Abstract:The current pandemic of sexually transmitted human immunodeficiency virus (HIV) infection--the causative agent of acquired immunodeficiency syndrome (AIDS), has created an urgent need for a new type of contraceptive: one that is both a spermicide and a microbicide. Because most women at risk for HIV infection are of reproductive age (15-44 years), effective use of dual-function contraceptives is important to prevent HIV transmission and unintended pregnancies. In the absence of an effective prophylactic anti-H… Show more
“…1 The emergence of AIDS as a disease spread through sexual intercourse has prompted the search for new, effective, safe and female-controlled vaginal microbicides for curbing mucosal and perinatal viral transmission. 2 Microbicides would provide protection by inactivating viruses or preventing viruses from replicating either in semen or the infected host cells that line the vaginal wall.…”
5-bromo-6-methoxy-5,6-dihydro-3(')-azidothymidine-5(')-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel bromo-methoxy-substituted aryl phosphate derivative of zidovudine (ZDV), is a potent dual-function contraceptive agent with anti-HIV activity. Its potential for reproductive toxicity was assessed in a series of experiments using CD-1 mice under the conditions of its intended use as an intravaginal microbicide. Female CD-1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0% or 2.0% WHI-07 for up to 13 weeks. On a molar basis, these concentrations represent 1400-5700 times its in vitro spermicidal IC(50) and 1.4-5.7(x10(6)) times its in vitro anti-HIV IC(50). We examined the effects of intravaginally administered WHI-07 on: ovulation efficiency; in vivo fertilization and early embryonic, fetal development; and reproductive outcome, including neonatal survival and pup development. Compound WHI-07 was administered intravaginally during superovulation, organogenesis and prior to mating for 5 and 10 consecutive days and for 13 weeks, respectively. Mice were evaluated for ovulation efficiency and fertilization rate and cleavage 14 and 40 h after human chorionic gonadotropin (hCG) injection, respectively. Pregnant mice were administered 2% WHI-07 intravaginally during gestation days (GD) 6-15 and measures of teratogenicity were evaluated on GD 17. For short-term toxicity study, mice were given intravaginal treatment of gel-microemulsion containing 0%, 0.5%, 1.0% and 2.0% WHI-07 for 13 weeks and then mated with untreated males to evaluate potential reproductive and developmental effects. Repeated intravaginal exposure of mice to 2% WHI-07 had no adverse effects on ovulation response, mean number of eggs recovered or the percentage of eggs fertilized or cleaved. No evidence of reproductive toxicity, fetal toxicity or teratogenicity was found following repetitive intravaginal application of 2% WHI-07 during the period of organogenesis. Furthermore, repeated intravaginal exposure of mice to 0.5-2.0% WHI-07 for 13 weeks had no adverse effect on the subsequent reproductive capability, perinatal outcome or growth and development of the offspring. Compound WHI-07 shows unique clinical potential as a safe, dual-function vaginal contraceptive for curbing mucosal and perinatal HIV transmission.
“…1 The emergence of AIDS as a disease spread through sexual intercourse has prompted the search for new, effective, safe and female-controlled vaginal microbicides for curbing mucosal and perinatal viral transmission. 2 Microbicides would provide protection by inactivating viruses or preventing viruses from replicating either in semen or the infected host cells that line the vaginal wall.…”
5-bromo-6-methoxy-5,6-dihydro-3(')-azidothymidine-5(')-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel bromo-methoxy-substituted aryl phosphate derivative of zidovudine (ZDV), is a potent dual-function contraceptive agent with anti-HIV activity. Its potential for reproductive toxicity was assessed in a series of experiments using CD-1 mice under the conditions of its intended use as an intravaginal microbicide. Female CD-1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0% or 2.0% WHI-07 for up to 13 weeks. On a molar basis, these concentrations represent 1400-5700 times its in vitro spermicidal IC(50) and 1.4-5.7(x10(6)) times its in vitro anti-HIV IC(50). We examined the effects of intravaginally administered WHI-07 on: ovulation efficiency; in vivo fertilization and early embryonic, fetal development; and reproductive outcome, including neonatal survival and pup development. Compound WHI-07 was administered intravaginally during superovulation, organogenesis and prior to mating for 5 and 10 consecutive days and for 13 weeks, respectively. Mice were evaluated for ovulation efficiency and fertilization rate and cleavage 14 and 40 h after human chorionic gonadotropin (hCG) injection, respectively. Pregnant mice were administered 2% WHI-07 intravaginally during gestation days (GD) 6-15 and measures of teratogenicity were evaluated on GD 17. For short-term toxicity study, mice were given intravaginal treatment of gel-microemulsion containing 0%, 0.5%, 1.0% and 2.0% WHI-07 for 13 weeks and then mated with untreated males to evaluate potential reproductive and developmental effects. Repeated intravaginal exposure of mice to 2% WHI-07 had no adverse effects on ovulation response, mean number of eggs recovered or the percentage of eggs fertilized or cleaved. No evidence of reproductive toxicity, fetal toxicity or teratogenicity was found following repetitive intravaginal application of 2% WHI-07 during the period of organogenesis. Furthermore, repeated intravaginal exposure of mice to 0.5-2.0% WHI-07 for 13 weeks had no adverse effect on the subsequent reproductive capability, perinatal outcome or growth and development of the offspring. Compound WHI-07 shows unique clinical potential as a safe, dual-function vaginal contraceptive for curbing mucosal and perinatal HIV transmission.
