blood pressure in response to enalapril 20 mg/day. A multiple linear regression analysis showed that the AA genotype for the g.-2578C〉A polymorphism and the AGG haplotype are associated with more intense decrease in blood pressure in response to enalapril 20 mg/day, while the CC genotype for the g.-2578C〉A polymorphism and the CGG haplotype are associated with the opposite effect. Conclusions These findings suggest that polymorphisms in VEGFA gene may affect the antihypertensive responses to enalapril.

Description: Objective This study aimed to estimate the total healthcare costs associated with elderly chronic pain (CP) patients, define cost-related factors in this population, and examine cost evolution over two years. Method This is an ancillary study from the CP S.AGE subcohort, including non-institutionalized patients aged over 65 suffering from CP. 1190, 1108, 1042, and 950 patients were reviewed with available healthcare data at follow-up visits at 6, 12, 18, and 24 months, respectively. Healthcare components included medical and paramedical visits, medication prescription, and hospitalization. Result The mean total cost in the first semester was estimated at €2548 ± €8885 per patient. Hospitalization represented the largest cost component (50 %) followed by paramedical care (24 %), medications (21 %), and medical visits (5 %). Significant cost-associated factors were comorbidity (OR 1.49, 95 % CI 1.35–1.64), dependency in daily activities (OR 1.85, 95 % CI 1.39–2.47), probable depression (OR 1.71, 95 % CI 1.09–2.69), permanent pain (OR 1.48, 95 % CI 1.18–1.86), neuropathic pain (OR 1.94, 95 % CI 1.38–2.73), living alone (OR 1.45, 95 % CI 1.16–1.82), chronic back pain (OR 1.35, 95 % CI 1.07–1.71), and vertebral fracture/compression (OR 1.47, 95 % CI 1.08–2.01). Healthcare costs increased significantly by 48 % ( p  〈 0.0001) during follow-up namely due to hospitalizations. Elevated costs were associated with a higher risk of future hospitalization (OR 1.95, CI 95 % 1.33–2.87). Conclusion Healthcare costs increased rapidly over time, largely due to hospitalization. Prevention strategies to limit hospitalizations in elderly appear to be the most useful in order to achieve cost savings in the future.

Description: Purpose The long-term efficacy of tolvaptan, a vasopressin V2 receptor antagonist, has been reported. However, the safety of long-term treatment remains to be fully elucidated. We assessed the safety profile of tolvaptan with respect to hypernatremia. Methods This retrospective study included 371 patients treated with tolvaptan. Risk factors for hypernatremia (serum sodium concentration ≥147 mEq/L) were determined. Results Hypernatremia occurred in 95 patients (25.6 %), of whom 71 (19.1 %) developed hypernatremia within 7 days of tolvaptan treatment (early onset). Stepwise logistic regression analysis demonstrated that baseline serum sodium ≥140 mEq/L, an initial tolvaptan dosage 〉7.5 mg, and a BUN/serum creatinine ratio ≥20 were independent risk factors for early onset of hypernatremia. Tolvaptan was prescribed for more than 7 days to 233 patients, of whom 123 were administrated tolvaptan for more than 1 month. Hypernatremia occurred in 24 of these patients (10.3 %) (late onset). Predictive factors for late onset of hypernatremia were an average daily dosage of tolvaptan 〉7.5 mg and age ≥75 years. Conclusions A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia.

Description: Purpose Up to 30–40 % of the major depressive disorder patients do not respond sufficiently to antidepressant treatment. Genetic variations in the serotonin transporter gene have been implicated in modulating treatment response to selective serotonin reuptake inhibitors, and this association is influenced by ethnicity. We investigated the influence of serotonin transporter gene variants 5-HTTLPR and rs25531 in Indian population on fluoxetine response. Methods One hundred and two major depressive disorder patients were started on fluoxetine treatment and after 6 weeks, classified as responders ( n  = 56) and non-responders ( n  = 46) using Hamilton depression rating scale and genotyped. Fisher’s exact test was used to compare genotype frequencies between responders and non-responders. One-way analysis of variance and student t test were used to compare the percentage reduction (week 0–6) in Hamilton depression rating scores between genotype and haplotype groups. Results We observed a significant association between LL genotype of 5-HTTLPR and fluoxetine treatment response ( p  = 0.0066, OR (95 %) = 4.0 (1.45–11.03)) but not with the functional groups of 5-HTTLPR –rs25531 . However, there was a significant difference in percentage reduction in HAM-D scores (week 0–6) between 5-HTTLPR genotypes (LL vs. LS + SS, p  = 0.0036; LL vs. LS, p  = 0.0109) as well as the functionally grouped haplotypes of 5-HTTLPR –rs25531 (L A L A carriers vs. non-carriers of L A L A , p  = 0.0118; L A L A vs. L A S+ L A L G , p  = 0.0419). Conclusion The LL genotype and L A L A haplotype of SLC6A4 are associated with favorable treatment response to fluoxetine in south Indian major depression patients.

Description: Aim To investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity. Methods Thirty-six healthy volunteers who tested CYP2B6 and POR polymorphisms were enrolled in the study. CYP2B6 activity was measured by bupropion hydroxylation with LC/MS/MS. The ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup) in terms of area under the time-concentration curve (AUC) was used to represent the CYP2B6 activity. Results The volunteers carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/ AUC_bup than those CYP2B6*1/*6 and CYP2B6*6/*6 variants (15.66 ± 1.65 vs. 9.25 ± 1.92, P  = 0.008 and 15.66 ± 1.65 vs. 8.21 ± 1.74, P  = 0.006, respectively). POR rs2868177 (6593 A 〉 G) AA homozygotes showed a significantly lower mean AUC_hyd/ AUC_bup than that of POR rs2868177 AG heterozygotes or GG homozygotes (8.13 ± 1.37 vs. 12.15 ± 2.97, P  = 0.005 and 8.13 ± 1.37 vs. 17.59 ± 3.25, P  = 0.001, respectively). Moreover, POR rs2868177 AG heterozygotes and GG homozygotes showed a significantly increased mean AUC_hyd/AUC_bup than AA homozygotes in the CYP2B6*1/*1 and CYP2B6*6 carriers (16.40 ± 2.01 vs. 12.40 ± 1.45, P  = 0.006 and 10.65 ± 1.47 vs. 6.54 ± 1.25, P  = 0.004, respectively). Meanwhile, a strong correlation between the genetic variations ( POR rs2868177 and CYP2B6*6 ) and AUC_hyd/ AUC_bup was found ( P  = 0.009 and P  = 0.001, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR *28 genotypes ( P  〉 0.05) . Conclusion POR rs2868177 and CYP2B6*6 variants contribute to the interindividual variability in human CYP2B6 activity, which may affect the disposition and interaction of other CYP2B6 substrate drugs.

