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A CCR5 antagonist-based HIV entry inhibitor exhibited potent spermicidal activity: Potential application for contraception and prevention of HIV sexual transmission.
- Source :
-
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2018 May 30; Vol. 117, pp. 313-320. Date of Electronic Publication: 2018 Feb 26. - Publication Year :
- 2018
-
Abstract
- B07 is a small-molecule CCR5 antagonist-based HIV-1 entry inhibitor that is being developed as an anti-HIV microbicide for preventing sexual transmission of HIV. Here we evaluated its spermicidal and contraceptive potential, including sperm motility, plasma membrane integrity, and contraceptive efficacy tested in rabbits. We found that B07 inhibited sperm motility and movement patterns in a concentration- and time-dependent manner. Within 30 min, B07 induced sperm immobilization with the minimum 100% effective concentration and median effective concentration of 640.0 and 64.4 μg/mL, respectively. The hypo-osmotic swelling test showed that plasma membranes of B07-treated sperms exhibited slight disruption, as verified by electron micrographs. In both B07 gel and N-9 gel groups, not a single implantation site or embryo was observed based on the contraceptive efficacy test in rabbits, indicating that B07 could effectively block the potential of sperm to reach and/or fertilize oocytes. The safety profile of B07 in vivo was evaluated by use of an optimized rabbit vaginal irritation test. While the pathological scores of the N-9 gel group was 14.67 ± 1.21, those of the blank control and B07 gel groups were 2.17 ± 0.76 and 4.00 ± 0.89, respectively, which were within the clinically acceptable range (<8). The proportion of inflammatory cells and CD45 <superscript>+</superscript> cells in the cervicovaginal lavages of the B07 gel group showed no significant change compared to those of the control group. Therefore, our results confirmed that B07 exhibited significant spermicidal and contraceptive effects, suggesting its potential for development as a microbicidal spermicide for contraception and prevention of HIV sexual transmission.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Subjects :
- Administration, Intravaginal
Animals
CCR5 Receptor Antagonists administration & dosage
Dose-Response Relationship, Drug
Female
Gels
HIV Fusion Inhibitors administration & dosage
HIV Infections transmission
HIV Infections virology
Humans
Male
Piperazines administration & dosage
Pregnancy
Pregnancy Rate
Rabbits
Receptors, CCR5 metabolism
Sperm Motility drug effects
Sperm-Ovum Interactions drug effects
Spermatocidal Agents administration & dosage
Spermatozoa metabolism
Spermatozoa ultrastructure
Time Factors
CCR5 Receptor Antagonists pharmacology
HIV Fusion Inhibitors pharmacology
HIV Infections prevention & control
Piperazines pharmacology
Receptors, CCR5 drug effects
Spermatocidal Agents pharmacology
Spermatozoa drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0720
- Volume :
- 117
- Database :
- MEDLINE
- Journal :
- European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 29496533
- Full Text :
- https://doi.org/10.1016/j.ejps.2018.02.026