This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Oseltamivir is an ester prodrug of the active metabolite [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a potent and selective inhibitor of neuraminidase enzyme of influenza virus. Oseltamivir is rapidly hydrolyzed by hepatic carboxylesterases to Ro 64-0802, which is then exclusively excreted by glomerular filtration and active tubular secretion without further metabolism. In vivo and in vitro studies were conducted to evaluate the renal drug-drug interaction potential of oseltamivir. Crossover studies were conducted in healthy subjects in which oral oseltamivir was administered alone and coadministered with probenecid, cimetidine, or amoxicillin. Probenecid completely blocked the renal secretion of Ro 64-0802, increasing systemic exposure (area under the curve) by 2.5-fold, but no interaction was observed with cimetidine or amoxicillin. These in vivo data show that Ro 64-0802 is secreted via an organic anion pathway, but Ro 64-0802 does not inhibit amoxicillin renal secretion. In vitro effects of Ro 64-0802 on the human renal organic anionic transporter 1 (hOAT1) were investigated using novel Chinese hamster ovary cells stably transfected with hOAT1. Ro 64-0802 was found to be a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOAT1-mediated transport of p-aminohippuric acid (PAH). Ro 64-0802 did not inhibit the hOAT1-mediated transport of amoxicillin. In contrast, probenecid effectively inhibited the transport of PAH, Ro 64-0802, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data, validating the usefulness of the in vitro system for evaluating such drugdrug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.Oseltamivir is an orally bioavailable prodrug of Ro 64-0802 1 (GS4071), a potent and selective inhibitor of influenza A and B neuraminidase (Bardsley-Elliot and Noble, 1999). After oral administration, the prodrug is extensively hydrolyzed to its active metabolite Ro 64-0802, which is then extensively excreted by glomerular filtration and renal tubular secretion without further metabolism (He et al., 1999a).Active renal secretion occurs via specific transport proteins located in the basolateral and apical membrane of the proximal tubule (Pritchard and Miller, 1993). Two general drug secretion pathways exist in proximal tubules, one for basic compounds (organic cation transport system) and another for acidic compounds (organic anion transport system). Thus far, two active pathways capable of transporting organic cations have been identified in kidney, OCT1 and OCT2 (Grundemann et al., 1994;Okuda et al., 1996). Similarly, several renal organic anion transporters have been recently cloned and characterized. Of these, organic anion transporter 1 (OAT1) is the main component mediating tubular secretion of organic acids (Sekine, 1...

The intracellular pharmacokinetics of lamivudine phosphorylation in PBMC from asymptomatic HIV-1-infected patients are highly variable and do not differ statistically between the 150- and 300-mg twice a day regimens. The variations in intracellular lamivudine-TP concentrations following these two lamivudine dosage regimens are unlikely to result in differences in clinical effect. This was confirmed by the results of a large phase III study in HIV-1-infected patients which showed no differences in HIV-1 RNA or CD4+ lymphocyte counts between the 150- and 300-mg lamivudine regimens in combination with zidovudine.

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Objectives: To determine the prevalence of five mental disorders in primary care and to identify patient groups that have a relatively high prevalence of these disorders.Design: Two-stage case identification design that involves administration of a 16-item screening instrument followed by an independent diagnostic assessment.Setting: Three family practice offices in Rhode Island.Subjects: A total of 937 primary care patients completed the brief screen, 388 of whom completed the independent diagnostic assessment.Prevalence Estimation: A Bayesian procedure was used to estimate prevalence of mental disorder from screening and assessment results. Independent assessments were based on the Structured Clinical Interview for DSM\x=req-\ III-R administered by a mental health professional.Results: The prevalence estimates were alcohol abuse or dependence, 3.2%; generalized anxiety disorder, 2.8%; major depressive disorder, 14.1%; obsessive\x=req-\ compulsive disorder, 2.2%; panic disorder, 6.2%; and any of the five disorders, 22.0%. The prevalence of any of the five disorders was higher in patients returning for follow-up visits (27.9%) than in those either presenting with a new illness (21.7%) or seeking a routine physical examination (11.8%). The combined prevalence was also higher in patients with a chronic medical problem (25.8%) than in those without (16.7%).Conclusions: Patients returning for follow-up care and, to a lesser extent, those with chronic medical problems appear to be at increased risk of having a mental disorder. The practice of selectively screening new patients for mental health problems is questioned. Screening efforts in primary care should include established patients and those with chronic medical illnesses as well as new patients.

Competition and consumer brand attitudes make introducing a new brand risky and very expensive, increasing the attractiveness of brand extensions. Brand extension research has established that original brand quality perceptions, product category fit, consumer perceptions of the product category complementarity and substitutability, plus the transferability of design and manufacturing capability significantly influence extension attitude formation. However, these studies fail to differentiate between brand types and have aggregated out category effects. Using a national survey we show that brand type (prestige, functional) and extension category are important variables in consumer brand extension attitude formation. Perceived quality influences functional brands more than prestige brands as prestige brand attitudes assume quality. Functional brands experience less dilution than prestige brands, implying less risk and greater expandability than argued by previous authors.

Rectal swabs and stool specimens were compared for the detection of Campylobacter fetus subsp. jejuni in marmosets. Rectal swabs were superior to stool specimens for detection of Campylobacter fetus subsp. jejuni (P = 0.016). Preliminary human data are also presented. Campylobacter fetus subsp. jejuni (Cfj) is one

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