[Rationale for an oral thrombin inhibitor from a pharmacological point of view]

Direct thrombin inhibitors are in focus of interest for hereditary or acquired thrombophilic indications. Besides thrombosis prophylaxis in surgery, life-threatening cardiac diseases and stroke are of special interest for this new drug class. For long-term prophylaxis of genetically caused thrombophilia the only drug class currently available are the orally active dicoumarol derivatives. Their application is a time and cost intensive procedure and associated with side effects, too. Active site-directed inhibitors block the catalytic triad of the active centre of thrombin responsible for hydrolytic cleavage. Inhibitor ratios (K(j)) are in the nanomolar or picomolar range. As these substances are eliminated via liver or kidneys with an elimination half-life of 0.3-2 hours, parenteral administration should be used for acute therapy and prophylaxis. For long-term prophylaxis, orally absorbable derivatives of these direct thrombin inhibitors are available with absorption rates of 10-30%. They are converted into their parent substance in blood. Therapeutical range is relatively large so that an oral long-term prophylaxis using standard dose is possible without monitoring. The first representative of this new drug class, Ximelagatran, an orally absorbable variant of Melagatran, is currently undergoing phase III trials for different indications. Using oral administration of two partial doses per day, a good compliance is expected.