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- Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation. [JOURNAL ARTICLE]
- Kidney Int 2014 Sep 17.
Although cold ischemia time has been widely studied in renal transplantation area, there is no consensus on its precise relationship with the transplantation outcomes. To study this, we sampled data from 3839 adult recipients of a first heart-beating deceased donor kidney transplanted between 2000 and 2011 within the French observational multicentric prospective DIVAT cohort. A Cox model was used to assess the relationship between cold ischemia time and death-censored graft survival or patient survival by using piecewise log-linear function. There was a significant proportional increase in the risk of graft failure for each additional hour of cold ischemia time (hazard ratio, 1.013). As an example, a patient who received a kidney with a cold ischemia time of 30 h presented a risk of graft failure near 40% higher than a patient with a cold ischemia time of 6 h. Moreover, we found that the risk of death also proportionally increased for each additional hour of cold ischemia time (hazard ratio, 1.018). Thus, every additional hour of cold ischemia time must be taken into account in order to increase graft and patient survival. These findings are of practical clinical interest, as cold ischemia time is among one of the main modifiable pre-transplantation risk factors that can be minimized by improved management of the peri-transplantation period.Kidney International advance online publication, 17 September 2014; doi:10.1038/ki.2014.304.
- Presystemic Elimination of Tilidine: Localisation and Consequences for the Formation of the Active Metabolite Nortilidine. [JOURNAL ARTICLE]
- Basic Clin Pharmacol Toxicol 2014 Sep 15.
The therapeutic activity of tilidine, an opioid analgesic, is mainly related to its active metabolite nortilidine. Nortilidine formation mainly occurs during the high intestinal first-pass metabolism of tilidine by N-demethylation. Elimination of the active nortilidine to the inactive bisnortilidine is also mediated by N-demethylation and is supposed to take place in the liver, probably at a smaller rate. The aim of this study was the investigation of the pre-systemic elimination of tilidine using grapefruit juice as an intestinal CYP3A4 inhibitor and efavirenz as a CYP3A4 activator. A randomised, open, placebo-controlled, cross-over study was conducted in 12 healthy volunteers using 100 mg tilidine solution p.o., regular strength grapefruit juice 250 mL (3 times at 12-hr intervals) and efavirenz 400 mg (12 hr before tilidine administration). Tilidine, nortilidine and bisnortilidine in plasma and urine was quantified by a validated LC/MS/MS analysis. Grapefruit juice did not change any pharmacokinetic parameter of tilidine and its metabolites which suggests that intestinal CYP3A4 does not contribute to the first-pass metabolism of tilidine. No effect of efavirenz on the pharmacokinetics of the active nortilidine was observed except a significant reduction of the terminal elimination half-life by 15%. Overal elimination (renal and metabolic clearances) was unaffected by every treatment. CYP3A4 does not seem to play a major role in tilidine first-pass and overall metabolism. Other unknown metabolites and their enzymes responsible for their formation have to be investigated since they account for the majority of renally excreted metabolites. This article is protected by copyright. All rights reserved.
- Risk management plans as tool for proactive pharmacovigilance: a cohort study of newly approved drugs in Europe. [JOURNAL ARTICLE]
- Clin Pharmacol Ther 2014 Sep 15.
Risk Management Plans (RMPs) have become a cornerstone in pharmacovigilance of new drugs in Europe. The RMP was introduced in 2005 to support a proactive approach in gaining knowledge on safety concerns, through early planning of pharmacovigilance activities. The rate at which uncertainties in the safety profile are resolved through this proactive approach is, however, unknown. We therefore examined the evolution of safety concerns in the RMP after initial approval for a selected cohort of 48 drugs, to provide insight into the knowledge gain over time. We found that 20.7% of the uncertainties existing at approval had been resolved five years after approval. Since new uncertainties were included in the RMP at a similar rate, their overall number remained approximately equal. The relatively modest accrual of knowledge, as demonstrated in this study through resolution of uncertainties, suggests that opportunities for optimization exist while ensuring feasible and risk proportionate pharmacovigilance planning.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 15 September 2014. doi:10.1038/clpt.2014.184.
