ABSTRACT
The oral direct thrombin inhibitor ximelagatran is the first oral anticoagulant since the introduction of the vitamin K antagonists in the early 1940s. A comparison of the discovery and early clinical development of the two classes of oral anticoagulants reveals some similarities but also several differences that illustrate the change in drug discovery over the last half century.
KEYWORDS
Ximelagatran - vitamin K antagonists - oral anticoagulation - oral direct thrombin inhibitors
REFERENCES
-
1 Owen C A. In: Nichols WL, Bowie EJW A History of Blood Coagulation. Rochester, MN; Mayo Foundation for Medical Education and Research 2001
-
2
Link K P.
The discovery of dicumarol and its sequels.
Circulation.
1959;
19
97-107
-
3
Segal J B, McNamara R L, Miller M R et al..
Prevention of thromboembolism in atrial fibrillation. A meta-analysis of trials of anticoagulants and antiplatelet drugs.
J Gen Intern Med.
2000;
15
56-67
-
4
Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E.
The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest.
2004;
126
204S-233S
-
5
Elg M, Gustafsson D, Carlsson S.
Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat.
Thromb Res.
1999;
94
187-197
-
6
Wittkowsky A K.
Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions.
Semin Vasc Med.
2003;
3
221-230
-
7
Gullov A L, Koefoed B G, Petersen P.
Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation.
Arch Intern Med.
1999;
159
1322-1328
-
8
Biverkningsnytt .
Rekordantal rapporter.
Lakartidningen.
1992;
90
2533-2534
-
9
Pirmohamed M, James S, Meakin S et al..
Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients.
BMJ.
2004;
329
15-19
-
10
Chiquette E, Amato M G, Bussey H I.
Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs.
Arch Intern Med.
1998;
158
1641-1647
-
11
Campbell H A, Smith W K, Roberts W L, Link K P.
Studies on the hemorrhagic sweet clover disease. II. The bioassay of hemorrhagic concentrates by following the prothrombin level in the plasma of rabbit blood.
J Biol Chem.
1941;
138
1-20
-
12
Campbell H A, Link K P.
Studies on the hemorrhagic sweet clover disease. IV. The isolation and crystallization of the hemorrhagic agent.
J Biol Chem.
1941;
138
21-33
-
13
Dale D U, Jaques L B.
Prevention of experimental thrombosis by dicoumarin.
Can Med Assoc J.
1942;
46
546-548
-
14
Thill C J, Stafford W T, Spooner M, Meyer O O.
Hemorrhagic agent 3,3′-methylene-bis (4-hydroxycoumarin); its effects in prevention of experimental thrombosis.
Proc Soc Exp Biol Med.
1943;
54
333
-
15
Bollman J L, Preston F W.
Effects of experimental administration of dicoumarin 3,3′-methylene-bis (4-hydroxycoumarin).
JAMA.
1942;
120
1021-1024
-
16
Bell R G, Sadowski J A, Matschiner J T.
Mechanism of action of warfarin. Warfarin and metabolism of vitamin K1.
Biochemistry.
1972;
11
1959-1961
-
17
Boyle M.
A case of apparent resistance of Rattus norvegicus to anticoagulant poisons.
Nature.
1960;
4749
519
-
18
Zimmermann A, Matschiner J T.
Biochemical basis of hereditary resistance to warfarin in the rat.
Biochem Pharmacol.
1974;
23
1033-1040
-
19
Li T, Chang C Y, Jin D Y, Lin P J, Khvorova A, Stafford D W.
Identification of the gene for vitamin K epoxide reductase.
Nature.
2004;
427
541-544
-
20
O'Reilly R A, Aggeler P M, Hoag M S, Leong L S, Kropatkin M L.
Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs. The first reported kindred.
N Engl J Med.
1964;
271
809-815
-
21
Rost S, Fregin A, Ivaskevicius V et al..
Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.
Nature.
2004;
427
537-541
-
22
Stenflo J.
