To better understand the antileishmanial effects of antimonial agents we synthesized complexes of tri-and pentavalent antimony with mannan. The 50% inhibitory concentrations (IC 50 s) of these agents, along with those of potassium antimony tartrate [Sb(III)] and sodium stibogluconate [Sb(V)], were determined for promastigotes and intramacrophage amastigotes. The trivalent antimonial agents were more potent than the pentavalent agents. Although the IC 50 s were 60-to more-than-600-fold higher for promastigotes than for amastigotes, similar intracellular antimony concentrations in both life forms were measured after incubation with all four drugs at their respective IC 50 s. Macrophages accumulated antimony during a 4-h exposure that was retained intracellularly for at least 3 days. Amastigotes inside macrophages had a higher antimony content 6 days after a single 4-h treatment than they did immediately after treatment, suggesting that macrophages serve as a reservoir for antimonial agents and prolong parasite exposure. Macrophages concentrated antimony from the medium with potassium antimony tartrate, trivalent antimony-mannan, and pentavalent antimonymannan treatments. N-Acetylcysteine antagonized the antileishmanial effects of these three drugs against intracellular amastigotes; in contrast, it had minimal effects on the action of sodium stibogluconate.The leishmaniases are a group of diseases produced by invasion of the reticuloendothelial system of a vertebrate host by a parasite of the genus Leishmania followed by parasite multiplication inside macrophages. Symptomatic visceral leishmaniasis (kala-azar) is characteristically fatal if untreated. Antimonial chemotherapy increases the survival rate to over 90% (1). One of the first antimonial agents used was tartar emetic [potassium antimony(III) tartrate]. Unfortunately, this agent was highly toxic to humans as well as to Leishmania parasites. In the search for agents with higher therapeutic indices, a number of other antimonial agents were prepared and evaluated (for a review, see reference 24). This process produced the current drugs of choice, two closely related pentavalent antimony-carbohydrate complexes, sodium stibogluconate (Pentostam) and meglumine antimoniate (Glucantime). Pentavalent antimony salts are 10-fold less toxic to mammals than trivalent salts (15). Likewise, these pentavalent antimony-containing drugs are less toxic to humans and have a higher therapeutic index than organic trivalent antimony preparations. Despite their clinical use for over half a century, the mechanism of action and basis for selective toxicity of these antileishmanial agents remain unknown.Several properties of the pentavalent antimonial agents have been suggested to contribute to their activity. Carbohydrates form water-soluble complexes with antimony and may serve to deliver antimonial drugs to host macrophages. Relatively nontoxic pentavalent antimony may be a prodrug that is converted to more toxic trivalent antimony at or near the site of action. Interactions of an...

This study examines the pharmacokinetic/pharmacodynamic interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV disease, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone, an opiate frequently used in substance abuse pharmacotherapy for opioid (heroin)-dependent injection drug users, many of whom are infected with HIV. L/R was associated with significant reductions in the methadone area under the concentration-time curve (P<.001), maximum concentration (P<.001), and minimum concentration (P<.001), as well as increased methadone oral clearance (P<.001) and increased opiate withdrawal symptoms (P=.013), whereas ritonavir use alone modestly and nonsignificantly increased methadone concentrations. Lopinavir is a potent inducer of methadone metabolism, and treatment with L/R requires clinical monitoring and increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism.

This report is about applying a Fisher ratio method to entire four dimensional (4D) data sets from third-order instrumentation data. The Fisher ratio method uses a novel indexing scheme to discover the unknown chemical differences among known classes of complex samples. This is the first report of a Fisher ratio analysis procedure applied to entire 4D data sets of third-order separation data, which, in this case, is comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry analyses of metabolite extracts using all of the collected mass channels. Current analysis methods for third-order separation data use only user-defined subsets of the 4D data set. First, in a validation study, the Fisher ratio method was demonstrated to objectively evaluate and determine the chemical differences between three controlled urine samples that differed by known spiked chemical components. It was determined that, out of more than 600 recognizable chemical components in a single sample, the six spiked components, along with only two other matrix components, differed most significantly in concentration among the control samples. In a second study, the Fisher ratio method was used in a novel application to discover the unknown chemical differences between urine metabolite samples from pregnant women and nonpregnant women. A brief list of the top 11 components that were most significantly different in concentration between the pregnant and nonpregnant samples was generated. Because the Fisher ratio calculation statistically differentiates regions of the chromatogram with large class-to-class variations from regions containing large within-class variations, the Fisher ratio method should generally be robust against biological diversity in a sample population. Indeed, application of principal component analysis in this second study failed due to biological diversity of the samples.