Description: Purpose We systematically reviewed published observational studies and randomized controlled trials (RCT) reports of clinical trials on erythropoiesis-stimulating agents (ESA’s). Only studies evaluating the risk of developing anti-drug antibodies (ADA) of both original and biosimilar drugs were chosen. Methods Databases including PubMed, EMBASE and Cochrane Library were searched up to 17 March 2015. Two reviewers independently assessed the relevant studies for risk of bias. Results Twenty-one publications were included. The overall prevalence of ADA in the studies was about 0.2 to 0.5 %. Most studies were not designed to monitor the development of ADA and often the study duration was too short (less than 6 months) and the patient population too small. Moreover, in many studies, the assays used only determined the presence of ADA and did not measure therapy failure due to ADA. In one RCT, as many as 13 cases (4 %) of ADA were identified. Conclusion ADA development seems to be low in short-term studies with ESA. None of the efficacy and safety issues for ESA biosimilars were judged to be adequately addressed in the evaluated literature, with respect to ADA formation, due to the study design and the assay method used.

Description: Purpose Recurrent ischemic events in Chinese patients with symptomatic extracranial or intracranial stenosis caused by aspirin or clopidogrel resistance are well known. We aimed to identify the contribution of genetic variants to the events. Methods Patients with symptomatic extracranial or intracranial stenosis receiving dual antiplatelet treatment for at least 5 days were enrolled in this study. The primary endpoint was a composite of ischemic events, including recurrent transient ischemic attack, stroke, myocardial infarction, and vascular-related mortality. Twenty-four single nucleotide polymorphisms (SNPs) were assessed and genotyped. The clinical characteristics of enrolled patients were collected from medical records. The influence of genetic polymorphisms on the recurrent ischemic events of the patients was examined. Results A total of 377 patients were included. During a 12-month follow-up, the composite primary endpoint was observed in 64 patients. The CYP2C19*3 (rs4986893) may increase the occurrence of the primary composite endpoint (OR = 2.56, 95 % CI = 1.29–5.10, P  = 0.007), and the mutation of CES1 rs8192950 was associated with the decreased recurrence of ischemic events (OR = 0.53, 95 % CI = 0.30–0.94, P  = 0.029). The other SNPs that were tested did not have statistically significant associations with the composite endpoint. Conclusions For Chinese patients with symptomatic extracranial or intracranial stenosis treated with clopidogrel, CYP2C19*3 mutation was associated with an increased risk of ischemic events, and the mutation of rs8192950 in CES1 is associated with a decreased risk of recurrent ischemic events. Testing these two SNPs could be of value in the identification of patients at risk for recurrent ischemic events.

Description: Purpose The effects of nonhormonal drugs on menopausal hot flashes are still not well quantified. We therefore did a model-based meta-analysis (MBMA) to quantitate and compare the efficacy features of nonhormonal drugs on menopausal hot flashes. Methods Literature was searched in the public databases to extract data of clinical trials on nonhormonal drugs, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), gabapentin, clonidine, and soy isoflavones. Pharmacodynamic models were used for the quantitative analysis of each drug. Results Thirty-nine studies were included in the analysis. The results revealed a classic pharmacodynamic maximal effect (E max ) model could describe the time course of hot-flash reduction by nonhormonal drugs. After deducting placebo effects, the E max of SSRIs/SNRIs, gabapentin, clonidine, and soy isoflavones was 13.9 %, 14.8 %, 18.5 %, and 25.0 %, respectively. The time to achieve half of the maximal effect (ET 50 ) of SSRIs/SNRIs, gabapentin, clonidine, and soy isoflavones was 0.18 weeks, 0 weeks, 0 weeks, and 11.6 weeks, respectively. The results showed that SSRIs/SNRIs, gabapentin, and clonidine had a rapid onset, which could reach the maximum effect immediately. However, the onset of soy isoflavones was very slow, and a duration of 16.6 weeks was needed to surpass the efficacy of paroxetine (a type of SSRIs). Conclusions The information provided in this study can be used as valuable supplementary information for treatment guidelines of nonhormonal drugs on menopausal hot flashes.

Description: Purpose The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have both implemented procedures in order to shorten review time for marketing authorizations with potential therapeutic added value, called priority review and accelerated assessment procedure, respectively. The aim of this study is to compare the new molecular entities (NME) assessed in shorter review time by both agencies and to investigate whether granting a shorter review time status subsequently predicts its therapeutic value attributed by a health technology assessment agency, the French Haute Autorité de Santé (HAS). Methods All NME approved by the EMA and the FDA with a therapeutic added value between 2007 and June 30, 2015 were extracted. We assessed the sensibility, the positive predictive value, and the EMA review time. Results One hundred seventy-eight NME were approved by the FDA and the EMA and a therapeutic value was available for 160 NME. Eighty-eight (55.0 %) NME were on FDA priority review, 24 (15.0 %) on EMA accelerated procedure and 43 (26.9 %) were considered of high clinical added value. The sensibility was 86.0 % for the FDA and 30.2 % for the EMA. The positive predictive value was, respectively, 42.0 and 54.2 %. Twenty-five NME on FDA priority review and of high therapeutic added value were not on EMA accelerated assessment procedure, leading to a supplementary mean EMA review time of 146 days. Conclusion The EMA was restrictive to grant a shorten review time status for products with therapeutic interest during the study period.

