The whole truth about aspirin: from willow bark to the Nobel Prize past heroin. How did aspirin come about?
Aspirin is the colloquial name for acetylsalicylic acid. Today this drug is included in the list of essential medicines of the World Health Organization (WHO) and in the list of vital and essential medicines in Russia.
But in the pre-aspirin era, most diseases had no treatment and were often referred to in one word - “fever”, and only not always effective and far from fast-acting herbal decoctions and expensive opiates could alleviate suffering and relieve pain.
willow bark
Only at the end of the 18th century was salicin discovered - the element responsible for the therapeutic effects of willow bark decoction, which had a powerful antipyretic effect. But salicin was also expensive due to the complexity of production, and salicylic acid worked worse and had a strong side effect - it destroyed the patient’s gastrointestinal tract.
Thus, scientists were faced with the task of creating a universal remedy for fever and pain, the cost of which would be affordable for many.Acetylsalicylic acid was first synthesized by a French scientist Charles Frederic Gerard in 1853, the same willow tree bark served as the basis. But acetylsalicylic acid in a form suitable for medical use was created in Bayer laboratories. August 10, 1897 German chemist Felix Hoffmann told his colleagues - Arthur Eichengrün, doctor Karl Duisberg and the professor Heinrich Dreser, who headed the company’s research department, said that he managed to obtain acetylsalicylic acid.
Clinical trials lasted a year and a half. In fact, aspirin became an official trademark of Bayer on March 6, 1899.
According to the laws of the German Empire at the time, chemical compounds were not subject to patenting, but a unique trademark could be registered. Therefore, the word “aspirin” was invented to name the new drug. "A" was taken from "acetyl", "spir" from the Latin name for the herb meadowsweet - spirea, rich in salicin, "in" - as a typical ending for a word denoting a drug.
At first, aspirin was sold in powder form, and since 1904 - in tablet form, and since 1915 - without a prescription. Aspirin, being inexpensive, effective and relatively harmless, quickly became the most popular painkiller.
Stories and destinies
Until the 1930s, it was believed that great medicine was the fruit of the collective work of “Bayer specialists.” But historical justice is that the discovery of Felix Hoffmann was based on the work of predecessor scientists - the Frenchman Charles Gerhardt and an Englishman Alder Wright. After the triumphant discovery of aspirin, Hoffman worked for Bayer all his life. The fate of his boss Heinrich Dreser was sadder.
Working on the process of converting salicylic acid into acetylsalicylic acid, Hoffmann conducted experiments on the acylation of morphine, resulting in medicinal heroin. It was intended to be used as a strong pain reliever, but the side effects of heroin use became immediately apparent. Despite this, it was Heinrich Dreser who became the first official heroin addict, popularizer of the new drug and its first victim: he died of cardiac arrest in 1924.Arthur Eichengrün went to a concentration camp in 1944, and 5 years later, before his death, he published an article dedicated to the 50th anniversary of aspirin, in which he attributed the invention of aspirin to himself. The debate about who exactly was the real inventor of aspirin did not subside for a long time after the publication of this article.
From fever and pain, for the heart and for children
Initially, only the antipyretic effect of aspirin was known, but later its analgesic and anti-inflammatory properties were discovered. After World War II, Californian physician Lawrence Craven experimentally discovered that aspirin significantly reduced the risk of heart disease. Today, most aspirin is used for precisely this purpose - to prevent cardiovascular diseases.
In 1952, a gentle concentration of baby aspirin was introduced, and in 1969, aspirin tablets were included in the first-aid kits of Apollo astronauts.Research activity around the properties of aspirin continues to this day. Thus, according to research by Professor Peter Rothwell from the University of Oxford, regular intake of acetylsalicylic acid reduces the 20-year risk of developing prostate cancer by 10%, lung cancer by 30%, intestinal cancer by 40%, and cancer of the esophagus and throat by 60%. .
According to researchers from the University of Alabama (USA) and the University of Ottawa (Canada), aspirin also reduces the risk of developing liver cancer. Those subjects who took aspirin for 10 years were less likely to suffer from hepatocellular carcinoma and were 45% less likely to die from chronic liver disease.
Scientists from the University of Western Australia in Perth say aspirin helps older people fight depression. And Dutch specialists from the Institute of Neuroscience and the Academic Medical Center have found that taking aspirin daily to prevent heart disease is fraught with vision loss for older people. The risk is doubled compared to those who do not take aspirin. But the benefits of aspirin in preventing heart disease are considered more significant than the harm it causes to the eyes.
Instructions for use
Today, aspirin is used as an antipyretic and analgesic, as a means of preventing heart attacks and thrombosis, in the complex treatment of certain diseases, for example in gynecology. Aspirin is widely used to combat hangover symptoms.
Safe daily dose of aspirin: 4 g per day. You can take the drug only after meals and wash it down with enough water.
But aspirin should never be used uncontrolled and without a doctor’s prescription. An overdose leads to severe pathologies of the kidneys, brain, lungs and liver; the first symptoms of an overdose are sweating, tinnitus and hearing loss, swelling, skin and other allergic reactions. Taking aspirin daily can cause gastrointestinal or even cerebral bleeding.
Aspirin(acetylsalicylic acid) is a salicylate drug that is often used as an analgesic to relieve minor pain and ailments, as an antipyretic to reduce fever, and as an anti-inflammatory drug. Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane, which binds platelet molecules together under normal circumstances to create a patch on damaged blood vessel walls. Because the platelet patch can become too large and also block blood flow, both locally and downstream, aspirin is also used long-term in low dosage to prevent heart attacks, strokes, and blood clots in people in the group. high risk of blood clots. In addition, it has been found that low-dose aspirin can be given immediately after a heart attack to reduce the risk of heart tissue death or recurrent myocardial infarction. In addition, it may be effective in preventing certain types of cancer, especially colorectal cancer.
...used as a non-addictive alternative to drugs. Among the best-known representatives of this class of drugs are ibuprofen and naproxen, which are available without a prescription in most countries. Paracetamol (acetaminophen) is generally not considered an NSAID because...The main side effects of aspirin are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially at high dosages. For children and adolescents, it is not recommended in case of flu-like symptoms or viral illnesses due to the risk of Reye's syndrome.
Aspirin is part of a group of medications called nonsteroidal anti-inflammatory drugs (NSAIDs), but has a different mechanism of action than most other NSAIDs. Although it and other drugs with a similar structure are called salicylates, have similar effects to other NSAIDs (antipyretic, anti-inflammatory, analgesic) and inhibit the same enzyme cyclooxygenase (COX), aspirin (other than other salicylates) does this in an irreversible manner and, unlike others, affects more on the COX-1 variant than the COX-2 variant of the enzyme.
