Vinpocetine Mediation of Prior Fetal Alcohol Exposure - Project Summary/Abstract: There is a compelling need to develop treatments for mental deficiencies from fetal exposure to alcohol. The impairments are often lifelong and while early intervention services may help reduce some of the effects of alcohol exposure, there are no cures or adequate specific medical treatments for Fetal Alcohol Spectrum Disorders (FASD) presently available. Results from studies in humans and animal models suggest that a disruption in neuronal plasticity is the underlying mechanism responsible for the cognitive impairments caused by fetal alcohol exposure. Vinpocetine, a phosphodiesterase inhibitor, has been shown in multiple animal studies, including multiple models of FASD, to improve neuronal plasticity. Therefore, we hypothesize that vinpocetine may ameliorate the deficits observed in this condition. However, we recently found that the doses of vinpocetine that are commonly used in humans produce blood levels that are much lower than effective levels in animal models. Thus, higher doses in humans are needed to produce levels that match effective levels in animals. Further, dose-response curves are not available from the prior animal studies. Therefore, in the R61, specific aim 1 is designed to characterize the dose/plasma concentrations response curve for vinpocetine effects in several FASD animal models. Although vinpocetine is well tolerated in humans at doses that are typically used, the tolerability of the higher doses is not known. Specific aim 2 in the R61 will determine the maximum tolerated oral dose of vinpocetine in healthy adult volunteers and develop pilot data on pharmacokinetic time curve for vinpocetine effects. The data gathered in the proposed series of animal studies and the Phase I healthy human dose escalation study in the R61 portion will guide specific aim 3, which will establish a multicenter research team, develop tools for data management and research oversight, develop the experimental research design, refine a protocol including dosages for the subsequent Phase I and Phase II studies in the R33, and prepare an operations and procedures manual for the FASD human studies. In the R33, we propose Phase I and Phase II studies to assess safety and potential cognitive efficacy of doses of vinpocetine (guided by the findings of the R61 studies) in treating adolescents and adults with FASD. Therefore, specific aim 4 will assess the safety of doses of vinpocetine in adolescents, while specific aim 5 will assess the efficacy and safety of vinpocetine to enhance cognition in adolescents and adults with FASD in a Phase II study. The Phase II study will provide data to determine optimal dose, effect sizes, and best neuropsychological assessment to be used as the main outcome for a future Phase III trial.