- Adverse drug events among adult inpatients: a meta-analysis of observational studies. [JOURNAL ARTICLE]
- J Clin Pharm Ther 2014 Sep 15.
Studies in a number of countries have shown that adverse drug events (ADE) occur frequently among hospital inpatients. The objective of this study was to conduct a systematic review of observational studies of the frequency of ADE in adult inpatients and to examine factors associated with observed heterogeneity in the reported results.The systematic review included observational studies, which identified and analysed ADE during hospitalization of adult inpatients. The literature search was conducted on MEDLINE, Embase, Lilacs and Google Scholar (January of 2000 to June of 2013). Article selection, quality assessment and information extraction were performed by two of the authors, working independently. Using the random-effects model, the proportion of patients with adverse events was used as an outcome measure. Proportion was estimated for subgroups based on event identification method: stimulated reporting (SR), retrospective monitoring (RM) and prospective monitoring (PM). For the latter group, meta-regression was used to identify sources of heterogeneity in the estimates.Twenty-eight articles from the 7550 identified met our inclusion criteria. The articles were heterogeneous in terms of quality, outcome definition and event identification method and in the corresponding descriptions. Of the 28 articles selected, 25 were included in the corresponding quantitative summary: four used SR, six RM and 15 PM, returning incidences of 2·3% (CI 95%: 1·6-4·5), 8·7% (CI 95%: 4·8-15·3) and 21·3% (CI 95%: 15·7-28·3), respectively, and I(2) greater than 95%. There were other sources of heterogeneity, including the use of combined strategies within each subgroup. In the PM subgroup, using multivariate meta-regression model, no variables were found to associate with proportion.Event frequency seems to associate with the event identification method. PM returned the highest estimates. This subgroup used a greater diversity of approaches for event identification and more diverse data sources. Improved recording of information on the event identification method, the characteristics of the events and the conduct of the study would enable more reliable and precise estimates of the frequency of ADE among hospital inpatients.
- Pharmacovigilance in China: Current Situation, Successes and Challenges. [JOURNAL ARTICLE]
- Drug Saf 2014 Sep 14.
With the integration of the global pharmaceutical economy and the gradual transformation of the healthcare insurance system in China, the legislative framework for a comprehensive regulatory system monitoring the whole process including drug development, manufacture, distribution and use has been established by the China Food and Drug Administration (CFDA) to ensure the safety and effectiveness of medication use. China has established a relatively comprehensive pharmacovigilance system covering regulation, organisation and technology from 1989 to 2014. As of 2013, one national centre, 34 provincial centres and more than 400 municipal centres for adverse drug reaction (ADR) monitoring were included in the four-level pharmacovigilance network (national, provincial, municipal and county) with more than 200,000 grassroot organisation users. The China Adverse Drug Reaction Monitoring System (CADRMS) is an online spontaneous reporting system which connects the four-level pharmacovigilance network. By 2013, CADRMS had received over 6.6 million ADR case reports. After integrating and analysing pharmacovigilance data, the National Centre for ADR Monitoring (NCADRM) publishes medication safety information by releasing ADR bulletins, National ADR Annual Reports and International Pharmacovigilance Newsletters. The NCADRM also routinely provides CADRMS data feedback to manufacturers. The CFDA implemented risk management through several approaches, including arranging 'manufacturer communication meetings', modification of medication package inserts, and restriction, suspension or withdrawal of marketing authorisations. Seamless information exchange with overseas regulatory authorities and organisations remains an area for improvement. Further development of the China pharmacovigilance system in terms of signal generation, post-marketing pharmacoepidemiology research and education is also needed.
- Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations. [JOURNAL ARTICLE]
- Diabetologia 2014 Sep 12.
Recent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved.We reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges.From the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods.Observational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.
- Adverse drug events with hyperkalaemia during inpatient stays: evaluation of an automated method for retrospective detection in hospital databases. [Journal Article]
- BMC Med Inform Decis Mak 2014; 14(1):83.
