Ximelagatran

Ximelagatran (marketed under the names Exanta or Exarta, and known as H 376/95) is an anticoagulant previously investigated as a potential substitute for warfarin. Its development was spurred by the aim to address the dietary restrictions, drug interactions, and consistent monitoring requirements associated with warfarin therapy. However, in 2006, the manufacturing company, AstraZeneca, decided to withdraw its applications for marketing approvals and stop its distribution in various countries due to reports of hepatotoxicity during clinical trials.[2]

Method of Action

Ximelagatran, identified as a direct thrombin inhibitor,[3] held the distinction of being the first drug in its class to be administered orally. It works primarily by counteracting the effects of thrombin. Upon oral administration, it is swiftly absorbed by the small intestine. Ximelagatran operates as a prodrug, undergoing in vivo conversion to the active compound, melagatran. This transformation happens in the liver and several other tissues, facilitated by dealkylation and dehydroxylation processes.

Uses

The drug was anticipated to supplant warfarin, and occasionally aspirin and heparin, in numerous therapeutic scenarios. This includes applications like deep venous thrombosis prevention, thwarting secondary venous thromboembolism, and mitigating complications stemming from atrial fibrillation, such as stroke. Though ximelagatran's efficacy in these areas has been well established,[4][5][6] its efficacy for non valvular atrial fibrillation remained undocumented.

According to initial reports from AstraZeneca, a noteworthy advantage of ximelagatran was its oral administration without the necessity for monitoring its anticoagulant effects. This characteristic would differentiate it from warfarin and heparin, which need consistent checks on the international normalized ratio (INR) and the partial thromboplastin time (PTT) respectively. A recognized limitation, however, was the lack of a readily available antidote for instances of acute bleeding. In contrast, warfarin's effects can be neutralized with vitamin K, and heparin with protamine sulfate.

Side-effects

Though ximelagatran was predominantly well-received among trial groups, a minor segment (5-6%) exhibited elevated liver enzyme levels. This prompted the FDA to decline the initial application for its approval in 2004. Subsequent development ceased in 2006 when it was discovered that liver damage could manifest after discontinuing the medication. AstraZeneca has indicated that a chemically distinct yet pharmacologically akin substance, AZD0837, is presently under evaluation for similar therapeutic applications.[2]

Melagatran synthesis

Sobrera, L. A.; Castaner, J.; Drugs Future, 2002, 27, 201.