Historical lessons in translational medicine: cyclooxygenase inhibition and P2Y12 antagonism.

The development of drugs that inhibit platelets has been driven by a combination of clinical insights, fundamental science, and sheer luck. The process has evolved as the days of stumbling on therapeutic gems, such as aspirin, have long passed and have been replaced by an arduous process in which a drug is designed to target a specific protein implicated in a well-characterized pathophysiological process, or so we would like to believe. The development of antiplatelet therapy illustrates the importance of understanding the mechanisms of disease and the pharmacology of the compounds we develop, coupled with careful clinical experimentation and observation and, yes, still, a fair bit of luck.

Clinical use of aspirin in ischemic heart disease: past, present and future.

Aspirin is an antiplatelet drug, inhibiting the cyclooxygenase activity of platelet prostaglandin H synthase-1 and almost complete suppressing platelet capacity to generate the prothrombotic and proatherogenic thromboxane A2. Antiplatelet therapy with aspirin reduces the risk of serious vascular events by about a quarter in patients who are at high risk because they already have occlusive vascular disease. However, the inhibition of thromboxane-dependent platelet function by aspirin is effective for the prevention of thrombosis, but is also associated with excess bleeding, although the absolute increase in major gastrointestinal or other major extracranial bleeds is an order of magnitude smaller. For secondary prevention of vascular events, the benefits of aspirin therapy substantially exceed the risks. Therefore, aspirin is a cornerstone of antithrombotic therapy in acute coronary syndromes, in chronic ischemic heart disease and in percutaneous coronary intervention. On the other hand, the role of aspirin in primary prevention remains uncertain and it is still debated, because the absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis and the reduction in vascular events needs to be weighed against any increase in major bleeds. Future data from ongoing studies will help us to identify people at high vascular risk who take advantage from aspirin therapy for primary prevention or will indicate if specific category of high risk patients, like patients with diabetes, could be better protected from an increase in the frequency of aspirin administration.

50th anniversary of the discovery of ibuprofen: an interview with Dr Stewart Adams.

2011 marks the 50th anniversary of the discovery of ibuprofen. This article is a focus on the personal reflections and career of Dr Stewart Adams OBE, the scientist whose research lead to the discovery of the cyclooxygenase inhibitor. When Dr Adams discovered ibuprofen, he was working as a pharmacologist in the Research Department for the Boots Pure Drug Company Ltd. Dr Adams was assigned to work on rheumatoid arthritis (RA) and chose in 1953 to search for a drug that would be effective in RA but would not be a corticosteroid. He was one of the first workers in this field that later became known as NSAIDs (Non-Steroidal Anti Inflammatory Drugs). In 1961, Dr Adams with John Nicholson, the organic chemist, filed a patent for the compound 2-(4-isobutylphenyl) propionic acid, later to become one of the most successful NSAIDs in the modern world, ibuprofen. In this article, Dr Adams gives his modest insight into the early stages and initial observations which led to this world-wide success.

[A short history of anti-rheumatic therapy. III. Non steroidal anti-inflammatory drugs]. / Piccola storia della terapia antireumatica. III. I farmaci antiflogistici non steroidei.

The chemical advances of the 20th century led to the synthesis of non steroidal anti-inflammatory drugs (NSAIDs), beginning from phenylbutazone and indomethacin and continuing with other new drugs, including ibuprofen, diclofenac, naproxen, piroxicam and, more recently, the highly selective COX-2 inhibitors (coxibs). This progress derived from the discovery of the mechanism of action of these drugs: the inhibition of synthesis of prostaglandins due to the cycloxigenase enzyme system, according to the experimental contributions of John R. Vane.

COX-2 chronology.

The role of selective cyclooxygenase (COX)-2 inhibitors in medical practice has become controversial since evidence emerged that their use is associated with an increased risk of myocardial infarction. Selective COX-2 inhibitors were seen as successor to non-selective non-steroidal anti-inflammatory drugs, in turn successors to aspirin. The importance of pain relief means that such drugs have always attracted attention. The fact that they work through inhibition of cyclooxygenase, are widespread, and have multiple effects also means that adverse effects that were unanticipated (even though predictable) have always emerged. In this paper I therefore present an historical perspective so that the lessons of the past may be applied to the present.

Arthropathy in art and the history of pain management--through the centuries to cyclooxygenase-2 inhibitors.

