Source:http://linkedlifedata.com/resource/pubmed/id/10338365
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
5
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| pubmed:dateCreated |
1999-7-16
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| pubmed:abstractText |
In a systematic effort to develop a microbicide contraceptive capable of preventing transmission of human immunodeficiency virus (HIV), as well as providing fertility control, we have previously identified novel phenyl phosphate derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine ring and halo substitution in the phenyl moiety respectively. Here, we describe the synthesis, characterization, and successful preclinical formulation of our lead compound, 5-bromo-6-methoxy-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), which exhibits potent anti-HIV and sperm immobilizing activities. 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). WHI-07 inhibited replication of HIV in a concentration-dependent fashion with nanomolar IC50 values. 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). WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion. 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. Unlike N-9, WHI-07 had no effect upon sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of 2% gel-microemulsion of WHI-07 was studied in the rabbit model. The sperm immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a 10 day period, there was no irritation or local toxicity to the vaginal epithelia or systemic absorption of WHI-07. Therefore, as a potent anti-HIV agent with spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical potential to become the active ingredient of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/5-bromo-6-methoxy-5...,
http://linkedlifedata.com/resource/pubmed/chemical/Anti-HIV Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Dideoxynucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Emulsions,
http://linkedlifedata.com/resource/pubmed/chemical/Spermatocidal Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Monophosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Zidovudine
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| pubmed:status |
MEDLINE
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| pubmed:month |
May
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| pubmed:issn |
1360-9947
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
5
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
421-32
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| pubmed:dateRevised |
2007-11-15
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| pubmed:meshHeading |
pubmed-meshheading:10338365-Acrosome Reaction,
pubmed-meshheading:10338365-Animals,
pubmed-meshheading:10338365-Anti-HIV Agents,
pubmed-meshheading:10338365-Cell Membrane,
pubmed-meshheading:10338365-Cervix Uteri,
pubmed-meshheading:10338365-Dideoxynucleotides,
pubmed-meshheading:10338365-Drug Evaluation, Preclinical,
pubmed-meshheading:10338365-Emulsions,
pubmed-meshheading:10338365-Epithelial Cells,
pubmed-meshheading:10338365-Female,
pubmed-meshheading:10338365-HIV-1,
pubmed-meshheading:10338365-Humans,
pubmed-meshheading:10338365-Male,
pubmed-meshheading:10338365-Rabbits,
pubmed-meshheading:10338365-Sperm Motility,
pubmed-meshheading:10338365-Spermatocidal Agents,
pubmed-meshheading:10338365-Spermatozoa,
pubmed-meshheading:10338365-Thymidine Monophosphate,
pubmed-meshheading:10338365-Vagina,
pubmed-meshheading:10338365-Virus Replication,
pubmed-meshheading:10338365-Zidovudine
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| pubmed:year |
1999
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| pubmed:articleTitle |
Synthesis, characterization and preclinical formulation of a dual-action phenyl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) with potent anti-HIV and spermicidal activities.
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| pubmed:affiliation |
Department of Reproductive Biology, Hughes Institute, St Paul, MN 55113, USA.
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| pubmed:publicationType |
Journal Article
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