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---The story of Tylenol:
“The so-called coal tar analgesics, phenacetin and its active metabolite acetaminophen, are effective alternatives to aspirin as analgesic-antipyretics” Phenacetin: an update (Valle et al., 1979)
“In the late 1880s the dyestuffs manufacturer Friedrich Bayer & Co was looking to diversify its commercial interests and to find a use for 4-nitrophenol, a side product available in vast amounts from its synthesis of the blue dye Benzazurin G. Research director, Carl Duisberg, challenged his team to come up with an exploitable use for this compound. One of them, Oscar Hinsberg, found that, in three steps - ie reduction of NO2 to NH2; ethylation of the OH group; and finally acylation of the NH2 group - he had made a well-tolerated antipyretic and analgesic, which possessed all the advantages of Antipyrin and Antifebrin and (apparently) none of their disadvantages. His new product, phenacetin, enjoyed much popularity for almost a century as an over-the-counter remedy (often combined in tablets with caffeine and aspirin) for headaches and hangovers. However, in the 1960s evidence was mounting to suggest that phenacetin might be causing renal failure and renal tumours in some heavy users. In 1980 phenacetin was banned in the UK.” Pain relief: from coal tar to paracetamol (Brown et al., 2005)
“Typically, the nitration of phenol yields 30-40% of the 2-isomer and about 15% of the 4-isomer. Bayer was accumulating vat-loads of the latter product with no apparent commercial use. Works chemist Oskar Hinsberg was given the job of converting the waste nitrophenol into a marketable medication. Success came within a matter of weeks. Presumably he was guided by knowledge of the formulae of the existing antipyretic drugs.” The Rise and Fall of Phenacetin (Dronsfield & Ellis, 2021)
"Drugs were at first "special foods" used during times of unpleasant symptoms or during illness. Consequently most drugs were vegetable or animal, since mineral technology was undeveloped. The earliest knowledge of dyestuffs was also acquired from the vegetable and animal kingdoms, especially the former. ''Red dyestuffs were prepared from kermes, arachil, madder and henna; yellows from safflower, saffron, turmeric and pomegranate; blue from indigo and woad; purple from certain Mediterranean snails. Mordants containing iron, aluminium and copper were in use. These latter were components of readily available earths." Relationships between synthetic dyes and drug entities (Paterson, 1984)
---Here’s some Tylenol for your headache and some cocaine for your stuffy nose:
“Occasionally the coal-tar products-phenacetin, acetanilide, etc.-may be of some benefit, and no harm will come from giving them a trial… It is a good thing to apply cocaine to the vicinity of the infundibulum and turbinate fossa, either as a fine spray or on a pledget of cotton carefully adjusted. This may relieve the congestion sufficiently to allow the exudate to escape, and it will relieve the pain for a time. An oily spray with menthol is cooling to the patient, and tends to relieve congestion.” THE ANATOMY AND SURGERY OF THE FRONTAL SINUS AND ANTERIOR ETHMOIDAL CELLS. (Lothrop, 1898)
---Aspirin with Tylenol, an explanation for toxic effects:
“The first stage in the elimination of phenacetin from the body is its conversion into acetaminophen (itself later marketed as paracetamol), and aspirin potentiates the nephrotoxicity of this product. Most of the acetaminophen is converted into water-soluble glucuronides and sulfates and excreted via the urine, but 5-15% is oxidised to N-acetyl-pbenzoquinoneimine (NAPQI). If the phenacetin is consumed alone, there is usually sufficient glutathione in the kidneys’ papillae to detoxify this imine safely, by formation of the glucuronuride. If the phenacetin is ingested alongside aspirin (acetyl salicylic acid), the latter is hydrolysed to salicylate, which depletes the glutathione in both the kidney’s cortex and papillae. Thus the imine, deprived of its excretory route via the urine, remains longer within the kidney with the potential to inflict damage. There it reacts with proteins forming sulphur bridges that can cause mitochondrial dysfunction and cell destruction.” The Rise and Fall of Phenacetin (Dronsfield & Ellis, 2021)
"...phenacetin, especially in large quantities does cause alarming symptoms, chief among which may be mentioned a markedly disordered circulation accompanied with symptoms of collapse." PHENACETIN AS A TOXIC AGENT. (Cerna, 1895)
---The guy that synthesized aspirin also gave us heroin, which is another acetylated compound:
“1897 Motivated by his father’s intolerance of salicylic acid, Felix Hoffman synthesises acetyl salicylic acid, named aspirin (derived from Acetyl Spirea). This had been done before in 1853 (Carl Friedrich Gerhardt) and 1869 (Kraut) but Hoffman’s method is quantitative (mixing salicylic acid and acetic hydride 2:3 before adding acetic acid) and yields pure stable aspirin. Aspirin causes less dyspepsia than salicylic acid.
1897 Eleven days later Hoffman synthesises another new compound also by acetylation (of di acetyl morphine). Bayer employees try the new substance and find it makes them feel heroic so it is called heroin. Heinrich Dreser prefers to market heroin than aspirin.
1898 Aspirin is shown to have a negative inotropic affect on frogs’ hearts. Despite this, a secret clinical trial is conducted which shows effectiveness against pain, inflammation, and fever.
1899 Aspirin is registered as a tradename.
1900 Aspirin is patented in the USA and UK. Patents are refused in Germany. Aspirin rapidly becomes popular, endorsed by Caruso and Kafka (who claimed it eased the unbearable pain of being).” COX-2 chronology (Hawkey, 2005)
---I found an interesting bit about methyl salicylate and air-borne plant defense:
“Shulaev et al. showed that methyl salicylate, commonly known as oil of winter-green, is produced as a volatile liquid by tobacco plants inoculated with tobacco mosaic virus. The methyl salicylate is synthesized from salicylic acid and can be dispersed through the air. Methyl salicylate then acts by being converted back to salicyclic acid in other nearby plants in which it carries out its protective functions. Methyl salicylate, found in many plants, may therefore be an airborne signal which activates disease resistance through the expression of defence-related genes in neighbouring plant tissue.” From plant extract to molecular panacea: a commentary on Stone (1763) ‘An account of the success of the bark of the willow in the cure of the agues’ (Wood, 2015)
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