Ximelagatran
Encyclopedia
Ximelagatran is an anticoagulant
that has been investigated extensively as a replacement for warfarin
that would overcome the problematic dietary
, drug interaction
, and monitoring
issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca
announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity
(liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).
, was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of thrombin
. It is taken orally twice daily, and rapidly absorbed by the small intestine
. Ximelagatran is a prodrug
, being converted in vivo
to the active agent melagatran. This conversion takes place in the liver and many other tissues through dealkylation and dehydroxylation (replacing the ethyl
and hydroxyl
groups with hydrogen
).
and sometimes aspirin
and heparin
in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation
such as stroke. The efficacy of ximelagatran for these indications had been well documented.
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin
and heparin
, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time
(PTT), respectively. A disadvantage recognised early was the absence of an antidote
in case acute bleeding develops, while warfarin can be antagonised by vitamin K
and heparin by protamine sulfate
.
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
that has been investigated extensively as a replacement for warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
that would overcome the problematic dietary
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
, drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
, and monitoring
Therapeutic drug monitoring
- Background :Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed...
issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
(liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).
Method of action
Ximelagatran, a direct thrombin inhibitorDirect thrombin inhibitor
Direct thrombin inhibitors are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development...
, was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
. It is taken orally twice daily, and rapidly absorbed by the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
. Ximelagatran is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, being converted in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
to the active agent melagatran. This conversion takes place in the liver and many other tissues through dealkylation and dehydroxylation (replacing the ethyl
Ethyl group
In chemistry, an ethyl group is an alkyl substituent derived from ethane . It has the formula -C2H5 and is very often abbreviated -Et.Ethylation is the formation of a compound by introduction of the ethyl functional group, C2H5....
and hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
groups with hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
).
Uses
Ximelagatran was expected to replace warfarinWarfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
and sometimes aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
such as stroke. The efficacy of ximelagatran for these indications had been well documented.
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
and heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time
Partial thromboplastin time
The partial thromboplastin time or activated partial thromboplastin time is a performance indicator measuring the efficacy of both the "intrinsic" and the common coagulation pathways...
(PTT), respectively. A disadvantage recognised early was the absence of an antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
in case acute bleeding develops, while warfarin can be antagonised by vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
and heparin by protamine sulfate
Protamine sulfate
Protamine sulfate is a drug that reverses the anticoagulant effects of heparin by binding to it.Protamine was originally isolated from the sperm of salmon and other species of fish but is now produced primarily through recombinant biotechnology. It is a highly cationic peptide...
.