Vitamin K and the biosynthesis of prothrombin. IV. Isolation of peptides containing prosthetic groups from normal prothrombin and the corresponding peptides from dicoumarol-induced prothrombin.
J Biol Chem.
1974;
249
5527-5535
-
23
Sadler J E.
Medicine: K is for koagulation.
Nature.
2004;
427
493-494
-
24
Lammle B, Griffin J H.
Formation of the fibrin clot: the balance of procoagulant and inhibitory factors.
Clin Haematol.
1985;
14
281-342
-
25
Mann K G.
Thrombin formation.
Chest.
2003;
124
4S-10S
-
26
Brass L F.
Thrombin and platelet activation.
Chest.
2003;
124
18S-25S
-
27
Narayanan S.
Multifunctional roles of thrombin.
Ann Clin Lab Sci.
1999;
29
275-280
-
28
Haycraft J B.
On the action of a secretion obtained from the medicinal leech on the coagulation of the blood.
Proc R Soc London.
1884;
36
478-487
-
29
Markwardt F.
The development of hirudin as an antithrombotic drug.
Thromb Res.
1994;
74
1-23
-
30
Maraganore J M, Bourdon P, Jablonski J, Ramachandran K L, Fenton J W.
Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin.
Biochemistry.
1990;
29
7095-7101
-
31
White H D, Chew D P.
Bivalirudin: an anticoagulant for acute coronary syndromes and coronary interventions.
Expert Opin Pharmacother.
2002;
3
777-788
-
32
Walenga J M.
An overview of the direct thrombin inhibitor argatroban.
Pathophysiol Haemost Thromb.
2002;
32(Suppl 3)
9-14
-
33
Gustafsson D, Bylund R, Antonsson T et al..
A new oral anticoagulant: the 50-year challenge.
Nat Rev Drug Discov.
2004;
3
649-659
-
34
Gustafsson D, Elg M.
The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a minireview.
Thromb Res.
2003;
109(Suppl 1)
9-15
-
35
Klement P, Carlsson S, Rak J et al..
The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.
J Thromb Haemost.
2003;
1
587-594
-
36
Eriksson U G, Bredberg U, Hoffmann K J et al..
Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans.
Drug Metab Dispos.
2003;
31
294-305
-
37
Gustafsson D, Nystrom J, Carlsson S et al..
The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.
Thromb Res.
2001;
101
171-181
-
38
Beaumont K, Webster R, Gardner I, Dack K.
Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist.
Curr Drug Metab.
2003;
4
461-485
-
39
Ettmayer P, Amidon G L, Clement B, Testa B.
Lessons learned from marketed and investigational prodrugs.
J Med Chem.
2004;
47
2393-2404
-
40 Clement B. Pharmaceutical preparations with an active principle containing modified amidin groups. (PCT Patent Application, Publication No. WO 95/01168) 2004
-
41
Müller T H, Weisenberger H, Brickl R, Narjes H, Himmelsbach F, Krause J.
Profound and sustained inhibition of platelet aggregation by Fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, Lefradafiban, in men.
Circulation.
1997;
96
1130-1138
-
42
Clement B, Lopian K.
Characterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester prodrug.
Drug Metab Dispos.
2003;
31
645-651
-
43 Halse M, Lunde P K, Norway . In: Wardell WM Controlling the Use of Therapeutic Drugs, vol 2. Washington, DC; American Enterprise Institute 1978: 187-210
-
44
Lee P R, Herzstein J.
International drug regulation.
Annu Rev Public Health.
1986;
7
217-235
-
45 Hutt P. The legal requirement that drugs be proved safe and effective before their use. In: Lasagna L Controversies in Therapeutics Berlin; Arzeneimittel-Informations-Dienst GmbH 1980: 495-506
-
46
Allen E V, Baker N W, Waugh J M.
A preparation from spoiled sweet clover [3,3′-methylene-bis-(4-hydroxy-coumarin)] which prolongs coagulation and prothrombin time of the blood: a clinical study.
