Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey.

BACKGROUND: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients. METHODS: Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines. RESULTS: Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey-Bradshaw Index (HBI) was observed under CZP therapy (12.2 ± 4.9 at week 0 versus 6.3 ± 4.7 at week 6 and 6.7 ± 5.3 at week 26, both P < 0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. CONCLUSIONS: In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice.

Is pretreatment with Beta-blockers beneficial in patients with acute coronary syndrome?

OBJECTIVES: The role of beta-blockers in the treatment of hypertension is discussed controversially and the data showing a clear benefit in acute coronary syndromes (ACS) were obtained in the thrombolysis era. The goal of this study was to analyze the role of pretreatment with beta-blockers in patients with ACS. METHODS: Using data from the Acute Myocardial Infarction in Switzerland (AMIS Plus) registry, we analyzed outcomes of patients with beta-blocker pretreatment in whom they were continued during hospitalization (group A), those without beta-blocker pretreatment but with administration after admission (group B) and those who never received them (group C). Major adverse cardiac events defined as composed endpoint of re-infarction and stroke (during hospitalization) and/or in-hospital death were compared between the groups. RESULTS: A total of 24,709 patients were included in the study (6,234 in group A, 12,344 in group B, 6,131 in group C). Patients of group B were younger compared to patients of group A and C (62.5, 67.6 and 68.4, respectively). In the multivariate analysis, odds ratio for major adverse cardiac events was 0.59 (CI 0.47-0.74) for group A and 0.66 (CI 0.55-0.83) for group B, while group C was taken as a reference. CONCLUSIONS: beta-Blocker therapy is beneficial in ACS and they should be started in those who are not pretreated and continued in stable patients who had been on chronic beta-blocker therapy before.

Urological surgery and antiplatelet drugs after cardiac and cerebrovascular accidents.

PURPOSE: The perioperative treatment of patients on dual antiplatelet therapy after myocardial infarction, cerebrovascular event or coronary stent implantation represents an increasingly frequent issue for urologists and anesthesiologists. We assess the current scientific evidence and propose strategies concerning treatment of these patients. MATERIALS AND METHODS: A MEDLINE and PubMed search was conducted for articles related to antiplatelet therapy after myocardial infarction, coronary stents and cerebrovascular events, as well as the use of aspirin and/or clopidogrel in the context of surgery. RESULTS: Early discontinuation of antiplatelet therapy for secondary prevention is associated with a high risk of coronary thrombosis, which is further increased by the hypercoagulable state induced by surgery. Aspirin has recently been recommended as a lifelong therapy. Clopidogrel is mandatory for 6 weeks after myocardial infarction and bare metal stents, and for 12 months after drug-eluting stents. Surgery must be postponed beyond these waiting periods or performed with patients receiving dual antiplatelet therapy because withdrawal therapy increases 5 to 10 times the risk of postoperative myocardial infarction, stent thrombosis or death. The shorter the waiting period between revascularization and surgery the greater the risk of adverse cardiac events. The risk of surgical hemorrhage is increased approximately 20% by aspirin and 50% by clopidogrel. CONCLUSIONS: The risk of coronary thrombosis when antiplatelet agents are withdrawn before surgery is generally higher than the risk of surgical hemorrhage when antiplatelet agents are maintained. However, this issue has not yet been sufficiently evaluated in urological patients and in many instances during urological surgery the risk of bleeding can be dangerous. A thorough dialogue among surgeon, cardiologist and anesthesiologist is essential to determine all risk factors and define the best possible strategy for each patient.

The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study.

BACKGROUND: European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. METHODS: The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996-2000 was summarised for 15 out of 25 responding full members. RESULTS: Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. CONCLUSIONS: Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry.