Description: Purpose The study aims to identify the occurrence and remission of statin-induced myopathy including patient perception and symptom characteristics with a gender perspective. Methods The study was designed as a prospective, non-interventional investigation in 192 outpatients receiving statin treatment in usual care with 12 months follow-up. Main outcome measure was myopathy related to statin treatment and classified as probable using WHO criteria for adverse drug reaction (ADR) assessment. Results Fourteen percent developed myopathy, risk ratio for women 1.52 [95 % CI 1.37; 1.66] as compared to men. The majority graded their pain as “severe.” CK values were within normal range. Eighty percent of the women compared to 43 % of the men reported that the muscular symptoms affected their daily life activities to a moderate or severe extent. For those who stopped treatment, mypopathy was the reason for 70 % of the women and 25 % of the men. There was a difference in mean dose between men with and without myopathy, but not in women. Among the patients with myopathy, 76 % reported other ADRs as compared to 21 % of the patients without myopathy ( p  = 0.002). Twenty-nine percent of the women and 18 % of the men reported other ADRs. Conclusion Women reported a higher frequency of myopathy and other ADRs as well as a larger impact on daily life activities. In men, but not in women, the risk of myopathy was dose-dependent. Patients with myopathy were more susceptible to other statin-induced ADRs which raises the question about common underlying mechanisms.

Description: Background Healthcare professionals and patients could be negatively influenced in their judgments by articles and meta-analyses presenting selective outcome reporting. Clinical trials should be transparent from inception to the publication of results. To this end, trial prospective registration is an ethical and scientific requirement that have shown to be effective in preventing selective reporting of outcomes. However, even journals with a clear pre-registration policy publish trial results that were retrospectively registered. Situation Analyses of registration of randomized clinical trials recently published in top specialty journals and of meta-analyses with suspicion of including trials with outcome reporting bias have shown that retrospective registration is in the range from 56 to 76 %. This translates into publication of primary endpoints that differ from those included in the registry: some 30 % of trials showed discrepancies between the primary endpoint in the trial registry and the article. Furthermore, it has been shown that 8 % of all clinical trials published by 6 high-impact ICMJE-member journals was retrospectively registered after primary endpoint ascertainment could have had taken place, raising concerns that endpoints may not have been pre-specified, or were changed. With regards to meta-analyses, 34 % of Cochrane systematic reviews included one or more trials with a high suspicion of selective reporting bias for the primary outcome. Proposal Retrospective registration of trials may foster selective outcome reporting unless journal editors implement specific quality control processes aiming to prevent or minimize this type of bias. Prospective registration of trials—and protocol public disclosure if proven effective in future studies—prevents outcome reporting bias, a must to ensure clinicians and patients have access to reliable clinical trial results. Journal editors should enforce, rather than encourage, appropriate measures to ensure publication of trials free of outcome reporting bias.

Description: Purpose The purpose of this study was to investigate changes in utilisation of antiepileptic drugs (AEDs) in epilepsy and non-epilepsy disorders in Norway and furthermore to study the retention rates of the most commonly used AEDs in these indications in long-term use. Methods The data consisted of all prescriptions of AEDs from Norwegian pharmacies in the Norwegian Prescription Database (NorPD) (2004–2012). Variables included anonymous data regarding age, gender, diagnosis specific reimbursement codes and utilisation of AEDs. Results In recent years (2008–2012), the utilisation of AEDs in non-epilepsy disorders accounted for 45–53 % of the total use. In epilepsy, the most commonly used AED was lamotrigine, followed by levetiracetam, carbamazepine and valproate. Lamotrigine was also the predominant AED used in psychiatry, while pregabalin and gabapentin were mostly used in neuropathic pain. In migraine, topiramate predominated but accounted for 〈1 % of the total utilisation of AEDs. The majority of prescriptions were by general practitioners and only 20 % by specialists. Regardless of indication, newer AEDs had higher retention rates (34–48 %) and were used for a longer period before discontinuation. Conclusions The use of AEDs in non-epilepsy disorders is increasing and accounted for 53 % in 2012. Newer AEDs were predominantly used and demonstrated higher retention rates than older AEDs in all indications. This nationwide study demonstrates an increased exposure to AEDs in new patient groups, and details in prescription patterns and clinical and safety considerations should be closely monitored. This contributes to long-term post-marketing data of AED and accordingly improved pharmacovigilance.

Description: Purpose Cases of local anaesthetic systemic toxicity (LAST) periodically occur following transversus abdominal plane (TAP) blocks. The aim of this study was to characterize levobupivacaine absorption pharmacokinetics, with and without epinephrine, and estimate the risk of LAST, based on a previously reported toxic threshold. Methods Previously reported data from 11 volunteers receiving ultrasound-guided TAP blocks with and without epinephrine on two independent occasions were analysed. Serial venous concentrations were measured for 90 min. A pharmacokinetic analysis was performed using the NONMEM statistical programme. The use of epinephrine in the solution was included in the analysis of covariates. The associated risk of LAST symptoms associated with different levobupivacaine dose schemes with and without epinephrine was estimated in 1000 simulated subjects. Results A one-compartment first-order input and elimination model adequately fit the levobupivacaine data. Epinephrine prolonged the levobupivacaine absorption half-life {4.22 [95 % confidence interval (CI) 2.53–6.50] vs. 7.02 [95 % CI 3.74–14.1]; p  〈 0.05} and reduced its relative bioavailability (0.84; 95 % CI 0.72–0.97; p  〈 0.05) The derived model predicts that levobupivacaine dose schemes should be halved from 3 mg kg −1 body weight with epinephrine to 1.5 mg kg −1 without epinephrine to obtain a comparable risk of anaesthetic toxicity symptoms of approximately 0.1 %. Conclusions Our results strongly support the addition of epinephrine to the local anaesthetic solution, especially when doses of levobupivacaine of 〉1.5 mg kg −1 are required. Recommendations regarding the maximum allowable doses of local anaesthetics should consider population analysis to determine safer dosage ranges.

