Biodyl, Franck's Pharmacy, and Florida Polo Horse Deaths: Guaranteed It's the Decimal Point

Great post, Abel-props to you and to PharmGirl MD! I favor the selenium overdose hypothesis, and commented accordingly over at the Chimpanzee Refuge last night. The symptoms of selenium toxicity fit with some of those displayed by the horses: altered heart rhythms, labored breathing, motor problems, and high temperature. The vets and players had ice packs on the horses, as well as water-misting fans.

I've never understood the widespread use of high-dose vitamin/mineral supplements in polo. It's puzzling that the Lechuza team was so insistent on having the Biodyl formula compounded so that they could use it in Florida. Most likely the horses that died had been in Wellington for the Palm Beach season, several months perhaps; they hadn't just been brought in from Venezuela. Lechuza won the Piaget Gold Cup there in March, and they have been playing (slightly different human team) US Open matches throughout April.

Another thing I don't understand is why Biodyl is not approved for use in the US, since it's just Vitamin B12, minerals, and the ATP. Would some sort of preservative or stabilizer block FDA approval?

I think your right. Selenium.

Underlying reason is indeed the placement of the decimal. Specifically I think you nailed it as misreading of mcg as mg.

It is an easy mistake to make. A slightly too quick reading, a slight smearing of ink, or sloppy doctor's handwriting are on the top of my list for underlying causes. It could come down to something as simple as fatigue, eyestrain, or a failure to clean their glasses.

I have no idea what killed the horses (which is so, so friggin sad), but the exact type of error you described actually happened to me!
I had to have fentanyl lozenges compounded because I had a problem with Actiq, and when I went to pick them up, the order was outrageously expensive - fentanyl's expensive, at least in retail, but I'm talking a bill more than my $20,000 credit card limit. When I was like, "WTF?", the pharmacist showed me the prescription and the cost of the ingredients - turned out that he had compounded the lozenges in milligrams instead of micrograms.
Apparently, I was lucky it was so expensive, because otherwise I never would have noticed, and I could have died!
The really crazy thing - he actually wanted me to pay for all the fentanyl he ordered + wasted! I was like, "no way dude, I'm not paying 20K for your error!" and he told me not to come back.

I never went back again and they went out of business about a year later.

I hope, though, that the FDA doesn't take these sorts of negative incidents and use them to really clamp down on compounded medications. The compounding pharmacy I've used ever since is wonderful, ethical, and has never made any mistakes.

Posted by: Art | April 24, 2009 5:51 PM wrote, in part, "It is an easy mistake to make."

While I agree that is the most likely explanation given what we think we know- a pharmacist who makes that mistake must be brain-damaged. It is not an "easy mistake" for a sober pharmacist.

Aside from that, iatrogenic damage from standard procedures is unavoidable; but there is no excuse for it from magical potions; which I think is the case here. I doubt the amount of aspartate (or calcium and magnesium in the salts) and B12 were nutritionally significant. We agree that ATP is of dubious benefit.

Even if the product (as mistakenly produced) was lethal, the proximal cause of death was the person who thought it was beneficial.

sam | April 24, 2009 7:33 PM wrote "The compounding pharmacy I've used ever since is wonderful, ethical, and has never made any mistakes."

May I add "yet"? "Compounding Pharmacies" cater to the woo crowd. Any pharmacy can make a personalized prescription. However, there is little need for that in actual practice.

sam | April 24, 2009 7:33 PM wrote "The compounding pharmacy I've used ever since is wonderful, ethical, and has never made any mistakes."

May I add "yet"? "Compounding Pharmacies" cater to the woo crowd. Any pharmacy can make a personalized prescription. However, there is little need for that in actual practice

Unless, of course, you're my mother-in-law, and have multiple chemical sensitivities, probably because she has Barter's Syndrome. She's also left-handed and color blind. Her genetic luck is just terrible.

Anyway, she has to special order most of her very expensive medications. A few years back, she went in for a routine MRI to check for uterine cancer and brought her own saline flushes (preservative free). The radiologist on duty thought, "WTF? No one has a problem with saline" and didn't use them. She had a severe anaphylactic shock, and had to be hospitalized.

They were running out of rooms in the CCU, and so put her in a negative pressure room, without warning labels on the doors. That night, a janitor came in and mopped the floor with a chemical detergent that the hospital already knew that she was allergic to (because she was an LPN and worked there), and because it was a negative pressure room, the air concentration of the detergent was high. She went into another severe anaphylactic shock, this one so bad that they had to take an hour to bring her out of it.

