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Research Confirms Bisphosphonates Can Linger In Horses’ Bones For Years

Bisphosphonates continue to be a topic of concern in the racing world, most notably raised by a report of a positive test from John Salder trainee Flagstaff, but researchers are still learning about how to find and regulate the drugs in horses. Although two drugs, sold under the trade names Osphos and Tildren, were approved by the Food and Drug Administration for use in horses several years ago, research into the drugs' action in young horses and the length of its life inside the equine body is still catching up. (FDA-mandated testing is focused on safety and efficacy of a new drug, not necessarily the ability of a state racing commission to detect it in a post-race sample from a young racehorse.)

Read more about bisphosphonates in our archives here and here.

Dr. Heather Knych, renowned equine pharmacologist at the University of California-Davis, gave an overview of current research on bisphosphonates at the most recent, virtual convention of the American Association of Equine Practitioners (AAEP).

A few takeaways:

Bisphosphonates may be new to the horse world, where they are FDA-approved for the management of navicular syndrome in older horses, but the drug class has actually been in use in different settings for a couple of centuries. Knych explained that the substance was first used in the detergent industry in the 1800s as a water softener, anti-corrosive or anti-scaling agent. Their action on calcium carbonate made them effective in these settings. They were adapted as therapeutic drugs for human bone conditions in the 1970s.
While we've most often heard of bisphosphoantes in humans as part of osteoporosis treatment, they've also been used in metastatic bone disorders, and multiple myeloma.
We know that after an administration, bisphosphonates disappear from blood fairly quickly – their half life is one to two hours in plasma, but they can linger on bone surfaces for months or years.
Bisphosphonates seem to prefer settling in trabecular bone – bones like skulls and ribs that take less mechanical stress – over cortical bone, like the long bones in limbs. It withdraws from bones based on the amount of turnover in that bone, which can vary depending on age, exercise, and trauma.
Concentrations of bisphosphonates continues to increase as concentrations of it elsewhere decreases. It can also release from bone back into blood in small amounts and move into other bone surfaces, though we don't know a lot about why and when it does that.
Knych presented the results of a two-part study led by researchers across multiple universities to learn more about how long bisphosphonates linger in the skeleton. The first part of the project required administration of the two FDA-approved bisphosphonates – Osphos and Tildren – to a total of four horses in university research programs who were already slated for euthanasia for unrelated reasons. Bone samples were taken after euthanasia, which came four days or 30 days after administration in each drug group. Samples from the radial bones showed detectable amounts of both drugs four days after administration, with levels of Tildren being higher in both samples. Thirty days after administration, both drugs could be found in all bones sampled, even right and left molars. Concentrations of both drugs were highest in the tuber coxae (hips).
In the second phase of the study, researchers tested blood and fluid samples from four horses euthanized due to on-track injuries in California – three whose connections said they'd never had bisphosphonates, and one who had a treatment 18 months prior. The team could find no evidence of bisphosphonates in the three horses with no treatment history. The horse who had been treated 18 months before had no detectable amounts of the drug in serum, urine, or synovial fluid, but did have a detectable level in a sample from the radial bone.
These results suggest, in line with what veterinarians had expected based on human data, that the drug does linger on the surfaces of bone for considerable periods of time, and lives on different bones in different ways.
Knych acknowledged that both parts of the study came from extremely small sample sizes, as is often true in academic research with horses, and that further study is needed to better understand how bisphosphonates work in the equine body.

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What Will That Extra Urine Testing In The Medina Spirit Case Actually Tell Us?

Attorneys for Medina Spirit's connections spilled a lot of ink last week to ensure their clients will have the opportunity to run extra tests on a split sample of the horse's urine. They hope to demonstrate that the betamethasone detected in two rounds of testing after the Kentucky Derby was the result of a topical ointment applied for a skin rash, not an injected treatment to relieve pain or inflammation. The eventual goal, according to a civil suit filed in Franklin Circuit Court over that extra testing, will be to argue that a topical application of betamethasone isn't prohibited by Kentucky regulations and that repercussions for trainer Bob Baffert and owner Zedan Racing should therefore be mitigated. A judge ruled on June 11 that the extra testing will go on, and it only remains for the Kentucky Horse Racing Commission and the horse's connections to agree on how much urine will be tested.