Pharmacokinetic and pharmacogenetic factors influencing plasma and cellular antiretroviral drug disposition

Abstract: The improvement in antiretroviral drug therapy has transformed HIV infection into a chronic disease. However, treatment failure and drug toxicity are frequent. Inadequate response to treatment is clearly multifactorial and, therefore, dosage individualisation based on demographic factors, genetic markers and measurement of cellular and plasma drug level may enhance both drug efficacy and tolerability. At present, antiretroviral drugs levels are monitored in plasma, whereas only drugs penetrating into cells are able to exert an antiviral activity, suggesting that cellular drug determination may more confidently reflect drug exposure at the site of pharmacological action. The overall objective of this thesis is to provide a better understanding of the Pharmacokinetic and pharmacogenetic factors influencing the plasma and cellular disposition of antiretroviral drugs. To that endeavour, analytical methods for the measurements of plasma and cellular drug levels have been developed and validated using liquid chromatography methods coupled with ultraviolet and tandem mass spectrometry detection, respectively. Correlations between plasma and cellular exposures were assessed during observational and experimental studies. Cytochrome (CYP) 2B6, efflux transporters (ABCB1, ABCC1, ABCC2 and ABCG2) and orosomucoid (ORM) polymorphisms were determined and were related to plasma and cellular exposures, as well as toxicity of antiretroviral drugs. A Pharmacokinetic population model was developed to characterise inter- and intra-patient variability of atazanavir pharmacokinetics, and to identify covariates influencing drug disposition. In that context, a Pharmacokinetic interaction study between atazanavir and lopinavir, both boosted with ritonavir, has beén conducted to assess the safety and pharmacokinetics of this boosted double-protease inhibitors regimen. Well to moderately-correlated cellular and plasma drug levels are .observed or protease inhibitors, whereas for efavirenz and nevirapine these correlations are weak. Cellular exposure, and CYP2B6 genotype (516G>T) are predictors of efavirenz neuropsychological toxicity. Nevirapine plasma exposure is also influenced by CYPZB6 polymorphism. Nelfinavir cellular exposure appears to be significantly associated only with ABCB1 genotype (3435C>T and intron 26 + 80T>C). Indinavir and lopinavir clearance and lopinavir cellular/plasma exposure ratio are influenced by the concentration of the variant S of ORM, suggesting-a specific binding of these drugs to this variant. Nelfinavir and efavirenz are not influenced by ORM concentration and phenotype. The Pharmacokinetic parameters of atazanavir are adequately described by our population model. The atazanavir-lopinavir interaction study indicates no influence on plasma and cellular atazanavir pharmacokinetics, while limited decrease in lopinavir concentrations was observed after atazanavir addition. The residual variability unexplained by the considered variables suggests that other covariates either uncontrolled at present or remaining to be identified, such as genetic and environmental factors influence antiretroviral drug pharmacokinetics, with substantial impact on treatment efficacy and tolerability. In that context, a comprehensive approach taking into account drug pharmacokinetics and patient genetic background is expected to contribute to increase treatment success, and to reduce the occurrence of adverse drug reactions by stratifying patients in an individualised antiretroviral therapy approach. Résumé Facteurs pharmacocinétiques et pharmacogénétiques influençant l'exposition plasmatique et cellulaire des antirétroviraux Les progrès de la thérapie antirétrovirale ont transformé l'infection par le VIH d'une affection mortelle à une maladie chronique. En dépit de ce succès, l'échec thérapeutique et la toxicité médicamenteuse restent fréquents. Une réponse inadéquate au traitement est clairement multifactorielle et une individualisation de la posologie des médicaments qui se baserait sur les facteurs démographiques et génétiques des patients et sur les taux sanguins des médicaments pourrait améliorer à la fois l'efficacité et la tolérance de la thérapie. Par ailleurs, seules les concentrations plasmatiques sont actuellement considérées pour le suivi thérapeutique des médicaments, alors que les taux cellulaires pourraient mieux refléter l'activité de ses médicaments qui agissent au niveau intracellulaire. L'objectif global de cette thèse était de mieux comprendre les facteurs pharmacocinétiques et pharmacocénétiques influençant l'exposition plasmatique et cellulaire des médicaments antirétroviraux. A cet effet, des méthodes pour quantifier les concentrations plasmatiques et cellulaires des antirétroviraux ont été développées et validées en utilisant la chromatographie liquide couplée à la détection ultraviolette et la spectrométrie de masse en tandem, respectivement. La corrélation entre l'exposition cellulaire et plasmatique de ces médicaments a été étudiée lors d'études observationnelles et