| Infections by Leishmania parasites which cause cutaneous Leishmaniasis (CL) encompass range clinical symptoms, including skin lesions to serious disfigurement and fatal systemic infection. The mainstays of CL treatment are pentavalent antimonials (SbV), however in recent years a large-scale increase in clinical resistance to SbV has been reported. The current antileishmanial therapy is suboptimal presenting a series of problems such as low efficacy, high toxicity and the emergence of resistant strains. Nowadays, there is a renewed effort to develop drugs that can shorten the duration of therapeutic regimen to Leishmaniasis. Pharmacokinetic studies include enhancing efficacy and decreasing toxicity of a patient's drug therapy. Meanwhile, pharmacodynamics goal is the use of time-kill curve experiments to characterize the activity of an antimicrobial agent often with the intention of using this information to optimize the dosing regimen. Pyrazinamide (PZA) is an antibiotic usually effective in treating infections caused by Mycobacterium tuberculosis. An in vitro study not only suggests PZA sensitivity of Leishmania during parasite stages, but also indicates collateral immunostimulation. Pharmacokinetics/Pharmacodynamics parameters like clearance, volume of distribution, half-life, and maximal effect of the drug (Emax), half maximal effective concentration (EC50) are used to correlate effect and drug levels. However, to further characterize the pharmacokinetics profile, the concentration in the dermal tissue after a single 25 mg/kg and 50 mg/kg intravenous bolus was determined by microdialysis (muD) and compared to plasma concentrations. To evaluate the pharmacodynamics activity of pyrazinamide over time, a time-kill experiment was performed with Leishmania (Leishmania) amazonensis. Both pharmacodynamics and kinetic estimated parameters were then correlated to model and simulate outcomes of various dosing regimens. |