Adverse drug reactions and adverse drug events (ADEs) are major public health issues. Many different prospective tools for the automated detection of ADEs in hospital databases have been developed and evaluated. The objective of the present study was to evaluate an automated method for the retrospective detection of ADEs with hyperkalaemia during inpatient stays.We used a set of complex detection rules to take account of the patient's clinical and biological context and the chronological relationship between the causes and the expected outcome. The dataset consisted of 3,444 inpatient stays in a French general hospital. An automated review was performed for all data and the results were compared with those of an expert chart review. The complex detection rules' analytical quality was evaluated for ADEs.In terms of recall, 89.5% of ADEs with hyperkalaemia "with or without an abnormal symptom" were automatically identified (including all three serious ADEs). In terms of precision, 63.7% of the automatically identified ADEs with hyperkalaemia were true ADEs.The use of context-sensitive rules appears to improve the automated detection of ADEs with hyperkalaemia. This type of tool may have an important role in pharmacoepidemiology via the routine analysis of large inter-hospital databases.
- Regulating incremental innovation in medical devices. [Editorial]
- BMJ 2014.:g5303.
- Behavioral and clinical factors associated with self-reported abnormal papanicolaou tests in rheumatoid arthritis. [Journal Article]
- J Womens Health (Larchmt) 2014 Sep; 23(9):771-6.
Abstract Background: Some evidence suggests that women with rheumatoid arthritis (RA) are at increased risk for the development of cervical cancer; however, it is unclear how this increase risk is conferred. We aimed to assess the factors related to abnormal Papanicolaou (Pap) tests in women with RA to determine whether they are similar to those reported for the general population.A structured questionnaire was mailed to 503 female patients from a longitudinal RA cohort. The survey included items on sociodemographic, behavioral, and gynecological factors. Univariate and multivariable logistic regression models examined the association of self-reported abnormal Pap results with a number of potential behavioral risk factors.The questionnaire response rate was 57.5% (n=289). Median age was 61 years and 97% had ≥1 Pap test previously. Twenty-nine percent of respondents reported a previous abnormal Pap result. In the multivariable logistic model adjusted for age, number of lifetime sexual partners, age at menarche, birth control use, and history of sexually transmitted disease (STD), ever using birth control (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.18-4.52) and previous STD (OR 3.38, 95% CI 1.70-6.70) were associated with an increased risk of abnormal Pap result. Compared with either the state or national population, a greater proportion of the respondents was older, married, and previous smokers, and completed postsecondary education and obtained a Pap test.In this cross-sectional study, self-reported abnormal Pap results were associated with use of birth control and history of STD in RA patients.
- Body mass index and mortality among Japanese patients with type 2 diabetes: Pooled analysis of the Japan Diabetes Complications Study and the Japanese Elderly Diabetes Intervention Trial. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2014 Sep 9.:jc20141855.
Context: Previous studies on the association between BMI and mortality in diabetes do not necessarily provide a comprehensive view in terms of the global population because of the exclusion of individuals with BMI <18.5 kg/m(2). Objective: To examine the association between BMI and mortality. Design, Setting, and Participants: We analyzed pooled data from 2 cohorts of 2620 Japanese patients with type 2 diabetes followed for 6.3 years. Patients with a history of cardiovascular disease or cancer were excluded. Main outcome measure: The endpoint was all-cause mortality. Hazard ratios were estimated by Cox regression adjusted for age, smoking, leisure-time physical activity and other confounders. Results: Analysis using BMI categories of 14.4-18.5 (5.2%), 18.5-22.4 (37.3%), 22.5-24.9 (31.0%), and 25.0-37.5 kg/m(2) (26.6%) revealed no significant trend in mortality among patients with BMI ≥18.5 kg/m(2) (trend p=0.69). In contrast, the hazard ratio of patients with BMI <18.5 kg/m(2) versus 22.5-24.9 kg/m(2) was 2.58 (95% confidence interval, 1.38 to 4.84; p<0.01). Exclusion of deaths in the first 4 years of follow-up decreased the hazard ratio only slightly. Conclusions: The lowest mortality rate was observed among patients with BMI of 18.5-24.9 kg/m(2) and obesity had no benefits regarding mortality. Further research is needed in lean patients, especially among aging populations in East Asia.