Leading articles in medical journals in 1966.

The British Journal of Hospital Medicine is 50 years old. This article takes a look back at articles published during the year of its inception from the British Medical Journal, the Lancet and the Journal of the American Medical Association.

Acetaminophen/paracetamol: A history of errors, failures and false decisions.

Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side-effect 'epidemy' (phenacetin nephropathy, drug-induced interstitial nephritis) and ends with the discovery of second-generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound.

Clinical toxicology in Edinburgh, two centuries of progress.

The Scottish Poisons Information Bureau was established in Edinburgh in September 1963 and shortly afterwards one of the wards of the city's Royal Infirmary was designated a Regional Poisoning Treatment Centre. Both units were soon to be brought under one roof. To mark this 50th anniversary, we review how they built upon a history dating from the early 19th century and highlight their influence on current clinical toxicological practice and the delivery of poisons information. While many centres worldwide seek to improve the care of poisoned patients, the contribution of Edinburgh over the past 50 years has been notable.

Medicine, poison, and mystic potion: a personal perspective on paracetamol Louis Roche lecture, Stockholm, 2009.

BACKGROUND: Paracetamol poisoning has been a clinical problem for over 40 years. This article reflects the content of the Louis Roche lecture given on this topic in 2009. HISTORICAL CONTEXT: Initially key work illustrated the relationship between plasma paracetamol concentration and risk of liver injury facilitating the development of antidote strategies. Much of this work was done in the Edinburgh clinical toxicology unit. DISCUSSION: The antidote most widely used, acetylcysteine, was developed in Edinburgh and subsequently shown to be associated with adverse effects. Studies on this aspect and on key problems remaining in patient management are described. These include the identification of patients at greatest risk of toxicity, in order that they may be targeted for appropriate early intervention. More recent work suggests that the inflammatory response to paracetamol-induced liver injury may offer new targets for drug therapy in this major poisoning. CONCLUSION: Paracetamol poisoning remains a challenging problem, but new approaches to treatment seem possible based on recent experimental studies in animals and humans.

Paracetamol: new vistas of an old drug.

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.

Julius Axelrod: 20 May 1912 - 29 December 2004.

Julie Axelrod was a laboratory technician until the age of 42, when he finally achieved his PhD and independence. He worked at the National Institutes of Health for most of his career. Among his early pioneering research achievements in applying chemical and biochemical approaches to neuroscience were the discoveries of the painkiller acetaminophen (Tylenol, Paracetamol) and the liver microsomal drug-metabolizing enzymes, and the establishment of catechol-O-methyltransferase as an important enzyme in catecholamine metabolism. He shared the Nobel Prize in Physiology or Medicine in 1970 for his discovery that the reuptake of noradrenaline (norepinephrine) into the nerve endings from which it was released represented a novel method of neurotransmitter inactivation. An important corollary was the finding that antidepressant drugs acted as inhibitors of this uptake process. Subsequent work in his laboratory on the control of melatonin biosynthesis in the pineal gland provided new insights into the way in which the nervous system controls circadian rhythms, and offered an early model system in which to study the rapid control of mammalian gene expression. Axelrod continued actively in research until shortly before his death, and trained many students who have gone on to become leaders of the new field of biochemical neuropharmacology.

Acetaminophen overdose.

N-acetylcysteine (NAC) is the treatment of choice for acetaminophen overdose. With this therapy, morbidity from overdose can be held to a minimum. Mortality is rare in any case and virtually nonexistent in treated patients. Unless a high index of suspicion is maintained, the diagnosis may be missed until it is too late for effective antidotal treatment.

History of antipyretic analgesic therapy.

The use of naturally occurring plant materials for the relief of pain dates back to 3,000 B.C., although rapid advances in antipyretic analgesic therapy have been made more recently. Salicylic acid was synthesized in 1860, and the pyrazolone group, first represented by antipyrine, in 1883. Phenacetin was developed in 1886. Acetaminophen has been in use since the 1890s.