The active ingredient in aspirin was first discovered from willow bark in 1763 by Edward Stone of Wadham College, Oxford University. He discovered salicylic acid, an active metabolite of aspirin. Aspirin was first synthesized in 1897 by chemist Felix Hoffmann with the German company Bayer. Aspirin is among the most widely used drugs in the world, with an estimated 40,000 tons consumed each year. In countries where aspirin is a registered trademark of Bayer, the generic term is acetylsalicylic acid (ASA). It is included in the WHO List of Essential Medicines, a list of the most important medicines needed in a basic healthcare system.
Aspirin appears to provide little benefit for people with a reduced risk of heart attack or stroke, such as those without a history of them or with pre-existing conditions. This is called primary prevention. Some studies recommended it on a case-by-case basis, while others suggested that the risks of other events, such as gastrointestinal bleeding, were significant enough to outweigh any potential benefits and recommended against using aspirin for primary prevention entirely.
The use of the drug for prevention is complicated by the phenomenon of aspirin resistance. For patients with resistance, the drug's effectiveness is reduced, which may lead to an increased risk of stroke. Some authors have proposed trial regimens to identify patients who are resistant to aspirin or other antithrombotic agents (eg, clopidogrel).
Aspirin has also been proposed as a component in a multidrug for the prevention of cardiovascular diseases.
Postoperative period
The US Agency for Healthcare Research and Quality guidelines recommend taking aspirin indefinitely after percutaneous coronary interventions (PCI), such as coronary artery stent placement. It is often used in combination with an ADP receptor inhibitor, such as clopidogrel, prasugrel or ticagrelor, to prevent blood clots. This is called dual antiplatelet therapy (DAPT). US and European Union guidelines disagree somewhat on the timing and indications for which this combination therapy should be continued after surgery. US guidelines recommend DAPT for at least 12 months after drug-eluting stent placement, while EU guidelines recommend 6–12 months. However, they agree that aspirin can be continued indefinitely after completion of DAPT.
Cancer Prevention
Aspirin overdose
There are acute and chronic aspirin overdose. When we talk about acute poisoning, we mean that one large dose was taken. In the case of chronic poisoning, we are talking about taking doses higher than usual over a certain period of time. The mortality rate for acute overdose is 2%. Chronic overdose is more likely to be fatal, with a mortality rate of 25%. In children, chronic overdose can be particularly severe. Toxicity is treated through a number of potential treatments, including activated charcoal, intravenous dextrose and saline, sodium bicarbonate, and dialysis. The diagnosis of poisoning usually involves measuring plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma levels of salicylate generally range from 30-100 mg/L after usual therapeutic doses, 50-300 mg/L in patients taking high doses, and 700-1400 mg/L after acute overdose. Salicylate is also produced by exposure to bismuth subsalicylate, methyl salicylate, and sodium salicylate.
Aspirin interactions
Aspirin is known to interact with other drugs. For example, acetazolamide and ammonium chloride are known to enhance the effects of salicylate intoxication, and alcohol also increases gastrointestinal bleeding mediated by these types of drugs. Aspirin is known to displace a number of drugs from protein binding sites in the blood, including the antidiabetic drugs tolbutamide and chlorpropamide, warfarin, methotrexate, phenytoin, probenecid, valproic acid (as well as interfering with beta-oxidation, an important part of valproate metabolism), and other NSAIDs. Corticosteroids may also decrease aspirin concentrations. Ibuprofen may antagonize its antiplatelet effects used for cardioprotection and stroke prevention. The pharmacological activity of spironolactone can be reduced by administration of aspirin, which is known to compete with penicillin G for renal tubular secretion. In addition, it may inhibit the absorption of vitamin C.
Chemical properties
Aspirin quickly decomposes in solutions of acetates or ammonium acetate, citrates, carbonates or hydroxides of alkali metals. It is stable in dry air, but gradually hydrolyzes in contact with moisture into acetic and salicylic acids. In a solution with alkalis, hydrolysis proceeds quickly, and the resulting transparent solutions can consist entirely of acetate and salicylate.
Physical properties
Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, slightly acidic substance with a melting point of 136°C and a boiling point of 140°C. Its acid dissociation constant (pKa) is 3.5 at 25°C.
Synthesis
The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is treated with acetic anhydride, a derivative of the acid, resulting in a chemical reaction in which the hydroxyl group of salicylic acid is transformed into an ester group (R-OH → R-OCOCH3). This reaction produces aspirin and acetic acid, which is considered a byproduct of this process. Sulfuric acid (and sometimes phosphoric acid) is almost always used in small quantities as a catalyst. Typically, this method is used in student teaching laboratories.
Products containing high concentrations of aspirin often smell like vinegar because it can degrade through hydrolysis under humid conditions, producing salicylic and acetic acids.
Polymorphism
In the development of pharmaceutical ingredients, polymorphism, that is, the ability of a substance to form multiple crystal structures, plays an important role. Many drugs receive regulatory approval for only one crystalline form or polymorph. For a long time, only one crystal structure of aspirin was known. Since 1960, it has been suspected that it may have a second crystalline form. The elusive second polymorph was first discovered by Vishweshwar and colleagues in 2005, and fine structural details were determined by Bond et al. After attempting to cocrystallize aspirin and levetiracetam from hot acetonitrile, a new type of crystal was discovered. Form II is the only one stable at 100 K and transforms into form I at ambient temperature. The two salicylic molecules in unambiguous Form I form centrosymmetric dimers via acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds, and each salicylic molecule in the newly reported Form II forms identical hydrogen bonds with two neighboring molecules instead of one. With respect to hydrogen bonds formed by carboxylic acid groups, both polymorphs form identical dimeric structures.
Mechanism of action of aspirin
In 1971 D.R. Vane, a British pharmacologist who later worked at the Royal College of Surgeons of London, discovered that aspirin suppressed the production of prostaglandins and thromboxanes. For this discovery he was awarded the Nobel Prize in Physiology or Medicine in 1982 together with S.K. Bergstrom and B.I. Samuelson. In 1984 he became the holder of the title of Knight Bachelor.
Inhibition of prostaglandins and thromboxanes
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the enzyme cyclooxygenase (COX; formally known as prostaglandin endoperoxide synthase, PTGS), required for prostaglandin and thromboxane synthesis. Aspirin acts as an acylating agent, where the acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme. This makes it different from other NSAIDs (eg, diclofenac and ibuprofen), which are reversible inhibitors.
