Pharmacokinetic and Pharmacodynamic Modeling to Determine the Human Dose of ST-246(R) to Protect Against Smallpox

Although smallpox has been eradicated, the United States government considers it a “material threat” and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted […]

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Pharmacokinetic and Pharmacodynamic Analysis of Efavirenz Dose Reduction Using an In Vitro-In Vivo Extrapolation Model

The pharmacokinetics (PK) of efavirenz (EFV) is characterized by marked inter-patient variability that correlates with its pharmacodynamics (PD). In vitro-in vivo extrapolation (IVIVE) is a “bottom-up” approach that combines drug data with system information to predict PK and PD. The aim of this study was to simulate EFV PK and PD after dose reductions. At […]

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3,4,5-trisubstituted-1,2,4-4H-triazoles as WT and Y188L Mutant HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors: Docking-based CoMFA and CoMSIA Analyses

3,4,5-Trisubstituted-1,2,4-4H-triazoles (TTs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Two series of triazoles have been studied, one of which was also screened against the Y188L mutant. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices […]

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A Discovery of Novel Mycobacterium Tuberculosis Pantothenate Synthetase Inhibitors Based on the Molecular Mechanism of Actinomycin D Inhibition

Mycobacterium tuberculosis pantothenate synthetase is a potential anti-tuberculosis target, and a high-throughput screening system was previously developed to identify its inhibitors. Using a similar system, we screened a small library of compounds and identified actinomycin D (ActD) as a weak inhibitor of pantothenate synthetase. A new method was established to discover more effective inhibitors by […]

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Pharmacokinetics and Pharmacodynamics of TBR-652, a Novel CCR5 Antagonist, in HIV-1-Infected, Antiretroviral Treatment-experienced and CCR5 Antagonist-naive Patients

TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this study was to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652 in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naive patients. A double-blind, placebo-controlled, randomized, dose-escalating study of TBR-652 monotherapy given once daily orally for 10 days was performed followed by […]

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3D-QSAR Studies on Triclosan Derivatives as Plasmodium Falciparum Enoyl Acyl Carrier Reductase Inhibitors

3D-QSAR studies were carried out on a training set of 53 structurally highly diverse analogues of triclosan to investigate the correlation of the structural properties of triclosan derivatives with the inhibition of the activity of enoyl acyl carrier protein reductase in Plasmodium falciparum (PfENR) by employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity […]

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In Vitro Biological Activity and Structural Analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine Inhibitors of Candida Albicans

In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and […]

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Combining Drug-disease and Economic Modeling to Inform Drug Development Decisions

Drug-disease models and clinical trial simulations are increasingly being used to support trial design and treatment optimization decisions.  Less widely recognized is their potential for guiding strategic development decisions.  These decisions require economic valuation of the potential product profile of efficacy, safety, ease of use, and so on.  This review presents a disguised case study […]

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