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Written by|Cheng Taozhu Zhen Orange
Antipyretics, a not-so-tall category of drugs, focus on dealing with fever, the world's oldest disease.
In the past three years, antipyretic drugs, such ordinary but important drugs, have experienced from "banning" to crazy robbery, and have become the focus of attention from time to time. The craze receded, and we decided to turn our attention to the fever reducers themselves, revisiting all the drugs in the world that had been identified as antipyretics, from physical fever reduction to cinchona peel to ibuprofen... Behind this, there is the dazed and unyielding human beings in the face of unknown diseases, the development of modern medicine and the growth of the pharmaceutical industry.
An ancient disease: fever
In ancient times, human understanding of diseases and their causes was in a state of obscurantism, and it was not yet possible to distinguish the nature of fever. Symptoms become the main basis for judging the disease, and fever is one of the most common diseases.
In the 11th century, a very severe malignant fever was endemic in Europe, characterized by fever and a very high case fatality rate. The "sweating" epidemic in Renaissance England is frightening, and "sweating" appears in the form of an acute with high fever, and the patient may lose his life within a few hours of fever, and death becomes almost an inescapable end.
In ancient Indian medical texts, fever is described as the "king of all diseases" and fever is considered most dangerous on days 7, 10, and 12 of the course of the disease. Ancient Indian doctors, who cherished their reputation, refused to treat three types of critically ill patients (fever, cough, bloody sputum), and fever ranked first.
According to the ancient Greek physician Hippocrates' four-humoral theory, disease is caused by an imbalance of the four humors. Fever is both due to heat in the body and manifests as a surface fever and often occurs in the form of delirium. Hippocrates made a detailed observation of fever and summarized the characteristics of poor prognosis when people with fever sweat and the heat does not subside.
In the 13th century, fever was a mandatory subject in the medical course of the University of Oxford in England. In the 17th century, L. Bellini devoted himself to the causes of fever. In the 18th century, F. Hoffmann believed that fever originated in the spine and was secondary to the contraction of arteries and veins; H. Burhaf Boerhaave believed that the fever was caused by the heart beating increased due to resistance from capillaries.
In fact, it was not until the establishment of organ pathology in the 18th century that people began to look for "the location and cause of disease", and the idea of fever as a disease diagnosis gradually faded out of the medical stage.
From spa, bloodletting to cinchona peel
In addition to praying to the gods, nature endows humans with many instincts to fight heat. Animals know to relieve fever with cold water and lick sores with their tongues to relieve pain, and humans have followed suit.
In the 15th century, there were records of treating fever with cold baths. At the end of the 18th century, J. Currier Currie encouraged people with fever to drink cold water, and Rush (B. Currie) Rush) Cool down with crushed ice cubes placed on the head of the person with a fever. In the 19th century, W. Wintenitz invented "night wrap therapy" to treat fever, wrapping his body in a cold and damp cloth on a cold night, and almost freezing to his death.
Bloodletting was once considered a panacea, and it was also a common treatment for fever. Doctors thought that bloodletting would rule out toxins and defervescence, and pathologists later explained that too much iron in the blood caused fever. At the end of the 16th century, some doctors realized that phlebotomy was ineffective for all fevers.
The most important therapeutics event in the 17th century was the import of cinchonapi into Europe by the Jesuits. Lancisi advocates the treatment of wet marsh fever (malaria) with cinchona peel. Ramazzzini opposes the abuse of cinchona peel to treat all fevers. In the 18th century, missionaries cured the Kangxi Emperor of China of malaria with cinchona peel, which led to the acceptance of missionary doctors in China.
In the 19th century, the pharmaceutical industry began to take off, and pharmaceutical companies were born in Germany, Britain, France and the United States, and a number of new drugs were introduced into the treatment.
Antipyretic analgesics inspired by willow bark:
aspirin
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In 4000 BC, or even 5000 BC, the ancient Sumerians discovered that eating willow bark made pain disappear. More than 2800 years ago, the Ebers Papyrus recorded that the ancient Egyptians used dried willow leaves to relieve pain. China's earliest herbal work "Shennong Materia Medica" records that willow roots, skins, branches and leaves can be used in medicine, with expectorant and eyesight, clear heat and detoxification, diuretic and windproof effects, external application can also cure toothache.
In 1758, the Englishman E. Stone Stone) proved that willow bark crushed powder can treat fever when eaten, and is effective for myalgia and headache symptoms. In the 19th century, the active ingredients of drugs were discovered. In 1828, the German J. Bushner Buchner) for the first time extracted the yellow crystal-like active ingredient, namely salicin, from willow bark. In 1838, the French pharmacist H. Le Roux (H. Leroux) Leroux) and the Italian chemist R. Piria Piria) isolated and purified the active ingredient salicin, named salicylic acid because of its acidic taste. In 1852, the Frenchman C. Gerhart discovered the molecular structure of salicylic acid and synthesized salicylic acid chemically for the first time. In 1876, T. J. MacLagan published an article in The Lancet confirming that salicin relieves rheumatic fever and joint inflammation.