Low doses of the drug irreversibly block the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation during the life of the affected platelets (8-9 days). This antithrombotic property makes aspirin useful in reducing the incidence of heart attacks. A dose of 40 mg per day was able to inhibit most of the maximal release of acutely provoked thromboxane A2, although prostaglandin I2 synthesis was slightly affected. However, to achieve further inhibition, doses of aspirin must be higher.
Prostaglandins, local hormones produced in the body, have a variety of effects, including transmitting pain information to the brain, modulating the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets, which form blood clots. Heart attacks are caused primarily by blood clots, and low-dose aspirin is considered an effective medical intervention for acute myocardial infarction. An undesirable side effect of the drug's antithrombotic effect is that it may cause excessive bleeding.
Inhibition of COX-1 and COX-2
There are at least two different types of cyclooxygenase: COX-1 and COX-2. The action of aspirin is aimed at irreversibly inhibiting COX-1 and changing the enzymatic activity of COX-2. Typically, COX-2 produces prostanoids, most of which are proinflammatory. Aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. New NSAID drugs, the COX-2 inhibitors (coxibs), have been developed to inhibit only PTGS2, with the goal of reducing the incidence of gastrointestinal side effects.
However, some new COX-2 inhibitors, such as rofecoxib (Vioxx), were withdrawn recently after evidence emerged that PTGS2 inhibitors increase the risk of heart attack and stroke. Endothelial cells lining microvessels in the body presumably secrete PTGS2, and, through selective inhibition of PTGS2, prostaglandin (specifically PGI2; prostacyclin) production is suppressed relative to thromboxane levels, since PTGS1 in platelets remains intact. Thus, the protective anti-clotting effect of PGI2 is removed, increasing the risk of blood clots and associated heart attacks and other circulatory problems. Because platelets do not have DNA, they are unable to synthesize new PTGS, since aspirin irreversibly inhibits the enzyme, an important difference from reversible inhibitors.
Additional mechanisms
Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative phosphorylation in cartilage (and liver) mitochondria by diffusion from the interior of the membrane as a proton carrier back into the mitochondrial matrix, where it ionizes again to release protons. In short, aspirin buffers and transports protons. When high doses are administered, it can actually cause fever due to the heat generated from the electron transport chain, in contrast to its antipyretic effect observed at lower doses. In addition, aspirin causes the formation of NO radicals in the body, which in mice had an independent mechanism to reduce inflammation. This resulted in decreased leukocyte adhesion, an important step in the immune response to infections. Currently, however, there is insufficient evidence to suggest that aspirin helps fight infection. More recent data also suggest that salicylic acid and its derivatives modulate signaling through NF-kB. NF-κB, a transcription factor complex, plays a central role in many biological processes, including inflammation.
Aspirin is easily broken down in the body into salicylic acid, which itself has anti-inflammatory, antipyretic and analgesic effects. In 2012, salicylic acid was found to activate AMP-activated protein kinase, and this has been proposed as a possible explanation for some of the effects of both salicylic acid and aspirin. The acetyl part of the drug molecule is not without its own purposes. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Recent studies have shown that aspirin is able to acetylate several other targets in addition to COX isoenzymes. These acetylation reactions may explain its many hitherto unexplained effects.
Hypothalamic-pituitary-adrenal action
Like other drugs that affect prostaglandin synthesis, aspirin has profound effects on the pituitary gland, which indirectly affects a number of other hormones and physiological functions. Direct effects were observed on growth hormone, prolactin and TSH (with corresponding effects on T3 and T4). Aspirin reduces the effects of vasopressin and enhances the effects of naloxone on ACTH and cortisol secretion in the hypothalamic-pituitary-adrenal (HPA) axis, which is thought to occur through interactions with endogenous prostaglandins and their role in regulating the HPA axis.
Pharmacokinetics of aspirin
Salicylic acid is a weak acid and very little of it ionizes in the stomach after oral administration. Acetylsalicylic acid is poorly soluble in acidic gastric conditions, which may delay the absorption of large doses for 8-24 hours. The increased pH and larger surface area of the small intestine causes aspirin to be absorbed more quickly into the small intestine, which in turn allows more salicylate to dissolve. Due to this solubility problem, however, it is absorbed much more slowly in overdose, and plasma concentrations may continue to rise for up to 24 hours after administration.
About 50-80% of salicylic acid in the blood is bound to the albumin protein, while the rest remains in an active, ionized state; protein binding is concentration dependent. Saturation of binding sites results in more free salicylate and increased toxicity. The volume of distribution is 0.1-0.2 l/g. Due to acidosis, the volume of distribution increases due to increased penetration of salicylates into tissues.
Up to 80% of therapeutic doses of salicylic acid are metabolized in the liver. Combined with glycine it forms salicyluric acid, and with glucuronic acid it forms salicylic acyl and phenolic glucuronide. These metabolic pathways have only limited capabilities. Salicylic acid is also hydroxylated to gentisic acid in small amounts. At high doses of salicylate, the kinetics switch from first order to zero order as metabolic pathways become saturated and renal excretion becomes increasingly important.
Salicylates are excreted from the body mainly by the kidneys in the form of salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%) and acyl glucuronides (5%), gentisic acid (<1 %) и 2,3-дигидроксибензойной кислоты. При поглощении малых доз (менее 250 мг для взрослого) все пути возобновляются кинетикой первого порядка, с периодом полувыведения около 2-4,5 часов. При поглощении более высоких доз салицилата (более 4 г) период полураспада становится намного больше (15-30 часов), так как пути биотрансформации, связанные с образованием салицилуровой кислоты и салицилового фенольного глюкуронида, становятся насыщенными. Почечная экскреция салициловой кислоты становится все более важной, когда метаболические пути становятся насыщенными, потому что она чрезвычайно чувствительна к изменениям рН мочи. Когда рН мочи увеличивается от 5 до 8, происходит увеличение почечного клиренса в 10-20 раз. Использование мочевого подщелачивания эксплуатирует этот аспект выведения салицилата.
History of aspirin
Since ancient times, plant extracts including willow bark and spirea, whose active ingredient is salicylic acid, have been known to help relieve headaches, aches and fevers. The father of modern medicine, Hippocrates (c. 460-377 BC), left historical records describing the use of a powder made from willow bark and leaves to help with these symptoms.
French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid in 1853. In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with the sodium salt of salicylic acid (sodium salicylate). A violent reaction followed, and the resulting melt soon solidified. Since a structural theory did not exist at the time, Gerhardt named his compound "salicylic acetic anhydride." This aspirin preparation was one of many reactions Gerhardt carried out for his reports on anhydrides and which he did not pursue further.
