Investigation of pre-clinical pharmacokinetic parameters of atovaquone nanosuspension prepared using a pH-based precipitation method and its pharmacodynamic properties in a novel artemisinin combination.

OBJECTIVES: Recently, a growing resistance to antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, artemisinin derivatives and mefloquine has been observed. The pharmacokinetic limitation of the current therapy and multi-drug resistance has resulted in an urgent need to study the new antimalarial combinations with existing drugs. This study investigated the activity of a novel triple combination of atovaquone (nanosized)-proguanil-artesunate as an alternative artemisinin combination therapy. Atovaquone in this combination was formulated as a freeze-dried nanosuspension and its pharmacokinetic parameters were also evaluated. METHODS: The suppressive and curative effect of atovaquone nanosuspension, proguanil, and artesunate were studied in a murine model. The in vivo pharmacokinetics of the newly developed atovaquone nanosuspension with particle size less than 200 nm was investigated. RESULTS: Prophylactic efficacy of atovaquone nanosuspension alone at 1/80th the therapeutic dose was proven. In the curative test, atovaquone nanosuspension and proguanil at 1/10th the therapeutic dose was the minimum effective dose that resulted in complete cure of parasitaemia. As a triple combination, atovaquone nanosuspension in combination with proguanil at 1/80th the therapeutic dose of each and 1/5th the therapeutic dose of artesunate resulted in a complete cure. The in vivo pharmacokinetics of the nanosuspension showed a significant (three times) reduction in Tmax value and the area under the curve of the nanosuspension was 1.9 times greater as compared with the plain suspension. CONCLUSIONS: The potential of the synergistic combination of atovaquone nanosuspension-proguanil-artesunate in curing the multi-drug resistant malarial infection at reduced doses of all three drugs could be a solution to pill burden observed with the current therapy.

Development of collateral vessels: A new paradigm in CAM angiogenesis model.

The chorioallantoic membrane (CAM) assay is one of the most widely used models to study angiogenesis. In this study, collateral vessel development is reported in CAM assay useful in analysis of angiogenesis. Four days old white Leghorn fertilized chicken eggs were inoculated with vehicle, standard or test angiogenesis inhibitor using standard protocol. Central vessel growth was seen tapering down and collateral vessels were developed from the lower side of the chorioallantoic membrane moving upward in 12 days old standard or test treated CAMs. In the absence of the central vessel, collateral blood supply helped in survival of embryos. Hence, development of collateral vessels was used for ranking of blood vessels and angiogenesis in addition to well-known standard parameters related to central vessel. The finding could differentiate molecules inhibiting angiogenesis with or without collateralization which is crucial in anti-angiogenic therapy used for cardiovascular diseases and cancer. This study proposes a new avenue to distinguish pro-angiogenic molecules from anti-angiogenic ones as well as anti-angiogenic molecules which may or may not support alternative vascularization pathway that would have great impact on future angiogenic and anti-angiogenic therapy.

Design, synthesis and evaluation of benzotriazole derivatives as novel antifungal agents.

Considering the need for discovery of new antifungal drugs with greater potency and broader spectrum of activity, a new series of 5-substituted benzotriazole derivatives were designed, through structure based design, as inhibitors of fungal cytochrome P450 lanosterol 14-α demethylase. These were further optimized by a combination of iterative medicinal chemistry principles and molecular docking. Based on the best docking scores, some benzotriazole derivatives were synthesized and characterized by IR, (1)H NMR and MS/MS. The molecules were evaluated for their antifungal action against Candida albicans by cup plate method and ergosterol quantification method by UV spectroscopy. Reasonably good correlation between docking scores and antifungal activity were observed. The computational predictions were in consensus with the experimental results.

Comparison of Conventional and Microwave-assisted Synthesis of Benzotriazole Derivatives.

A green chemistry approach for organic synthesis is described here, which involves microwave exposure of reactants in presence or absence of solvents. A novel and simple method has been developed for the synthesis of some benzotriazole derivatives under microwave irradiation. In addition, these compounds were synthesised also by conventional heating procedures for comparison. All the compounds synthesised were characterised by melting point, TLC, IR and (1)H NMR spectroscopy. Comparison between conventional and microwave-assisted synthesis was done by comparing total reaction time and percentage yield. The results suggest that microwave-assisted syntheses lead to higher yields within very short reaction times. On antifungal evaluation by cup plate method, all compounds showed antifungal activity. One compound showed activity similar to and two compounds showed better activity than standard antifungal drug flucanazole.

Microwave-assisted Synthesis of an Important Intermediate of Benazepril.

Rapid and efficient methods for the synthesis of an important intermediate of benazepril ethyl 3-phthalimido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one-1-acetate under the influence of microwave irradiation are described. A comparative study of conventional and microwave assisted method is briefly discussed.