Last weekend, 21 Venezuelan polo horses collapsed and died at the US Open championship match at the International Polo Club Palm Beach in Wellington, Florida (AP, CNN). The deaths have now been associated with injection of a veterinary mineral supplement produced by a compounding pharmacy in Ocala, Florida. Located in central Florida about 45 min south of the University of Florida, Ocala is well-known for its density of equestrian farms and training centers.
Precisely how this supplement killed the animals is not yet known but I can guarantee that it was a calculation error involving an errant decimal point, the bane of any professor in the STEM disciplines.
The compounding pharmacy that provided the supplement was apparently trying to reproduce the formula of a swine and equine supplement sold worldwide under the brand name, Biodyl. Biodyl is produced by Merial, an animal health product company run as a joint venture of Merck and Sanofi-Aventis. Merial conducts business in about 150 countries and lists annual sales at $2.6 billion; while they have operations in Duluth, Georgia, the Biodyl product is not sold in the US and their pressroom site does not have any information on this case as of this afternoon.
However, and to be clear, the product in question was not made by Merial. Rather, it was a custom formulation apparently commissioned by a veterinarian from Franck’s Pharmacy, a compounding pharmacy that has been in the business for over 25 years. Compounding pharmacies do what comes to mind when one thinks of an old-fashioned pharmacist in a Norman Rockwell painting.
Today, compounding pharmacies continue to play an important role in human and veterinary medicine in providing specialty products made to specific doses not available commercially, free of preservatives or potential allergens, or otherwise meet individual patient needs. The International Academy of Compounding Pharmacists has an excellent primer on the role of this practice of pharmacy.
The practice of compounding, however, has come under attack by FDA in recent years as some operations skirt the law and sometime produce what the agency calls unapproved drugs: preparations of compounds not currently approved in other forms. For example, compounding pharmacies the subject of FDA action for hormone creams defined as unapproved drug products or topical local anesthetics with inadequate labeling for use and safety.
So where do I think things went wrong? Well, what is in the Biodyl supplement and what is it used for?
The supplement contains sodium selenite, vitamin B12, and salts of potassium and magnesium. From their Philippine product site:
Injection solution containing metabolic constituents (adenosine triphosphoric acid or ATP, magnesium and potassium aspartate, sodium selenite and vitamin B12) for debility, convalescence and myopathies.
It is used to prevent a type of rhabdomyolysis, or life-threating skeletal muscle degradation, that can follow physical exertion after a period of inactivity (as one might expect for horses being transported to south Florida from Venezuela. Also known as equine rhabdomyolysis syndrome (EMS), tieing-up, or azoturia, the syndrome has been associated with high carbohydrate diet and selenium deficiency. I don’t quite understand the inclusion of ATP in the supplement since it does not readily cross cell membranes.
I must offer a mega hat tip: much of the information provided here today came from PharmGirl, MD. She dug up a lot of this info while I was on a plane yesterday and then while I was asleep and she wasn’t. I keep telling her to start her own blog.
However, we have differing opinions on the compound whose content was mistakenly calculated.
Having been trained originally as a toxicologist, my money is on the sodium selenite. Selenium is an essential element but is toxic at surprisingly low doses; as a trace element, adults only need about 55 micrograms per day (abbreviated mcg or µg). Methinks it would be quite easy for a pharmacist to mistake mcg or µg for mg or milligrams. So my bet is that the supplement had 1000 times the amount of sodium selenite than intended. The LD50 for sodium selenite in rodents and rabbits via the oral, intravenous, subcutaneous, or intraperitoneal routes is in the range of 2 to 7.5 mg per kg body weight (LD50 is an experimental term used to describe a dose of chemical required to kill 50% of animals in a given sample size)
Dr PharmGirl contends that the deaths were due to a miscalculation of either the magnesium or potassium, with potassium being the more likely culprit. Intravenous potassium chloride is one of three chemicals used for execution by lethal injection. Potassium, together with sodium, are among the most exquisitely regulated cations in physiology. The oral LD50 of potassium chloride, for example, is 1500 mg/kg in the mouse and 2600 mg/kg in the rat but I am unable to find these figures for injection.
What’s your guess?
Regardless of the cause, this is an extremely sad case that will draw much attention to the practice of pharmacy compounding. I wrote two years ago about a fatality in an Oregon integrative medicine clinic due to a 10-fold error in an injectable colchicine product that was being used unconventionally for back pain.
Compounding pharmacies that operate ethically provide an important service for physicians and their patients. And, sadly, contacts I have inform me that Franck’s Pharmacy in Ocala has a very good reputation in veterinary circles.
These cases should give the profs among our readers more fuel to respond to students about placement of decimal points and the importance of calculations in their respective careers.
UPDATE (25 Apr, 9:40 am EDT): While writing this post yesterday, GrrlScientist wrote an excellent story where she learned of an anonymous source who told an Argentinian newspaper that there was a ten-fold error in the amount of sodium selenite used.