Description: Purpose The effect of prehospital epinephrine on neurological outcome in out-of-hospital cardiac arrest (OHCA) is still controversial. We sought to determine whether prehospital epinephrine administration was associated with improved outcomes in adult OHCA. Methods A nationwide, population-based, propensity score-matched study of OHCA patients from January 1, 2011, to December 31, 2012, in Japan was conducted. We included adult OHCA patients treated by emergency medical service personnel without an excessive delay. The primary outcome was neurologically favorable survival 1 month after OHCA. Results A total of 237,068 patients (16,616 with a shockable rhythm and 220,452 with a non-shockable rhythm) were included in the final cohort. A total of 4024 out of the 16,616 shockable OHCAs and 29,393 out of the 220,452 non-shockable OHCAs received prehospital epinephrine. In the propensity score-matched cohort, prehospital epinephrine was associated with a decreased chance of neurologically favorable survival (shockable OHCA 7.6 vs. 17.9 %, OR 0.38 [95%CI 0.33–0.43]; non-shockable OHCA 0.6 vs. 1.2 %, OR 0.47 [95%CI 0.39–0.56]). In the subgroup analyses, prehospital epinephrine was significantly associated with poor neurological outcome in all subgroups. In the ancillary analyses, although the neurological outcome was worse as the number of epinephrine doses increased or the time to epinephrine increased, patients had a greater chance of a favorable neurological outcome only when a single dose of epinephrine was administered within 15 min of the emergency call in shockable OHCA. Conclusions Among adult OHCA patients, prehospital epinephrine was associated with a decreased chance of neurologically favorable survival. Situations in which prehospital epinephrine is effective may be extremely limited.

Description: Purpose An analysis of Italian spontaneous adverse drug reactions (ADR) reporting database highlighted a potential association between hypothermia and ibuprofen in children. Hypothermia is defined as a core body temperature of 35 °C (95 °F). Ibuprofen is the most prescribed NSAID for the treatment of fever and moderate pain in children. We aimed to analyze the cases of ibuprofen-associated hypothermia retrieved in the Italian database in order to contribute to the discussion on this potential association. Methods We extracted all suspected cases of ibuprofen-associated hypothermia from the Italian spontaneous reporting database and from VigiBase up to December 2015. We considered the proportional reporting ratio (PRR) as a measure of disproportionality for the Italian cases and the information component (IC) for the reports from VigiBase. We performed a case-by-case analysis to exclude duplicates. Results Nineteen cases of hypothermia associated with ibuprofen use were retrieved from the Italian spontaneous reporting database (PRR 19.8, CI 95 %, 12.0–32.9). The reports concerned ten females and nine males with an average age of 2.5 years. Up to 31 December 2015, 168 cases of hypothermia associated with ibuprofen were reported to VigiBase, with an IC of 2.05 (IC 025 , 1.82). Among these, 126 cases involved children (49 % males) with an average age of 4.4 years. Conclusions Although the risk of this ADR is unknown so far, the widespread use of this drug recommends the need for further studies to better characterize this possible association. Clinicians and pharmacists but also parents should be aware that this risk is theoretical as not yet been confirmed.

Description: Purpose The purpose of this study are to analyse adherence to antidepressant treatment over 2 years in Sweden among women and men who initiated treatment with citalopram and to identify groups at risk of non-adherence using trajectory models. Methods The study population, including individuals 18–85 years who initiated citalopram use between 1 July 2006 and 30 June 2007, was identified in the Swedish Prescribed Drug Register and followed for 2 years. Adherence was estimated with continuous measure of medication acquisition (CMA) and group-based trajectory modelling, a method which describes adherence patterns over time by estimating trajectories of adherence and the individual’s probability of belonging to a specific trajectory. Results The study population included 54,248 individuals, 64 % women. Mean CMA was 52 % among women and 50 % among men ( p  〈 0.001). Five different adherence patterns (Trajectories) were identified. Similar proportion of women and men belonged to each Trajectory. Around 29 % of the women and 27 % of the men belonged to the Trajectory which showed full adherence throughout the 2-year study period. The other four Trajectories showed adherence that declined to different degrees and at different stages in time. Having low socioeconomic status was more common among individuals in Trajectories showing declining adherence than in the adherent Trajectory. Conclusions Using trajectory modelling, five Trajectories describing different patterns of adherence to citalopram treatment over time were identified. A large proportion discontinued treatment early and having low socioeconomic status increased the risk of being non-adherent.

Description: Purpose The aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. Methods A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs ( CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 −1639C〉T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system. Results A predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3 , CYP4F2 rs2108622, VKORC1 −1639C〉T, and POR*37 831–35C〉T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831–35C〉T to warfarin dose variation was only 3.9 %. Conclusions For the first time, the SNP POR*37 831–35C〉T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses.

Description: Purpose AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior. Methods Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution ( R d ) and absorption ( R a ) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a ( R dth and R ath ) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds. Results The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased. Conclusion A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs.

Description: Purpose Rosuvastatin disposition is modulated by the expression and activity of several membrane transporters including BCRP (ABCG2). The objective of our study was to investigate the effects of pantoprazole, a previously proposed BCRP inhibitor, on the disposition of rosuvastatin. Methods The impact of pantoprazole (40 mg ID for 2 days) on rosuvastatin pharmacokinetics was evaluated in healthy volunteers ( n  = 16) who received a single oral dose of rosuvastatin (10 mg) either alone or with pantoprazole. Rosuvastatin, N -desmethylrosuvastatin, and rosuvastatin lactone levels were quantified in plasma while rosuvastatin and N -desmethylrosuvastatin excretion were measured in urine. Results Ratios and 90 % standard confidence interval of geometric means for C max (1.03 [0.91–1.16]), AUC 0–∞ (1.03 [0.89–1.19]) and renal clearance (0.96 [0.85–1.09]) were all within the pre-specified range of 0.8–1.25, indicating a lack of drug-drug interaction between pantoprazole and rosuvastatin. Conclusions Concomitant administration of pantoprazole with rosuvastatin did not affect rosuvastatin plasma concentrations. The use of pantoprazole as a BCRP inhibitor should be revisited when characterizing BCRP-mediated transport in humans.