German chemist H. Kolbe Kolbe) realized the artificial synthesis of salicylic acid, but found its taste extremely unbearable and extremely irritating to the stomach. In 1897, F. Hoffman of Bayer AG in Germany was killed by A. Hoffman in Eichinglin. Eichengrün), high-purity acetylsalicylic acid was synthesized by modifying salicylic acid. Acetylsalicylic acid was later shown to be clinically effective in pain, inflammation and fever.
In March 1899, Bayer Pharmaceutical Company registered acetylsalicylic acid as "aspirin", and aspirin became the world's first non-steroidal anti-inflammatory drug.
Touching analgesic medicine: ibuprofen
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Although aspirin is effective, it is used in large doses, which can easily lead to side effects such as allergies, bleeding and indigestion. With the advent of new analgesics, such as ibuprofen, aspirin's position was gradually weakened.
In 1952, the inventor of ibuprofen, S. Adams, became part of the British company Boots, specializing in the development of drugs for rheumatoid arthritis.
After a drunkenness, he developed a severe headache and thought of the newly synthesized compound p-isobutylphenylpropionic acid (ibuprofen). After he tried it, the analgesic effect was surprisingly good. After waking up, Adams immediately devoted himself to follow-up research.
In 1962, Boots registered the patent Ibuprofen. In 1969, ibuprofen was approved as a prescription drug in the United Kingdom, and in 1983, ibuprofen became an over-the-counter antipyretic analgesic. Ibuprofen has taken the world by storm because of its low price and rapid analgesic effect, and has a significant role in relieving menstrual cramps, toothache, low back pain and joint pain in women, becoming one of the best-selling drugs in the world.
Adams did not have an exclusive patent for ibuprofen, lived a simple life all his life, and when he was unwell, he went to the pharmacy to buy ibuprofen. In January 2019, Adams passed away at the age of 95.
Synthetic antipyretic analgesics:
paracetamol
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Paracetamol, Chinese known as paracetamol, is one of the over-the-counter medications currently used primarily for antipyretic and analgesic medications.
After the 80s of the 19th century, due to the dwindling number of cinchona trees, people began to look for alternatives to cinchona. In 1886, scientists invented antipyretic ice (acetanilide), and in 1887 finacetine (acetyl-p-aminophenethyl ether). In 1893, American scientist Von Meting discovered acetaminophen, which later determined that acetaminophen is the main active metabolite of acetanilide and phenacetine in the human body.
After the 50s of the 20th century, acetaminophen was widely used as an antipyretic analgesic. In 1960, acetaminophen was listed as an over-the-counter antipyretic and analgesic. Because it is clinically safe and effective, gastrointestinal adverse reactions are less than ibuprofen and aspirin, and acetaminophen is included in the WHO standard list of essential drugs.
Once one of the Big Three, now an analgesic that has almost disappeared: metamizole sodium
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Metamizole sodium is a pyrazolone antipyretic analgesic that was first synthesized by Germany in 1920. In the history of medicine, metamizole has been listed as the three giants of antipyretic analgesics, along with aspirin and acetaminophen.
Analgoximity was widely used in the era when antipyretic and analgesic drugs were scarce due to its precise efficacy, ease of use and variety of dosage forms. In China, Analwood has recently become the "king of feverishness".
After the 80s of the 20th century, the adverse reactions of metamizole sodle increased, and some developed countries began to restrict or ban metamizole sodium. In March 2020, the China Food and Drug Administration announced that children under the age of 18 would ban the use of metamizole sodium, and at the same time stop the production, sale and use of metamizole injection, metamizole chloropromazine injection, pediatric metamizole enema, metamizole drops, metamizole nasal drops, metamizole solution tablets for nasal drops, and pediatric antipyretic thrombosis in China.
Rationally understand the relationship between disease and drugs
Looking back at the history of the invention and application of fever and antipyretic analgesics, we see the difficulty of identifying diseases, the uncertainty of drug invention and application, the complexity of treating diseases, in the face of medicine related to life and health, human beings should be in awe, face diseases with a rational attitude, accept the epochs of medicine and the limitations of drugs, face the test of diseases with an open-minded attitude, and work together with doctors to deal with the invasion of diseases and jointly defend human health.
(The author of this article, Zhen Cheng, is a professor of medical history and doctoral supervisor at the School of Medical Humanities, Peking University; Cheng Taozhu is a doctoral candidate in social medicine and health management at the School of Public Health, Peking University. ）
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