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Nonclinical Pharmacology, Toxicology and Pharmacokinetics
Nonclinical pharmacology studies have demonstrated that Ribose can increase adenine nucleotide levels in general and adenosine triphosphate (ATP) levels in particular in the myocardial cells of rats, guinea pigs, and dogs. Under hypoxic conditions, Ribose has been shown to maintain ATP levels compared to untreated controls and also enhance the recovery of ATP levels vs. untreated controls following an ischemic event. In one animal model of heart failure, Ribose treated dogs lived 40% longer than untreated control animals. In combination, these preclinical data support the clinical application of Ribose in several cardiovascular indications such as heart failure, coronary heart disease, and myocardial infarction. In another model evaluating remodeling effects caused by heart failure, mice treated with ribose exhibited significantly lower ventricular dimensions, total wall thickness and fractional shortening values compared to untreated controls. Furthermore, histological analysis confirmed these remodeling effects revealing significantly smaller myocyte dimensions (cross sectional area) and lower levels of fibrosis in ribose-treated vs. untreated controls.
Several toxicology studies have been performed using both oral and IV (continuous infusion) administration of Ribose to rats and dogs at doses substantially higher than proposed for clinical applications. No significant drug-related toxicities were observed, clearing the way for clinical development. In addition, an embryotoxicity/teratogenicity study in rats and several genotoxicity studies have been completed. These studies are included in the two active INDs RiboCor has on file in two different divisions at FDA.
The pharmacokinetics of intravenous Ribose in rats and dogs was evaluated in the toxicity studies mentioned above. In addition, the pharmacokinetics of bolus oral Ribose in dogs was fully characterized. The results of these pharmacokinetic analyses are fully described in the toxicity study final reports and have been submitted to FDA. .
The safety, tolerability, pharmacokinetics, pharmacodynamics, dose proportionality and food effect of oral Ribose has been evaluated in normal volunteers. Ribose was found to be safe and well tolerated at all doses tested and the pharmacodynamic effects (transient insulin spikes with accompanying hypoglycemia) well characterized. Furthermore, the safety, tolerability, pharmacokinetics and pharmacodynamics of Ribose were studied in a heart failure population in which Ribose was shown to be safe and well tolerated at the target clinical doses. Final reports for these studies have been submitted to FDA.
Extensive clinical and preclinical studies have been conducted by RiboCor.