Ximelagatran: an Oral Direct Thrombin Inhibitor

Molecules of the Millennium

Ximelagatran: An oral direct thrombin inhibitor

Anticoagulants have been in use for more than 50 years time.[8] It does not inhibit other serine proteases except trypsin. for the prevention and treatment of thromboembolic disorders. Adverse effects Vitamin K antagonists such as warfarin are widely used for the prevention of arterial and venous thromboembolosm in Hepatotoxicity is a major side effect noticed in patients patients with atrial fibrillation, coronary artery disease and taking ximelagatran. An elevation in alanine transferase values following some orthopedic procedures. The drawbacks of us- was observed within 6 weeks to 6 months of treatment with ing warfarin are the slow onset and offset of its antithrombotic ximelagatran. In most of the cases, it was asymptomatic and action, an unpredictable and variable pharmacological reversible even on continuation of ximelagatran. But this response, a narrow margin of safety and numerous food and warrants monitoring of liver function tests at least once a drug interactions.[1] The need for intensive laboratory month.[9] monitoring to control its anticoagulant effects and the risk of Interactions bleeding has reduced the compliance of the patients. So there is need for well-tolerated, convenient, and effective alternatives The metabolism of ximelagatran is independent of the he- to oral warfarin to improve the management of patients patic P450 system, and has no affinity to bind to plasma pro- requiring anticoagulation therapy. teins or platelets. Hence a lower propensity to cause drug in- Ximelagatran is an orally active direct thrombin inhibitor. teractions.[10] Food-drug interactions have not been reported After absorption, ximelagatran is rapidly converted into its either. active form melagatran, a potent inhibitor of thrombin that Uses prevents both thrombin activity and generation. Melagatran has a very poor oral absorption due to the presence of a • Treatment and prevention of venous thromboembolism carboxylic acid, a secondary amine and an amide residue – 24 mg b.d. resulting in a charged molecule at physiological pH.[2] • Prevention of stroke in atrial fibrillation- 36 mg b.d. Concomitant food intake further reduces its bioavailability. So, Advantages ximelagatran, a prodrug of melagatran was developed which has better oral absorption due to better lipophilicity and • Administered orally at fixed doses without coagulation uncharged nature at intestinal pH.[3] monitoring. • Offers more predictable anticoagulant response as it Pharmacokinetics is not protein cofactor-dependent. Ximelagatran, after oral ingestion is absorbed from the • Wider therapeutic index. small intestine and undergoes rapid biotransformation, via two • Anticoagulant action develops immediately. intermediates, ethyl melagatran and hydroxy melagatran, to • No inter-subject variability. melagatran. About 20% of an oral dose is absorbed. The • No drug-drug and drug-food interactions. maximum plasma concentration of melagatran is achieved 2- Disadvantages 3 h after the oral administration with a plasma half-life of 4-5 h.[4] The drug is excreted entirely by the kidney with a mean • Hepatotoxicity. elimination half-life of 3 h. Studies have shown that body • No antidote available (but dialysis can help in reversal) weight, sex and ethnicity do not affect the pharmacokinetic Clinical trials profile of ximelagatran.[5] There is no dose adjustment required in patients with mild to moderate hepatic impairment.[6] But An open-label SPORTIF III treatment trial found dose reduction or prolongation of dose interval is necessary ximelagatran to be as effective as warfarin for stroke in patients with renal disease.[7] prevention in non-valvular atrial fibrillation.[11] The results of SPORTIF V study showed the efficacy of fixed dose oral Pharmacodynamics ximelagatran with well controlled warfarin for prevention of Thrombin is a serine protease involved in the formation of thromboembolism in patients with atrial fibrillation requiring a stable insoluble clot. It is also involved in the activation of chronic anticoagulant therapy.[12] THRIVE treatment study platelets and factors V and VIII. Ximelagatran is a potent, rapidly indicated that ximelagatran was as effective as enoxaparin/ binding, competitive and reversible direct inhibitor of thrombin. warfarin for the treatment of deep vein thrombosis with similar It causes inhibition of thrombin activity, thrombin generation, or low rates of bleeding.[13] platelet activation and thrombus formation. It acts on both In Europe, ximelagatran has been recently approved for soluble and clot-bound thrombin resulting in the prolongation short-term use and results of post-marketing surveillance are of prothrombin time, partial thromboplastin time and thrombin awaited in the near future. US FDA has not yet approved