JAMA.
1942;
120
1009-1015
-
47
Lehmann J.
Historical notes on the early development of anticoagulant therapy with dicumarol in Sweden.
Circulation.
1959;
19
122-126
-
48
Laurence D R.
Clinical pharmacology.
Lancet.
1964;
13
1173-1176
-
49
Dorani H, Schützer K, Sarich T, Wall U, Ohlsson L, Eriksson U G.
The pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran when administered with erythromycin.
Pathophysiol Haemost Thromb.
2004;
33(Suppl 2)
99
-
50
Flint A.
A contribution toward the natural history of articular rheumatism; consisting of a report of thirteen cases treated solely with palliative measures.
Am J Med Sci.
1863;
46
17-36
-
51 Box J F. R.A. Fisher: The Life of a Scientist. New York; Wiley 1978
-
52
Medical Research Council .
Streptomycin treatment of pulmonary tuberculosis.
BMJ.
1948;
ii
769-782
-
53
Butt H R, Allen E V, Bollman J L.
A preparation from spoiled sweet clover [3,3′-methylene-bis-(4-hydroxycoumarin)] which prolongs coagulation and prothrombin time of the blood: preliminary reports of experimental and clinical studies.
Proc Staff Meet Mayo Clin.
1941;
16
388-395
-
54
Wright I S, Prandoni A.
The dicoumarin 3,3′-methylene-bis-(4-hydroxycoumarin): its pharmacological and therapeutic action in man.
JAMA.
1942;
120
1015-1021
-
55
Butsch W L, Stewart J D.
Clinical experiences with dicumarin 3,3′-methylene-bis-(4-hydroxycoumarin).
JAMA.
1942;
120
1025-1026
-
56
Lehmann J.
On experimental hypo-prothrombinemia produced by methylene-bis-(hydroxycoumarin) and its use in the treatment of thrombosis.
Lancet.
1942;
I
318
-
57
Eriksson B I, Agnelli G, Cohen A T et al..
Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement.
Thromb Haemost.
2003;
89
288-296
-
58
Eriksson B I, Agnelli G, Cohen A T et al..
The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study.
J Thromb Haemost.
2003;
1
2490-2496
-
59
Francis C W, Berkowitz S D, Comp P C et al..
Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement.
N Engl J Med.
2003;
349
1703-1712
-
60
Eriksson B I, Bergqvist D, Kälebo P et al..
Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial.
Lancet.
2002;
360
1441-1447
-
61
Olsson S B.
Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial.
Lancet.
2003;
362
1691-1698
-
62
Albers G W, Diener H C, Frison L et al..
Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.
JAMA.
2005;
293
690-698
-
63
Fiessinger J N, Huisman M V, Davidson B L et al..
Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.
JAMA.
2005;
293
681-689
-
64
Schulman S, Wåhlander K, Lundström T, Clason S B, Eriksson H. THRIVE III Investigators .
Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.
N Engl J Med.
2003;
349
1713-1721
-
65
Wallentin L, Wilcox R G, Weaver W D et al..
Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.
Lancet.
2003;
362
789-797
-
66
Colwell C, Mouret P.
Ximelagatran for the prevention of venous thromboembolism following elective hip or knee replacement surgery.
Semin Vasc Med.
2005;
5
266-275
-
67
Huisman M, Bounameaux H.
Treating patients with venous thromboembolism: initial strategies and long-term secondary prevention.
Semin Vasc Med.
2005;
5
276-284
-
68
Olsson S B, Halperin J L.
Prevention of stroke in patients with atrial fibrillation.
Semin Vasc Med.
2005;
5
285-292
-
69
Wallentin L.
Prevention of cardiovascular events after acute coronary syndrome.
Semin Vasc Med.
2005;
5
293-300
David GustafssonM.D. Ph.D.
Department of Cardiovascular Pharmacology, AstraZeneca R&D
Mölndal, S-431 83, Sweden
