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101.
Kristini K Miles Stephan T Stern Philip C Smith Fay K Kessler Shazia Ali Joseph K Ritter 《Drug metabolism and disposition》2005,33(10):1513-1520
Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n = 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p < 0.001) and higher apparent affinity for MPA (K(m) = 0.082 mM versus 0.20 mM, p < 0.001) compared with rat liver microsomes. MPA UGT activities were reduced >80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liver-expressed UGT1A enzyme with significant activity and exhibited both high affinity (K(m) = 0.077 mM) and high activity (V(max) = 28 nmol x min(-1) x mg(-1)). Spearman correlation analyses revealed a stronger relationship between HLM MPA UGT activities and 1A9-like content (r(2) = 0.79) relative to 1A1 (r(2) = 0.20), 1A4-like (r(2) = 0.22), and 1A6 (r(2) = 0.41) protein. A different profile was observed for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies. 相似文献
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The authors report on three patients suffering from coexistent trigeminal neuralgia (TGN) and Charcot-Marie-Tooth disease who, based on preoperative magnetic resonance tomographic angiography findings, underwent microvascular decompression. All patients had demonstrable neural compression and all experienced immediate postoperative pain relief. Symptoms recurred in one patient and required a second procedure in the form of a neurotomy. Two patients suffered from bilateral TGN. When a patient with TGN suffers coexistent neurological disease and experiences bilateral symptoms, preoperative imaging and subsequent decompressive surgery may avoid the unacceptable risk of morbidity associated with bilateral ablative procedures. 相似文献
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Long‐term follow‐up of a large prospective cohort of patients with nonfunctioning pituitary adenomas: The outcome of a conservative management policy
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108.
Heart failure is a progressive illness that carries significant morbidity and mortality. This highly prevalent illness leads
to frequent, costly hospitalizations with approximately 50% of patients being readmitted within 6 months of initial hospitalization.
While rehospitalization has been extensively studied in the past, little progress has been made in terms of reducing readmission
rates of heart failure patients in the last decade despite increasing costs with impending resource limitations. We discuss
disease-centered, physician-centered, and patient-centered factors that lead to rehospitalization as well as community/resource
availability factors that contribute to rehospitalization of patients suffering from chronic heart failure. In addition, predictors
of hospitalization and interventions that reduce hospitalization will be critically evaluated. With a complete understanding
of heart failure rehospitalization, we hope the future holds more effective ways to prevent heart failure progression and
thus rehospitalization, improved risk-stratification models to identify patients high-risk for rehospitalization, and sustained
interventions that are customized according to the etiology of the clinical decline of heart failure patients that ultimately
results in frequent rehospitalizations. 相似文献
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