Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase (TM) Unified List Based on International Collaborative Work

BACKGROUND Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans. OBJECTIVE (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase). DATA SOURCES AND EXTRACTION (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of >or=2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase. DATA SYNTHESIS After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF. CONCLUSIONS This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

A large study of androgen receptor germline variants and their relation to sex hormone levels and prostate cancer risk. Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes. Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels. Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 × 10−5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively). Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.

Why Public Health Agencies Cannot Depend on Good Laboratory Practices as a Criterion for Selecting Data: The Case of Bisphenol A

In their safety evaluations of bisphenol A (BPA), the U.S. Food and Drug Administration (FDA) and a counterpart in Europe, the European Food Safety Authority (EFSA), have given special prominence to two industry-funded studies that adhered to standards defined by Good Laboratory Practices (GLP). These same agencies have given much less weight in risk assessments to a large number of independently replicated non-GLP studies conducted with government funding by the leading experts in various fields of science from around the world. OBJECTIVES: We reviewed differences between industry-funded GLP studies of BPA conducted by commercial laboratories for regulatory purposes and non-GLP studies conducted in academic and government laboratories to identify hazards and molecular mechanisms mediating adverse effects. We examined the methods and results in the GLP studies that were pivotal in the draft decision of the U.S. FDA declaring BPA safe in relation to findings from studies that were competitive for U.S. National Institutes of Health (NIH) funding, peer-reviewed for publication in leading journals, subject to independent replication, but rejected by the U.S. FDA for regulatory purposes. DISCUSSION: Although the U.S. FDA and EFSA have deemed two industry-funded GLP studies of BPA to be superior to hundreds of studies funded by the U.S. NIH and NIH counterparts in other countries, the GLP studies on which the agencies based their decisions have serious conceptual and methodologic flaws. In addition, the U.S. FDA and EFSA have mistakenly assumed that GLP yields valid and reliable scientific findings (i.e., "good science"). Their rationale for favoring GLP studies over hundreds of publically funded studies ignores the central factor in determining the reliability and validity of scientific findings, namely, independent replication, and use of the most appropriate and sensitive state-of-the-art assays, neither of which is an expectation of industry-funded GLP research. CONCLUSIONS: Public health decisions should be based on studies using appropriate protocols with appropriate controls and the most sensitive assays, not GLP. Relevant NIH-funded research using state-of-the-art techniques should play a prominent role in safety evaluations of chemicals.

Amniotic fluid iodine concentrations do not vary in pregnant women with varying iodine intake.

Iodine deficiency is an important clinical and public health problem. Its prevention begins with an adequate intake of iodine during pregnancy. International agencies recommend at least 200 microg iodine per d for pregnant women. We assessed whether iodine concentrations in the amniotic fluid of healthy pregnant women are independent of iodine intake. This cross-sectional, non-interventional study included 365 consecutive women who underwent amniocentesis to determine the fetal karyotype. The amniocentesis was performed with abdominal antisepsis using chlorhexidine. The iodine concentration was measured in urine and amniotic fluid. The study variables were the intake of iodized salt and multivitamin supplements or the prescription of a KI supplement. The mean level of urinary iodine was 139.0 (SD 94.5) microg/l and of amniotic fluid 15.81 (SD 7.09) microg/l. The women who consumed iodized salt and those who took a KI supplement had significantly higher levels of urinary iodine than those who did not (P = 0.01 and P = 0.004, respectively). The urinary iodine levels were not significantly different in the women who took a multivitamin supplement compared with those who did not take this supplement, independently of iodine concentration or multivitamin supplement. The concentrations of iodine in the amniotic fluid were similar, independent of the dietary iodine intake. Urine and amniotic fluid iodine concentrations were weakly correlated, although the amniotic fluid values were no higher in those women taking a KI supplement. KI prescription at recommended doses increases the iodine levels in the mother without influencing the iodine levels in the amniotic fluid.

National Health System Virtual Library Viability Project (Spain)

Introduction: The ICT progress and development are making the set up of virtual libraries easier, with great advantages for users in terms of immediate access to vast amounts of library information, online resources, and services. Most of the Autonomous Spanish Regions are presently working on the establishment of virtual libraries with the aim of optimising economic resources destined to subscribe bibliographic information sources and offering qualified documentary services to Public Health System Professionals. The Ministry of Health and Social Policy, an institution unifying health matters, issued this Project to study the National Health System Virtual Library creation viability, in order to guarantee relevant scientific information access equity. Objectives: - To study the National Health System (NHS) Virtual Library set up viability. - To elaborate the Spanish territory health information resource map. - To identify the appropriate technological model. - To identify the documentary services to be offered. - To identify the more optimum functional, structural model. - To identify the economic model. Method: - To create a chart organization for the project´s management. - To organize Work groups. - To elaborate a standardised survey model for the libraries of the autonomous regions. Results: - Identification of the different Autonomous Region libraries of health models. - Recommendations for the NHS Virtual Library: - Functional, structural model - Technological model - Financial-economic model Conclusions: The fact that the Virtual Library would be an invaluable space for access to quality scientific information, as well as that the minimum services could be offered to every NHS user regardless of geographical situation, is confirmed. Accordingly, we thought about three different models to develop the Virtual Library, depending on this initial analysis, which will allow us to establish the most suitable model for the Spanish National Health System, considering its economic, functional and technological recommendations. It would be necessary to do a study for the NHS Virtual Library Set Up following the recommendations arising from this Project.

Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study.

BACKGROUND Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. METHODS AND FINDINGS The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10-4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10-3) and waist circumference (p for interaction  = 7.49×10-9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. CONCLUSIONS The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.