The main objective of the application is to establish under controlled conditions whether DDAVP is an effective hemostatic therapy for patients with chronic renal and liver disease and to identify novel analogues devoided of antidiuretic or vasopressor properties but with selective action on hemostasis. DDAVP is hemostatically effective in hemophilia and von Willebrand's disease. Its use in chronic liver and renal disease, the most common acquired bleeding disorders, has been recently suggested on the basis of changes on laboratory tests. However no controlled clinical studies have demonstrated the therapeutic value of DDAVP in the above mentioned conditions. Thus we propose to set up two double-blind controlled trials of DDAVP in patients with chronic renal failure undergoing major surgery and in patients with liver cirrhosis bleeding from esophageal varices. An additional problem for a wide use of DDAVP as a hemostatic agent is that of potential side effects of the compound. In this context one of the objectives of the program will be to design and synthesize novel analogues of vasopressin devoided of antidiuretic action but still active on hemostasis. The design of novel analogues will be based on existing knowledge of structure- activity relationships for vasopressin analogues. Synthesis of the peptides will take place by the solid phase method followed by HPLC purification. Absence of antidiuretic and vasopressor properties will be tested in rats while screening of the analogues for factor VIII-releasing activity will be done in primates (Marmocet-monkeys). Then promising analogues will be tested in humans. The long-term objective is that such analogues might replace the antidiuretic peptide DDAVP in the treatment of bleeding in patients with congenital or acquired hemostatic disorders, and thereby help reduce the clinical use of blood and blood products.
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