The history of acetylcholinesterase inhibitors in the treatment of myasthenia gravis.

The beneficial effects of acetylcholinesterase inhibitors for the treatment of myasthenia gravis (MG) was a major discovery that came about through one young physician putting together a string of previous observations. To understand how this discovery came to light, we must first go back to earlier times when men hunted by bow-and-arrow to capture their prey. The substance used to poison the prey was eventually was identified as curare. Centuries later, a connection was made between the physiological effects of curare and a disease entity with no known pathological mechanism or treatment, myasthenia gravis. In 1935, house officer Dr. Mary Walker was the first physician to try physostigmine in the treatment of MG, which had previously been used to treat curare poisoning. What she saw was a dramatic improvement in the symptoms experienced in patients with MG, and thus became the first documented case of use of physostigmine, an acetylcholinesterase inhibitor, in the treatment of MG. This article is a summary of the history of the use of acetylcholinesterase inhibitors in the treatment of myasthenia gravis. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Curare--a curative poison: a scientometric analysis.

INTRODUCTION: Curare is one of the best-examined neurotoxins of the world, which has empirically been used for centuries by American Indigenes. Research on curare has been performed much later, a global scientometric analysis on curare research or its derivates does not yet exist. This bibliometric analysis is part of the global NewQis-project and should illuminate both toxic and historic issues of research on curare. METHODS: The ISI Web of Science was searched for data covering 1900 to 2013 using a term which included as many original articles on curare as possible. 3,867 articles were found and analyzed for common bibliometric items such as the number of citations, language of the articles or the (modified) Hirsch-Index (h-index). Results are illustrated utilizing modern density equalizing map projections (DEMP) or beam diagrams. RESULTS: Most publications were located in North America and Europe. The USA has the highest number of publications as well as the highest h-index. The number of publications overall rose until the late 1990s and later decreased. Furthermore, sudden increases of research activity are ascribable to historic events, like the first use of curare as muscle relaxant during surgery. DISCUSSION: This scientometric analysis of curare research reflects several tendencies as previously seen in other bibliometric investigations, i.e. the scientific quality standard of North America and Europe. Research on curare decreased however, due to the declining attention towards this muscle relaxant. This work exemplifies also how scientometric methods can be used to illuminate historic circumstances immediately stimulating scientific research.

[French survey of neuromuscular relaxant use in anaesthetic practice in adults]. / Enquête de pratique sur l'utilisation en France des curares chez l'adulte en anesthésie.

Guidelines about the use of neuromuscular blocking agents based on a national consensus conference have been published in 2000. A survey was carried out to assess adherence to these guidelines. An online questionnaire was designed from the different guidelines concerning the use of muscle relaxant for tracheal intubation and surgery, monitoring and antagonism of neuromuscular blockade. In addition, question about the knowledge of the pharmacodynamics of neuromuscular blocking agents were asked. Analysis concerned 1230 answers from senior anaesthetists. Tracheal intubation is facilitated by the use of a competitive agent or by succinylcholine by 58 and 8% of responders respectively. Atracurium and cisatracurium were most frequently used (49 and 44%, respectively). The duration of effect of an intubating dose of atracurium, vecuronium or rocuronium was estimated equal or below 60 min by more than half of responders, whereas that of cisatracurium was longer. Fifty-two or 74% of responders used neuromuscular monitoring, whether a single or repeated dose of muscle relaxant was administered. Antagonism of neuromuscular blockade was systematic, frequent, and episodic or excluded by 6, 26, 55 and 13% of responders, respectively. Monitoring and antagonism of neuromuscular blockade are underused despite the guidelines. Underestimation of the risk of postoperative residual curarization is linked to the underestimation of the duration of competitive neuromuscular blocking agents.

[Neuromuscular monitoring: methods and machines]. / Uberwachung der neuromuskulären Blockade - Methoden und Geräte.

Muscle relaxing agents are clinically in use for general anaesthesia to optimize the conditions to the endotracheal intubation as well as the surgical conditions. Therefore different musclerelaxants with specific pharmacological characteristics are available. Many factors that depend on the condition of the patient and the used musclerelaxant agent influence the duration of the neuromuscular blockade. Rapid reversal of their effects, particularly in cases of profound blockades, proved to be difficult. In cases of postoperative residual paralysis hypoxic complications because of failure of the ventilation increase the morbidity and mortality of the perioperative period. To avoid these complications in cause of postoperative residual neuromuscular blockade it seems to be necessary to evaluate the status of the muscle function. For the tactile or visual assessment or the objective measurement of stimulation the train-of-four (TOF), double-burst (DBS) or tetanus-stimulation of peripheral nerves like the ulnar nerve may be used. Established methods for the objective monitoring of neuromuscular function is the mechanomyography (MMG), the acceleromyography (AMG), the electromyography (EMG), the kinemyography (KMG) and the phonomyography (PMG). A sufficient recovery of the neuromuscular transmission is reached to a TOF-ratio of 0,9 and should be aimed before the extubation at the end of surgery. No subjective evaluation of the neuromuscular recovery is able to identify residual paralysis above a TOF-ratio of 0,5. Recent studies suggest that objective methods should be used to monitor neuromuscular function to avoid postoperative residual blockades.