Long story short, she ended up spending nine months in the hospital, and suffering brain, heart, eye, inner ear, and lung damage. She ended up being permanently disabled, and now lives on SSI-Disability.

Compounding pharmacies have their place. And FWIW, her board-certified, medical doctors order all her medications - she doesn't get them herself.

@Courtney,

Go to www.quackwatch.org and search for 'multiple chemical' and read about it. Unfortunately, MCS is a bogus diagnosis for people with other, serious problems. People who are told they have that problem are being victimized by the notion that they need to special-order nearly everything. Even board-certified MDs get caught up in that nonsense.

i'm betting on the selenium too- the LD50 is pretty low. i'm sure that injection of K+ has a lower LD50 than oral, but surely not down to the 2-7.5 mg/kg range. thanks to you and Pharmgirl for putting this together... it's been in the back of my mind, but i'm engaged in heavy battle with endnote x2 for the time being...

Excellent post. I'd put my money on potassium. No doubt you are on the money regarding the ease of confusing mcg and mg, but what is the death process like for high selenium? I've seen lots of people drop dead PDQ from high potassium...

Having worked on drug development, I know that conventional drug good manufacturing practices (GMPs) have multiple layers of checks and QC to prevent this kind of thing. For example, under GMP you'd typically need one person to calculate the amounts for each ingredient, and then have a second person check to confirm the calculations. Then you'd have one person actually add each ingredient, while a second watched to confirm the the correct amount of the correct ingredient was added. And of course, they'd be following a pre-written procedure that had been approved by the quality unit, and they'd each be initialing every step as it was completed, and on and on.

Anybody know what checks are required for a compounding pharmacy?

A couple of things come to mind. Pharmacists infrequently are presented orders or prescriptions that are uncommon to them. They conscientiously fill them and dispense them when confidence, discretion and intuition dictate to do so. The vast majority of times pharmacists handle orders that are very familiar. Unlike physician specialties, which have adequate back-up within their respective specialties, the practice of pharmacy does not have that luxury. It's a long story. This will likely boil down to an unfortunate mistake.
Lastly, there seems to be little attention paid to the horse owners who subject their horses to a sport that pushes them to the physical edge. When owners inject horse to prevent rhabdomyolysis the selfishness of the owners deserves inquiry.

I should clarify that those GMP procedures apply for human drugs. I don't know what rules apply for veterinary drugs.

I think joe and Scott Parrish have the focus where it belongs.

1, Why is it OK to subject these horses to routines that expose them to risk of rhabdomyolysis? and

2, Why does no one seem to suspect foul play? I don't buy the micrograms-for-milligrams "mistake" -- what, do vet pharmacists routinely do that kind of work drunk? It's not an "easy mistake to make", it's a bonehead mistake that professional training and work practices are designed to eliminate. Not minimise, eliminate.

Plus, we're talking about a mixture of rich people (the kind who think it's just fine to spend hundreds of thousands or millions of dollars a year to play dressup and ride ponies), high-ticket entertainment, sudden deaths -- Se or K, my money's on deliberate rather than accidental. Worldwide 95% rule applies: find the rich white man who benefits from this, and there's your perp.

@Catharine: death by selenium "nausea and vomiting, followed by pulmonary edema and rapid cardiovascular collapse approximately 3 to 4 h after ingestion" see http://www.astm.org/DIGITAL_LIBRARY/JOURNALS/FORENSIC/PAGES/JFS2004247…

That's just from a quick google -- couldn't find much decent info easily accessible. I'm thinking the pulmonary edema might make this a particularly nasty death, distinct from (and slower than?) potassium overload. Presumably blood work will confirm whether Se or K was elevated to toxic levels.

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.

Couldn't agree more with Bill and Scott about the reason these kinds up supplements are used.

qetzal, great comment about the multiple levels of checks in GMP facilities. I'm also not clear on the chain in compounding pharmacies, human or veterinary.

Joe is also correct that compounding pharmacies have run into most problems in trying to skirt drug regulatory procedures to provide "alternative" drugs to clients. But once again, we see co-opting of good old pharmacology by the CAM community - using an unapproved pharmacological agent is NOT alternative medicine.

@ #13: Why is it OK to subject these horses to routines that expose them to risk of rhabdomyolysis?

The fact that the Lechuza team injects Biodyl, touted as a treatment for rhabdomyolysis, into their horses does not necessarily mean that all, or even most, polo horses develop rhabdomyolysis after games. Azoturia, or reddish-brown urine due to myoglobin content, reflects the most severe consequences of rhabdomyolysis; if polo horses were routinely voiding dark red urine at the trailers or washracks after matches, don't you think grooms, spectators, and vets would notice?

