Incomplete protection against simian immunodeficiency virus vaginal transmission in rhesus macaques by a topical antiviral agent revealed by repeat challenges.

The rising prevalence of human immunodeficiency virus type 1 (HIV-1) infection in women, especially in resource-limited settings, accentuates the need for accessible, inexpensive, and female-controlled preexposure prophylaxis strategies to prevent mucosal transmission of the virus. While many compounds can inactivate HIV-1 in vitro, evaluation in animal models for mucosal transmission of virus may help identify which approaches will be effective in vivo. Macaques challenged intravaginally with pathogenic simian immunodeficiency virus (SIV(mac251)) provide a model to preclinically evaluate candidate microbicides. 2-Hydroxypropyl-beta-cyclodextrin (BCD) prevents HIV-1 and SIV infection of target cells at subtoxic doses in vitro. Consistent with these findings, intravaginal challenge of macaques with SIV(mac251) preincubated with BCD prevented mucosal transmission, as measured by plasma viremia and antiviral antibodies, through 10 weeks postchallenge. In an initial challenge, BCD applied topically prior to SIV(mac251) prevented intravaginal transmission of virus compared to controls (P < 0.0001). However, upon a second virus challenge following BCD pretreatment, the majority of the previously protected animals became infected. The mechanism through which animals become infected at a frequency similar to that of controls after prior exposure to BCD and SIV(mac251) in subsequent intravaginal virus challenges (P = 0.63), despite the potent antiviral properties of BCD, remains to be determined. These results highlight the unpredictability of antiviral compounds as topical microbicides and suggest that repeated exposures to candidate treatments should be considered for in vivo evaluation.

Assessing activity onset time and efficacy for clinically effective antidepressant and antimanic drugs in animal models based on dominant-submissive relationships.

There is confusion in the literature on the measurement of the drug activity onset time (AOT) for both clinical and non-clinical studies of antidepressant and antimanic drugs. The questions asked are: How often and at which time points should drug effects be measured? At what level of a drug effect should AOT be determined? Is the placebo (control) effect important for consideration of drug AOT? This paper reviews approaches taken to answer these questions and to assess drug therapeutic AOT. The first part of the paper is devoted to a review of methods used in clinical trials with depression as an indication. The second part is focused on approaches taken in animal models of depression and how they could help in assessing drug AOT. Finally, a summary of pharmacological values on which the AOT depends is presented and a new statistical approach to data analysis method proposed. The allied experimental design for pre-clinical and clinical studies may help to characterize and differentiate AOT for available and new generation of antidepressants and antimanic drugs.

Preconceptional fasting of fathers alters serum glucose in offspring of mice.

OBJECTIVE: Maternal nutrition has long-term effects on offspring characteristics. Similar effects mediated through fathers have not been tested. METHODS: Outbred Swiss male mice were fasted one or six times 1 to 4 wk before mating. Offspring were killed at age intervals of 4 to 10 wk and their sera were analyzed for glucose, corticosterone, and insulin-like growth factor-1. Statistical linear mixed effects models were used to determine treatment (paternal diet restriction versus control) differences and possible effects of covariates, including sex, litter membership, and litter size. RESULTS: Paternal food deprivation resulted in a consistent decrease in average serum glucose in male and female offspring. Significant changes in corticosterone and insulin-like growth factor-1 were found for some groups. The results indicated a male-mediated transgenerational effect on metabolism- and growth-related parameters, in particular glucose. CONCLUSIONS: Effects of paternal nutritional experiences on offspring metabolism, if confirmed, would be novel and could have far-reaching implications in the context of transgenerational effects on chronic diseases.