Preserved human remains, artefacts and works of art contain records of the existence and prevalence of arthropathies, even in the absence of medical texts or formal written accounts, although these also exist for some epochs and cultures. Example objects from the Museum of Medical History in Brussels have been used to illustrate the magnitude of the burden of pain throughout the ages and how rheumatic diseases have indiscriminately afflicted people regardless of their positions in life or occupations. These include both osteoarthritis (OA) and rheumatoid arthritis (RA), as well as the seemingly ubiquitous gout and various skeletal deformities. Adequate pain management has been severely hampered, historically, by obstacles to a comprehensive and systematic classification of diseases posed by the social, religious and philosophical mores of the time, which made differential diagnosis almost impossible to achieve. However, despite this shortcoming, serendipitous events meant that precursors of modern medicines, such as willow bark extracts, were in routine use from the earliest recorded times. It has taken several millennia, however, before empirical treatment has given way to pharmacological rationale. The first clinically acceptable synthetic derivative of the active principle in willow, aspirin, became available only at the turn of the nineteenth century, while non-steroidal anti-inflammatory drugs (NSAIDs) did not arrive on the market until some 60 yr later. At the cusp of the twentieth and twenty-first centuries, physicians have a wider choice of analgesics available than ever before, including the cyclooxygenase-2 inhibitors, which represent the first major advance in NSAID development since the synthesis of the latter compounds themselves.

Tracing the origins of COX-2 inhibitors' structures.

This review traces the origins of the chemical structure of the cyclooxygenase inhibitors celecoxib and rofecoxib. Early results from the search for non-steroid estrogens led to the triaryl-ethylenes such as chlortrianisene. A congener that incorporated a water-solubilizing basic ether grouping unexpectedly led to an estrogen antagonist and eventually the drug clomiphene. Elaboration of the structure gave the widely used drug used to treat breast cancer tamoxifen. Cyclized analogues such as nafoxidine showed equivalent activity but were not pursued. Later elaboration of those structures gave the now-marketed drug raloxifene. An indole analogue, indoxole, (2,3-dianisylindole) surprisingly showed anti-inflammatory activity. An analogue program designed to reduce photosensitivity from that compound eventually led to the discovery that the indole ring could be replaced by a simple thiazole, This resulted in the experimental cyclooxygenase inhibitor itazagrel. This compound incorporates many of the structural features found in celecoxib.

[Aspirin throughout the ages: a historical review]. / L'aspirine à travers les siècles: rappel historique.

Even at the beginning of the next millennium, aspirin will still offer surprises. Its relatively young pharmacological history compares with the early use of salicylate-containing plants since antiquity. The Assyrians and the Egyptians were aware of the analgesic effects of a decoction of myrtle or willow leaves for joint pains. Hippocrates recommended chewing willow leaves for analgesia in childbirth and the Reverend Edward Stones is acknowledged as the first person to scientifically define the beneficial antipyretic effects of willow bark. At the beginning of the 19th century salicin was extracted from willow bark and purified. Although a French chemist, Charles Gerhardt, was the first to synthesize aspirin in a crude form, the compound was ignored, and later studied by Felix Hoffmann. He reportedly tested the rediscovered agent on himself and on his father, who suffered from chronic arthritis--a legend was born and Bayer Laboratories rose to the heights of the pharmacological world. First used for its potent analgesic, antipyretic and anti-inflammatory properties, aspirin was successfully used as an antithrombotic agent. Sir John Vane elucidated aspirin's active mechanism as an inhibitor of prostaglandin synthetase and received the Nobel Price in Medicine for this work in 1982. Two isoform of cyclooxygenase (COX-1 and COX-2) have now been identified, each possessing similar activities, but differing in characteristic tissue expression. The cox enzyme is now a target of drug interventions against the inflammatory process. After two centuries of evaluation, aspirin remains topical, and new therapeutic indications are increasingly being studied.

[Aspirin and hemostasis]. / Aspirine et hémostase.

Aspirin is one hundred years old, though its use has clearly evolved during the last 25 years. Identifying its action mechanism has allowed us to better understand the antithrombotic impact. Prostaglandin H synthetase (PGHS) is a bifunctional enzyme with cyclooxygenase and peroxydase activities. There are two isoforms: constitutive PGHS-1 and inducible PGHS-2. Aspirin irreversive acetylates the platelet cyclooxygenase involved in the formation of thromboxane A2, a powerful proaggregating agent and vasoconstrictor. More than 95% of inhibition of this synthesis takes place in two to three days using very weak doses of aspirin, on the order of 30 to 50 mg per day. Under some circumstances, this inhibition requires higher dosages. Certain clinical and biological circumstances could lead to a resistance to aspirin, making a readjustment of doses and sometimes complementary explorations necessary. The ISIS 2 study showed in an apparently irrefutable way the entry of aspirin into the antithrombotics arsenal, with a significant risk reduction of vascular death and recurrence of infarctus. Numerous studies have confirmed this efficacy. Consensus studies are based on information showing total coherence between the dose necessary to acetylate the enzyme to inhibit thromboxane A2 platelet production and the clinical antithrombotic effect. Aspirin seems to have a secure place, and it begins the third millennium in relative peace with new extra-platelet potentialities outside the framework of hemostasis and thrombosis.