PHI-443: A Novel Noncontraceptive Broad-Spectrum Anti-Human Immunodeficiency Virus Microbicide1

Abstract

PHI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea) is a rationally designed novel thiophene thiourea nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent anti-HIV activity against the wild-type and drug-resistant primary clinical human immunodeficiency virus (HIV-1) isolates. This study examined the potential utility of PHI-443 as a nonspermicidal microbicide for prevention of sexual transmission of HIV. Our goal in this study was to test the effects of PHI-443 on in vivo sperm functions under conditions shown to inactivate viruses in human cells. PHI-443 completely prevented the vaginal transmission of a genotypically and phenotypically drug-resistant HIV-1 isolate in the humanized severe combined immunodeficient (Hu-SCID) mouse model of sexually transmitted AIDS. Exposure of human sperm to PHI-443 at doses 30 000 times higher than those that yield effective concentrations against the AIDS virus had no adverse effect on sperm motility, kinematics, cervical mucus penetrability, or the viability of vaginal and cervical epithelial cells. Exposure of rabbit semen to PHI-443 either ex vivo or in vivo had no adverse impact on in vivo fertilizing ability in the rabbit model. Reproductive indices (i.e., pregnancy rate, embryo implantation, and preimplantation losses) were not affected by pretreatment of rabbit semen with PHI-443. Likewise, intravaginal application of 2% PHI-443 via a self-emulsifying gel at the time of artificial insemination resulted in healthy offspring with no apparent peri- or postnatal repercussions. Repeated intravaginal administration of 0.5%- 2% PHI-443 gel was found to be safe in rabbits and lacked systemic absorption. PHI-443 has clinical potential as a prophylactic broad-spectrum anti-HIV microbicide without contraceptive activity.

A Review of Current Intravaginal Drug Delivery Approaches Employed for the Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted Infections

“…Thermosensitive gels are systems that alter the physical characteristics of the gel with exposure to environmental changes within the vagina usually in the range of 25-37°C (96)(97)(98). Commonly used thermosensitive polymers for intravaginal microbicide delivery include the polysaccharides, polyacrylamides, poloxamers, polyoxides, polyesters, and a few liposome-based systems.…”

“…Commonly used thermosensitive polymers for intravaginal microbicide delivery include the polysaccharides, polyacrylamides, poloxamers, polyoxides, polyesters, and a few liposome-based systems. Poloxamer hydrogels represent the most extensively studied thermosensitive polymeric systems, while polysaccharides usually demonstrate good biocompatibility and/or biodegradability (96). Gels, which present mucoadhesive behaviour, are prepared with mixtures of poloxamers and polycarbophil (96,98,100).…”

A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

“…Among the 45 vanadocene complexes that were synthesized and tested for human spermicidal activity, vanadocene dithiocarbamate (VDDTC) was identified as the lead candidate for preclinical studies (D'Cruz et al, 2001(D'Cruz et al, , 2004cD'Cruz and Uckun, 2001b). Among the 30 thiourea nonnucleoside reverse transcriptase inhibitors (NNRTI) of HIV-1 that were rationally designed, synthesized, and tested for anti-HIV activity, PHI-443 (N -[2-(2-thiophene)ethyl]-N -[2-(5-bromopyridyl)]thiourea), was identified as a broad-spectrum noncontraceptive anti-HIV microbicide (D'Cruz et al, 2000(D'Cruz et al, , 2003(D'Cruz et al, , 2004a. Both compounds lacked mucosal toxicity in the rabbit vaginal irritation model (D'Cruz and Uckun, 2001b;D'Cruz et al, 2004a).…”

Vaginal Drug Delivery Systems for HIV Prevention

“…These drugs encompass different mechanisms of action which require different drug targeting strategies for successful delivery (49)(50)(51)(52)(53)(54)(55). The mechanism of action of each microbicide agent will define the appropriate vaginal drug delivery system for those products.…”