Description: Purpose The efficacy of routine antibiotic prophylaxis for prevention of surgical site infection (SSI) after elective inguinal hernia repair with a mesh patch remains uncertain. The authors of a recent Cochrane meta-analysis based on 17 randomized trials were unable to draw a definitive conclusion on this subject. The purpose of this study was to determine the effectiveness of prophylactic antibiotics for prevention of SSI after elective inguinal hernia repair with mesh and the risk factors for SSI. Methods All low-risk patients who underwent elective inguinal hernia repair with mesh at our institution between 2010 and 2015 were enrolled in this study, with the exception of patients with recurrent hernias or immunosuppressive diseases. All patients received a single intravenous (i.v.) injection of cefuroxime (1.5 g) within 2 h prior to surgery at the discretion of the surgeon. SSI was defined using criteria of the Centers for Disease Control and Prevention. The variables which could influence the rate of SSI were analyzed by multivariate analysis to determine the independent risk factors for SSI. Results Among the 605 patients who underwent elective inguinal hernia repair with mesh during the study period, 553 were eligible for enrolment in the study. Of these, 331 received a single dose of cefuroxime preoperatively. The overall SSI rate was 5.4 %; 9.4 % of those patients who did not receive preoperative antibiotic prophylaxis developed SSI versus 2.8 % of those who did receive prophylaxis ( P  = 0.001). All infections were superficial. Factors independently associated with SSI were advanced age, smoking and preoperative stay. Conclusions The incidence of SSI among low-risk patients who did and did not receive preoperative antibiotic prophylaxis after elective inguinal hernia repair with mesh differed significantly, particularly among patients of advanced age, smokers and patients with a prolonged preoperative stay in the hospital.

Description: Aims Incretin-based antihyperglycemic therapies increase intestinal mucosal expansion and polyp growth in mouse models. We aimed to evaluate the effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1ra) initiation on colorectal cancer incidence. Methods We conducted a cohort study on US Medicare beneficiaries over age 66 from 2007 to 2013 without prevalent cancer. We identified three active-comparator and new-user cohorts: DPP-4i versus thiazolidinediones (TZD), DPP-4i versus sulphonylureas (SU), and GLP-1ra versus long acting insulin (LAI). Follow-up started from 6 months post-second prescription and ended 6 months after stopping (primary as-treated analysis). We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident colorectal cancer adjusting for measured confounders using propensity score weighting. Results The median duration of treatment ranged 0.7–0.9 years among DPP-4i cohorts. Based on 104 events among 39,334 DPP-4i and 63 events among 25,786 TZD initiators, there was no association between DPP-4i initiation and colorectal cancer (adjusted HR = 1.17 (CI 0.88, 1.71)). There were 73 events among 27,047 DPP-4i and 266 events among 76,012 SU initiators with the adjusted HR 0.98 (CI 0.74, 1.30). We identified 5600 GLP-1ra and 54,767 LAI initiators and the median duration of treatment was 0.8 and 1.2 years, respectively. The adjusted HR was 0.82 (CI 0.42, 1.58) based on 〈11 events among GLP-1ra versus 276 events among LAI initiators. Conclusion Although limited by the short duration of treatment, our analyses based on real-world drug utilization patterns provide evidence of no short-term effect of incretin-based agents on colorectal cancer.

Description: Purpose Use of β-blockers (BBs) in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular diseases is supported by increasing evidence. However, most of these studies focused on the survival outcome and used a non-active comparison, prevalent-user design. We aimed to examine the risk of overall death and cardiovascular outcomes associated with use of cardioselective BBs using an active comparison, incident cohort approach. Methods We identified COPD patients initiating cardioselective BBs or non-dihydropyridine calcium channel blockers (CCBs) between 2007 and 2011 in the population-based Taiwan database. A Cox regression model was applied to estimate hazard ratios (HRs) for overall death, cardiovascular death, and cardiovascular events comparing cardioselective BBs and non-dihydropyridine CCBs after propensity score matching. We also conducted sensitivity analyses to quantify the unmeasured confounding effect from COPD severity. Results A total of 107,902 patients were included. Cardioselective BBs were associated with a modest, lower risk of overall death (HR, 0.85; 95 % CI, 0.81–0.88). The reduced risk of overall death, however, was vulnerable to distribution of COPD severity and was easily weakened with lower prevalence of severe COPD patients in the initiators of cardioselective BBs and higher prevalence of severe COPD patients in the initiators of non-dihydropyridine CCBs. No excess benefit for cardiovascular death (HR, 1.05; 95 % CI, 0.97–1.13) or cardiovascular events (HR, 0.98; 95 % CI, 0.94–1.03) was detected. Conclusion The present study demonstrated a potential effect of confounding by COPD severity and therefore did not suggest an association between use of cardioselective BB and survival benefit in COPD patients.

Description: Purpose Thrombocytopenia is a common complication in the intensive care unit (ICU), but the incidence of drug-induced thrombocytopenia (DIT) is not well defined. We investigate linezolid-induced thrombocytopenia in patients with impaired renal function. Since recent studies suggest that linezolid clearance is reduced in these patients and there are no precise data confirming that dose-adjustment should be required, we performed a systematic analysis in order to establish whether it is necessary to consider a dose adjustment and promote studies to confirm this concept. Methods We report a case of thrombocytopenia (nadir 32 × 10 3 /μl) in a patient with acute kidney injury who was treated with linezolid for a MRSA pulmonary infection. We performed a systematic review of the literature through PubMed with the aim to include every case report, case series, prospective and retrospective clinical study reporting linezolid-induced thrombocytopenia with concomitant impaired renal function. Results An increasing number of clinical studies suggest a correlation between the onset of linezolid-induced thrombocytopenia and renal dysfunction. Close monitoring of platelet count and hemoglobin is recommended in patients treated with linezolid, especially in those with impaired renal function because the reduction of its clearance causes drug accumulation, as some studies have reported. Conclusions Clinicians should consider the potential risk of this complication, especially in elderly patients with end-stage renal disease. Further studies should be encouraged to determine if the incidence of linezolid-related thrombocytopenia could be reduced by a dose adjustment according to renal function, for which currently there is still no specific recommendation.

