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Abstract

Zinc-carrageenan (PC-710): A novel microbicide 
Presentation at Microbicides 2006, Cape Town, 23-26 April
Maguire,Robin A.; Wallace,Andrea R.; Fernandez-Romero,Jose A.; Li,Jifan; Thorn,Mitchell; Sudol,Kristin M.; Titchen,Kanani; Buckheit Jr.,Robert W.; Hartman,Tracy L.; Phillips,David M.
Publication date: 2006

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Introduction
Carraguard, which employs carrageenan as the active ingredient, is currently being evaluated in a Phase 3 trial in South Africa. In order to improve the strength of this microbicide we have bound zinc (Zn) to carrageenan. Zn has been proven safe for human use and demonstrates strong antiviral activity including activity against HIV-1, foot-and-mouth virus, human rhinovirus, influenza A and B, Semliki Forest virus, Sindbis virus, and HSV.

Methods
Because zinc salts would be systemically absorbed via the vagina, we have developed a simple rapid method to bind zinc to carrageenan. PC-710 toxicity was determined by the MTT assay and a dye exclusion assay for trichomonas, as well as the impact on growth or inhibition of growth for several species of lactobacilli. Formulation efficacy was evaluated using peripheral blood mononuclear cells (PBMCs) to assay a panel of clinical isolates of Clade C viruses. The herpes simplex virus type 2 (HSV-2) mouse assay studied the effect of PC-710 in preventing vaginal and rectal infection by HSV-2. Formulation stability was assayed by analysis of zinc content, pH, viscosity, and in vitro HIV activity.

Results
PC-710 was found to be a stable, nontoxic microbicide that does not impact on the growth of lactobacilli. The EC of 10 different clinical isolates of Clade C HIV-1 was determined for Carraguard and PC-710. Carraguard blocked 9 of the 10 viruses at concentrations below 160µg/mL. PC-710 blocked all 10 viruses, on average, at concentrations an order of magnitude less than Carraguard. In the HSV-2 mouse system Carraguard protects almost all mice that are challenged with a 90%-100% infectious viral dose. However, PC-710 prevents infection at 1,000 times this challenge dose, and remains active in the mouse vagina for 24 hours. PC-710 is significantly more effective than Carraguard in preventing HSV-2 infection following rectal application as well as killing trichomonas. In addition, PC-710 can protect mice if administrated up to 4 hours post-viral challenge.

Conclusion
PC-710 is an exceptionally potent broad-spectrum microbicide. Our findings suggest that PC-710 could be effective if applied up to 24 hours prior to sexual activity, or even if applied 4 hours after sexual activity, as well as having potential as a rectal microbicide.

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