Characterisation of Human Cytochrome P450s Involved in the Bioactivation of Clozapine.
Characterisation of Human Cytochrome P450s Involved in the Bioactivation of Clozapine.
Filed under: Drug and Alcohol Rehabilitation
Drug Metab Dispos. 2013 Jan 7;
Dragovic S, Gunness P, Ingelman-Sundberg M, Vermeulen NP, Commandeur JN
Clozapine is known to cause hepatotoxicity in a small percentage of patients. Oxidative bioactivation to reactive intermediates by hepatic cytochrome P450s has be proposed as possible mechanism. However, in contrast to their role in formation of N-desmethylclozapine and clozapine N-oxide, the involvement of individual P450s in the bioactivation to reactive intermediates is much less well characterized. The results of the present study show that seven out of fourteen recombinant human P450s were able to bioactivate clozapine to a GSH-reactive nitrenium ion. CYP3A4 and CYP2D6 showed the highest specific activity. Enzyme kinetical characterization of these P450s showed comparable intrinsic clearance of bioactivation implicating that CYP3A4 would be more important because of its higher hepatic expression compared to CYP2D6. Inhibition experiments using pooled human liver microsomes confirmed the major role of CYP3A4 in hepatic bioactivation of clozapine. By studying bioactivation of clozapine in human liver microsomes from 100 different individuals, an 8-fold variability in bioactivation activity was observed. In two individuals bioactivation activity exceeded N-demethylation and N-oxidation activity. Quinidine did not show significant inhibition of bioactivation in any of these liver fractions, suggesting that CYP2D6 polymorphism is not an important factor in determining susceptibility to hepatotoxicity of clozapine. Therefore, interindividual differences and drug-drug interactions at the level of CYP3A4 might be factors determining exposure of hepatic tissue to reactive clozapine metabolites.
HubMed – drug
Regions with higher medicare part d spending show better drug adherence, but not lower medicare costs for two diseases.
Filed under: Drug and Alcohol Rehabilitation
Health Aff (Millwood). 2013 Jan; 32(1): 120-6
Stuart B, Shoemaker JS, Dai M, Davidoff AJ
A quarter-century of research on geographic variation in Medicare costs has failed to find any positive association between high spending and better health outcomes. We conducted this study using a 5 percent random sample of Medicare beneficiaries with diabetes or heart failure in 2006 and 2007 to see whether there was any correlation between geographic variation in Part D spending and good medication-taking behavior-and, if so, whether that correlation resulted in reduced Medicare Parts A and B spending on diabetes and heart failure treatments. We found that beneficiaries residing in areas characterized by higher adjusted drug spending had significantly more “therapy days”-days with recommended medications on hand-than did beneficiaries in lower-spending areas. However, we did not find that this factor translated into short-term savings in Medicare treatment costs for these two diseases. This result might not be surprising, since returns from medication adherence can take years to manifest. At the same time, discovering which regional factors are responsible for differences in drug spending and medication practices should be a high priority. If the observed differences are related to poor physician communication or lack of good care coordination, then appropriately designed policy tools-including accountable care organizations, medical homes, and provider quality reporting initiatives-might help address them.
HubMed – drug
The redistribution of graduate medical education positions in 2005 failed to boost primary care or rural training.
Filed under: Drug and Alcohol Rehabilitation
Health Aff (Millwood). 2013 Jan; 32(1): 102-10
Chen C, Xierali I, Piwnica-Worms K, Phillips R
Graduate medical education (GME), the system to train graduates of medical schools in their chosen specialties, costs the government nearly $ 13 billion annually, yet there is little accountability in the system for addressing critical physician shortages in specific specialties and geographic areas. Medicare provides the bulk of GME funds, and the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 redistributed nearly 3,000 residency positions among the nation’s hospitals, largely in an effort to train more residents in primary care and in rural areas. However, when we analyzed the outcomes of this recent effort, we found that out of 304 hospitals receiving additional positions, only 12 were rural, and they received fewer than 3 percent of all positions redistributed. Although primary care training had net positive growth after redistribution, the relative growth of nonprimary care training was twice as large and diverted would-be primary care physicians to subspecialty training. Thus, the two legislative and regulatory priorities for the redistribution were not met. Future legislation should reevaluate the formulas that determine GME payments and potentially delink them from the hospital prospective payment system. Furthermore, better health care workforce data and analysis are needed to link GME payments to health care workforce needs.
HubMed – drug
Slow Progress On Meeting Hospital Safety Standards: Learning From The Leapfrog Group’s Efforts.
Filed under: Drug and Alcohol Rehabilitation
Health Aff (Millwood). 2013 Jan; 32(1): 27-35
Moran J, Scanlon D
In response to the Institute of Medicine’s To Err Is Human report on the prevalence of medical errors, the Leapfrog Group, an organization that promotes hospital safety and quality, established a voluntary hospital survey assessing compliance with several safety standards. Using data from the period 2002-07, we conducted the first longitudinal assessment of how hospitals in specific cities and states initially selected by Leapfrog progressed on public reporting and adoption of standards requiring the use of computerized drug order entry and hospital intensivists. Overall, little progress was observed. Reporting rates were unchanged over the study period. Adoption of computerized drug order entry increased from 2.94 percent to 8.13 percent, and intensivist staffing increased from 14.74 percent to 21.40 percent. These findings should not be viewed as an indictment of Leapfrog but may reflect various challenges. For example, hospitals faced no serious threats to their market share if purchasers shifted business away from those that either didn’t report data or didn’t meet the standards. In the absence of mandatory reporting, policy makers might need to act to address these challenges to ensure improvements in quality.
HubMed – drug
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