Description: Purpose To identify patient characteristics that influence tacrolimus individual dose requirement in kidney transplant recipients. Methods Data on forty-four 12-h pharmacokinetic profiles from 29 patients and trough concentrations in 44 patients measured during the first 70 days after transplantation (1,546 tacrolimus whole blood concentrations) were analyzed. Population pharmacokinetic modeling was performed using NONMEM 7.2®. Results Standardization of tacrolimus whole blood concentrations to a hematocrit value of 45 % improved the model fit significantly ( p  〈 0.001). Fat-free mass was the best body size metric to predict tacrolimus clearance and volume of distribution. Bioavailability was 49 % lower in expressers of cytochrome P450 3A5 (CYP3A5) than in CYP3A5 nonexpressers. Younger females (〈40 years) showed a 35 % lower bioavailability than younger males. Bioavailability increased with age for both males and females towards a common value at age 〉55 years that was 47 % higher than the male value at age 〈40 years. Bioavailability was highest immediately after transplantation, decreasing steeply thereafter to reach its nadir at day 5, following which it increased during the next 55 days towards an asymptotic value that was 28 % higher than that on day 5. Conclusions Hematocrit predicts variability in tacrolimus whole blood concentrations but is not expected to influence unbound (therapeutically active) concentrations. Fat-free mass, CYP3A5 genotype, sex, age and time after transplant influence the tacrolimus individual dose requirement. Because hematocrit is highly variable in kidney transplant patients and increases substantially after kidney transplantation, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations.

Description: Purpose Codeine is an analgesic drug acting on μ-opioid receptors predominantly via its metabolite morphine formed almost exclusively by CYP2D6 . Genetic polymorphisms in CYP2D6 are associated with diminished pain relief and/or severe opioid side effects. In Chinese individuals, CYP2D6*10 is the most common allele with reduced enzyme activity. In this study, we investigated the effect of this allele on the pharmacokinetics of codeine and its metabolites. Method A blood sample was collected from healthy Mongolian volunteers for CYP2D6 genotyping using a PCR-RFLP assay. A pharmacokinetic study was then carried out in three groups with CYP2D6*1/*1 ( n  = 10) , CYP2D6*1/*10 ( n  = 10) and CYP2D6*10/*10 ( n  = 9) genotypes by collecting serial blood samples for determination of plasma levels of codeine and its metabolites, morphine, morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G) before and after a single 30-mg oral dose of codeine phosphate. Codeine and its metabolites were measured by LC-MS/MS. Results No significant differences were observed in the pharmacokinetic parameters of codeine in the three genotype groups. However, the C max and AUC 0-∞ of morphine, M3G and M6G were significantly different between the study groups ( P 〈  0.05). Compared with the *1/*1 group, the AUC 0-∞ for morphine in the *1/*10 and *10/*10 groups decreased by ratios (95 % CI) of 0.93 (0.26–1.59) and 0.494 (0.135–0.853) respectively. Corresponding ratios for M3G were 0.791 (0.294–1.288) and 0.615 (0.412–0.818) and for M6G were 0.643 (0.39–0.957) and 0.423 (0.267–0.579). Conclusion This study demonstrates that the CYP2D6*10 allele plays an important role in the pharmacokinetics of the O-demethylated metabolites of codeine after oral administration.

Description: Purpose The aim of this study was to examine whether educational meetings and group detailing could increase the use of drugs from the ward lists or the drug formulary in hospitals. Methods Twelve medical wards from two hospitals were randomized into three groups: control, basic and extended intervention. All wards had a ward list review before interventions. Moreover, the basic intervention consisted of an educational meeting, and the extended intervention included two group detailing sessions. The proportion of drugs used from the ward list or hospital drug formulary (HDF) was the primary outcome. Data (defined daily doses [DDDs], numbers and cost [Euros]) on drugs sold to the wards were retrieved from the two hospitals from 1 July 2011 to 31 August 2012. Baseline data: from July to September 2011, and follow-up data: from June to August 2012. Results The proportion of formulary drugs used increased for the extended intervention group (0.04, range −0.02 to 0.09) and basic intervention group (0.03, range −0.03 to 0.09) in comparison with a decrease in the control group (−0.01, range −0.03 to −0.02). The interventions did not significantly change odds for selecting drugs from the formulary in comparison with the control group (basic intervention: OR 1.09 [95 % CI 0.81 to 1.46]; extended intervention: OR 1.00 [95 % CI 0.75 to 1.35]). Conclusions In this study, educational meetings and group detailing do not significantly improve adherence to ward lists or HDF. The adherence to the formularies at baseline was relatively high, which may explain why the interventions did not have a significant effect.

Description: Purpose The results of analyses of patients’ health problems related to medication use have been highly variable due to various factors, such as different study methodology, diverse variables determined, fields of study. The aim of our study was to determine the prevalence and preventability of negative clinical outcomes of medication (NCOMs). Methods This was a cross-sectional study performed in the emergency departments (EDs) of nine Spanish hospitals during a 3-month period. A two-stage probabilistic sampling method was used , and a systematic appraisal tool was used to identify the NCOMs based on information gathered through patient interview and review of the medical records. Case evaluations were conducted in two phases by pharmacists and physicians. The prevalence and preventability of NCOM were calculated. A homogeneity test was performed to assess potential differences in the prevalence for each hospital. Results A total of 4,611 patients were included in the study. The overall prevalence of NCOMs was 35.7 % [95 % confidence interval (CI) 33.3–38.1]. These NCOMs could be divided into three categories: ineffectiveness (18.2 %; 95 % CI 16.2–20.1), necessity (14.9 %; 95 % CI 13.4–16.6), and lack of safety (2.4 %; 95 % CI 1.9–2.8). About 81 % (95 % CI 80.1–82.3) of the NCOMs could have been prevented. Conclusions NCOMs provoked approximately one-third of visits to the EDs, and a high percentage of these were preventable. Implementation of strategies for patient safety and pharmaceutical care could help to prevent these problems and optimize the use of medications.

