Frequency and clinical relevance of potential cytochrome P450 drug interactions in a psychiatric patient population – an analysis based on German insurance claims data

Background Numerous drugs used in the treatment of psychiatric disorders are substrates of cytochrome P450 enzymes and are potential candidates for drug- drug interactions (DDIs). Methods Claims data of a German statutory health insurance company from severely mentally ill patients who registered in an integrated care contract from August 2004 to December 2009 were analysed. We measured time periods of concomitant prescription of drugs that have been reported to interact via cytochrome P450, with a focus on drugs acting as strong inhibitors. Such drug-drug exposure (DDE) is an incontrovertible precursor of DDIs. We assessed whether potential DDIs were considered clinically relevant based on the prescribing information of the respective drugs. Results Among all 1221 patients, 186 patients (15.2 %; Clopper-Pearson 95 % confidence interval (CI): 13.3–17.4 %) had at least one DDE prescription, and 58 patients (4.8 %; 95 % CI 3.6–6.1) had at least one DDE prescription involving a strong cytochrome P450 inhibitor. In 59 patients, (4.8 %; 95 % CI: 3.7–6.2 %) five or more DDEs were identified, and five or more DDEs with a strong inhibitor were identified in 18 patients (1.5 %; 95 % CI: 0.9–2.3). The rates of DDEs were 0.27 (Garwood 95%CI: 0.25–0.28) per person-year and 0.07 (95 % CI: 0.07–0.08) for strong-inhibitor DDEs. Four of the ten most frequent DDEs were identified as clinically relevant, and seven of the eight most frequent DDEs involving a strong inhibitor were clinically relevant. Conclusions The number of patients with DDEs was not alarmingly high in our sample. Nevertheless, prescription information showed that some prescribed drug combinations could result in serious adverse consequences that are known to weaken or strengthen the effect of the drugs and should therefore be avoided

Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison

Additional data on meta-analyses and historical comparisons. (DOCX 18 kb

a meta-analysis and historical comparison

Background About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNα) and ribavirin (RBV) have been shown to be superior to PegIFNα + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1) / HIV coinfection are available. Methods This was a historical comparison of study C212 (simeprevir + PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNα-2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNα-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212. Results The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNα-2a + RBV from the random-effects meta- analysis was 28.2 % (95 % CI 23.8 % to 32.9 %). The comparison between study C212 (SVR24 = 72.6 %; 95 % CI 63.1 % to 80.9 %) revealed substantial superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV alone, with an absolute risk difference of 45 % (95 % CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies. Conclusion This historical comparison provides first systematic evidence for the superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV in patients with HCV-1 / HIV coinfection. Given the limitations of the historical comparison for safety endpoints, additional data on the comparative safety of simeprevir in patients with HCV-1 / HIV coinfection would be desirable. Trial registration Identifier for study TMC435-TiDP16-C212 (ClinicalTrials.gov): NCT01479868

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face- to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed

Magic Islands and Barriers to Attachment: A Si/Si(111)7x7 Growth Model

Surface reconstructions can drastically modify growth kinetics during initial stages of epitaxial growth as well as during the process of surface equilibration after termination of growth. We investigate the effect of activation barriers hindering attachment of material to existing islands on the density and size distribution of islands in a model of homoepitaxial growth on Si(111)7x7 reconstructed surface. An unusual distribution of island sizes peaked around "magic" sizes and a steep dependence of the island density on the growth rate are observed. "Magic" islands (of a different shape as compared to those obtained during growth) are observed also during surface equilibration.Comment: 4 pages including 5 figures, REVTeX, submitted to Physical Review

Modeling Frameworks for Representing the Mechanical Behavior of Tissues with a Specific Look at Vasculature

Many mechanicstic models aimed at predicting tissue behavior attempt to connect constitutive factors (such as effects due to collagen or fibrin concentrations) with the overall tissue behavior. Such a link between constitutive and material behaviors would allow for a better understanding of the mechanobiology of diseased states and how one might return the tissue to a healthy state. Therefore, a literature search into present mechanistic models was performed and yielded a variety of models that were analyzed in order to determine their uniqueness, a requisite characteristic for this aim. It was found that many of these models did not make uniqueness a defining characteristic in their development and thus cannot be used for multiscale modeling (connecting constitutive behavior to material behavior).The literature search was then extended and narrowed to specifically analyze mechanical models describing vascular wall behavior. Once again, it was found that uniqueness was lacking in these models. To develop a unique model for inflation strains, an inflation experiment utilizing a bladder, syringe, and a pressure sensor was conducted to provide pressure vs. volume data for a sheep aorta. The data was then used to develop a unique model for inflation strains in an aorta utilizing a constitutive framework developed by Dr. John Criscione

Beiträge zur Kenntniss der nichtzuckerführenden Harnruhr : Inaugural-Dissertation

http://tartu.ester.ee/record=b2501956~S1*es

Medical treatment of prolactinomas.

Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. The most important clinical problems associated with prolactinomas are hypogonadism, infertility and hyposexuality. In patients with macroprolactinomas, mass effects, including visual field defects, headaches and neurological disturbances, can also occur. The objectives of therapy are normalization of prolactin levels, to restore eugonadism, and reduction of tumor mass, both of which can be achieved in the majority of patients by treatment with dopamine agonists. Given their association with minimal morbidity, these drugs currently represent the mainstay of treatment for prolactinomas. Novel data indicate that these agents can be successfully withdrawn in a subset of patients after normalization of prolactin levels and tumor disappearance, which suggests the possibility that medical therapy may not be required throughout life. Nevertheless, multimodal therapy that involves surgery, radiotherapy or both may be necessary in some cases, such as patients who are resistant to the effects of dopamine agonists or for those with atypical prolactinomas. This Review reports on efficacy and safety of pharmacotherapy in patients with prolactinomas

Prevalence, incidence, and thromboembolic events in polycythemia vera : a study based on longitudinal German health claims data

There is little evidence, particularly in Germany, on the epidemiology and the cytoreductive management of polycythemia vera (PV). We performed an observational study based on anonymized health claims data to provide estimates of the epidemiology of PV in Germany, to describe the use of cytoreductive drugs in patients with PV, and to assess the occurrence of thromboembolic events (TEs) in prevalent patients on continuous treatment with relevant cytoreductive drugs over time. For the year 2021, we estimated a PV prevalence of 28.6 per 100,000 and an incidence of 3.3 per 100,000 in the German adult population (≥ 18 years). We identified 83.2% of prevalent patients in 2021 as being at high risk for thromboembolic complications, based on age (≥ 60 years) and/or history of TEs. Contrary to treatment guidelines, 43.6% of these high-risk patients did not receive cytoreductive drug treatment in 2021. 63.5% of patients in 2021 who were treated with hydroxyurea (but not ruxolitinib) in that year, met our defined proxy criteria for intolerance/resistance to hydroxyurea. Over time, we observed a lower proportion of patients with TEs in patients continuously treated with ruxolitinib compared to patients treated with hydroxyurea who also met our defined proxy criteria for intolerance/resistance to hydroxyurea (35.8% vs. 56.3% after three years). Our findings suggest that currently available cytoreductive therapies are not being fully utilized according to treatment guidelines, which may lead to avoidable thromboembolic complications in this patient population