The milder consequence of excess lactic acid in performance horses is tying-up syndrome, with tight muscles and excessive sweating. Most horses, even performance Thoroughbreds, have never tied up, and if you do have a horse that is prone to this, you have to be careful to warm up the animal before vigorous exercise. I'm a rank amateur, and I know this, so I'm sure the polo teams playing in Palm Beach are aware that proper conditioning and warming up horses are the best prevention for tying up. A high-goal team like Lechuza, with a wealthy patron, can certainly afford the grooms required to warm up horses before a match. And as I mentioned above, it's very unlikely that the Lechuza horses were coming off a period of inactivity - on days that polo horses are not competing, they are typically exercised by trotting, cantering, and galloping for extended periods. Some polo players who can't afford grooms will lunge horses, or work them in a round pen, before a game.

Grooms, spectators, and vets would also notice tying-up, which is more immediate and doesn't require watching for the horse to pee; the horse looks distinctly uncomfortable and crampy, and shouldn't be moved, not even into a trailer. It looks bad, and you know teh evul rich people are all about image. I think the problem lies with the unsupported myths and legends in the equestrian community, regarding the necessity of injected vitamin/mineral supplements.

@Barn Owl - thanks! That's an exceptionally useful comment. I'd have to say that while you may consider yourself a rank amateur, you've done an awful lot to educate us here at Terra Sigillata World Headquarters.

#15 But once again, we see co-opting of good old pharmacology by the CAM community - using an unapproved pharmacological agent is NOT alternative medicine.

Posted by: Abel Pharmboy | April 25, 2009 9:52 AM [italics added]

Sorry, I am having trouble understanding this. I can imagine three scenarios: Off-license (thus, unapproved) use can be rational, in which case you are right. On the other hand, off-license use of chelators, for example, to treat autism is irrational and quackery. In addition, if you mean using a drug that is not approved for anything- it is either quackery or a legitimate experiment.

I'm not a polo enthusiast, but I do know and understand the game.

In terms of physical demand on the contestants elite polo is probably most like elite soccer--repeated sprints, turns, etc.

I'd like to hear from some veterinarians with elite endurance-race experience on the actual utility of the vitamin/mineral supplements on equine performance.

That said, there's a tremendous amount of woo floating around equine circles.

I poked around on FDA.gov to try to answer my own question. I couldn't find any FDA regs on how drugs should be compounded, either for humans or animals. (I did find some rules on what drugs may be legally compounded). Several documents indicated that FDA leaves much of the oversight of compounding pharmacies to state and local jurisdictions.

USP might have a chapter on compounding, but I don't have a copy at home, nor do I have on-line access.

The symptoms of selenium toxicity fit with some of those displayed by the horses: altered heart rhythms, labored breathing, motor problems, and high temperature.

K+ toxicity could be similar.

#20, USP chapter 797 (published 2004) provides guidelines for compounding pharmacies (human or veterinary), particularly when the pharmacy is compounding for parenteral (injectable) use. This chapter classifies risk level for compounded sterile preparations, depending upon the manufacturing complexity, environmental and length of intended storage. There is significant risk (of microbial contamination and more) associated with any preparation intended for injection, and the USP recognizes this.

I also suspect a decimal point placement calculation error as a major underlying factor in this horrible tragedy. As a researcher, I count many compounding pharmacists and CAM practitioners among my friends and colleagues. There is a place for these specialty professions, and I hope this tragic event will not become a reason to criticize those who practice responsibly.

I don't know how k+ is measured in the horse world, but in humans we dose in mEq, not mg. This is another possible source of dosing error. Why aren't the autopsies back yet??

@22 A decimal point error is possible; but three decimal points (as suggested) is outrageous. That would create a pile of material that should be a speck.

I think most pharmacists dispense custom preps, usually for dermatologists. The ones that advertise the service often cater to quacks ("CAM" is a euphemism for quackery). Quacks are not useful in health-care. One cannot practice quackery responsibly.

@ 22 "I also suspect a decimal point placement calculation error as a major underlying factor in this horrible tragedy. As a researcher, I count many compounding pharmacists and CAM practitioners among my friends and colleagues. There is a place for these specialty professions, and I hope this tragic event will not become a reason to criticize those who practice responsibly."
Well said...as a trained technician myself..check, check and triple check those digits! Agree with post #12, it's a bonehead mistake, and very tragic.

