Toxic Fungi of Western North America

by Thomas J. Duffy, MD

Evaluation of amanitin treatment

Except for Florsheim's study, current therapy is largely based on animal experiments and the current treatments for liver and kidney malfunction. Most studies of survival are simply too small to be of statistical value. The problem of gathering enough patients to study the efficacy of new therapies occurs because of the few deaths that now occur. Researchers need to study additional end points, such as days of hospitalization, return to normal activity or avoidance of dialysis. As the death rate becomes smaller and smaller, it becomes more and more difficult to obtain the required numbers of poisoning cases to show likely efficacy. With a current mortality about 8%, even a 50% reduction to 4% is hard to demonstrate statistically.

High dose intravenous Penicillin G was efficacious in European studies, but this treatment has safety problems. It has to be given as the sodium salt. At 40 million units/day (or for children, 1 million units per kilogram of body weight), the dosage is close to the seizure threshold in children and makes sodium restriction difficult to achieve in adults. In the United States, this treatment has fallen out of favor and there is little likelihood of reaching the patient numbers needed for a North American study.

In addition to activated charcoal, European treatment also includes silibinin intravenously in a dose of 20-30 mg per Kg of body weight per day given in 4 equal doses over a period of 2 hours. Vogel did the original work showing that extracts of the European milk thistle antagonized phalloiden. The extracts also seemed to protect experimental animals from amanitin. A later study of his showed purified silibinin (the most potent compound from the milk thistle) to protect poisoned beagles. (69) The German drug company A.G. Mahaus was unable to get even an "orphan" drug approval from the FDA in this country. (70) The mechanism of silibinin protection appears to be interference with uptake by liver cells, thus interrupting the enterohepatic recirculation.

Glowing reports with silibinin claiming near-perfect survival rates use small numbers of patients. There are statistical methods (such as chi square) designed for small research numbers, but these methods are easily abused. The patients in question must be very homogenous with significant characteristics similar to that of a control or historical group of cases. Such characteristics include the variables of age and severity of poisoning (judged by the latency period before symptom onset and liver/kidney/coagulation tests). However, reports usually show marked improvement in liver function following the intravenous administration of silibinin. (87b)

A large co-operative study using multiple European, Asian and North American medical centers with a good clear protocol should be done on silibinin Its use in Europe is now standard, since the medication is readily available there and has no apparent side-effects. It is not generally available here, although it has been flown in for the treatment of at least one patient.

Hyperbaric oxygen in Floersheim's large study (3 atmospheres of pressure in the oxygen chambers) seemed possibly effective. Its use, however, was restricted to high-tech centers such as the one in Nancy. Few such centers exist and the care there would be presumed to be of the best available.