Neuromuscular block.

Descriptions of the South American arrow poisons known as curares were reported by explorers in the 16th century, and their site of action in producing neuromuscular block was determined by Claude Bernard in the mid-19th century. Tubocurarine, the most important curare alkaloid, played a large part in experiments to determine the role of acetylcholine in neuromuscular transmission, but it was not until after 1943 that neuromuscular blocking drugs became established as muscle relaxants for use during surgical anaesthesia. Tubocurarine causes a number of unwanted effects, and there have been many attempts to replace it. The available drugs fall into two main categories: the depolarising blocking drugs and the nondepolarising blocking drugs. The former act by complex mixed actions and are now obsolete with the exception of suxamethonium, the rapid onset and brief duration of action of which remain useful for intubation at the start of surgical anaesthesia. The nondepolarising blocking drugs are reversible acetylcholine receptor antagonists. The main ones are the atracurium group, which possess a built-in self-destruct mechanism that makes them specially useful in kidney or liver failure, and the vecuronium group, which are specially free from unwanted side effects. Of this latter group, the compound rocuronium is of special interest because its rapid onset of action allows it to be used for intubation, and there is promise that its duration of action may be rapidly terminated by a novel antagonist, a particular cyclodextrin, that chelates the drug, thereby removing it from the acetylcholine receptors.

Ethnopharmacology in drug discovery: an analysis of its role and potential contribution.

In this paper we discuss some examples of ethnopharmacological research as it has been conducted during the last two centuries and look at the current role of this discipline in drug discovery (especially with respect to the American and European markets) and the further development of these phytotherapeutical resources for local use in the countries of origin (ethnopharmacology). Examples from 19th century research on curare (Humboldt and Bernard), from the 20th century on hallucinogenic mushrooms (Wasson), on Mexican Indian indigenous plants (our own research) and of current industry based research are used to illustrate the development of this discipline and to highlight the challenges for the future.

Prelude to pancuronium and vecuronium.

The discovery of the neuromuscular blocking activity of malouetine isolated from Malouetia bequaertiana Woodson by Quevauviller and Lainé in 1960 stimulated interest in aminosteroids as potential neuromuscular blockers. Alauddin (a pharmacist) and Martin-Smith (a medicinal chemist) began research in this area, which was then taken up by pharmaceutical companies. Pure pancuronium was synthesised in 1964 by Savage and his co-workers, directed by Hewett. Pharmacologists headed by Buckett discovered that pancuronium was far more potent than d-tubocurarine and had minimal side-effects. Buckett quickly recognised the value of pancuronium, and his persistence resulted in successful clinical trials, followed by the commercial launch of pancuronium in 1968. Vecuronium was synthesised, tested and the studies published by Buckett, Hewett and Savage in 1973, but this was before anaesthetists called for a 'clean muscle relaxant' and, furthermore, it was unstable in aqueous solution. Hence, it was only promoted for clinical trials six years later.