期刊
REPRODUCTIVE TOXICOLOGY
卷 114, 期 -, 页码 9-21出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.reprotox.2022.09.007
关键词
Reproductive toxicity; Antiviral; Host -targeted antiviral; Broad-spectrum antiviral
资金
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services
- [HHS272201100030C]
UV-4 is a host-targeted antiviral agent with broad-spectrum activity and low potential for drug resistance mutations. Animal studies showed adverse effects on reproduction and development, including decreased fertility and abnormal embryonic development. These effects are similar to those seen with structurally related drugs, suggesting that UV-4 may have similar adverse outcomes in humans.
UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a host-targeted antiviral agent, which targets mammalian proteins (endoplasmic reticulum glucosidases) rather than virally encoded proteins. This mechanism confers both broad-spectrum activity and low potential for generation of viral drug resistance mutations. Reproductive and developmental studies of UV-4 evaluated effects on fertility and early embryonic development in rats, embryo-fetal development in rats and rabbits, and pre- and postnatal development including maternal function in rats. All reproductive and developmental studies conducted achieved dose levels where parental toxicity (generally decreased body weight, decreased food consumption and adverse clinical signs) were observed. Toxicokinetic evaluations confirmed UV-4 crossed the placenta exposing fetal rats and rabbits in utero. Adverse findings in reproductive and developmental studies included decreases in sperm motility with histopathology correlates, visceral and skeletal malformations, changes in eye opening, air drop reflex, vaginal opening and preputial separation. The combined results of the fertility and early embryonic developmental study and pre- and postnatal study suggested that there may be an increased risk for male fertility. These effects are similar to those reported in pre-clinical studies of the structurally related drug Miglustat (N-butyl-1-deoxynojirimycin), therefore UV-4 may have risk of developmental or reproductive adverse outcomes in humans similar to existing approved agents in this drug class.
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