6 years later, in 1859, Von Gilm obtained analytically pure acetylsalicylic acid (which he called acetylated salicylic acid) using the reaction of salicylic acid and acetyl chloride. In 1869, Schroeder, Prinzhorn and Kraut repeated the synthesis of Gerhardt (from sodium salicylate) and Von Gtlm (from salicylic acid) and concluded that both reactions gave the same compound - acetylsalicylic acid. They were the first to assign it the correct structure with an acetyl group attached to a phenolic oxygen.
In 1897, chemists working for Bayer AG produced a synthetically modified version of salicin, obtained from a species of meadowsweet. Filipendula ulmaria(meadowsweet), which caused less digestive upset than pure salicylic acid. The identity of the lead chemist on this project is a matter of debate. Bayer claims that the work was done by Felix Hoffmann, but Jewish chemist Arthur Eichengrun later claimed that he was the lead researcher and that records of his contributions were destroyed under the Nazi regime. The new drug, officially acetylsalicylic acid, was named aspirin by Bayer AG after the old botanical name for meadowsweet, Spiraea ulmaria. By 1899 Bayer was selling it worldwide. The name "aspirin" is derived from "acetyl" and "Spirsäure", the old German name for salicylic acid. Aspirin grew in popularity in the first half of the 20th century due to its supposed effectiveness as a result of the 1918 Spanish flu pandemic. However, recent research suggests that the high death rate from the 1918 influenza was partly due to aspirin, although this is highly controversial and is not widely accepted. The profitability of aspirin led to intense competition and proliferation of aspirin brands and products, especially after Bayer's American patent expired in 1917.
Aspirin's popularity declined following the market introduction of paracetamol (acetaminophen) in 1956 and ibuprofen in 1969. In the 1960s and 1970s, John Wayne and others discovered the underlying mechanism of action of aspirin, and clinical trials and other studies from the 1960s to the 1980s. have established the effectiveness of aspirin as an anticoagulant agent that reduces the risk of clotting disorders. Sales of aspirin increased significantly in the last decades of the 20th century, and remain strong into the 21st century due to its widespread use as a preventative treatment for heart attacks and strokes.
Trademark
As part of war reparations specified in the 1919 Treaty of Versailles following Germany's surrender after World War I, aspirin (along with heroin) lost its registered trademark status in France, Russia, the UK and the US, where it became a generic name. Today, aspirin is the generic name in Australia, France, India, Ireland, New Zealand, Pakistan, Jamaica, Colombia, the Philippines, South Africa, the UK and the USA. Aspirin, with a capital "A", remains a registered trademark of Bayer in Germany, Canada, Mexico and over 80 other countries where the trademark is owned by Bayer, using acetylsalicylic acid in all markets, but using different packaging and physical aspects for each .
Veterinary uses of aspirin
Aspirin is sometimes used for pain relief or as an anticoagulant in veterinary medicine, primarily in dogs and sometimes in horses, although newer medications with fewer side effects are usually used instead.
Both dogs and horses are susceptible to developing gastrointestinal side effects associated with salicylates, but it is a useful treatment for arthritis in older dogs, and is somewhat reassuring in cases of laminitis in horses. It is no longer commonly used for cases of laminitis as it may be counterproductive to treatment.
Aspirin should only be used in animals under the direct supervision of a veterinarian. In particular, cats lack the glucuronide conjugates that aid in the excretion of aspirin, making even low doses potentially toxic.
Do heroin and aspirin have the same creator?
Friedrich Bayer
Friedrich Bayer was born in 1825. He was the only son in a family of six children. His father was a weaver and dyer, and Bayer followed in his footsteps. In 1848, he opened his own paint manufacturing business, which quickly became successful. In the past, all paints were made from organic materials, but in 1856, paints that could be made from coal tar derivatives were discovered, sparking a revolution in the textile industry. 
Bayer and Friedrich Wescott (chief painter) saw great potential for the development of this area, and in 1863 they created their own paint production company, Friedrich Bayer et Compagnie.
Hoffman's aspirin.
Bayer died on May 6, 1880, while his company was still in the fabric dye business. The company continued to hire chemists to come up with innovative products. 
e paints and products, and in 1897 luck smiled on one of the chemists. His name was Felix Hoffman.
A persistent chemist sought a cure for his father's rheumatism. And as a result of experiments with a waste product of one of the paint components, he was able to chemically synthesize a stable form of salicylic acid powder.
The compound has become an active ingredient in many pharmaceutical products called aspirin. The name comes from “a” from acetyl, and “spir” from the name of the spirea plant (Filipendula ulmaria, also known as Spiraea ulmaria or meadowsweet), a source of salicin.
Another version of the origin of the name was the name of the patron saint of all headache sufferers, St. Aspirinus.
This medicine has already been used for 3500 years!
However, Hoffman was not the first to discover and synthesize “aspirin.” 40 years earlier, the French chemist Charles Gerhardt had already synthesized acetylsalicylic acid. In 1837, Gerhardt came to good results, but the procedure was complex and time-consuming. Therefore, he decided that this was not practical and postponed the experiments. However, Gerhardt was quite aware of the potential treatment possibilities with acetylsalicylic acid, because it had been known about it for more than 3500 years!
In early 1800, German Egyptologist Georg Ebers bought papyri from an Egyptian street vendor.
The Ebers Papyrus is known to have contained a collection of 877 medicinal recipes dating back to 2500 BC and specifically recommended the use of dried myrtle infusions to relieve rheumatic lower back pain.
As early as 400 BC, Hippocrates, the father of all doctors, recommended extracting a tea from the bark of the willow tree to treat fever and pain.
The active ingredient in this juice that actually relieves pain as we know it today is salicylic acid.
Scientists have confirmed that the bitter part of willow bark is a natural source of the chemical salicin. This chemical can be converted to salicylic acid. Aspirin is a member of this family of chemicals named after salicylic acid esters.
In China and Asia, among North American Indians and South African tribes, the beneficial effects of plants containing salicylic acid have been known since early times.
Breakthrough and authorship.
One of the first to try to satisfy the need for a synthetic substitute for natural antipyretics was the German company Heyden Chemical Co, which in 1874 built its own factory for the production of salicylic acid.
However, although salicylic acid, extracted from willow bark, reduced pain, its side effect was serious irritation of the stomach and mouth. Patients of that time were faced with a choice: harmless, expensive salicin (in 1877 in London it cost about 50 pence per ounce) or cheap salicylic acid (5 pence per ounce) with a risk to the stomach.
Hoffman's breakthrough came on August 10, 1897, when he produced the first 100% chemically pure form of acetylsalicylic acid, i.e. without natural salicylic acid.
On March 6, 1899, Bayer registered aspirin as a trademark. But still not without problems.