Description: Background Gabapentin exposure following administration of certain doses of gabapentin or its pro-drug gabapentin enacarbil has been previously reported in the literature, with variable results. Methods Meta-analyses of dose-exposure relationships were conducted to maximise precision and minimise bias. Study-level mean data for gabapentin systemic exposure, in terms of bioavailable dose and steady-state average plasma concentration, were modelled as a function of daily dose. Several linear and non-linear candidate models were tested. Results An Emax model best described the dose-exposure relationships for gabapentin. The ED50 was 3,080 mg/day for bioavailable dose or 3,370 mg/day for steady-state concentration; and the maximum exposure was 2,340 mg/day or 16.9 mg/L. For gabapentin enacarbil, a power model was most suitable, with a power of 0.925 for bioavailable dose or 0.844 for steady-state concentration. All parameters were estimated with 〈 20 % standard error. Simulations confirmed that these models accurately reflected the distribution of the respective data, and bootstrapping showed high precision for the estimated dose-exposure curves. Conclusion The meta-analyses addressed issues associated with between-study variability; and confirmed the highly non-linear nature of dose-exposure relationships for gabapentin and the essentially linear relationships for gabapentin enacarbil. The resulting models could be used to simulate exposure at any clinically relevant dose and bridge therapeutic dose range between the two drugs.

Description: Purpose Omeprazole has ( R )- and ( S )-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose ( R )-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals. Methods Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n  = 34), heterozygous EMs (htEMs; n  = 44), and poor metabolizers (PMs; n  = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. Results Mean plasma concentrations of ( R )- and ( S )-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of ( R )-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of ( S )-5-hydroxyomeprazole. Similarly, ( R )-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the ( S )-omeprazole HI. Conclusion Our findings demonstrate that ( R )-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment.

Description: 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.

Description: Purpose To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity. Methods An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1–300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance. Results Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID 50 of 3.4 mg. Using the measured ritonavir concentrations an exposure–inhibition effect curve was established with an IC 50 of 600 h pmol/L (AUC 2–4 ). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed. Conclusions Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.

Description: Aim The investigations reported here aimed to evaluate the incremental benefit for dose finding by concentration-response analysis versus dose-response analysis. Methods Trials were simulated using an Emax model for a range of scenarios of drug properties, trial design options and target response levels. The simulated data were analysed by concentration-response and dose-response modelling; a dose was then chosen to target a specific response level in a confirmatory trial. The two approaches were compared in terms of the quality of model parameter estimation and the success rate for the confirmatory trial. Results While the accuracy for ED50 estimation was comparably good with both approaches, the precision was up to 90 % higher with concentration-response approach. The difference was most notable when clearance was highly variable between subjects and the top dose was relatively low. The higher precision by the concentration-response analysis lead to better dose selection and up to 20 % higher success rate for the subsequent confirmatory trial. The relatively small difference in success rate translated into a remarkable difference in sample size requirement. Conclusion By customising these parameters, the approach and the findings can be applied to assessing the value of pharmacokinetic sampling in particular trial situations.

Description: Purpose Ticagrelor is a reversibly binding P2Y 12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability. Methods This was a randomized, double-blind, two-period crossover study in healthy volunteers ( n  = 20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co-administration of ticagrelor 400 mg qd or placebo on days 1–16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7–14). Results Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52–2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13–1.52); and mean area under the curve by 28 %, from 16.8 ng · h/ml to 21.0 ng · h/ml (GMR 1.28, 1.12–1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co-administration of ticagrelor and digoxin was well tolerated. Conclusions Collectively, these results indicate that ticagrelor is a weak inhibitor of the P-glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy.

Description: Purpose Cholinesterase inhibitors and memantine are the mainstay of pharmacological intervention for the cognitive symptoms of Alzheimer’s disease (AD). This study assessed the adequacy of dosing and persistence with AD medications and the predictors of these variables in the ‘real world’ (outside the clinical trial setting). Methods The Health Service Executive–Primary Care Reimbursement Services prescription claims database in the Republic of Ireland contains prescription information for 1.6 million people. Patients aged 〉70 years who received at least two prescriptions for donepezil, rivastigmine, galantamine and memantine between January 2006 and December 2010 were included in the study. Rates of dose-maximisation were recorded by examining the initiation dose of each AD drug commenced during the study period and any subsequent dose titrations. Non-persistence was defined by a gap in prescribing of more than 63 consecutive days. Predictors of dose-maximisation and non-persistence were also analysed. Results Between January 2006 and December 2010, 20,729 patients aged 〉70 years received a prescription for an AD medication. Despite most patients on donepezil and memantine receiving a prescription for the maximum drug dose, this dose was maintained for 2 consecutive months in only two-thirds of patients. Patients were significantly more likely to have their doses of donepezil and memantine maximised if prescribed in more recent years (2010 vs. 2007). Rates of non-persistence were 30.1 % at 6 months and 43.8 % at 12 months. Older age [75+ vs. 〈75 years; hazards ratio (HR) 1.16, 95 % confidence interval (CI) 1.06–1.27] and drug type (rivastigmine vs. donepezil; HR 1.15, 95 % CI 1.03–1.27) increased the risk of non-persistence. Non-persistence was lower for those commencing therapy in more recent years (2010 vs. 2007; HR 0.81, 95 % CI 0.73–0.89, p  〈 0.001) and for those on multiple anti-dementia medications (HR 0.59, 95 % CI 0.54–0.65, p  〈 0.001). Persistence was significantly higher when memantine was co-prescribed with donepezil ( p  〈 0.0001). Conclusion Future studies should explore the reasons underlying non-persistence and failure to maintain dose-maximisation in patients on AD medications. There may be scope to improve the dosing and persistence with these medications in the community.

Description: Purpose We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1 * 15 haplotype in healthy volunteers. Methods In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 ( n  = 6), with CYP2C19 * 1 /* 1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 ( n  = 4), with CYP2C19 EM and homozygous ( n  = 3) or heterozygous for SLCO1B1 * 15 ( n  = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3–14 and twice-daily oral doses of 500 mg clarithromycin on study days 11–14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin). Results Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (C max ) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and C max by 27 % ( n  = 10, both p  〈 0.05). No contribution of SLCO1B1 * 15 to the extent of this interaction was observed. Conclusions Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.

