Poly Metallo Liothyronine Complexes for Hypothyroidism Treatment

The work described in this proposal addresses the clinical deficiency of the currently available oral treatments for hypothyroidism Approximately of persons suffering from hypothyroidism report insufficient symptomatic improvement from levothyroxine T Synthroid alone This is thought to be related to a genetic variation in the enzyme that converts T to T the active form of thyroid hormone Liothyronine T Cytomel is believed to be too rapidly absorbed and too short lived to act as an effective complement to T If the value of combining T with T is to be realized for these patients a controlled release product producing T plasma concentrations similar to normal euthroid will be needed Euthroid plasma levels are important for achieving normal thyroid hormone concentrations in all tissues The broad long term objective of this project is to provide patients a new product that can produce euthroid like T levels with once daily oral dosing The immediate goal is to test the feasibility of coordinating T with specific metals to produce proprietary complexes that provide a sustained release of T relative to Cytomel The specific aims include a the synthesis and chemical characterization of a set of metallo labeled T complexes and b the demonstration in oral absorption studies in rats of controlled release compared with a liothyronine control in one or more complexes The metallo T complexes are designed to extend the transit time through the gastrointestinal tract where T molecules gradually break free from the metal complex and enter the blood stream This modulates the rate of delivery and thereby the rate of absorption Metal coordinated T complexes will constitute new compositions of matter with market exclusivity Moreover the sustained release properties conferred onto T can be applied to other drugs that would benefit from modulated delivery Finally deuterium labeled T T d will be used so that endogenous T can be distinguished from orally dosed T by mass spectroscopy This approach constitutes a significant practical advance when evaluating the absorption of thyroid hormones in vivo Optimal treatment with thyroid hormones in hypothyroid patients is a significant issue with respect to public health Although controversial in the past the addition of liothyronine T to levothyroxine T in those patients who have enzyme abnormalities or other conditions that leave them sub optimally treated with T alone has gained acceptance This project is focused on the development of a sustained release oral dosage form of T with a target product profile that includes producing normal T serum levels thus addressing the clinical deficiency associated with the currently marketed immediate release form of T