|
Page: Discovery
Main article
| Home > Circulation Problems > Discovery |
Hippocrates, a Greek physician, wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers. This remedy is also mentioned in texts from ancient Sumer, Lebanon, and Assyria. The Cherokee and other Native Americans used an infusion of the bark for fever and other medicinal purposes for centuries. The medicinal part of the plant is the inner bark and was used as a pain reliever for a variety of ailments. The Reverend Edward Stone, a vicar from Chipping Norton, Oxfordshire, England, noted in 1763 that the bark of the willow was effective in reducing a fever.
The active extract of the bark, called salicin, after the Latin name for the white willow (Salix alba), was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist. Piria was able to convert the substance into a sugar and a second component, which on oxidation becomes salicylic acid.
Salicylic acid was also isolated from the herb meadowsweet (Filipendula ulmaria, formerly classified as Spiraea ulmaria) by German researchers in 1839. While their extract was somewhat effective, it also caused digestive problems such as gastric irritation and bleeding and diarrhea, and even death when consumed in high doses. In 1853, a French chemist named Charles Frederic Gerhardt neutralized salicylic acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetosalicylic anhydride. Gerhardt's product worked, but he had no desire to market it and abandoned his discovery. In 1897, researcher Arthur Eichengru"n and Felix Hoffmann, a research assistant at Friedrich Bayer & Co. in Germany, derived one of the hydroxyl functional groups in salicylic acid with an acetyl group (forming acetylsalicylic acid, an acetyl ester). This thereby greatly reduced the negative effects caused by the free phenolic group of salicylic acid. When in the body, the ester (aspirin) is hydrolyzed to free the active drug. This was the first synthetic drug, not a copy of something that existed in nature, and the start of the pharmaceuticals industry.
Hoffmann made some of the formula and gave it to his father, who was suffering from the pain of arthritis and could not stand the side-effects of salicylic acid. With good results, he then convinced Bayer to market the new wonder drug. 'Aspirin' was patented on March 6, 1899. It was marketed alongside another of Hoffmann's products, an acetylated synthetic of morphine called 'Heroin' that he invented 11 days after aspirin. Heroin was initially the more successful of the two painkillers and it was common belief that it was healthier than aspirin. But, as heroin's shortcoming of addictiveness became more obvious, aspirin stepped to the forefront. Aspirin was originally sold as a powder (still the preferred form in many European countries) and was an instant success; in 1915, Bayer introduced aspirin tablets.
Several claims to invention of acetylsalicylic acid have arisen. Acetylsalicylic acid was already being manufactured by the Chemische Fabrik von Heyden Company in 1897, although without a brand name. Arthur Eichengru"n claimed in 1949 that he planned and directed the synthesis of aspirin while Hoffmann's role was restricted to the initial lab synthesis using Eichengru"n's process. In 1999, Walter Sneader of the Department of Pharmaceutical Sciences at the University of Strathclyde in Glasgow reexamined the case and agreed with Eichengru"n's account. Bayer continues to recognize Felix Hoffmann as aspirin's official inventor. Despite its argued origin, Bayer's marketing was responsible for bringing it to the world.
It was not until the 1970s that the mechanism of action of aspirin and similar drugs called NSAIDs was elucidated (see below).
Aspirin
In 1971, the British pharmacologist, John Robert Vane, who was then employed by the Royal College of Surgeons in London, showed that aspirin had suppressed the production of prostaglandins and thromboxanes. For this piece of research he was awarded both a Nobel Prize in Physiology or Medicine in 1982 and a knighthood.
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its non-competitive and irreversible inhibition of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.
Prostaglandins are local hormones (paracrine) produced in the body and have diverse effects in the body, including but not limited to transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side-effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.
There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the hope for reduction of gastrointestinal side-effects.
However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.
Furthermore, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and anti-inflammatory properties:
* It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. In short, aspirin buffers and transports the protons. (Note: This effect in high doses of aspirin actually causes fever due to the heat released from the electron transport chain, instead of its normal antipyretic action.)
* It induces the formation of NO-radicals in the body that enable the white blood cells (leukocytes) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005.
More recent data suggest that salicylic acid and its derivatives will modulate NF?B signaling. NF?B is a transcription factor complex that plays a central role in many biological processes, including inflammation.
• Circulation Problems - Aspirin...
• Circulation Problems - Aspirin as Genericized Trademark...
• Circulation Problems - Discovery...
• Circulation Problems - Synthesis of Aspirin...
• Circulation Problems - Mechanism of Action...
• Circulation Problems - Indications...
• Circulation Problems - Toxicity of Low-dose Aspirin...
• Circulation Problems - Contraindications and Warnings...
• Circulation Problems - Common side-effects...
• Circulation Problems - Interactions...
• Circulation Problems - Overdose...
• Circulation Problems - Research Into Cancer Prevention...
• Circulation Problems - Aspirin in Pets...
|
|
Important notice:
The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other
qualified health provider with any questions you may have regarding a medical condition.
|