As a show horse exhibitor and lab technologist some of this doesn't add up. First, why not simply bring the Biodyl with you, the brought thousands of pounds of equip. including lot of drugs, why get this compounded? Only a few horses are prone to tying up- most horses in good condition, which animals at this level of competition are, do not have this problem, certainly not 21 of them. Drugging in the horse industry for pain, or endurance and stamina is very common. Maybe it was a lab math error, or maybe all of it was used as a carrier for something else, a banned drugged i.e. adrenaline?

AS far as Se vs. K being the culprit, I would tend to veer away from K. True, K can be lethal, but if it is injected IV, this happens almost immediately. AN IM or SQ injection of K would be incredibly painful and be absorbed over a period of hours.

I don't think it's a simple decimal point error. My guess is that it was a substitution error, probably substituting the Selenium which would be an extremely small dose for one of the salts which would have been a much larger amount. In this manner intended micrograms of selenium might have been increased since the K Chloride would have been in the tens or even hundreds of milligrams. Therefore the error might have been not one decimal point error but quite a bit larger such as many hundreds or even thousands of times greater. I'm presuming that this was infused IV in Ringers Lactate or Normal Saline otherwise severe pain from the salts would have occurred.

So my guess is acute Selenium poisoning, possibly by interference with hemoglobin resulting in asphyxia, almost like Carbon Monoxide poisoning, or severe liver damage resulting in multi-system failure.

These deaths are truly a tragedy. Many, many folks are grieving over this. Hopefully a lot will be learned and only good will come out of this going forward.

My understanding of FED regulations is that Biodyl could not have been legally brought into the country as it is not approved to be marketed here.

As it is possible to blood test for the level of Selenium, (my horse was just tested for Se & vita E levels) why not feed it regularly in safe amounts and monitor it this way? Then injections including Se would only be given to the horses whose levels needed to be brought up quickly before a match, if that practice is to be continued.

Question for the horse supplement makers: Since Se seems to be the most likely vitamin and mineral supplement to reach toxic levels that we horse owners know of, it would be nice if all of the makers of products would provide appropriate sized scoops in containers containing supplements including Selenium. For example I have a container that sasys E &SE Powder on it. The instruction says
"Feed horses 1/4 to 1/2 oz. per day
(1/2 oz. provides 1 mg. of selenium
1 oz. measure enclosed"

Why provide a 1 oz. scoop when it would be best not to give a horse 1 oz. of the supplement?

Also, there is no warning about toxicity levels, no mention of how to determine whether the horse needs 1/4 or 1/2 oz. such as by weight of horse, or per veterinary instructions. There is no caution to look at the total of Se being fed in the daily diet of the horse. If there is a not to exceed level per thousand pounds of horse weight without veterinary instructions, that would be nice to know.

Also, this same container says on it
"Guaranteed analysis per lb.
Vitamin E, min..........20,000 I.U.
Selenisum (Se), min.........32 mgs."

When I bought it I wondered why there wasn't also a guaranteed MAXIMUM per pound listed for Se.

This preparation also contains sodium saccharin, which I thought required a warning label. In 2000 the US Congress repealed the law requiring products containing saccharin to have health warning labels. As of 2007 saccharin was still banned in Canada, though that is now under review. It is good to know what the regulations are when one is crossing borders!

OSS | April 26, 2009 9:31 PM "Question for the horse supplement makers ..."

My question to you- is there any evidence in reliable, scientific literature that supports your use of these "supplements?" I note that there is nothing in medical lit. supporting "Biodyl."

Feeding EqSe daily as a supplement over time is exactly what my veterinarian prescribed for my competitive trail horse prone to tying up syndrome. That completely eliminated problems at competitions.
And yes the scoop included in the container was twice the dosage he'd have needed.
I must have be one of the lucky ones who has a veterinarian who does check and double check.
And I'm still using a compounding pharmacy for pergolide for my now retired horse who has developed Cushings Syndrome in his old age. The pergolide has turned back the clock for him as he now behaves as though he's 10 years old again. Sure wish I could say the same!

