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Enalapril type drugs were excluded; a dose-specific analysis in this cohort would have shown increased mortality rates during the first years of therapy with the same drugs. However, observed difference (5% risk reduction) was of similar order magnitude for patients with and without liver diseases. Although this association between antiheptacannabinoid medications and risk of nephrolithiasis has not been observed in a number of other studies involving patients with cirrhosis, it remains an important additional consideration. Liver function tests The following two test kits were used in our patients: a test developed as part of the Global Registry for Drug Safety identifying and testing interactions with hepatitis C medications; and a test originally developed to detect the use of acetaminophen (acetylsalicylic acid) that provides an indirect assay for liver function tests based on the interaction between acetylsalicylic acid and the antithrombin III (Anti-NHLBI3) anti-nucleoside phosphorylase inhibitor (anti-NHLBI4) drugs.14 In this study we used the International Laboratory Safety Assessment (ILSA) technique for identifying potential drug interactions between antiheptacannabinoid medications and various drugs in the management of patients with cirrhosis, particularly antiheptacannabinoids. It detects an interaction between a coadministration of an antithrombotic and antidiabetogen, also detects interactions with antiheptacannabinoid medication, including antiheptacannabinoids. Because of the small sample sizes, number of liver function tests available for these patients was limited. Nevertheless, the correlation of this test kit with the results obtained using ILSAD method is very strong, with an excellent correlation (r=0.94, P<0.0001) over the range of drug interaction studies using these two different methods.13,29,31 In a retrospective study of patients who were initially treated with antipsychotics to treat schizophrenia, this test kit was found to perform at comparable levels the test kit originally developed for acetaminophen use and is available through ILSAD (Lancet Diabetes and Endocrinology). Conclusion To our knowledge, the present study is first prospective analysis of long-term treatment with antiheptacannabinoid medication in patients cirrhosis. The current study suggests that a relatively modest increase in mortality associated with antiheptacannabinoid use during therapy antiheptacannabinoids is associated with increased risk of nephrolithiasis compared with a no-drug condition but does not provide a clear indication of threshold for risk. Our findings, however, should prompt re-evaluation with regard to risk of hepatic fibrosis in these patients who have already developed cirrhosis, and the development of a patient-centered approach is warranted. Back to top Article Information Accepted for Publication: May 24, 2011. Corresponding Author: Peter L. D'Annibale, PhD, Centre for Drug Safety and Evaluation at the University of British Columbia, 150 Avenue, Room A-931, Vancouver, B.C., V6T 0A9, Canada (lod@ubc.ca). Published Online: July 3, 2011. doi:10.1001/archinternmed.2010.1478 Author Contributions: Ms D'Annibale had full access to all the data in study and takes responsibility for the integrity of data and accuracy the analysis. Study concept and design: Luebke, Hildenbrand, D'Annibale. Acquisition, analysis, or interpretation of data: Luebke, Hildenbrand, Cichon, Oehlke, Degenhardt, Rauch, Eftekhari. Drafting of the manuscript: Luebke, D'Annibale. Critical revision of the manuscript for important intellectual content: D'Annibale, Luebke, Buhlen. Statistical analysis: Hildenbrand, Buhlen. Administrative, technical, or material support: Luebke, Fuhlmann, Pohl, Degenhardt, Oehlke, Märzer, Cichon, Rauch, Löwmark. Study supervision: Hildenbrand, Cichon, Luebke, Buhlen. Conflict of Interest Disclosures: A number patients had received financial compensation related to the study of antipsychotics and hepatic diseases for clinical work performed in our facility at University of British Columbia from the Pfizer Company; neither study author nor the patients has had an income from financial compensation related to the study of antipsychotics and hepatic diseases, including the use of data collected on patients.

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