Advances in HIV therapy have extended the life expectancy of thousands but have not significantly affected HIV transmission. Prevention or reduction in transmission worldwide may require identification of an effective anti-microbial agent. In keeping with this view, the applicant's laboratory and those of his collaborators have initiated scientific research of the anti-viral properties of the carrageenans. This proposal seeks to characterize the stability, toxicology and the pharmacokinetics (PK) of PDR 98-15 carrageenan, and it derivatives Zinc- and Lignosulfonic acid (LSA)-carrageenan with the ultimate goal of establishing their value as microbicides. Although toxicology on the carrageenans demonstrated their safety as food additives, their use as pharmaceuticals require more detailed evaluation of their toxicity profile. In addition, the generation and LSA-carrageenan from PDR 98-15 may have created new compounds with unknown physicochemical pharmacological and toxicological properties. The test compounds will be labeled with molecular tags to enable the detection. Detection and analysis , by viscosity, liquid scintillation, size exclusion/ permeation chromatography coupled to multi-angle laser light scattering refractive index detection and/or by immuno-detection. Information on binding studies may help to explain anti-viral mechanism, while stability is required for safe storage purposes, since the final product is expected to be predominantly used in the developing world where infrastructure may be problematic. The toxicology and irritation potentials will be evaluated in mice and rabbits during prolonged intra-vaginal application. An extended toxicity profile is necessary since the final product may be considered to be used chronically, due to its indication. PKs will be evaluated by the intravenous route because patients with vaginal lesions may also use vaginal microbicides, makes blood PK studies desirable. The overall data may provide new information needed for optimization of compounds, and in the design of the next generations of carrageenan-based microbicides.
