To follow on our recent discussions of a European herbal extract with efficacy against poisoning with certain species of Amanita mushrooms, I pulled out this post that I wrote in 2007 about the outstanding work of Dr. S. Todd Mitchell. Depending on the amount of mushrooms ingested, patients can experience severe liver damage that can be lethal. In these cases – about 10 percent or so – the only real “treatment” is a liver transplant.
In searching for potential remedies for his patients who ingested amatoxin-containing mushrooms, he learned of an intravenous preparation from Europe (Legalon-SIL) containing a salt of silibinin, a pair of hepatoprotective compounds from milk thistle (Silybum marianum). Mark Blumenthal, Executive Director of the American Botanical Council, has been questioning for over 15 years why the US FDA has not made this IV drug available in emergency rooms (personal comm.).
Although silibinin and its more crude relative silymarin are available in oral forms as herbal medicines around the US and the world, they lack sufficient bioavailability for emergency treatment. Mitchell gained emergency IND status (a waiver, actually) from the FDA for this intravenous formulation and subsequently saved several family members from what was likely to be certain death.
Another story appeared two years later in the Santa Cruz Sentinel where Mitchell had to retrace his steps to again procure the drug. In 2010, the Sentinel reported that he became sponsor of an open investigational clinical trial of Legalon-SIL in the United States. (This third article was also written by Sentinel reporter, Jondi Gumz.) This trial facilitates Legalon-SIL use by physicians anywhere in the US where qualified patients have suffered amatoxin poisoning. Such trials are most commonly led from large academic medical centers; that this one is from a community hospital speaks highly of Mitchell’s determination in providing widespread access to this drug.
This post appeared originally at the ScienceBlogs home of Terra Sigillata on 14 January 2007.
A thoughtful reader of mine and Kevin MD’s just brought to my attention the plight of six members of a California family who apparently ingested Amanita phalloides (deathcap) mushrooms following a New Year’s Day outing.
Jondi Gumz of the Santa Cruz Sentinel reported today on the circuitous route the attending physicians took to obtain a source and FDA emergency approval to try an intravenous formulation of an herbal medicine from Europe.
Using Google Scholar, a search engine of scholarly literature, he [Dr Todd Mitchell] found a promising avenue of treatment: Extract from milk thistle, a nuisance weed for farmers and used as a liver tonic in European folk medicine.
Milk thistle extract, or silymarin, has been used in Europe to treat cirrhosis of the liver, scarring that often proves fatal.
In a 1970s experiment, beagles that received milk thistle intravenously were protected from mushroom poisoning
That treatment, intravenous milk thistle extract, is not available in the United States and is not approved by the Food and Drug Administration.
The mushroom toxins from the Amanita family, amatoxins, are heat-stable cyclic peptides that inhibit RNA polymerase II and cause severe liver damage, often requiring liver transplant. German researchers in the 1960s first identified hepatoprotective compounds from extracts of milk thistle seeds, known also as silymarin or silibinin. In 1984, the German phytopharmaceutical company, Madaus AG, first offered an intravenous preparation called Legalon (silibinin hemisuccinate) that is widely kept in European emergency rooms to treat such cases of mushroom poisoning.
Very early Wednesday morning, Mitchell called the company and got the number of its office in Germany, where the drug is approved for use.
He reached Peter Odenthal of Madaus in Cologne, Germany, and explained the situation. It was already afternoon in Germany. Odenthal agreed to donate enough Legalon to treat all six family members.
However, the US FDA prohibits the explicit marketing of botanical medicines for disease treatment, and certainly is not keen on intravenous preparations of herbal products. Groups wishing to study botanical medicines in clinical trials must first obtain from FDA a botanical investigative new drug approval, a truncated but still laborious form of the IND required before a new prescription drug can be given to patients. And, of course, the physicians required approval of their Institutional Review Board (IRB) to administer an experimental medication.
Oral preparations of milk thistle are available in the US, but the purported active constituents have notoriously poor oral bioavailability, hence the Germans’ development of an intravenous product. The recommended intravenous dose of 20 mg/kg would produce a mean plasma concentration in the neighborhood of 500 micromolar. In contrast, an oral dose of 13 grams daily was shown recently to produce a blood concentration of just over 100 micromolar. (note: these calculations aren’t entirely accurate since milk thistle extracts contain anywhere from two to eight active compounds).
Mitchell also had read up on oral milk thistle in capsules. The FDA hasn’t approved that either, but a lot of companies sell milk thistle extract in that form as a supplement…The patients began taking the capsules that day, but Mitchell wasn’t sure it would be enough. The patients were already nauseous and vomiting.
Ultimately, five of the six family members had to be transferred to a San Francisco hospital capable of performing a liver transplant. The 83-year-old matriarch of the group had unfortunately died.
Long story made short: all of the patients received a standard therapy of N-acetylcysteine (usually used for acetaminophen overdoses), activated charcoal (to bind the amatoxins), and penicillin G (probably inhibits active transport of amatoxins into cells). The intravenous Legalon was reserved for the two of the sickest remaining patients.
Four of the five family members have been released from the hospital.
A blinded, controlled study this is not – always a major challenge in the study of any antidotal regimens for poisonings – and it would have been unethical to withhold the three standard therapies and test the intravenous milk thistle extract alone. But, hopefully, these cases will be written up for the medical literature to provide some insight as to the contribution of the botanical therapy in the recovery of these patients.
Gumz J. (2007) A life-or-death situation: Family poisoned by mushrooms first to receive experimental treatment. Santa Cruz Sentinel. 14 January 2007. As posted at the Bay Area Mycological Society.
Gumz J. (2009) Santa Cruz doctor helps save lives of family who ate poisonous mushrooms. Santa Cruz Sentinel. 12 January 2009.
Gumz J. (2010) Dominican doctors pioneering research on mushroom poisoning antidote. Santa Cruz Sentinel. 10 May 2010.
Clinical Trial: Intravenous Milk Thistle (Silibinin-Legalon) for Hepatic Failure Induced by Amatoxin/Amanita Mushroom Poisoning. ClinicalTrials.gov NCT00915681. Last accessed 31 January 2012.