Description: Purpose Ethanol and morphine are both substrates of uridine diphosphate glucuronosyl transferases (UGTs). A pharmacokinetic interaction between ethanol and morphine is suggested from in vitro studies, but to our knowledge not documented in vivo. The aim of this study was to compare the ratios between M6G and morphine and between M3G and morphine in blood samples from suspected drunk and drugged drivers, with and without presence of ethanol. Methods The data in the present study constitute all cases of suspected drunk and drugged driving positive for morphine, collected in Norway, in the period November 1st 2009 to December 1st 2012, during which all morphine positive cases were also routinely analysed for M6G and M3G. The cases were divided into two groups; one where morphine was present together with ethanol (group 1) and one where morphine was present in the absence of ethanol (group 2). Results The ratios between M3G and morphine was lower in the ethanol positive cases, i.e. mean 4.9 (95 % CI 4.03–5.79) in group 1 and mean 6.7 (95 % CI 6.35–7.00) in group 2 ( p  〈 0.001). The ratios between M6G and morphine was also lower in the ethanol positive cases, i.e. mean 0.62 (95 % CI 0.42–0.81) in group 1 and mean 0.96 (95 % CI 0.89–1.02) in group 2 ( p  = 0.001). Conclusions This study indicated that the metabolism of morphine may be changed in the presence of ethanol, resulting in less formation of the metabolites. This could lead to increased terminal half-life for morphine and also possibly more accumulation after repeated dosing.

Description: Purpose The aim of the study was to evaluate the incidence and type of actual drug–drug interactions (DDIs) that result in adverse drug reactions (ADRs) or diminished therapeutic effect in elderly patients within 30 days of discharge from an internal medicine clinic. Methods A prospective observational study was conducted at the Internal Medicine Clinic of University Hospital Dubrava, Zagreb, Croatia, between October and December 2011. Patients aged ≥65 years discharged from the Internal Medicine Clinic during the study period with a prescription for two or more medications were eligible for inclusion in the study. A total of 222 patients were ultimately enrolled in the study. For each patient, potential DDIs were identified using Lexi-Interact software. The follow-up visit was scheduled approximately 30 days after discharge. Causality between DDIs and ADRs or diminished therapeutic effect of drugs was assessed by two independent clinicians. Results Potential DDIs were identified in 190 (85.6 %) patients. Actual DDIs were detected in 21 (9.5 %) patients. In 19 patients, DDIs resulted in an ADR. Diminished therapeutic effect resulting from DDIs was detected in two patients. Angiotensin-converting enzyme inhibitors were the drug class most frequently associated with DDI-related ADRs. Conclusions A significant incidence of actual DDIs suggests that DDIs play an important role in patient safety. Drug therapy should be initiated if absolutely necessary, and the number of drugs used to treat elderly patients should be minimized to reduce the incidence of DDI-related adverse patient outcomes.

Description: Purpose To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection. Methods Four healthy men each received two single, 100 μg microdoses of 14 C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of 14 C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of 14 C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS. Results After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8–12 h after IV dosing, 14 C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, 14 C was still mostly associated with AR-709 at 12 h after dosing. Conclusions The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.

Description: Purpose Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification. Methods We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients’ clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone. Results During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64–1.07; HR 1.03; 95 % CI 0.88–1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82–1.18). Conclusion In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers.

Description: Purpose To analyze the quality of research on the use of benzodiazepines (BZDs) in the emergency room by the elderly population through the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. Methods A systematic review was carried out according to the following steps: (1) identification of studies , in which studies were selected from different combinations of the descriptors “elderly–aged,” “benzodiazepines,” and “emergency room” in the EMBASE–MEDLINE, SciELO, Scopus, and Web of Science databases; (2) evaluation of studies , in which the title, abstract, and full text of the studies were assessed; (3) evaluation of the methodological quality of the studies . The criteria used were those included in the STROBE recommendations. Results At the end of the selection process, only six articles were identified which met the specific criteria. The sample sizes in these studies varied from 118 to 1,611 patients. More than half (4) of the studies did not describe the type of design used, whereas all collected demographic data and analyzed details on the use of BZDs, such as type administered and/or its relationship to the symptoms, were shown. No article fully complied with the STROBE criteria. Conclusions This review shows a lack of methodological quality in the studies performed to date that have evaluated the use of BZDs in elderly patients in emergency rooms. These findings should guide future research in this subject area, providing a more complete approach on aspects related to the use of medications by this specific population.

Description: Background Statins are widely prescribed to reduce cholesterol levels in the prevention of atherosclerotic cardiovascular disease. However, the debate about the effect of statins on cancer risk remains unsettled. The aim of this study was to investigate the association of utilization of statins with the risk of gastric cancer by carrying out a meta-analysis. Methods A literature search was performed on PubMed and EMBASE up to March 2013 to identify the cohort or case–control studies or randomized controlled trials (RCTs) that examined the relationship between statins use and the risk of gastric cancer. The bibliographies of the retrieved articles were also reviewed to identify additional studies. A random-effects model was used to calculate the summary relative risks (RRs) with 95 % confidence intervals (CIs). Results Three post-hoc analyses of 26 RCTs involving 290 gastric cancers and eight observational studies totaling 7,321 gastric cancers were included. Statins use was shown to be significantly associated with a 27 % reduction in the risk of gastric cancer (RR = 0.73, 95 % CI = 0.58–0.93), with considerable heterogeneity among studies ( I 2  = 88.9 %). Excluding one study in which all subjects are diabetic patients obtained an attenuated, but homogeneous result (RR = 0.85, 95 % CI = 0.80–0.91, I 2  = 0.0 %). These findings were consistent in the subgroup analysis. Conclusion A meta-analysis of existing evidence, primarily from observational studies, indicates that use of statins reduces the risk of gastric cancer.

Description: Objectives The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers. Methods In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype ( n  = 9, CGC/CGC; n  = 10, CGC/TTT; n  = 10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin; in the other phase, participants received 40 mg of atorvastatin for 5 days, with a single 100 mg dose of sitagliptin administered on day 5. A 24-h pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period. Results Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with geometric mean ratios (90 % confidence intervals) for sitagliptin maximum plasma concentration, plasma concentration–time curve from zero to infinity, renal clearance, and fraction of sitagliptin excreted unchanged in the urine of 0.93 (0.86–1.01), 0.96 (0.91–1.01), 1.02 (0.93–1.12), and 0.98 (0.90–1.06), respectively. Conclusions ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes.