Mucosal safety of PHI-443 and stampidine as a combination microbicide to prevent genital transmission of HIV-1

Characterization of UC781-Tenofovir Combination Gel Products for HIV-1 Infection Prevention in an Ex Vivo Ectocervical Model

“…The benefits of combination microbicides include an increased barrier to infection, overcoming of resistance issues, and reduction of the required dose of each drug used when synergy is present, which could also decrease the potential for toxicity (19). Several combination microbicide products are currently under development (13,16,22,25,29). A combination product made of cellulose acetate 1,2-benzenedicarboxylate, a polymer that blocks HIV-1 entry by targeting gp120 and gp41, and UC781, a non-NRTI (NNRTI), was tested in vitro and exhibited significant synergistic and complementary effects against HIV-1 infection.…”

Recent Advances in Anogenital Antiretroviral Microbicides and Multimodal Delivery Systems

“…Stampidine is a promising microbicide candidate because of it exhibits (a) remarkable subnanomolar to low nanomolar in vitro ARV potency against genotypically and phenotypically NRTI-resistant primary clinical HIV isolates, NNRTI-resistant HIV-1 isolates, clinical non-B subtype HIV-1 isolates (subtypes A, C, F, and G) originating from South America, Asia, and sub-Saharan Africa with resistance to [170][171][172][173][174] (b) favorable pharmacokinetics profile in mice, rats, dogs, and cats with 25 mg/kg or 50 mg/kg tolerable dose levels yielding micromolar plasma concentrations of Stampidine in mice, cats, and dogs, which are 1,000-fold higher than its in vitro IC 50 value against HIV [175][176][177][178][179][180], (c) favorable, safety profile in mice, rats, dogs, and cats [177][178][179][180][181], (d) in vivo anti-retroviral activity in Hu-PBL-SCID mice as well as FIV-infected domestic cats [179,180], and (e) lacks adverse effects on human sperm functions and vaginal mucosa following prolonged exposure [182][183][184]. In a placebo-controlled Phase I study involving 30 therapy-naïve adult HIV-infected patients, formulated GMP-grade oral Stampidine capsules did not cause doselimiting toxicity at single dose levels ranging from 5 to 25 mg/kg [185].…”

“…HI-443 is capable of preventing vaginal transmission of a drug-resistant clinical HIV-1 isolate in the Hu-PBL-SCID mouse model [220]. HI-443 lacked toxicity following repeated oral, intraperitoneal, intravenous, and intravaginal administration at doses in excess of those predicted to be clinically effective -the microbicide gel formulation causes no vaginal inflammation in rabbits or pigs [184,221].…”

“…In the rabbit model, Conceival lacked mucosal toxicity following repeated intravaginal application and did not affect in vivo fertility and birth outcome when administered at the time of artificial insemination. Conceival was found to be a clinically useful, safe noncontraceptive vaginal vehicle for formulating lipophilic drugs as prophylactic microbicides [184].…”

Application of Design of Experiment and Simulation Methods in Liquid Chromatography Analysis of Topical HIV Microbicides Stampidine and HI443

“…It has nanomolar activity against primary HIV isolates, stable against a broad range of temperature and pH conditions [15] and in the vaginal environment, non-cytotoxic, non-inflammatory in the presence of human genital track epithelial cells, and has no adverse effect on human sperm motility [13,12]. Effectiveness and safety of STP [11,16], and HI443 [14,13] alone and in combination [17] as a potential anti-HIV vaginal microbicides has already been proven.…”