expérimentales. Les polymorphismes du cytochrome (CYP) 2B6, ainsi que des transporteurs d'efflux (ABCB1, ABCC1, ABCC2 et ABCG2) et de l'orosomucoïde (ORM) ont été déterminés et corrélés avec l'exposition plasmatique et cellulaire des antirétroviraux, ainsi qu'à leur toxicité. Un modèle de pharmacocinétique de population a été établi afin de caractériser la variabilité inter- et intra-individuelle de l'atazanavir, et d'identifier les covariables pouvant influencer le devenir de ce médicament. Dans ce contexte, une étude d'interaction entre l'atazanavir et le lopinavir a été effectuée afin de déterminer la sécurité et le profil pharmacocinétique de ce régime thérapeutique. Des corrélations modérées à bonnes ont été observées entre les taux cellulaires et plasmatiques des inhibiteurs de protéase, alors que pour l'efavirenz et la névirapine ces corrélations sont faibles. L'exposition cellulaire, ainsi que le génotype du CYP2B6 (516G>T) sont des indices de la toxicité neuropsychologique de l'efavirenz. L'exposition plasmatique de la névirapine est également influencée par le polymorphisme du CYPZB6. L'exposition cellulaire du nelfinavir est significativement associée au génotype du ABCB1 (3435C>T et intron 26 + 80T>C). La clairance de l'indinavir et du lopinavir, ainsi que le rapport entre exposition cellulaire et plasmatique du lopinavir sont influencés par la concentration du variant S de l'ORM, suggérant une liaison spécifique de ces médicaments à ce variant. La clairance du nelfinavir et de l'efavirenz n'est pas influencée ni par la concentration ni par le phénotype de l'ORM. Les paramètres pharmacocinétiques de l'atazanavir ont été décrits de façon adéquate par le modèle de population proposé. De plus, le lopinavir n'influence pas les concentrations plasmatiques et cellulaires de l'atazanavir; alors que celui-ci conduit à une baisse limitée des taux de lopinavir. L'importante variabilité pharmacocinétique des antirétroviraux suggère que d'autres facteurs génétiques et environnementaux -qui restent encore à découvrir- influencent également leur disponibilité. Dans un proche futur, une prise en charge qui tienne. compte de la pharmacocinétique des médicaments et des caractéristiques génétiques du patient devrait permettre d'individualiser le traitement, contribuant certainement à une amélioration de la réponse thérapeutique et à une diminution de la toxicité. Résumé grand public Facteurs pharmacocinétiques et pharmacogénétiques influençant l'exposition plasmatique et cellulaire des antirétroviraux Les progrès effectués dans le traitement de l'infection par le virus de l'immunodéficience humaine acquise (VIH), ont permis de transformer une maladie avec un pronostic sombre, en une maladie chronique traitable avec des médicaments de plus en plus efficaces. Malgré ce succès, de nombreux patients ne répondent pas de façon optimale à leur traitement et/ou souffrent d'effets indésirables médicamenteux entraînant fréquemment une modification de leur thérapie. Actuellement, le suivi de la réponse au traitement s'effectue par la mesure chez les patients de la quantité de virus et du nombre des cellules immunitaires dans le sang, ainsi que par la concentration sanguine des médicaments administrés. Cependant, comme le virus se réplique à l'intérieur de la cellule, la mesure des concentrations médicamenteuses au niveau intracellulaire pourrait mieux refléter l'activité pharmacologique au site d'action. De plus, il a été possible de mettre en évidence la grande variabilité des concentrations plasmatiques de médicaments chez des patients prenant pourtant la même dose de médicament. Comme cette variabilité est notamment due à des facteurs génétiques qui sont susceptibles d'influencer la réponse au traitement antirétroviral, des analyses génétiques ont été également effectuées chez ces patients. Cette thèse a eu pour objectif de mieux comprendre les facteurs pharmacologiques et génétiques influençant l'activité et la toxicité des médicaments antirétroviraux afin de réduire la variabilité de la réponse thérapeutique. A cet effet, une méthode de dosage permettant la quantification des médicaments anti-HIV au niveau intracellulaire a été développée. Par ailleurs, nos études ont également porté .sur les variations génétiques influençant la quantité et l'activité des protéines impliquées dans le métabolisme et dans le transport des médicaments antirétroviraux. Enfin, les conséquences de ces variations sur la réponse clinique et la toxicité du traitement ont été évaluées. Nos études ont mis en évidence des associations significatives entre les variations génétiques considérées et la concentration sanguine, cellulaire et la toxicité de quelques médicaments antirétroviraux. La complémentarité des connaissances pharmacologiques, génétiques et virales pourrait aboutir à une stratégie globale permettant d'individualiser le traitement et la dose administrée, en fonction des caractéristiques propres de chaque patient. Cette approche pourrait contribuer à une optimisation du traitement antirétroviral dans la perspective d'une meilleure- efficacité thérapeutique à long terme et d'une diminution des effets indésirables rencontrés.

