The pharmacological evaluation of natural products — general and specific approaches to screening ethnopharmaceuticals

When dealing with synthetic compounds, the usual sequence of pharmaceutical development continues to be (1) primary pharmacological screening, (2) secondary and tertiary acute pharmacological/toxicological evaluations, (3) chronic pharmacological/toxicological evaluations, (4) product formulation, (5) the various stages of clinical trials, and (6) release in commerce for therapeutic utilization. When dealing with natural drug products with centuries of ethnotherapeutic use, one can consider that the clinical trials for all practical purposes have been conducted successfully before screening even begins. The major problem for natural-product researchers then becomes how to define and isolate the useful chemical activity — activity which frequently may be unlike that of existing drugs on the market.

Pharmacological Approaches to Natural Product Screening and Evaluation

Several new mushroom poisoning syndromes have been described since the early 1990s. In these syndromes, the onset of symptoms generally occurs >6 hours after ingestion. Treatment is mainly supportive. The syndrome induced by Amanita smithiana/proxima consists of acute tubulopathy, which appears earlier and does not have the same poor prognosis as the orellanine-induced syndrome. It has been described since 1992 in the US and Canada with A. smithiana; in France, Spain and Italy with A. proxima; and in Japan with A. pseudoporphyria. The responsible toxin is probably 2-amino-4,5-hexadienoic acid. The erythromelalgia syndrome has been described as early as the late 19th century in Japan and South Korea with Clitocybe acromelalga, and since 1996 in France and then Italy with C. amoenolens. Responsible toxins are probably acromelic acids identified in both species. Several cases of massive rhabdomyolysis have been reported since 1993 in France and 2001 in Poland after ingestion of large amounts of an edible and, until then, valuable species called Tricholoma equestre. These cases of rhabdomyolysis are associated with respiratory and cardiac (myocarditis) complications leading to death. Rhabdomyolysis with an apparently different mechanism was described in Taiwan in 2001 with Russula subnigricans. Finally, cases of encephalopathy were observed twice after ingestion of Hapalopilus rutilans in Germany in 1992 and Pleurocybella porrigens in Japan in 2004, where a convulsive encephalopathy outbreak was reported in patients with history of chronic renal failure.

New Syndromes in Mushroom Poisoning

Introduction
In the Pacific Northwest a new pattern of mushroom ingestion has emerged, attributed toAmanita smithiana, in which renal failure has been the predominant manifestation.

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Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review.

Background. Renal failure as a consequence of eating mushrooms has been reported repeatedly after ingestion of webcaps of the Cortinarius orellanus group. But mushrooms of the genus Amanita can also cause renal failure: Amanita smithiana (North America) andAmanita proxima (Mediterranean area). Here, we discuss poisonings caused by other white amanitas. A German and—independently—two Portuguese patients reported the ingestion of completely white mushrooms with ring. Similar to intoxications with A. smithiana orA.proxima, the clinical picture was characterized by nausea and vomiting 10–12 h after ingestion, severe acute renal failure and mild hepatitis. Renal biopsy showed acute interstitial nephritis and tubular necrosis. Two patients were given temporary haemodialysis. All have fully recovered their renal function. Poisonings caused by mushrooms containing the toxin of A. smithiana were suspected. We tested 20 Amanita species for the presence of this toxin. Methods. Thin layer chromatography was applied to detect A. smithiana nephrotoxin in herbarium specimens using authentic material of A. smithiana as reference. Results. A. smithiana toxin could be detected in Amanita boudieri, Amanita gracilior and in Amanita echinocephala. A. boudieri was collected by the Portuguese patients. A. echinocephala is the only nephrotoxic Amanita growing North of the Alps and is suspected to be the cause of renal failure in the German patient. No A. smithiana toxin was detectable in the nephrotoxic A. proxima. Conclusions. A. boudieri, A. gracilior and A. echinocephala are nephrotoxic. These intoxications are clinically similar to that of A. smithiana, with acute reversible renal failure and mild hepatitis but are different in their clinical picture from Orellanus syndrome characterized by a delayed onset of severe and often irreversible renal failure.

/pdf/amanita-poisonings-resulting-in-acute-reversible-renal-whk8t6d2jl.pdf

Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms

The unsaturated norleucines of Amanita solitaria. Chemical and pharmacological studies.

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The unsaturated norleucines of Amanita solitaria. Chemical and pharmacological studies.