The second objective, the question of whether administration route matters, will come down to a long (and probably dry) legal argument. The first objective, the proof of where the betamethasone came from, hangs on that extra testing, which means this is a good time to ask – can extra urine testing actually prove the origin of the betamethasone in question?

Maybe, says equine drug testing expert Dr. Rick Sams. But maybe not.

There are two ways that drug testing could try to establish whether the betamethasone came from an ointment or an injectable: by looking for the other ingredients in Otomax, the topical cream Baffert eventually said was used to treat a rash on Medina Spirit's hindquarters, or by identifying the exact chemical makeup of the betamethasone in the sample.

Besides betamethasone, Otomax also contains gentamicin, an antibiotic, and clotrimazole, an anti-fungal. Post-race samples aren't tested for most antibiotics or antifungals because those drugs are not acting directly on the body of the horse — they're designed to combat bacteria or fungi. As such, most of them aren't regulated in racehorses the same way an anti-inflammatory is, so it's not surprising that these ingredients weren't reported on the initial post-race test or in the split sample.

(Procaine penicillin is the common exception to this, since procaine is a numbing agent also used in other ways, outside the combination with penicillin. Penicillin is known to cause some discomfort in horses when injected, so it's often formulated with procaine to make repeated administrations more tolerable.)

Sams worries however that it's unlikely either of those drugs would have made it into the horse's urine in a sufficient amount to be testable, because they were given as topicals. They were present in a topical application with the directive to work on a surface- level skin rash, so their purpose was to work on bacteria or fungi on the skin's surface. He suspects they weren't designed to be readily absorbed through the skin and into the bloodstream, since most of their work was to take place on the outside of the horse.

“I think the likelihood of gentamicin ever getting absorbed in sufficient quantities to show up in the urine is essentially zero,” he said.

In the case of clotrimazole, it's present in very low levels in Otomax, making it even less likely it would be absorbed.

“There are no studies I can find that demonstrate any appreciable absorption of clotrimazole after topical administration,” Sams said.

It's also not immediately clear how many accredited racing labs would be able to test for either substance, because it's not part of the usual battery of post-race tests. A civil court hearing June 11 revealed that New York's Equine Drug Testing Program housed at Morrisville State College will conduct the extra testing.

The other thing Zedan and Baffert hope the extra testing will reveal is the chemical makeup of the betamethasone detected in post-race sampling. Otomax contains betamethasone valerate, which is chemically different from betamethasone acetate and betamethasone sodium phosphate – the two versions of betamethasone used in injectable products. The words acetate, sodium phosphate, and valerate all refer to esters, which are chemical compounds derived from acids that are attached to a molecule of betamethasone.

“If one was to look for the valerate ester and find it, that would demonstrate that something other than the injectable preparation was administered to the horse,” said Sams. “But I think the chance of finding the valerate ester of betamethasone is zero, because the valerate ester has very low water solubility, and substances have to have water solubility to get excreted into the urine so I don't think it ever gets into the urine as valerate.”

It's possible that the legal team will ask the lab to look for betamethasone acetate and betamethasone sodium phosphate instead, with the idea that if they aren't found, that would demonstrate the horse wasn't given injectable betamethasone. Sams said the betamethasone acetate is, similarly to betamethasone valerate, not all that water soluble and therefore he wouldn't expect to find it in urine, even if it had been administered to the horse. The sodium phosphate ester however, is very water soluble and that may be excreted into the urine readily. Sams has done previous research on a chemically similar ester and found it was pretty easy to detect.

Racing labs aren't typically asked to determine which form of a drug like betamethasone is in a sample and Sams said he is not aware of any racing lab ever previously attempting to make this distinction.

