Periodontitis is the most prevalent form of bone pathology in the United States with 15-25% of all individuals suffering from moderate to severe forms. The progression of the disease, if untreated, leads to bone resorption and the eventual loss of the tooth. The objectives of this project are to bioengineer a novel, effective and low-maintenance therapy for periodontal disease which eliminates the bone resorption and tooth loss. This will be accomplished through the use of the (+) enantiomer of promethazine HCI or a hydrophilic analog Of (+) PMZ delivered through an implantable, control release device which maintains plasma levels of drug within the effective, bone loss preventing range for two to four weeks. To accomplish this goal, we proposed to 1) synthesize a biodegradable, controlled released (+) PMZ device. This device will be engineered to for zero order release kinetics over two months and will be implantable subdermally or in the oral cavity. 2) Determine the toxicity and release kinetics of the implant in a rat model. Release kinetics will be established by implanting the (+) PMZ device in rats and analyzing blood samples, drawn daily, for plasma (+) PMZ concentration. Toxicity will be determined at the end of the two week period by histologic examination of the tissues surrounding the implant site and from the liver, kidney, spleen and brain. 3) Determine the in vivo efficacy of the (+) PMZ device using a rat model for periodontal disease. (+) PMZ devices will be implanted as above. The upper left 1st molar of the rat will be ligated with surgical suture to induce periodontitis. Bone loss in the affected area will be determined and compared to that of untreated animals. 4) Synthesize and characterize a hydrophilic analog of (+) PMZ. (+) PMZ will be chemically altered by the addition of hydrophilic moieties at appropriate sites within the parent molecule. Cytotoxicity and efficacy of the analog will be determined in vitro and in vivo. The result of this project will be the preliminary development of a safe, effective and low maintenance treatment for periodontitis which will prevent tooth loss in affected patients. ? ?