To O55: Re labeling. The supplement industry is regulated by AAFCO ( American Association of Feed Control Officials ). Guarantees must follow a specific format which is different from human vitamin supplement labeling. The issue of scoop size is a valid one. The dose size for selenium in horses is determined by availability of selenium in the soil where feed is grown. For example, the Pacific Northwest is selenium deficient, so equines are supplemented to prevent serious conditions relating to that deficiency. There are loads of studies, especially by equine sports medicine research facilities (i.e. UC Davis, U. Edinborough, and many others) which have determined when and which supplements should be fed to performance horses. You are correct in thinking that most pleasure horses given a proper diet do not need much supplementation, however, as with humans, there are individuals (equine, canine, feline, etc.) which do require supplements. The horse-owning public is surprisingly savvy, relying on the internet and its vast resources for current information relating to their equine charges. They are neither gullible, nor subject to misleading adverts, as the FDA considers all advertising to be part of labeling. No intended use statements are allowed, except for biotin, which makes advertising almost useless.

Very interesting reading. As an equine veterinarian who just stumbled upon this site I have a few comments. It is very common in the competitive horse world to supplement with IV vitamins/minerals. I practice in southeastern arizona and I sell tons of injectable vitamins. do I think they are necessary, not entirely, but after years of trying to educate clients and then having them just go buy them from someone else, I have relented and just sell them what they ask for. I have had Biodyl compounded before at a clients request. there are multiple different formulations that are all similiar. Most people get stuck on a name. My clientle is mostly hispanic and everything has to be name brand and look exactly the same. I am sure that is why they wanted "Biodyl". Generations of training leads them to think that these things have to be done. Right or wrong, it will never stop. These horses are athletes and the trainers are going to pump this stuff into them irregardless of wether it is effective or not because if the horse doesnt win than it will be because they didnt give it. stupid, I know, but reality in the equine world.

Many very interesting and insightful comments - I am struck by the most recent comment from Dr Debbie that these horses are treated as elite athletes with owners and trainers who take the risks that coaches encourage their human clientele to take. Short-term performance over long-term life perhaps.

I've got to say that I've always been fascinated by the horse racing world since riding my bike around the Jersey Meadowlands racetrack when it was being built. FMEQ raises some great points about the NW US being low in selenium and influencing equine nutrition. Who knew amongst us garden variety biologists.

I really appreciate all of you coming by from your various specialty backgrounds to weigh in on this case. Terrible and tragic but illustrative of the risks we take with our performance animals, the ethics of performance racing and other similar sport, the often murky/sometimes reputable area of compounding pharmacy, and the importance of basic mathematics and communication in the human and veterinary health sciences.

Keep it coming - I have yet to hear a conclusive determination of what occurred in Wellington, Fla.

the AP reports that it's selenium:

http://news.yahoo.com/s/ap/20090429/ap_on_re_us/us_dead_polo_horses

I stumbled on this site when searching for an ESPN program coming up that is covering this tragedy. There are many issues involved in this, but in my opinion the most serious is the compounding phamacy issue. I am not talking about this particular phamacy. I would confirm an earlier comment that this particular pharmacy has a good reputation among veterinarians. However the compounding industry itself is a major problem in veterinary medicine under the current lack of regulation. Has anyone considered contamination. This was an injectable product. FDA approved facilities to produce these products cost 15-20 million dollars to achieve approval. FDA approved products similar to Biodyl are available in the U.S. Biodyl in not approved for use in the U.S. Why can a compounding pharmacy produce the product when an approved facility is not allowed to. Compounding pharmacies are like welfare. It was a good idea that truly helps a few people that our outside the system, but it has gotten out of hand. Much like Moonshine. Yes, it will get you drunk but it also might kill you because the motivation is profit with little consideration for "good manufacturing practices". Compounding pharmacies are profitable and on the increase because they can produce products with out the extremely expensive investment of an approved FDA facility. Why are they not more regulated ? Many regulatory agencies know that these pharmacies are operating on the edge or outside the current laws. They response is that they do not have the staff (budget) to do anything about it.
Issues here;
Was it contaminated ?
Was it incorrectly formulated ?
Was it legal to produce for sale in the U.S. ?
Will FDA do something about it ?

I know the pharmacy where the fatal mixture for the polo ponies was mixed, and they have a great reputation for guality work. It was the selenium, and being a pharmacist for 45 years, errors can occur. I can't tell you if the prescribing Vet. made an error or not. My son is a Vet. i n the Ocala area, and he uses this pharmacy for all his compounding med needs.

I am a compounding pharmacist. I am a competitor of Francks. It was a mistake! Sad but true. I still send all of our equine rx's to him. They are the experts. Did they do things wrong, beside the math error, that is to be determined. The rest of the ad hominums are ridiculous. Where some people come up with these things: they must of been drunk. duh.
The process of producing a formula for compounding is exactly the same as the cGMP's require. I have been in both industries. It was a mistake. Now all of you critics out there who have never made a mistake of any kind, wave your hands. Hmmmm.