Abstract
PurposeCMC 2.24, a chemically modified curcumin, was developed as a novel, pleiotropic MMP-inhibitor to treat various inflammatory/collagenolytic diseases including periodontitis. To date, this compound has shown efficacy in vitro, in cell culture, and in vivo (oral administration) in mice, rats and dogs. In preparation for possible Phase I human clinical trials, the current study describes the maximum-tolerated-dose (MTD), pharmacokinetics (PK), and toxicology of CMC 2.24 in the rat model.MethodsFor the MTD study, 30 Sprague-Dawley rats were randomly distributed into 5 groups (3M/3F per group): Placebo (vehicle; carboxymethylcellulose) and CMC 2.24 at various doses (50, 100, 500, 1000 mg/kg/day), were administered once daily by oral gavage for 5 days. For the PK study, 24 rats were administered either Placebo or CMC 2.24 (100mg/kg/day) once daily for 28 days or only once (500 or 1000 mg/kg). Analysis of this test compound was done using LC/MS/MS for PK evaluation on blood samples drawn from rats at multiple time points. The animals were sacrificed after 5 or 28 days of treatment, and blood chemistry and serology were analyzed. Major organs (heart, lung, liver, kidney, spleen, intestine, brain) were histologically examined at necropsy.ResultsOrally administered, CMC 2.24 did not produce significant changes in body weight, food consumption or adverse events in the MTD and toxicology studies. Moreover, no obvious pathologic changes were observed based on histology, hematology, serum biochemistry, or necropsy compared to placebo-treated controls. The PK study demonstrated a peak-blood concentration (Cmax) at 45 mins after oral administration of 2.24 and a serum half-life of 10 hours.ConclusionIn conclusion, CMC 2.24, orally administered to rats once a day, appears to be safe and effective at a wide range of doses, consistent with efficacy previously demonstrated in studies on animal models of various collagenolytic diseases, such as periodontitis, diabetes and cancer.
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