Dramatic effect of early clopidogrel administration in reducing mortality and MACE rates in ACS patients. Data from the Swiss registry AMIS-Plus.

BACKGROUND: Patients who have acute coronary syndromes with or without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy of early clopidogrel administration (300 mg) (<24 hours) when given with aspirin in such patients. METHODS: We included 30,243 patients who had an acute coronary syndrome with or without ST segment elevation. Data on early clopidogrel administration were available for 24,463 (81%). Some 15,525 (51%) of the total cohort were administrated clopidogrel within 24h of admission. RESULTS: In-hospital death occurred in 2.9% of the patients in the early clopidogrel group treated with primary PCI and in 11.4% of the patients in the other group without primary percutaneous coronary intervention (PCI) and no early clopidogrel. The unadjusted clopidogrel odds ratio (OR) for mortality was 0.31 (95% confidence interval 0.27-0.34; p <0.001). Incidence of major adverse cardiac death (MACE) was 4.1% in the early clopidogrel group treated with 1°PCI and 13.5% in the other group without primary PCI and no early clopidogrel (OR 0.35, confidence interval 0.32-0.39, p <0.001). Early clopidogrel administration and PCI were the only treatment lowering mortality as shown by mutlivariate analysis. CONCLUSIONS: The early administration of the anti-platelet agent clopidogrel in patients with acute coronary syndromes with or without ST-segment elevation has a beneficial effect on mortality and major adverse cardiac events. The lower mortality rate and incidence of MACE emerged with a combination of primary PCI and early clopidogrel administration.

Effectiveness of a drug dosing service provided by community pharmacists in polymedicated elderly patients with renal impairment a comparative study

Background: Drug dosing errors are common in renal-impaired patients. Appropriate dosing adjustment and drug selection is important to ensure patients" safety and to avoid adverse drug effects and poor outcomes. There are few studies on this issue in community pharmacies. The aims of this study were, firstly, to determine the prevalence of dosing inadequacy as a consequence of renal impairment in patients over 65 taking 3 or more drug products who were being attended in community pharmacies and, secondly, to evaluate the effectiveness of the community pharmacist"s intervention in improving dosing inadequacy in these patients when compared with usual care. Methods: The study was carried out in 40 Spanish community pharmacies. The study had two phases: the first, with an observational, multicentre, cross sectional design, served to determine the dosing inadequacy, the drug-related problems per patient and to obtain the control group. The second phase, with a controlled study with historical control group, was the intervention phase. When dosing adjustments were needed, the pharmacists made recommendations to the physicians. A comparison was made between the control and the intervention group regarding the prevalence of drug dosing inadequacy and the mean number of drug-related problems per patient. Results: The mean of the prevalence of drug dosing inadequacy was 17.5% [95% CI 14.6-21.5] in phase 1 and 15.5% [95% CI 14.5-16.6] in phase 2. The mean number of drug-related problems per patient was 0.7 [95% CI 0.5-0.8] in phase 1 and 0.50 [95% CI 0.4-0.6] in phase 2. The difference in the prevalence of dosing inadequacy between the control and intervention group before the pharmacists" intervention was 0.73% [95% CI (−6.0) - 7.5] and after the pharmacists" intervention it was 13.5% [95% CI 8.0 - 19.5] (p < 0.001) while the difference in the mean of drug-related problems per patient before the pharmacists" intervention was 0.05 [95% CI( -0.2) - 0.3] and following the intervention it was 0.5 [95% CI 0.3 - 0.7] (p < 0.001). Conclusion: A drug dosing adjustment service for elderly patients with renal impairment in community pharmacies can increase the proportion of adequate drug dosing, and improve the drug-related problems per patient. Collaborative practice with physicians can improve these results.

Schweizerisches Register für TNF-alpha-Blocker bei Kindern und Jugendlichen mit rheumatologischen Erkrankungen [Swiss registry for TNF-alpha blockers in children and adolescents with rheumatological diseases].

