Safety, Pharmacokinetics, and Biomarkers of an Amorphous Solid Dispersion of Genistein, a Radioprotectant, in Healthy Volunteers.

A pharmaceutical formulation of genistein, produced as an amorphous solid dispersion by hot melt extrusion (genistein HME), has been developed that can be administered prophylactically to improve outcomes and survival following radiation exposure. Here, genistein HME was evaluated in a phase 1, open-label, single ascending dose (SAD) and multiple single dose (MSD) study enrolling 34 healthy volunteers. In the SAD study, participants were administered a single dose (500, 1000, 2000, or 3000 mg) and in the MSD study, participants were administered a single daily dose for six consecutive days (3000 mg/day). The overall adverse event profile and pharmacokinetics of genistein HME were determined. Additionally, biomarkers of genistein HME were evaluated by profiling whole blood for changes in gene expression by RNA sequencing. Genistein HME was found to be safe at doses up to 3000 mg. Most toxicities were mild to moderate gastrointestinal events, and no dose-limiting toxicities were reported. The maximum tolerated dose was not determined and the no observable adverse effect level was 500 mg. Genistein HME bioavailability greatly increased between the 2000 mg and 3000 mg doses. RNA sequencing analysis revealed that the majority of drug-related changes in gene expression occurred 8-12 hours after the sixth dose in the MSD study. Based on these results, the putative effective dose in humans is 3000 mg.

Enteral feeding enriched with carotenoids normalizes the carotenoid status and reduces oxidative stress in long-term enterally fed patients.

BACKGROUND & AIMS: Circulating carotenoid levels decrease progressively in patients receiving long-term enteral tube feeding with carotenoid-free formulas. Low dietary intake and low blood levels of carotenoids are associated with a higher risk of morbidity and mortality from chronic diseases. The aim of this study was to examine the effects of a low dose carotenoid mixture (3-mg/1500kcal) for 3 months on serum carotenoid levels and oxidative stress in patients receiving long-term enteral nutrition as the sole source of nutrition. METHODS: This randomized, double blind, controlled study compared patients receiving enteral nutrition with carotenoids (N=26) and without carotenoids (control group; N=25). RESULTS: Patients on long-term enteral nutrition had low baseline serum carotenoid levels. Three months of enteral feeding enriched with carotenoids significantly (P<0.01) increased serum carotenoid levels compared with the control group. Oxidative stress as measured by NF-kappaB levels was decreased at 3 months compared with the control group (P<0.05). No significant changes in MDA levels were observed during the study period in either group. CONCLUSIONS: This study demonstrated that enteral nutrition containing small amounts of carotenoids (3-mg/1500kcal) in patients requiring long-term enteral feeding normalizes serum carotenoid levels to the lower end of the range found in age-matched controls. The NF-kappaB data indicate a reduction in oxidative stress in these patients. Therefore, the use of formulas containing a mixture of carotenoids should be recommended for long-term enteral nutrition.