Disease relevance of WHI-07

• WHI-07 was active against the feline immunodeficiency virus (FIV) [1].
• Furthermore, long-term (2 years) intravaginal administration of 2% WHI-07 gel-microemulsion was not associated with systemic toxicity or increased carcinogenicity in mice [2].
• The anti-human immunodeficiency virus (HIV) activity of Trp-containing WHI-07 analogues was also diminished [3].
• WHI-07 and its Trp analogues hold particular clinical promise for the development of novel, nondetergent-type prophylactic contraceptives for the prevention of heterosexual HIV/acquired immunodeficiency syndrome transmission [3].
• No effects related to WHI-07 treatments were observed on survival, mean body weight, and mean body-weight gain [4].

High impact information on WHI-07

• Pretreatment of the vagina or rectum with 2% WHI-07 alone or in combination with 0.25% VDDTC significantly (P = 0.004) protected cats from genital transmission by the highly infectious inoculum (7 million FIV(Bangston)-infected feline T cells) [1].
• WHI-05 and WHI-07 differ fundamentally from currently used surfactant microbicides that are cytotoxic to genital tract epithelial cells at spermicidal concentrations [2].
• The time- and concentration-dependent intracellular formation of ZDV metabolites following addition of WHI-05 and WHI-07 to normal human vaginal, ectocervical, and endocervical epithelial cells as well as motile sperm was studied by analytical HPLC [5].
• The IC50 (HIV) and EC50 (SIA) values for WHI-07 were 439-fold and 13.5-fold lower, respectively, than those for the detergent-based virucidal spermicide, nonoxynol-9 (N-9) [6].
• Unlike the intravaginal application of N-9, repetitive intravaginal application of WHI-07 did not damage the vaginal epithelium or cause local inflammation [6].

Chemical compound and disease context of WHI-07

• Compounds WHI-05 and WHI-07 may be useful as dual-function vaginal contraceptives for women who are at high risk for acquiring HIV/acquired immunodeficiency virus syndrome by heterosexual vaginal transmission [6].

Biological context of WHI-07

• Whereas AZT displayed potent anti-HIV activity (IC50 = 0.006 microM) but lacked SIA (EC50 > 300 microM), two 5-bromo-6-methoxy-aryl phosphate derivatives of AZT, compounds WHI-05 and WHI-07, exhibited potent anti-HIV activity as well as SIA [6].
• WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion [7].
• Furthermore, the 2% WHI-07 gel-microemulsion provided >90% inhibition of fertility even when insemination was delayed until 60 minutes after intravaginal application [8].
• Repeated intravaginal exposure of mice to WHI-07 for 13 weeks had no toxicologically significant effect on organ weights, and did not cause any adverse changes in hematology parameters or blood chemistry profiles [4].
• RESULT(S): Exposure of semen to WHI-07 at the time of artificial insemination completely inhibited pregnancy rates (WHI-07-pretreated, 0%, vs. control, 60%) and embryo implantation (WHI-07-pretreated, 0/175 vs. control, 68/170) [8].

Anatomical context of WHI-07

• Addition of WHI-05 and WHI-07 to vaginal and cervical epithelial cells resulted in their concentration- and time-dependent conversion to alaninyl ZDV monophosphate (Ala-ZDV-MP) and 5'-ZDV monophosphate as the major metabolites [5].
• In Experiment I, ovulated does in subgroups of 15 were artificially inseminated with semen mixed with WHI-07 or vehicle [8].
• External, and skeletal examinations of fetuses for malformations and variations did not reveal any evidence of teratogenicity in any WHI-07-treated groups [9].
• 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 [10].
• Prior studies of repeated intravaginal administration of WHI-07 gel-microemulsion revealed lack of local toxicity to rabbit vaginal mucosa [9].

Associations of WHI-07 with other chemical compounds

• The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N-9) were compared using normal human ectocervical and endocervical epithelial cells by the MTT cell viability assay [7].
• Glutathione was found to mediate the in vitro and in vivo detoxification pathway of WHI-07 to 3'-azidothymidine-5'-p-bromophenylmethoxyalaninyl phosphate and Ala-ZDV-MP, respectively [11].

Gene context of WHI-07

• The anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC) [7].
• The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM) [7].
• On a molar basis, these concentrations of WHI-07 are 1400- to 5700-times higher than its spermicidal EC(50) and 1.4 x 10(6) to 5.7 x 10(6) times higher than its in vitro anti-HIV IC(50) [4].
• Reproductive indices, ie, pregnancy rate, gravid uterine weights, litter size, number of corpora lutea, implantation sites, pre- and postimplantation losses, viable fetuses, resorptions, fetal body weights, and fetal sex ratio, were not affected by intravaginal exposure to WHI-07 [9].
• WHI-07 was cytotoxic to drug-sensitive (NALM-6, MOLT-3, HL-60, P388) and multi-drug resistant (MDR) leukemia cell lines (HL-60/VCR, HL-60/ADR, P388/ ADR) [11].

Analytical, diagnostic and therapeutic context of WHI-07

• WHI-07 applied intravaginally prior to artificial insemination of epididymal sperm drastically reduced fertility in hormonally primed CD-1 mice [6].

References