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Nevirapine Significantly Reduces the Levels of Racemic Methadone and (R)-Methadone in Human Immunodeficiency Virus-Infected Patients. Hartmut Stocker, 2004.Methadone is metabolized by various isoforms of the cytochrome P450 family, which can be induced by many drugs, including nevirapine . The objective of the present study was to determine the effects of coadministration of nevirapine and methadone on the dose-adjusted areas under the concentration-time curves (AUCs) of racemic and (R)-methadone . Twenty-five human immunodeficiency virus-infected subjects taking stable single daily doses of racemic methadone or (R)-methadone were included in this prospective, single-crossover trial . At the baseline, nevirapine was either started as part of a new regimen containing two nucleoside reverse transcriptase inhibitors (NRTIs) or added to an ongoing NRTI regimen . Patients could increase their methadone doses if withdrawal symptoms developed . Twelve-hour pharmacokinetic profiles were obtained before and 28 days after the start of nevirapine treatment . The total concentrations of methadone and its inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in serum were determined by liquid chromatography-tandem mass spectrometry . Among the 20 evaluable patients, coadministration of nevirapine significantly decreased the mean dose-adjusted AUC of methadone by 41% . AUC reductions were similar for patients taking racemic methadone (37%; n = 11) and (R)-methadone (44%; n = 9) . AUC changes ranged from mild increases in three patients to decreases of up to 70% . Fourteen of 20 patients required additional methadone due to withdrawal symptoms . However, the median dose increase was only 15%, which was less than that which would have been expected from the pharmacokinetic data . The AUC of EDDP increased significantly, by 35% . Methadone dose adjustments are justified when methadone is coadministered with nevirapine . Due to extensive variability, the adjustments must be tailored to the individual patient's needs . Differential Regulation of the Bordetella bipA Gene: Distinct Roles for Different BvgA Binding Sites. Rajendar Deora, 2002. Optimal Growth and Ethanol Production from Xylose by Recombinant Saccharomyces cerevisiae Require Moderate D-Xylulokinase Activity. Yong-Su Jin, 2003.D-Xylulokinase (XK) is essential for the metabolism of D-xylose in yeasts . However, overexpression of genes for XK, such as the Pichia stipitis XYL3 gene and the Saccharomyces cerevisiae XKS gene, can inhibit growth of S . cerevisiae on xylose . We varied the copy number and promoter strength of XYL3 or XKS1 to see how XK activity can affect xylose metabolism in S . cerevisiae . The S . cerevisiae genetic background included single integrated copies of P . stipitis XYL1 and XYL2 driven by the S . cerevisiae TDH1 promoter . Multicopy and single-copy constructs with either XYL3 or XKS1, likewise under control of the TDH1 promoter, or with the native P . stipitis promoter were introduced into the recombinant S . cerevisiae . In vitro enzymatic activity of XK increased with copy number and promoter strength . Overexpression of XYL3 and XKS1 inhibited growth on xylose but did not affect growth on glucose even though XK activities were three times higher in glucose-grown cells . Growth inhibition increased and ethanol yields from xylose decreased with increasing XK activity . Uncontrolled XK expression in recombinant S . cerevisiae is inhibitory in a manner analogous to the substrate-accelerated cell death observed with an S . cerevisiae tps1 mutant during glucose metabolism . To bypass this effect, we transformed cells with a tunable expression vector containing XYL3 under the control of its native promoter into the FPL-YS1020 strain and screened the transformants for growth on, and ethanol production from, xylose . The selected transformant had approximately four copies of XYL3 per haploid genome and had moderate XK activity . It converted xylose into ethanol efficiently .
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