Amanita muscaria (fly agaric): from a shamanistic hallucinogen to the search for acetylcholine.

The mushroom Amanita muscaria (fly agaric) is widely distributed throughout continental Europe and the UK. Its common name suggests that it had been used to kill flies, until superseded by arsenic. The bioactive compounds occurring in the mushroom remained a mystery for long periods of time, but eventually four hallucinogens were isolated from the fungus: muscarine, muscimol, muscazone and ibotenic acid. The shamans of Eastern Siberia used the mushroom as an inebriant and a hallucinogen. In 1912, Henry Dale suggested that muscarine (or a closely related substance) was the transmitter at the parasympathetic nerve endings, where it would produce lacrimation, salivation, sweating, bronchoconstriction and increased intestinal motility. He and Otto Loewi eventually isolated the transmitter and showed that it was not muscarine but acetylcholine. The receptor is now known variously as cholinergic or muscarinic. From this basic knowledge, drugs such as pilocarpine (cholinergic) and ipratropium (anticholinergic) have been shown to be of value in glaucoma and diseases of the lungs, respectively.

Asthma: one hundred years of treatment and onward.

There have been four types of drug treatment of asthma that have been used over the past 100 years. Belladonna alkaloids, derived from the thorn-apple plant were used in 1905, and chemically synthesized entities in this class are still in use today. Western medicine began to use adrenergic stimulants approximately 100 years ago, but they were likely used in Asian medicine long before that. Systemic treatment with corticosteroids was introduced into the treatment of asthma in the mid-20th century; inhaled corticosteroids have been in use for over 35 years. The last 40 years have also seen the development of the first targeted asthma treatments: cromones, antileukotrienes, and anti-IgE. As we learn more of the biology of asthma, we anticipate that more effective targeted asthma treatments will be developed.

How to treat tremor.

This paper presents an example of 18(th) century medical thinking. The author, Dr Georg Ernst Stahl (1659-1734) was the founder of the phlogiston theory in the field of chemistry, a medical professor, and a court physician in Saxony and Prussia. His description includes a definition of tremor, the internal and external causes of tremor, the types of tremor, the diagnostic and prognostic signs, and the treatment. From a present (contemporary) point of view, some compounds that were then used in treatment may have had a limited therapeutic effect on some kinds of tremor. Protopin has an anticholinergic and GABA-ergic effect, and rhoeadin (tetrahydrobenzazepin) may have had an effect similar to that of neuroleptics. Nevertheless, it is not clear whether the recommended quantity of these compounds was sufficient for a clinical effect. Most of the prescribed drugs could only have had a placebo effect.

Treatments of peptic ulcer.

From the late 19th century, Mount Sinai gastroenterologists declared their scepticism of the efficacy of all recommended treatments of peptic ulcer, and looked forward to trials which could distinguish between sequence and consequence, between association and causation. The rationale of all the early studies was to reduce gastric acidity, but it soon became clear that any neutralization by single doses of antacids was brief and ineffective. Winkelstein s demonstration that patients with duodenal ulcer had higher acidities not only before and after meals but also through the night hours led him to introduce a new treatment, the alkalinized intragastric milk drip together with atropine. One of the earliest controlled clinical trials at Mount Sinai compared different antacid regimes and showed that pH values above 3.5 were achieved in only about half of the patients on the various drips. When the new anticholinergic drugs were developed in the 1950s, they were found to produce sustained hypoacidity and were tried as maintenance treatment, as an alternative to acid-lowering operations. The third Mount Sinai approach was to attack the machinery of the acid-producing cell itself by an inhibitor of the enzyme producing hydrogen ions. In 1939, this enzyme had been thought to be carbonic anhydrase, but when Janowitz and Hollander tested its inhibitor, acetazolamide, and showed marked but very brief acid inhibition, they concluded that its action was too brief to be therapeutically useful. The problem was to be solved decades later by H2 receptor blockers from Britain and H+K+ATPase inhibitors from Sweden.