We created a registry to evaluate long term outcome, efficacy and adverse events for children treated wit TNF-alpha inhibitors in Switzerland. 106 patients (68 female/38 male) were included. 61 patients were treated with Etanercept (Enbrel) and 45 with Infliximab (Remicade). Concomitant treatment at baseline included corticosteroids in 26% and Methotrexate in 75% of the patients. Subjective disease activity three months after initiation of TNF-alpha was better in 81%, worse in 4% and stable in 15% of the patients. In total 24 adverse events in 21 patients were reported. Treatment with TNF-alpha inhibitors seems to be safe and effective for children and adolescents with rheumatologic diseases.

Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance.

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration. This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices.

The EU-ADR Web Platform: delivering advanced pharmacovigilance tools

PURPOSE: Pharmacovigilance methods have advanced greatly during the last decades, making post-market drug assessment an essential drug evaluation component. These methods mainly rely on the use of spontaneous reporting systems and health information databases to collect expertise from huge amounts of real-world reports. The EU-ADR Web Platform was built to further facilitate accessing, monitoring and exploring these data, enabling an in-depth analysis of adverse drug reactions risks.METHODS: The EU-ADR Web Platform exploits the wealth of data collected within a large-scale European initiative, the EU-ADR project. Millions of electronic health records, provided by national health agencies, are mined for specific drug events, which are correlated with literature, protein and pathway data, resulting in a rich drug-event dataset. Next, advanced distributed computing methods are tailored to coordinate the execution of data-mining and statistical analysis tasks. This permits obtaining a ranked drug-event list, removing spurious entries and highlighting relationships with high risk potential.RESULTS: The EU-ADR Web Platform is an open workspace for the integrated analysis of pharmacovigilance datasets. Using this software, researchers can access a variety of tools provided by distinct partners in a single centralized environment. Besides performing standalone drug-event assessments, they can also control the pipeline for an improved batch analysis of custom datasets. Drug-event pairs can be substantiated and statistically analysed within the platform's innovative working environment.CONCLUSIONS: A pioneering workspace that helps in explaining the biological path of adverse drug reactions was developed within the EU-ADR project consortium. This tool, targeted at the pharmacovigilance community, is available online at https://bioinformatics.ua.pt/euadr/. Copyright © 2012 John Wiley & Sons, Ltd.

Effectiveness of a drug dosing service provided by community pharmacists in polymedicated elderly patients with renal impairment a comparative study

Background: Drug dosing errors are common in renal-impaired patients. Appropriate dosing adjustment and drug selection is important to ensure patients" safety and to avoid adverse drug effects and poor outcomes. There are few studies on this issue in community pharmacies. The aims of this study were, firstly, to determine the prevalence of dosing inadequacy as a consequence of renal impairment in patients over 65 taking 3 or more drug products who were being attended in community pharmacies and, secondly, to evaluate the effectiveness of the community pharmacist"s intervention in improving dosing inadequacy in these patients when compared with usual care. Methods: The study was carried out in 40 Spanish community pharmacies. The study had two phases: the first, with an observational, multicentre, cross sectional design, served to determine the dosing inadequacy, the drug-related problems per patient and to obtain the control group. The second phase, with a controlled study with historical control group, was the intervention phase. When dosing adjustments were needed, the pharmacists made recommendations to the physicians. A comparison was made between the control and the intervention group regarding the prevalence of drug dosing inadequacy and the mean number of drug-related problems per patient. Results: The mean of the prevalence of drug dosing inadequacy was 17.5% [95% CI 14.6-21.5] in phase 1 and 15.5% [95% CI 14.5-16.6] in phase 2. The mean number of drug-related problems per patient was 0.7 [95% CI 0.5-0.8] in phase 1 and 0.50 [95% CI 0.4-0.6] in phase 2. The difference in the prevalence of dosing inadequacy between the control and intervention group before the pharmacists" intervention was 0.73% [95% CI (−6.0) - 7.5] and after the pharmacists" intervention it was 13.5% [95% CI 8.0 - 19.5] (p < 0.001) while the difference in the mean of drug-related problems per patient before the pharmacists" intervention was 0.05 [95% CI( -0.2) - 0.3] and following the intervention it was 0.5 [95% CI 0.3 - 0.7] (p < 0.001). Conclusion: A drug dosing adjustment service for elderly patients with renal impairment in community pharmacies can increase the proportion of adequate drug dosing, and improve the drug-related problems per patient. Collaborative practice with physicians can improve these results.