Deputy Dean of the Faculty of Pharmacy at the University of Strathclyde in Glasgow, Professor Walter Sneader, put forward his version of authorship. According to it, the creator of aspirin is Arthur Eichengrün, also a chemist at the Bayer company, but of Jewish origin, unlike Hoffman with Aryan roots. By the time it was published in a story with a sick father and authored by Hoffman in 1934 in Germany, this was quite relevant for well-known reasons.
Humanity still uses other inventions of Eichengrün to this day: these are fireproof films, fabrics, plastic furniture and antifreeze.
Despite the scientist’s successful collaboration with this largest German concern in 1944, the 76-year-old chemist was still sent to the Theresienstadt concentration camp in the Czech Republic, and his property was confiscated. 
In 1945, he was liberated by units of the Red Army. And only shortly before his death (“horrified by the very thought that injustice would triumph for another half a century”), in his article-testament in Pharmazie, he wrote the true development of events. Eichengrün survived his article by two weeks. Bayer AG does not support this version of the birth of aspirin.
Initially, the company's achievement in 1899 received marketing certificates only in the United States. In England and Germany, other companies insisted on their own authorship.
However, at the time, Hoffman's written evidence prevailed, and the company had also patented a process for mass-producing aspirin. And she decided to publish a 200-page catalog of her medicines, among which the new product stood out, and send it to 30 thousand practicing doctors in Europe. .
And when Hoffman retired in 1928, aspirin was known throughout the world. Despite this, the chemist lived until his death on February 8, 1946 in Switzerland as an unrecognized author.
Do aspirin and heroin have the same creator?
Aspirin was Bayer's most remarkable success, but not its only one. A few days after Hoffman succeeded in synthesizing acetylsalicylic acid, he produced another compound for which Bayer's company had big plans. Today this discovery is of dubious value.
Diacetylmorphine (or heroin), a substance that was also discovered several decades earlier by the English chemist C.R.A. Wright. Heroin was cautiously recommended by pharmacists during the First World War, but by 1931 it had disappeared from drug lists in almost all countries. In 1924, a federal law was passed in the United States banning its production, sale and consumption.
Additional facts.
Felix Hoffmann, born in Ludwigsburg in 1868. He conducted his pharmaceutical research at the University of Munich. April 1, 1894 joined Friedrich Bayer & Co. After the discovery of pure acetylsalicylic acid, he became the head of the pharmaceutical department.
Friedrich Bayer's company initially produced only anilines. Its founder died in 1880, unaware that Bayer was destined to become a pharmaceutical giant. By 1891, Bayer had introduced a different product range. Today, there are more than 10,000 products.
In the 1930s, a company employee with (an amazing coincidence) the same last name (Otto Bayer) invented polyurethane.
German microbiologist Gerhard Domagk (Bayer), together with his colleagues, discovered the therapeutic effect of sulfonamides. This discovery revolutionized the chemotherapy of infectious diseases, and brought Domagk the Nobel Prize in 1939.
Since 1950 aspirin has become known as a preventive drug in the fight against heart disease; in 37.6% of cases, people take aspirin in this capacity (to relieve headaches - only in 23.3%).
Aspirin was also used in space as part of the first aid package of the American astronauts of Apollo 11 (lunar module).
The Bayer company is constantly fighting against the “leftist” manufacturers of its famous aspirin. That is why the well-known “Soviet” aspirin was called acetylsalicylic acid for a long time.
Aspirin invention of German scientistsAspirin is very common and a well-known remedy among medications. This truly unique medicine, which has conquered the whole world, was developed in the chemical laboratories of the Bayer factory in 1897.
It is still unknown who exactly invented aspirin of two laboratory chemists: two workers argued among themselves for almost 50 years, but until the end of their lives the question remained hanging in the air. Felix Hoffmann died before his colleague Arthur Eichengreen for three years, maybe that's why Arthur Eichengreen believe in many sources inventor of aspirin.
Felix Hoffmann
Arthur Eichengrun
Aspirin base is salicylic acid, was also known long before aspirin was invented its analgesic properties. Back in 1875, salicylic acid began to be produced as a medicine. But that drug had 2 side effects: it was intolerable to the taste and had a rather serious effect on the health of the stomach. By working on the chemical properties of salicylic acid, German chemists managed to eradicate side effects and improve the properties of the drug. It is thanks to these two Germans, aspirin has become a truly popular medicine.
The inventors hoped to release aspirin, as a reliable and high-quality painkiller. But over time, the medicine showed other equally noteworthy properties. Even when the scientists were gone, aspirin continued to discover more and more new indications for use.
At least 3,000 scientific articles are published on the topic of aspirin every year.
For quotation: Laguta P.S., Karpov Yu.A. Aspirin: history and modernity // RMJ. 2012. No. 25. S. 1256
Platelet activation and subsequent thrombus formation play a key role in the development and progression of most cardiovascular diseases, so it is not surprising that the advances that have been made in their treatment and prevention over the past decades are largely associated with the use of various groups of antithrombotic drugs. Aspirin, the effectiveness and safety of which has been confirmed by numerous controlled studies and meta-analyses, is currently considered the “gold standard” of antithrombotic therapy. Approximately 40,000 tons of Aspirin are consumed worldwide each year, and in the United States alone, more than 50 million people take over 10 billion Aspirin tablets to prevent cardiovascular disease. In addition to the antiplatelet properties of the drug, which became known relatively recently, Aspirin has long been successfully used in general clinical practice due to its anti-inflammatory, antipyretic and analgesic effects. The history of the use of Aspirin goes back many hundreds and even thousands of years and has a close connection with the entire culture of human civilization.
History of the discovery of Aspirin
Ancient Egyptian papyri dating back to 1534 BC list more than 700 medicinal and herbal preparations as the most important plant, tjeret or salix, known today as willow. In the ancient world, this remedy was widely used as a general tonic. Hundreds of years later, in 1758 in England, Reverend Edward Stone published the results of the first clinical study on the use of willow bark as an effective treatment for patients with malaria. The beginning of the 19th century was marked by significant progress in science and technology. In 1828, Joseph Buchner, professor of pharmacology at the University of Munich, refined willow bark products and identified the active substance, which he named salicin. In 1838, the Italian chemist Raffaele Piria synthesized salicylic acid from salicin. In the early and mid-19th century, salicin and salicylic acid were widely used throughout Europe to treat various pains, fevers and inflammations. However, at that time, salicylic acid preparations had a terrible taste and were poorly tolerated with gastrointestinal side effects, which prompted most patients to abandon their use. In 1852, Charles Gerchard determined the molecular structure of salicylic acid, replaced the hydroxyl group with an acetyl group, and synthesized acetylsalicylic acid (ASA) for the first time. Unfortunately, the resulting compound was unstable and did not attract further attention from pharmacologists. Herman Kolbe was more successful in 1859, thanks to whom the industrial production of ASA became possible.
