Past, Present and Future of Dantrolene

As all of you who are reading this know, dantrolene sodium is THE drug to treat malignant hyperthermia.  There are some important and interesting changes and insights developing with this drug that I would like to explore with you.

First, a bit of history.  Dantrolene was developed by a small company in Upstate NY, Norwich Eaton Pharmaceuticals, Inc., not far from our home office in Sherburne, NY in the early 1970s.

A very bright scientist, Dr. Keith Ellis, found that a modification of a drug that Norwich Eaton had developed, Macrodantin, for the treatment of urinary tract infections, had rather peculiar properties.  When injected in animals, they appeared motionless, muscles flaccid, but they were still breathing.  Curious about this, he did some studies in the lab and found that the drug reduced muscle tone, but did not act on the nerves or the neuromuscular junction.  Dr. Ellis had been following the developing malignant hyperthermia story and noted that MH was a disorder involving increased muscle tone and increased metabolism arising from the muscle.  He was anxious to test the drug in the MH situation and was put in touch with Dr. Gai Harrison in South Africa who was investigating MH in susceptible swine. He had tried numerous compounds in the treatment of MH, with limited success. When he received the dantrolene compound, he was astonished to see that the drug rapidly and predictably reversed the syndrome. While I was attending the Second International workshop on MH in Denver in 1975, the news was announced about this wonderful compound.  However, the drug was not yet in an intravenous form, so all sorts of homemade brews were developed using the crushed dantrolene pills.

Somewhere around this time Procter & Gamble acquired Norwich Eaton and developed the intravenous formulation we know of today. However, the drug had to be approved by the FDA first. Mary Elizabeth Kolb was given that task.  She arranged for the drug to be available to certain centers and within a few years about 30 cases of MH or presumed MH were collected, scrutinized by a panel (I participated) and concluded that the drug was indeed effective.  The drug was approved in record time by the FDA in 1979.  It was one of the seminal advances in the field of anesthesia (Dantrolene in Human Malignant Hyperthermia A Multicenter Study, Anesthesiology 56(4):254-262, April 1982.)

However, intravenous dantrolene is a difficult drug to get into solution.  The compound comes as a freeze dried powder to which sterile water must be added.  Furthermore, the drug is packaged in 20mg vials only.  For the average person, at least nine vials must be reconstituted and injected.  P&G and their advisors then felt that in order to make sure an adequate amount of the drug was available for treatment of MH, 36 vials should be purchased, no less.  This created problems for some, because at that time the cost of the drug was over $2000 for a supply with a 28- month shelf life.  However, no one could deny that without dantrolene the likelihood of dying from MH was over 50%, but with its use, less than 5%.  So, the company and MHAUS, which was created in 1981, began to urge that all hospitals, ambulatory centers and office surgery suites using the MH trigger agents have a full supply of dantrolene available.  There must be thousands of patients whose lives were saved by this drug over the years.

This is how the situation stood until 2007 when a start-up company, US World Meds, LLC began to market a generic version of dantrolene at a considerably lower cost than the P&G product.  However, it was still the same compound.  The only other company that I know of who makes dantrolene is a Brazilian company, Cristalia.

This past month P&G announced the sale of its product to two companies, JHP Pharma and SPE Pharm.  The former acquired the rights to North America, the latter to Europe, Chile and certain other countries.  These two relatively new companies distribute a variety of generic drugs. They will work with P&G to insure that the product is available during the transition.  Both companies are committed to providing the drug and perhaps improving its formulation.

However, there is yet another company, Lyotropic Therapeutics, based in Virginia that has developed a concentrated, soluble form of dantrolene containing 50mg /ml of the drug.  This means no more reconstitution and the entire dose can be stored in a syringe. The compound, called Ryanodex, has been used to treat and reverse MH crises in swine successfully, but has yet to be approved by the FDA or the European regulators. However, they are moving ahead with product testing.  As far as I know it has not been used in any humans to date.

Competition is always helpful in improving products and lowering costs.  We now have three companies (four including Cristalia) distributing dantrolene and a fifth with a new formulation.  This can only be of benefit for those who deal with MH.

Meanwhile, there are some other interesting developments regarding the therapeutic value of dantrolene.  It has been known for a while that in many cases dantrolene is effective in reversing extreme temperature elevation from a variety of causes.  For example, it has been used successfully and sometimes dramatically in the treatment of neuroleptic malignant syndrome and in the treatment of hyperthermia, acidosis and muscle breakdown from drugs of abuse such as MDMA (Ecstasy).  An animal model of MDMA toxicity has been developed by researchers Wappler and colleagues from Cologne, Germany and they have demonstrated that Ryanodex reverses the biochemical changes of MDMA toxicity.  Another peculiar and rare syndrome is extreme temperature elevation and muscle breakdown in new onset diabetes in young people.  A number of case reports have shown that when this occurs, unless dantrolene is given, fatality is likely.  It is not known whether this syndrome occurs in MH susceptibles only or in those who are not MH susceptible.

What is the link between these hyperthermic and hypermetabolic syndromes and dantrolene?  Is it a non-specific effect on reducing muscle tone which is capable of generating heat or is it a specific effect of dantrolene’s action on the calcium channel (the ryanodine receptor) to which it binds as demonstrated by Dr. Jerry Parness?  Although this is still speculative, the recent finding that the ryanodine receptor is involved in the development of heat-induced MH in the genetically-engineered MH mouse, by Susan Hamilton’s group may be informative. (RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knock-in mice. Cell 133(1):53-65, 2008) on exposure to high environmental temperature leading to high body temperature, a variety of reactive nitrogen compounds are produced that bind to the ryanodine receptor.  At least in the mouse model, with the abnormal ryanodine receptor, these compounds will open the channel, thereby releasing calcium into the cytoplasm, which leads to all the changes found in MH.

One possibility is that in certain hypermetabolic states, such as develops in cocaine and Ecstasy overdose, even with normal ryanodine receptors, the reactive intermediates may alter the ryanodine receptor sufficiently to lead to the typical changes of MH.  The investigators, Feige, Wappler and colleagues from Cologne, have shown that MDMA toxicity in even non-MH swine will produce an MH-like picture that is reversed by dantrolene.

One other intriguing aspect of this subject is that from time to time the hotline is called concerning a young patient who, after open heart surgery develops hyperthermia, acidosis and other signs of MH, but without a family history of MH.  If untreated, the patient becomes progressively unresponsive to pressor drugs, develops muscle breakdown and may die. There is only one report on such cases published many years ago in the now defunct journal, the American Journal of Anesthesiology, by investigators from Johns Hopkins. There were similarities to MH, but none of the patients were tested for MH, but there were differences as well. Dantrolene reverses this syndrome though.  Because this problem is so uncommon and there is no animal model there is, to my knowledge, no ongoing investigation of the phenomenon.

Another untapped area is the role of dantrolene in heat stroke. Certainly, most heat stroke is not related to MH, but is environmentally induced, but there is definite evidence that some small number of patients who develop heat stroke are MH susceptible.  Unfortunately, this is another area that is virtually devoid of controlled scientific studies except in the military where the relationship between heat, exercise and muscle breakdown is under investigation in the laboratory of Dr. Deuster at the Uniformed Services University.

With the advent of molecular genetic testing and more widespread awareness of MH and other drug-induced hyperthermic syndromes, we undoubtedly will learn more about dantrolene, its mode of action and its utility in the treatment of disorders other than classic MH.