Effectiveness of a drug dosing service provided by community pharmacists in polymedicated elderly patients with renal impairment a comparative study

Background: Drug dosing errors are common in renal-impaired patients. Appropriate dosing adjustment and drug selection is important to ensure patients" safety and to avoid adverse drug effects and poor outcomes. There are few studies on this issue in community pharmacies. The aims of this study were, firstly, to determine the prevalence of dosing inadequacy as a consequence of renal impairment in patients over 65 taking 3 or more drug products who were being attended in community pharmacies and, secondly, to evaluate the effectiveness of the community pharmacist"s intervention in improving dosing inadequacy in these patients when compared with usual care. Methods: The study was carried out in 40 Spanish community pharmacies. The study had two phases: the first, with an observational, multicentre, cross sectional design, served to determine the dosing inadequacy, the drug-related problems per patient and to obtain the control group. The second phase, with a controlled study with historical control group, was the intervention phase. When dosing adjustments were needed, the pharmacists made recommendations to the physicians. A comparison was made between the control and the intervention group regarding the prevalence of drug dosing inadequacy and the mean number of drug-related problems per patient. Results: The mean of the prevalence of drug dosing inadequacy was 17.5% [95% CI 14.6-21.5] in phase 1 and 15.5% [95% CI 14.5-16.6] in phase 2. The mean number of drug-related problems per patient was 0.7 [95% CI 0.5-0.8] in phase 1 and 0.50 [95% CI 0.4-0.6] in phase 2. The difference in the prevalence of dosing inadequacy between the control and intervention group before the pharmacists" intervention was 0.73% [95% CI (−6.0) - 7.5] and after the pharmacists" intervention it was 13.5% [95% CI 8.0 - 19.5] (p < 0.001) while the difference in the mean of drug-related problems per patient before the pharmacists" intervention was 0.05 [95% CI( -0.2) - 0.3] and following the intervention it was 0.5 [95% CI 0.3 - 0.7] (p < 0.001). Conclusion: A drug dosing adjustment service for elderly patients with renal impairment in community pharmacies can increase the proportion of adequate drug dosing, and improve the drug-related problems per patient. Collaborative practice with physicians can improve these results.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Medication incidents in primary care medicine: protocol of a study by the Swiss Federal Sentinel Reporting System.

BACKGROUND/RATIONALE: Patient safety is a major concern in healthcare systems worldwide. Although most safety research has been conducted in the inpatient setting, evidence indicates that medical errors and adverse events are a threat to patients in the primary care setting as well. Since information about the frequency and outcomes of safety incidents in primary care is required, the goals of this study are to describe the type, frequency, seasonal and regional distribution of medication incidents in primary care in Switzerland and to elucidate possible risk factors for medication incidents. Label="METHODS AND ANALYSIS" ="METHODS"/> <AbstractText STUDY DESIGN AND SETTING: We will conduct a prospective surveillance study to identify cases of medication incidents among primary care patients in Switzerland over the course of the year 2015. PARTICIPANTS: Patients undergoing drug treatment by 167 general practitioners or paediatricians reporting to the Swiss Federal Sentinel Reporting System. INCLUSION CRITERIA: Any erroneous event, as defined by the physician, related to the medication process and interfering with normal treatment course. EXCLUSION CRITERIA: Lack of treatment effect, adverse drug reactions or drug-drug or drug-disease interactions without detectable treatment error. PRIMARY OUTCOME: Medication incidents. RISK FACTORS: Age, gender, polymedication, morbidity, care dependency, hospitalisation. STATISTICAL ANALYSIS: Descriptive statistics to assess type, frequency, seasonal and regional distribution of medication incidents and logistic regression to assess their association with potential risk factors. Estimated sample size: 500 medication incidents. LIMITATIONS: We will take into account under-reporting and selective reporting among others as potential sources of bias or imprecision when interpreting the results. ETHICS AND DISSEMINATION: No formal request was necessary because of fully anonymised data. The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT0229537.