132 Indian J Pharmacol | April 2005 | Vol 37 | Issue 2 | 132-134 Ximelagatran ximelagatran for concerns about hepatotoxicity.[14] 6. Wahlander K, Eriksson-Lepkowska M, Frison L, Fager G, Eriksson UG. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and Conclusion pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003;42:755-64. The novel oral anticoagulant ximelagatran has a 7. Eriksson UG, Johansson S, Attman PO, Mulec H, Frison L, Fager G, et al. favorable pharmacokinetic and dynamic profile as compared Influence of severe renal impairment on the pharmacokinetics and to warfarin. It has the potential to initiate the beginning of the pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin end of warfarin. But the propensity to cause hepatotoxicity Pharmacokinet 2003;42:743-53. and the non-availability of an antidote causes concern. So the 8. BrightonTA. The direct thrombin inhibitor melagatran/ximelagatran. Med J Aust 2004;181: 432–7. therapeutic benefits should be weighed against the risks before 9. Schulman S, Wahlander K, Lundstrom T, Clason AB, Eriksson H. Secondary prescribing it to patients. prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-21. C. Girish, M. Jayanthi 10. Bredberg E, Andersson TB, Frison L, Thuresson A, Johansson S, Eriksson- Department of Pharmacology, Lepkowska M, et al. Ximelagatran, an oral direct thrombin inhibitor, has a low JIPMER, Pondicherry- 605 006. India potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003;42:765-77. E-mail: [email protected] 11. Olsson SB. Executive Steering Committee on behalf of the SPORTIF III References Investigators. Stroke prevention with the oral direct thrombin inhibitor 1. Wells PS, Howbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with ximelagatran compared with warfarin in patients with non-valvular atrial drugs and food: review. Ann Intern Med 1994;121:676-83. fibrillation (SPORTIF III): Randomised controlled trial. Lancet 2003;362:1691- 2. Clement B, Lopian K. Characterization of in vitro biotransformation of new, 8. orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester 12. Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S, et al. prodrug. Drug Metab Dispos 2003;31:645-51. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. 3. Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: atrial fibrillation: a randomized trial. JAMA 2005;293:690-8. A mini-review. Thromb Res 2003;109 Suppl 1:9-15. 13. Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, 4. Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005;105:453-63. Eriksson H, et al. THRIVE Treatment Study Investigators. Ximelagatran vs 5. Boos CJ, More RS. Anticoagulation for non-valvular atrial aibrillation – towards low-molecular-weight heparin and warfarin for the treatment of deep vein a new beginning with ximelagatran. Curr Control Trials Cardiovasc Med thrombosis: a randomized trial. JAMA 2005;293:681-9. 2004;5:3. 14. Gurewich V. Ximelagatran-promises and concerns. JAMA 2005;293:736-9.

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Ghrelin: A potential drug target for obesity

The suffix “ghre” means “to grow”. Ghrelin (pronounced R is ghrelin. The receptors are present on the cells in the GRELL-in) was discovered in 1999 as a peptide hormone that pituitary that secrete the growth hormone and also have been potently stimulates the release of growth hormone from the identified in the hypothalamus, heart and adipose tissue.[1] anterior pituitary. It was subsequently determined that ghrelin, Control and physiological effects of ghrelin along with several other hormones, has significant effects on appetite and energy balance. At least two major biological activities have been ascribed to ghrelin Synthesis and receptor 1. Stimulation of growth hormone secretion: Ghrelin, as Ghrelin is synthesized as a pre-prohormone, and then the ligand for the growth hormone secretagogue receptor, proteolytically processed to yield a 28-amino acid peptide. A potently stimulates the secretion of the growth hormone. The modification necessary for biological activity is the binding of ghrelin signal is integrated with that of the growth hormone- n-octanoic acid to one of its amino acids, carried out during releasing hormone and somatostatin to control the timing and its synthesis. Synthesis of ghrelin occurs predominantly in the magnitude of growth hormone secretion.[2] epithelial cells lining the fundus of the stomach, with smaller 2. Regulation of energy balance: In rodents and humans, amounts produced in the placenta, kidney, pituitary and ghrelin functions to increase hunger through its action on the hypothalamus. hypothalamic feeding centers. The plasma ghrelin The ghrelin receptor was known well before ghrelin was concentrations increase during fasting.[3] Humans injected with discovered. Cells within the anterior pituitary have a receptor ghrelin reported sensations of intense hunger.[4] Ghrelin also that, when activated, potently stimulates the secretion of the appears to suppress fat utilization in the adipose tissue, which growth hormone. The receptor was named the growth hormone is somewhat paradoxical considering that the growth hormone secretagogue receptor (GHS-R). The natural ligand for the GHS- has the opposite effect. Overall, ghrelin seems to be one of

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