In 1897, the young chemist Felix Hoffmann of Friderich Bayer & Co developed a stable and more convenient form of ASA, while trying to minimize the side effects of the drug, and in 1899 the new drug was released under the brand name Aspirin. At that time, and for more than 50 years, ASA was used exclusively as an anti-inflammatory, antipyretic and analgesic agent. The effect of ASA on platelets was first described in 1954 by Bounameaux. In 1967, Quick discovered that ASA increases bleeding time. However, the inhibitory effect of ASA on thromboxane synthesis was not known until the 70s of the last century. In 1971, Vane et al. A Nobel Prize-winning work was published in which the dose-dependent effect of ASA on the synthesis of prostaglandins was described. Hemler et al. in 1976, the pharmacological target of Aspirin, the enzyme cyclooxygenase (COX), was identified and isolated.
Mechanism of action
and optimal dose of ASA
According to modern concepts, ASA irreversibly acetylates the hydroxyl group at position 530 in the molecule of the COX enzyme, which occurs in two isoenzyme forms (COX-1 and COX-2) and catalyzes the biosynthesis of prostaglandins and other eicosanoids. COX-1 is the major form of the enzyme found in most cells and determines the physiological functions of prostaglandins, including control of local tissue perfusion, hemostasis, and mucosal protection. COX-2 is found in the body in small quantities, but its level increases sharply under the influence of various inflammatory and mitogenic stimuli. COX-2 is 50-100 times less sensitive to the action of ASA than COX-1, which explains why its anti-inflammatory doses are significantly higher than antithrombotic ones. The antiplatelet effect of ASA is associated with irreversible inhibition of platelet COX-1, which results in a decrease in the formation of thromboxane A2, one of the main inducers of aggregation, as well as a powerful vasoconstrictor released from platelets upon their activation (Fig. 1).
The effectiveness of ASA for the treatment and prevention of cardiovascular diseases has been established for a wide range of doses - from 30-50 to 1500 mg/day. . In recent years, ASA, according to recommendations, has been prescribed in small doses, which is quite reasonable from both pharmacological and clinical points of view. It has been shown that a single dose of ASA at a dose of 160 mg is sufficient to almost completely suppress the formation of thromboxane A2 in platelets, and the same effect is achieved after a few days with regular intake of 30-50 mg/day (cumulative effect). Considering that ASA acetylates COX-1 in all tissues, including endothelial cells, simultaneously with a decrease in the synthesis of thromboxane A2, it, at least in high doses, can inhibit the formation of prostacyclin, a natural antiplatelet and vasodilator (Fig. 1).
A decrease in the synthesis of prostacyclin in conditions of inadequate suppression of the formation of thromboxane A2 explains the negative effect of COX-2 inhibitors - non-steroidal anti-inflammatory drugs - on the risk of cardiovascular diseases. However, data from clinical studies did not confirm a significant weakening of the antithrombotic effect when using higher doses of ASA. It should be noted that, unlike thromboxane A2, in the synthesis of which the main role belongs to COX-1, both isoenzymes take part in the formation of prostacyclin. In this regard, in small doses (30-100 mg), ASA, blocking only COX-1, causes a predominant decrease in the formation of thromboxane A2, while the level of prostacyclin remains quite high due to the preservation of COX-2 activity. Platelets are anucleate cells that are unable to synthesize proteins. Irreversible inhibition of COX-1 and the absence of the possibility of its resynthesis leads to the fact that the blockade of the formation of thromboxane A2 under the influence of ASA persists throughout the life of platelets - for 7-10 days, while its effect on the synthesis of prostacyclin is shorter and depends on frequency of taking the drug. It is also important to note that the greatest effect of ASA on platelet COX-1 occurs in the portal circulation system, therefore the antiplatelet effect of the drug does not depend on its distribution in the systemic circulation. This is precisely what is associated with the biochemical selectivity of small doses of ASA, which explains why their use has a greater inhibitory effect on platelets rather than on the vascular wall, where prostacyclin formation occurs.
Currently, a dose of ASA of 75-100 mg/day is considered sufficient for long-term use. . In urgent clinical conditions, such as acute coronary syndrome or acute ischemic stroke, when rapid and complete inhibition of thromboxane-A2-dependent platelet activation is required, the use of a loading dose of Aspirin of 160-325 mg is indicated.
Secondary prevention of cardiovascular diseases
In 2002, the results of a large meta-analysis evaluating the effectiveness of antiplatelet drugs were published, covering 287 studies of more than 200,000 patients at high risk of developing vascular complications. It has been shown that the use of antiplatelet agents reduces the total risk of vascular events by approximately 1/4, nonfatal myocardial infarction (MI) by 1/3, nonfatal stroke by 1/4, and vascular death by 1/6. At the same time, there was a significant decrease in the absolute risk of vascular complications in various subgroups, which amounted to 36 per 1000 in people who had an MI; 38 per 1000 among patients with acute MI; 36 per 1000 in patients who have had a stroke or transient cerebrovascular accident; 9 per 1000 in persons with acute stroke; 22 per 1000 among patients with stable angina, peripheral atherosclerosis, and atrial fibrillation (Table 1). We would like to emphasize that more than 2/3 of this information was obtained from studies using Aspirin and that the effectiveness of antiplatelet therapy for each of the high-risk patient categories was confirmed in individual placebo-controlled studies with a statistical difference obtained for each of the groups. It should also be noted that Aspirin refers primarily to the original product of the Bayer company, for which the name Aspirin was patented. This clarification needs to be made due to the fact that most of the results of large studies and, consequently, international recommendations were based precisely on the use of the original form of the drug, and not its generics. In Russia, a drug from Bayer under the trade name Aspirin Cardio is registered for the treatment and prevention of cardiovascular diseases; it is available in doses of 100 and 300 mg.
Primary prevention of cardiovascular diseases
Aspirin is the only antithrombotic drug currently recommended for use in the primary prevention of cardiovascular disease. The effect of Aspirin therapy is more obvious, the higher the risk of developing vascular complications (Fig. 2). This circumstance should be taken into account when prescribing the drug to patients with a relatively low risk of vascular events, namely for the purpose of primary prevention. Correction of the main risk factors for cardiovascular diseases: quitting smoking, normalizing blood lipid levels, stabilizing blood pressure numbers, in some cases is sufficient in these patients, and the benefit of additional Aspirin will not be so great.
