Human immunodeficiency virus (HIV), the causative agent of AIDS is the fastest growing cause of death in women of reproductive age. Heterosexual transmission accounts for >80% of all HIV infections world- wide, and constitutes a growing proportion of new HIV infections in the United States. The currently used topical vaginal microbicide, nonoxynol-9 (N-9)-a detergent-based virucidal spermicide in addition to its high contraceptive failure rates also causes mucosal erosion and local inflammation which might increase the risk of HIV transmission. Therefore, new, effective, safe, and female-controlled vaginal microbicides are urgently needed to curb vaginal transmission of HIV infection. With an attempt to identify a microbicide contraceptive potentially capable of preventing sexual transmission of HIV as well as providing fertility control, a series of bromo-methoxy substituted novel derivatives of the anti-HIV drug, azidothymidine (AZT; zidovudine), were synthesized and examined for dual anti-HIV activity and spermicidal activity. Two lead compounds, WHI-05 and WHI-07, exhibited potent anti- HIV as well as spermicidal activity. Results of in vivo spermicidal efficacy and lack of local toxicity in the mouse model indicated that SHI-05 and WHI-07 would be attractive candidates as dual function vaginal microbicides. The applicants are now proposing preclinical studies to further evaluate the clinical potential of these dual- function AZT derivatives.
The specific aims are: (i) to evaluate the in vivo contraceptive activity of WHI-05 and WHI-07 in rabbits; (ii) to evaluate the ability of WHI-05 and WHI-07 to prevent transmucosal and perinatal transmission of feline immunodeficiency virus in cats as the natural host model; (iii) to evaluate the ability of WHI-05 and WHI-07 to prevent transmucosal transmission of HIV-1 in chimpanzees as a surrogate host model; and (iv) to perform in vivo developmental, reproductive toxicology, and carcinogenesis studies of WHI-05 and WHI-07 in rodent models. The development of dual function vaginal microbicides to curb HIV transmission and prevent fertility will be a significant step forward to protect sexually active women from vaginal HIV transmission. The preclinical data on in vivo efficacies of WHI-05 and WHI-07 will be essential to further explore the utility of these novel drugs for clinical studies in human patients.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD037357-01
Application #
2799089
Study Section
Special Emphasis Panel (ZRG5-AARR-3 (01))
Program Officer
Kaufman, Steven
Project Start
1998-12-15
Project End
2001-11-30
Budget Start
1998-12-15
Budget End
1999-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Parker Hughes Institute
Department
Type
DUNS #
City
St. Paul
State
MN
Country
United States
Zip Code
55113
Uckun, Fatih M; Tai, Hung-Liang; D'Cruz, Osmond J (2005) Antileukemic activity and cellular metabolism of the aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07). Arzneimittelforschung 55:50-65
D'Cruz, Osmond J; Samuel, Peter; Uckun, Fatih M (2005) Conceival, a novel noncontraceptive vaginal vehicle for lipophilic microbicides. AAPS PharmSciTech 6:E56-64
D'Cruz, Osmond J; Waurzyniak, Barbara; Uckun, Fatih M (2004) Antiretroviral spermicide WHI-07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats. Antimicrob Agents Chemother 48:1082-8
D'Cruz, Osmond J; Samuel, Peter; Uckun, Fatih M (2004) PHI-443: a novel noncontraceptive broad-spectrum anti-human immunodeficiency virus microbicide. Biol Reprod 71:2037-47
D'Cruz, Osmond J; Uckun, Fatih M (2004) Stampidine is a potential nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide. Fertil Steril 81 Suppl 1:831-41
D'Cruz, Osmond J; Uckun, Fatih M (2003) Contraceptive activity of a spermicidal aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07) in rabbits. Fertil Steril 79:864-72
D'Cruz, Osmond J; Samuel, Peter; Waurzyniak, Barbara et al. (2003) Development and evaluation of a thermoreversible ovule formulation of stampidine, a novel nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide. Biol Reprod 69:1843-51
D'Cruz, Osmond J; Erbeck, Douglas; Uckun, Fatih M (2003) Developmental toxicology studies of WHI-07, a novel nucleoside analogue-based dual-function microbicide, administered intravaginally to rabbits. Toxicol Pathol 31:698-708
D'Cruz, Osmond J; Uckun, Fatih M (2003) Contraceptive activity of a spermicidal aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-05) in rabbits. Arzneimittelforschung 53:515-21
D'Cruz, Osmond J; Waurzyniak, Barbara; Uckun, Fatih M (2002) A 13-week subchronic intravaginal toxicity study of the novel broad-spectrum anti-HIV and spermicidal agent, N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-346) in mice. Toxicol Pathol 30:687-95

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