“…[3][4][5][6] Consequently, the development of safe, efficacious vaginal microbicides capable preventing the transmission of HIV-1 from infected leukocytes via semen is of paramount importance in the fight against the spread of sexually transmitted AIDS. [7][8][9] WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl)-methoxyalaninyl phosphate), a novel aryl phosphate derivative of zidovudine (ZDV) is an anti-HIV-1 prodrug with in vivo microbicidal and contraceptive properties. [10][11][12][13][14] WHI-07 was rationally designed to bypass the kinase activation step, especially in thymidine kinase deficient or lacking monocytes/macrophages, the main carriers of HIV-1 in semen and female genital tract secretions.…”
The objective of this study was to evaluate the long-term stability of the antiretroviral spermicide WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl)-methoxyalaninyl phosphate) in a polymer-based microemulsion. The recovery and stability of WHI-07 in gelmicroemulsion was examined by a validated high-performance liquid chromatography (HPLC) method. The stability was examined over a period of 24 weeks at 3 controlled temperatures (4ºC, 25ºC, and 40ºC). The recovery of the prodrug from 0.5% to 2.0% WHI-07-loaded gel-microemulsion was 99.8%. HPLC analysis revealed that a 2% WHI-07-loaded gel-microemulsion stored at room temperature and cold temperatures for 24 weeks retained 990% of the prodrug, whereas those stored at 40ºC maintained 90% of initial WHI-07 for at least 10 weeks. The observed stability of WHI-07 in gel-microemulsion is of great importance for its widespread utility in various climatological conditions.
“…7 The emergence of HIV/AIDS as a disease spread through sexual intercourse, combined with growing public awareness about the problems associated with other viral sexually transmitted infections (STIs), has prompted the search for new, cost-effective, and safe vaginal microbicides for curbing transmucosal viral transmission. 8,9 Microbicides would provide protection by inactivating viruses or preventing viruses from replicating either in semen or the infected host cells that line the vaginal wall. Microbicides that are currently being investigated are directed mainly at preventing pregnancy as well as protection against STIs.…”
The objective of this study was to develop a nontoxic and noncontraceptive vaginal drug delivery vehicle for lipophilic anti-human immunodeficiency virus (HIV) microbicides. Three representative poorly water-soluble novel broad-spectrum anti-HIV microbicides, PHI-113, PHI-346, and PHI-443, were evaluated in 11 different solvent systems. Based on their solubility profiles, a novel nonspermicidal self-emulsifying gel (viz Conceival) composed of pharmaceutical excipients, sorbitol, polyethylene glycol 400, polysorbate 80, microcrystalline cellulose, xanthan gum, and water was optimized. Conceival enhanced the solubility of these poorly water-soluble (<0.001 mg/mL) anti-HIV drugs by at least 150-to 270-fold. Conceival was evaluated in vivo in the New Zealand white rabbit model for the preservation of sperm function based on pregnancy outcome and the potential for vaginal irritation following single and multiple intravaginal applications, respectively. Conceival administered intravaginally immediately prior to artificial insemination with semen had no adverse effects on subsequent reproductive performance, neonatal survival, or pup development when compared with untreated control group. Histologic evaluation of vaginal tissues of rabbits exposed intravaginally to Conceival for 14 consecutive days revealed lack of epithelial, submucosal, and vascular changes at the gel application site (total irritation score <3 out of a possible 16). These findings indicate that Conceival has potential to become a clinically useful, safe noncontraceptive vaginal vehicle for lipophilic microbicides.
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