The use of curare during anesthesia to prevent iatrogenic muscle damage caused by lumbar spinal surgery through a posterior approach.

STUDY DESIGN: Prospective randomized study of patients undergoing lumbar arthrodesis. OBJECTIVES: To evaluate the use of curare during anesthesia to limit muscle lesions caused by surgery. SUMMARY OF BACKGROUND DATA: It has been shown that lumbar spine surgery through a posterior approach can induce iatrogenic lesions in the erector spinae. The prevention of these lesions by intraoperative cholinergic blockade has never been evaluated. METHODS: Twenty patients scheduled to undergo pedicle-screw enhanced L4-L5 arthrodesis were enrolled in this study. The average age was 48.9 years. Ten patients received curare during anesthesia and 10 patients did not. Postoperative pain was assessed using a visual analog scale (VAS) and the consumption of morphine by patient-controlled analgesia during the first 24 hours. Intramuscular pressure (IMP) in the multifidus was monitored during the intervention. A biopsy of the multifidus muscle was performed at the end of the intervention for histologic study. Serum activity of the MM iso-enzyme of the creatine phosphokinase (CPK-MM) was measured 24 hours after surgery. RESULTS: The average consumption of morphine and the mean value of the VAS at 24 hours were not statistically different between these 2 groups. The use of a self-retaining retractor during lumbar surgery resulted in a substantial increase in IMP, resulting in histologic muscle lesions and an increase in serum CPK-MM activity. There was no significant difference between the 2 groups of patients. CONCLUSIONS: The use of curare during anesthesia did not limit the muscle damage caused by surgery.

Curare: the South American arrow poison.

The history of curare is both curious and convoluted. A product of South American culture it emerged in the sixteenth century from the mists of antiquity at the same time as quinine, coca, and chocolate. Like quinine, at first came the extract but no plant, and later the plant but no chemical compound. It took more than 300 years and the efforts of many explorers and scientists to resolve the problem. These included Condamine, Humboldt, Brodie, Waterton, Bernard, Dale, Walker, and King. Finally, the pure compound d-tubocurarine was isolated from the liana Chondrodendron and synthesised. Its specific physiological action was blockade of the effect of acetylcholine at the neuro-muscular junction. Such a paralytic poison could be used to kill oneself or others. The bizarre plot to kill the Prime Minister, Lloyd George, during the First World War is described. Fortunately this nefarious plan was thwarted by the Secret Service!

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.

[A new toy: upswing in curare use in Spanish anesthesia]. / A new toy: la irrupción del curare en la anestesia española (1946).

The introduction of curare for general anesthesia by Harold Griffith in 1942 was one of the most important moments in the development of anesthesiology. However, several years passed before curare came to be used in Spain. We review the early application of curare and the role played by Robert Macintosh, Professor of Anaesthesia at Oxford, in introducing the drug to Spain.

Generalized periarticular myositis ossificans as a complication of pharmacologically induced paralysis.

To our knowledge, no previous direct associations have been made between generalized myositis ossificans and pharmacological therapy. We report a case of generalized periarticular myositis ossificans associated with the use of curare and diazepam. The previously reported associations of myositis ossificans with tetanus and burns may be misleading. It is possible that it is not the disease process itself (e.g., tetanus, severe burn) that precipitates heterotopic ossification, but the treatment of these ailments. These observations suggest the importance of early mobilization and restrained use of immobilizing drugs. Further investigation is warranted with regard to the predisposing factors of generalized myositis ossificans and to its prevention.

Direct negative chronotropic and inotropic efects of curare on isolated and perfused frog's heart

It has been stated that curare has no direct effect upon the heart because the cardiac muscle is deprived of nicotine receptors. While performing an experimental work, we noticed that when high doses of curare were administered to frogs, a change in cardiac activity occurred. In order to elucidate whether the cardiac effects of curare wee the results of a direct action or a reflex response, we studie the effects of increasing doses of d-tubocurarine on the rate and contractility of 8 isolated and perfused frogs'hearts. After testing the d-tubocurarine effects on the heart rate and contractility, we added either acetylcholine, atropine, atenonol or verapamil in orden to find out whether any change ocurred in the cardiac effects produced byd-tubocurarine. Thirty seven measurements were carriet out and it wasfound that 1) high doses (between 1 and 15 micrograms) of d-tubocurarine produced a highly significant decrease in heart rate an contractility; 2) d-tubocurarine did not avoid the acetycholine effect; 3) atropine, atenonol and verapamil did not interfere with d-tubocurarine effects. We conclude that high doses of d-tubocurarine produce "dosis-dependent" heart rate and contratility reductions. These effects are not mediated by muscarinic receptors beta-1 receptors or the show calcium channels