In 2009, the results of a large meta-analysis organized by the International Antiplatelet Trials Group were published, which compared the effectiveness of aspirin for primary and secondary prevention of cardiovascular events. Six large controlled studies on primary prevention were selected for analysis, including 95,000 patients at low/moderate risk of developing vascular complications (Physicians Health Study, British Doctors Study, Thrombosis Prevention Trial, Hypertension Optimal Treatment Study, Primary Prevention Project, Women’s Health Study). There were 16 secondary prevention studies (6 post-MI studies, 10 stroke/transient ischemic attack studies) and included 17,000 high-risk patients.
The reduction in the risk of vascular events in patients taking Aspirin in primary prevention studies was 12%, which was significant (p = 0.0001) (Table 2). However, in absolute numbers, this difference was as follows: 1671 events in those taking Aspirin (0.51% per year) versus 1883 events in the control group (0.57% per year). Thus, the above benefit of taking Aspirin was only 0.07% per year. By comparison, in secondary prevention trials, a 19% reduction in the risk of vascular events with aspirin was accompanied by an absolute difference of 6.7% and 8.2% (p<0,0001) в год среди получавших и не получавших препарат.
The reduction in the total number of vascular events in patients taking Aspirin was achieved primarily through a reduction in major coronary events (all MI, death from coronary causes, sudden death) and non-fatal MI. The proportional reductions in major coronary events and nonfatal myocardial infarction were similar in primary and secondary prevention trials, but there were significant differences in absolute values: 0.06 (0.05)% per year in primary and 1 (0.66)% in primary prevention. year - for secondary prevention (Table 2).
Aspirin did not significantly affect the total number of strokes in primary prevention studies, but did significantly reduce the risk of ischemic stroke by 14%. At the same time, in studies on secondary prevention, Aspirin significantly reduced the total number of strokes by 19%, including ischemic strokes by 22%. The majority of strokes (84%) in secondary prevention studies occurred recurrently in patients with a history of stroke or transient ischemic attack. The number of hemorrhagic strokes increased during Aspirin therapy in both primary and secondary prevention: 116 vs 89 (p=0.05) and 36 vs 19 (p=0.07), respectively.
Prescription of Aspirin in primary prevention did not have a significant effect on the incidence of fatal coronary events, fatal strokes, vascular and overall mortality. At the same time, in secondary prevention studies, Aspirin reduced vascular mortality by 9% (p-0.06), and overall mortality by 10% (p = 0.02).
It should be noted that the primary prevention studies presented varied widely in terms of inclusion criteria, demographic characteristics, number of participants, risk of vascular events in the control group, doses of aspirin used, and other parameters. In addition, the majority of participants in primary prevention studies were individuals with a low and very low annual risk of developing vascular events, several times lower than in patients with existing vascular lesions, which affected the significant difference in the absolute risk reduction values of the studied indicators .
The meta-analysis also assessed the risk of vascular complications and major bleeding among participants in primary prevention trials. The presence of each of the following factors: age (per decade), male gender, diabetes, smoking, increase in mean blood pressure (by 20 mm Hg) was associated not only with an increased risk of coronary events, but also with the risk of hemorrhagic complications (Table 3 ). The authors of the meta-analysis believe that existing recommendations for the use of Aspirin for the purpose of primary prevention do not take this circumstance into account at all. The question of prescribing Aspirin is determined by a simple summation of risk factors taking into account the patient’s age, while it is believed that the risk of hemorrhagic complications is a constant and unchangeable value. It is emphasized that the prescription of Aspirin should be carried out strictly individually, and its use is not always justified even in patients of average risk. Based on the results of the meta-analysis, the possible benefit of taking Aspirin for primary prevention in absolute values is only 2 times greater than the risk of hemorrhagic complications. It has been estimated that the use of aspirin for primary prevention will prevent the development of five non-fatal coronary events with a risk of three gastrointestinal and one intracranial bleeding per 10,000 patients per year.
Side effects
Aspirin therapy
Aspirin is generally well tolerated by patients, but sometimes its use is accompanied by the development of side effects (5-8%), the frequency and severity of which are primarily related to the dose of the drug. Thus, according to the results of a meta-analysis of 31 randomized placebo-controlled studies, the incidence of major bleeding was: in those taking low (30-81 mg/day) doses of Aspirin - less than 1%, medium (100-200 mg/day) - 1.56 %, and high (283-1300 mg/day) - more than 5%.
The greatest danger is cerebral (hemorrhagic stroke or intracranial hemorrhage) complications and gastrointestinal bleeding, but these complications are quite rare. A meta-analysis conducted by the International Antiplatelet Trials Group in 2002 found that antiplatelet therapy was associated with a 1.6-fold increase in major bleeding. At the same time, there were 22% more hemorrhagic strokes, but their absolute number in each study did not exceed 1 per 1000 patients per year. Importantly, taking antiplatelet drugs led to a 30% reduction in the risk of ischemic stroke, and the overall number of strokes decreased by 22%. Arterial hypertension is sometimes considered a contraindication to taking Aspirin, because it is believed that in this case its use is associated with an increased risk of cerebral bleeding. However, as the results of the NOT study showed, the use of small doses of Aspirin in patients with arterial hypertension in the context of selected antihypertensive therapy leads to a reduction in the risk of developing MI without increasing the risk of hemorrhagic stroke.
There are several mechanisms for the development of gastrointestinal bleeding associated with taking Aspirin. The first is due to the main antithrombotic effect of Aspirin, namely the inhibition of platelet COX-1. The second is associated with the effect of Aspirin on the synthesis of prostaglandins in the gastric mucosa and depends on the dose of the drug taken (see Fig. 1). Thus, it would be a mistake to assume that the use of even very low doses (30-50 mg/day) of Aspirin can completely eliminate the risk of serious gastrointestinal bleeding. However, it has been found that the ulcerogenic effect of Aspirin increases with increasing dosage of the drug. Thus, when comparing three regimens of Aspirin administration in doses of 75, 150 and 300 mg/day. the relative risk of developing gastrointestinal bleeding was 2.3, 3.2, 3.9, respectively, i.e. use of the drug in a minimal dose was accompanied by a reduction in the risk of developing this complication by 30 and 40% in comparison with Aspirin doses of 150 and 300 mg/day.
Based on the results of large population-based studies, the risk of gastrointestinal bleeding with low-dose aspirin is comparable to the risk associated with other antiplatelet drugs and anticoagulants. The main risk factors for the development of gastrointestinal bleeding with long-term use of Aspirin are: a previous history of gastrointestinal bleeding, combined use of non-steroidal anti-inflammatory drugs, anticoagulants, corticosteroids, age over 60, and especially over 75 years. Some studies also consider the presence of Helicobacter pylori as a risk factor. The risk of recurrent gastrointestinal bleeding during aspirin therapy in individuals with a previous history of bleeding is 15% over the course of a year. The use of proton pump inhibitors, misoprostil (a synthetic analogue of prostaglandin E2) and treatment of Helicobacter pylori significantly reduce the incidence of gastrointestinal bleeding in patients at high risk of developing it. However, the routine use of antiulcer drugs as concomitant therapy when prescribing Aspirin cannot be considered acceptable in most patients.
