6 VIEWS & REVIEWS

Antitbrombotics - a tale m dog &Vet; mjdcm feed and ooinddence

The history of the development of antithrombotics is indeed a tale of stunning medical advances. Dr Richard Mueller and Dr Stephen Scheidt reviewed the discovery of anti platelet agents, anticoagulants and thrombolytics, compounds which helped to elucidate much basic science and provided medical research with an insight into not only antithrombotic processes, but procoagulant systems as well.

From marsh plants to modem surgery The most commonly used anti thrombotic agent,

aspirin, is also the oldest of this class of drugs. Hippocrates first recorded therapeutic benefits of willow bark extracts and other sources of salicylates 2400 years ago. He recommended chewing willow leaves for analgesia in childbirth and treated eye diseases with juice of the poplar tree.

In the centuries to follow, subsequent physicians would report potent antipyretic and anti-inflammatory actions of salicylates, but the agents' antiplatelet activity was not recognised until 1940. By a remarkable coincidence the histories of acetylsalicylic acid (ASA) and oral anticoagulants became intertwined, when Karl Link discovered that dicoumarol spontaneously breaks down into salicylic acid. By experimenting on himself, he found that ASA was a weak anticoagulant which reduced prothrombin activity, and published his findings in 1943. However, Link considered this to be a dangerous side effect rather than a therapeutic effect.

Current research is still attempting to define the optimal effective dose of ASA for a variety of anti thrombotic indications. Oddly, FDA approval is

, still lacking for the agent's use in primary prophylaxis of MI, acute MI and post-surgery, say Mueller and Scheidt.

Dog liver; pork gut and heparin Heparin was discovered in 1915 by Jay McLean,

searching for a pure procoagulant in dog liver and heart, but finding anticoagulants instead. McLean's insight and perseverance in pursuing this strange lead resulted in the discovery of heparin, which became standard treatment for a variety of thrombotic disorders in the 1940s. Heparin is now also under great scrutiny for its promise as a cellular growth factor modulator, and other diverse new properties of this complex glycosaminoglycan continue to be elucidated. As in the case of McLean's original animal source, current commercially available heparins are still prepared from beef lung or pork gut.

Oral anticoagulants - dues from sweet clover and chickenfeed

Around the tum of the century in rural US, the mysterious sweet clover disease caused cattle to develop fatal spontaneous bleeding, puzzling

26 Feb 1994 INPHARMA"'

veterinarians. Karl Link (an agricultural researcher at the time) found answers to the puzzle, when he was asked to develop a strain of sweet clover low in, or free of, coumarin, because cattle disdained its bitter taste. Link found the 'link' between sweet clover and the cattle disease by coincidence - after being supplied by a desperate farmer with a dead cow, a milk can containing blood that would not clot, and loolb of spoiled sweet clover. A pure crystalline haemorrhagic agent was detected. isolated from spoiled clover. and chickenfeed which had been processed to extract all sterols (and had also been associated with haemorrhagic chicken disease). The researcher investigated vitamin K in this context, showing that it completely reversed the actions of either spoiled clover or dicoumarol. However, the exact involvement of vitamin K in the mechanism of anticoagulants was not delineated until the 1970s. The newly discovered haemorrhagic agent.- named dicoumarol, was reported to the world in 1940.

Link later developed warfarin, initially as a rodenticide, and subsequently in the 1950s for therapeutic use in humans. Interestingly, the precise mechanism of action of warfarin was not elucidated until 1974.

Thrombolytics from Chinese hamsters and vampire bats?

These agents are relatively new clinical tools; however, their history reaches as far back as 1861, with a first report of the proteolytic activity of human urine.

Fundamental advances in general science at that time catalysed the development of thrombolytics, which are cofactors or secondary enzymes that activate endogenous fibrinolysis. All currently known thrombolytics are large proteins; however. their sources are diverse, for example: • streptokinase from bacterial cultures • urokinase from human kidney cell tissue cultures • alteplase (tissue-type plasminogen activator; TPA)

from recombinant DNA, derived from human melanoma cell lines and expressed in Chinese hamster ovary cell cultures. Recent research into new thrombolytics involves

modified or fibrin-antibody bound TPA with improved fibrin specificity, chimeric molecules combining TPA and prourokinase, and entirely novel agents such as vampire bat TPA and staphy lokinase.

In conclusion. the fascinating history of the development of antithrombotics seems to share a common theme of good fortune, coincidence and perseverance. and researchers rewarded by maintaining an open. sceptical and active mind.

Mueller RL. Scheidt S. History of drugs for thrombotic disease. Discovery. development, and directions for the future. Circulation 89: 432-449. Jan 1994

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