Visceral leishmaniasis is a neglected tropical disease that causes significant morbidity and mortality worldwide. Characterization of the pharmacokinetics and pharmacodynamics of antileishmanial drugs in preclinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of liposomal amphotericin B (AmBisome) in Leishmania donovani-infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver, and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome, >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 h and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome was administered at the advanced stage of infection and compared to those in uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to L. donovani-infected livers and spleens. Taken together, our data suggest that organ enlargement and other pathophysiological factors cause infection- and organ-specific drug distribution and elimination after administration of single-dose AmBisome to L. donovani-infected mice. Plasma drug levels were not reflective of changes in drug levels in tissues.
Compliant mechanisms are typically designed for varying stiffness from nearly zero to rigid. However, targeted design for fine tuning within an application's sensitive range of stiffness remains more desirable for practical implementation in accurate loading or positioning systems. To achieve these various competing objectives a “Generalized Spiral Spring” (GSS) is proposed which achieves small size and other objectives by using a reduced number of parameters as provided by the spiral shape description of the components. An analytical model based on virtual work and curved beam theory is developed for accurate prediction of the stiffness. Moreover, Finite Element (FE) models are also developed for verification of the proposed designs. Multiobjective Design Optimization (MDO) is conducted to maximize the linearity in the stiffness versus control parameter response and improve resolution. The proposed analytical model is validated experimentally and computationally. This approach may be used to achieve finesse by accurate positioning with force control for industrial robots and elegant prostheses.
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