However, the most common reason for stopping taking Aspirin is aspirin-induced gastropathy, which occurs due to the irritating effect of Aspirin on the gastric mucosa upon direct contact, which can manifest itself as various sensations of discomfort in the abdominal area, heartburn, nausea, etc. These effects can be partially reduced by reducing the dose of the drug, but in addition, another way to improve the subjective tolerability of Aspirin is to use its safer forms. These include enteric-coated Aspirin tablets, the contents of which are released in the small intestine without, therefore, damaging the gastric mucosa.
Enteric-soluble forms of Aspirin Cardio can significantly improve the tolerability of the drug and reduce the manifestations of gastrointestinal discomfort. There is evidence from endoscopic studies in which the administration of enteric forms of Aspirin Cardio caused significantly less damage to the mucous membrane of the stomach and duodenum compared to conventional forms of the drug. The effectiveness of the use of enteric forms of Aspirin Cardio is confirmed by the results of large studies in various high-risk groups.
Problems of Aspirin Therapy
and future directions
In recent years, the term “Aspirin resistance” has often been used in the medical literature, although a clearly formulated definition of this concept is not currently given. From a clinical point of view, resistance to Aspirin means the development of thrombotic complications against the background of its regular use. It also indicates the lack of ability of Aspirin to adequately suppress the production of thromboxane A2, cause an increase in bleeding time and have an effect on other indicators of the functional activity of platelets in a number of patients. Among the possible mechanisms that can influence the clinical effect of Aspirin are considered: polymorphism and/or mutation of the COX-1 gene, formation of thromboxane A2 in macrophages and endothelial cells via COX-2, polymorphism of platelet IIb/IIIa receptors, competitive interaction with non-steroidal anti-inflammatory drugs for binding platelets to COX-1, platelet activation through other pathways that are not blocked by Aspirin, etc.
The frequency of detection of Aspirin resistance varies greatly depending on the pathology studied and the laboratory method used for determination (from 5 to 65%). In a number of patients, this effect is observed initially or appears after several months of regular use of Aspirin. There are very few studies that have assessed how the lack of effect of aspirin on laboratory parameters affects the clinical prognosis of cardiovascular disease. In some patients, increasing the dose of Aspirin or adding omega-3 unsaturated fatty acids overcomes Aspirin resistance in vitro, although the number of such observations is small. The Antiplatelet Resistance Working Group opined that “there is currently insufficient evidence to indicate that routine testing/monitoring of platelet function while on antiplatelet agents can lead to clinically meaningful benefits.” The recommendations of the All-Russian Society of Cardiology and the National Society of Atherothrombosis emphasize that antiplatelet drugs should be prescribed in accordance with clinical indications in doses whose effectiveness is documented in large controlled clinical trials.
Among other antithrombotic properties of Aspirin, not related to inhibition of thromboxane A2 formation, its effect on the fibrinolysis system, reduction of thrombin formation, improvement of endothelial function and a number of others are noted. However, these effects are observed, as a rule, with the use of high doses of Aspirin, and their clinical significance has not been established.
Recently, the possibility of antineoplastic action of Aspirin has been discussed. In 2012, data were published from a meta-analysis of 34 studies using Aspirin (total 69,224 patients), in which information on the causes of non-cardiovascular mortality was available. It was found that those taking Aspirin had a significantly lower risk of death from cancer by 15%. A more obvious reduction in the risk of cancer mortality was observed after 5 years of taking the drug (by 37%). In a separate analysis of eight primary prevention studies, which included individual data from 25,570 patients, the observed benefits of Aspirin were observed regardless of drug dose, gender, or smoking history, but were more evident in older age groups (65 years and above). Similar but less dramatic results were obtained in a large observational study in the United States that included more than 100,000 initially healthy patients. The reduction in the risk of cancer mortality in patients taking Aspirin was more modest at 8 or 16%, depending on the analytical approach used. Those taking the drug for more than 5 and less than 5 years had the same risk reduction.
Data from the above meta-analysis and the results of observational studies indicate a greater effect of Aspirin against tumors of the gastrointestinal tract, especially the colon and rectum. The results presented have caused many criticisms. A number of large primary prevention studies, such as the Women's Health Study and the Physicians Health Study, did not report an antineoplastic effect of Aspirin. In addition, the actual duration of Aspirin use was not analyzed in the data presented. The effect of drug dose has not been clearly established, although the proposed mechanism of action is inhibition of COX-2. However, despite all the obvious shortcomings, the information obtained appears to be extremely important and needs serious confirmation in further large studies.
Conclusion
Aspirin has a long history of use, but today it remains one of the most popular drugs. The clinical effectiveness of Aspirin in reducing the incidence of myocardial infarction, stroke and vascular death in various high-risk groups has been confirmed by the results of numerous controlled studies and meta-analyses. At the same time, the benefit of its administration to patients at low and average risk for the purpose of primary prevention of cardiovascular events is not so obvious. Currently, a number of large studies have been organized and are being conducted using Aspirin in primary prevention among various groups: in elderly people, patients with diabetes mellitus without clinical manifestations of atherosclerosis, in people with an average risk of cardiovascular diseases (10-20% within 10 years ), in patients with cardiovascular risk factors undergoing non-cardiac surgery. When prescribing Aspirin to each individual patient, it is necessary to weigh the expected benefits and possible risks of such therapy. The need for long-term antithrombotic therapy raises questions regarding its safety. There are several approaches that can significantly reduce the incidence of side effects and ensure long-term use of Aspirin. First of all, this is the administration of the drug in a minimum dose (including when it is used in combination with other antithrombotic drugs), which has proven its effectiveness in a particular clinical situation. Today, a dose of Aspirin of 75-100 mg/day is recognized as sufficient for long-term use in patients at high risk of vascular complications. Proton pump inhibitors have been shown to be effective in reducing the incidence of gastrointestinal bleeding in patients at high risk of developing it. At the same time, it is impossible to recommend prescribing these drugs to all patients who take Aspirin. In these conditions, an important task in ensuring long-term Aspirin therapy is the use of its safer forms. Routine testing and monitoring of platelet function while taking Aspirin is considered inappropriate. Other additional properties of Aspirin are currently being actively studied. “Aspirin is an amazing drug, but no one understands how it works,” wrote the New York Times in 1966, and part of this statement is still true today.
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