The pharmacokinetics of cis-dichlorodiam-minoplatinum (II) (cisplatin) have been studied in seven patients, of whom four received the drug as a one hour infusion and three received it as a 20 h infusion. The patients receiving the drug over one hour exhibited biphasic clearance of total platinum with a rapid initial phase (8.7-22.5 min) and a prolonged second phase (30.5-106 h). Free (ultrafilterable) cisplatin was readily detectable in this group and was rapidly cleared (half-life about 22 min). The volume of distribution of the drug was 50.3-65.6 liters and it was 26.6-50% excreted in the urine in 48 h. In the patients receiving the 20 h infusion, a more complex plasma elimination curve was seen, with the appearance of a secondary peak. Free drug was not detectable in these patients and they showed less urinary excretion (21.4-25.9% at 48 h) than the one hour group. Cisplatin was bound to several plasma proteins, including albumin, transferrin, and gamma-globulin. The data indicate that cisplatin is retained in the body more extensively after a 20 h infusion than after a one hour infusion.
The development of methods to prevent HIV infection is critical to curbing the rising epidemic. Topical microbicides represent a potential new strategy for reduction of HIV transmission. The purpose of this article is to update and expand upon the nonclinical recommendations of a previously published document on the development of microbicides prepared by the International Working Group on Microbicides. The nonclinical studies discussed here represent general concepts and regulatory considerations that are pertinent to the development of topical microbicides for prevention or reduction of HIV transmission. Essential early steps in product development include the determination of antiviral activity, cytotoxicity, mechanism of action, pathways to resistance, and cross-resistance to approved drugs. Other parameters to consider include activity against vaginal microflora and pathogens that cause sexually transmitted diseases. Before and during clinical trials, nonclinical data on toxicology and pharmacokinetics should be obtained. Finally, product quality issues, including microbicide formulation characteristics, interaction with other products, and stability, should be addressed.
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