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Biomedical subjects

Charles Flexner

Publications and source records attributed to Charles Flexner.

27 records · Page 2Linked to original sources
PubMed2002

Differential effects of p-glycoprotein and multidrug resistance protein-1 on productive human immunodeficiency virus infection.

P-glycoprotein (P-gp) and multidrug-resistance protein-1 (MRP-1) are adenosine triphosphate-binding cassette proteins that may decrease intracellular concentrations of anti-human immunodeficiency virus (HIV) drugs. After HIV-1(IIIB) infection, HIV-1 protein and infectious virus production were decreased by at least 70-fold in CEM cells overexpressing P-gp but were increased by at least 50-fold in CEM cells overexpressing MRP-1, compared with control CEM cells. After transfection with the HIV-1(IIIB) genome, cells overexpressing P-gp and MRP-1 expressed similar amounts of HIV protein. Selective inhibitors of MRP-1 and P-gp partially reversed the effect of these transporters in a concentration-dependent manner. P-gp preferentially associated with glycolipid-enriched membrane (GEM) domains, which may be an important site for cellular binding and egress of HIV. In contrast, MRP-1 was not preferentially found in GEM domains. These results suggest that the inhibition of HIV productive infection by P-gp and augmentation by MRP-1 occur predominantly at a preintegration step but act through different mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Model-based analysis of the pharmacokinetic interactions between ritonavir, nelfinavir, and saquinavir after simultaneous and staggered oral administration.

Eighteen healthy human immunodeficiency virus-negative subjects participated in an open-label, six-period, incomplete Latin-square crossover pharmacokinetic study. Each subject received two of the three possible pair-wise combinations of single-dose oral ritonavir (R) (400 mg), nelfinavir (N) (750 mg), and saquinavir (S) (800 mg), each pair on three occasions (simultaneous or staggered administration), each occasion at least 2 days after the last. A model-based analysis reveals the following major drug interactions under the conditions of this study: 1). R given simultaneously with S decreases S hepatic intrinsic clearance almost 50-fold relative to that predicted for S given alone and increases its gut bioavailability 90% (but decreases its rate of absorption 40%) relative to when N is given simultaneously; 2). N given simultaneously with S decreases S hepatic intrinsic clearance 10-fold relative to that predicted for S given alone; and 3) R inhibits S hepatic intrinsic clearance even after R plasma levels have become undetectable (>48 h after dosing), implying that R, when used as a pharmacokinetic enhancer, can be dosed less frequently than might be predicted from the duration of detectable systemic concentrations.

Administration, Oral↗
PubMedDate not supplied

Psychological distress and physical pain appear to have no short-term adverse impact on plasma HIV-1 RNA levels in patients on successful HAART.

PURPOSE: Previous studies have linked depression and stressful life events in HIV disease with a more rapid decline in CD4 count and progression to AIDS. However, the short-term effect of psychological and physical distress on HIV-1 RNA levels in patients on successful HAART has not been well studied. METHOD: Ten asymptomatic HIV-infected adults with suppression of viremia to <50 copies/mL on a stable HAART regimen for > or =6 months were studied. Participants donated blood every 2-3 days over a 3-4 month period for duplicate independent viral load measurements and drug level monitoring. At each time point, psychological distress was measured using the Mental Health Inventory-5 (MHI-5) and an 11-point numeric rating scale for emotional stress. Physical pain was assessed using an 11-point numeric rating scale. RESULTS: All patients maintained successful viral suppression throughout the study. Twenty-six of 713 (3.6%) viral load measurements were >50 copies/mL. Psychological distress and physical pain were not associated with episodes of detectable viremia. CONCLUSION: Using frequent monitoring of HIV-1 RNA levels and patient ratings of mood, stress, and pain, we found that psychological distress and physical pain had no short-term adverse impact on HIV-1 RNA levels in highly adherent patients with stable suppression of viremia on HAART.

Adult↗