So how helpful could this additional testing be? Its usefulness to Bob Baffert and Zedan Racing may be more about what it doesn't show than what it does. If the testing confirms betamethasone but can't determine which form is present, or finds no evidence of either injectable version, the attorneys may point out that there is no evidence to refute Baffert's version of events.

Of course, Sams and many others have stated that they don't believe Kentucky's rules differentiate between routes of administration for regulated substances like betamethasone. Whatever Baffert and Zedan hope to learn from the extra testing they've fought for, they will no doubt look to challenge that belief in court proceedings that may stretch on for months or years to come.

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HISA: Details Are Scant, But You Can Bet More OOCT Is Coming

Charles Scheeler, newly-elected chairperson of the board of directors for the Horseracing Integrity and Safety Authority, said that there's a lot which is still TBD for the new governing authority for horse racing. Scheeler appeared on a media call June 2 to discuss the authority's progress so far after being elected at the authority's inaugural meeting on May 27.

The authority, which is set to take over horse racing regulation in summer 2022, is still finding its feet. Scheeler was unable to specifically site any one state or organization's rules or model rules that would be picked up by the new group to govern medication use or safety policy. The rule-making for medication use and safety practices is left up to separate committees, which were just formed in early May.

It also remains unclear where the money will come for drug testing under the new authority — or how much that will cost. Scheeler anticipated that as work continues on the new group, committee members will come up with a budget for drug testing and other costs, and then determine how to charge the portions of the industry covered by Horseracing Safety and Integrity Act. He said he hoped that a larger scale drug testing contract and improved test selection procedures could reduce the per-test bill from what jurisdictions currently pay.

Scheeler pointed out that the authority could allow for more intelligence-based post-race testing, rather than requiring tests be conducted on finishers in certain positions (although that is already an option for stewards in some places). He also emphasized that boots on the ground will be a big part of the new anti-doping controls, acknowledging, as many experts have before him, that the most sophisticated cheaters tend to stay a step ahead of testing technology.

“Another piece that we want to add in a very powerful way is an investigative component to serve as a deterrent,” he said. “You will see in other sports that the greatest deterrents have often come out of non-test cases, like BALCO, like Biogenesis, like the recent work of 5Stones … some folks look at it, not as 'Should I play fair or not?' but as a very cold cost/benefit analysis. We have to make them see the costs or the risks are greater than the rewards.”

Scheeler also believes that there will be an increased focus on out-of-competition testing (OOCT) under the new authority to complement that investigative component.

“There is definitely going to be more emphasis on out-of-competition testing, but I would not necessarily assume it comes at the expense of after-competition testing because that will remain in a fully robust form,” he said.

Scheeler also anticipates that the authority will adopt some kind of system like the current multiple medication violation penalty scheme, which increases the minimum fines and suspensions handed to a trainer or owner for repeated drug offenses in the same category.

Scheeler declined to speculate too much on how the Medina Spirit case may have been handled differently under the new authority, but did point out that the case has revealed some differences in betamethasone regulation between states. Under the new authority, rules and testing will be uniform. He also hopes the new authority can serve as a central communication center to the general public to help them understand how the sport is regulated and why — something the current state commission system can't allow for.

Scheeler is a retired partner from DLA Piper and served as head counsel to former Sen. George Mitchell during his investigation of doping in Major League Baseball. Scheeler has also been involved in investigations of the Pennsylvania State University's compliance with national athletic organizations and the health and safety practices at the University of Maryland's football program.

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Split Sample Confirms Betamethasone Positive In Kentucky Derby Winner Medina Spirit

The New York Times reported Wednesday morning that a split sample from Bob Baffert-trained Medina Spirit, who crossed the wire first in this year's Kentucky Derby, has confirmed the presence of betamethasone. A statement from Baffert's lawyer, attorney Craig Robertson, said the confirmed concentration was 25 pg/ml.

One week after this year's Derby, Baffert told media that he had been informed initial testing on post-race samples from Medina Spirit had detected the corticosteroid, which is not permitted for use within 14 days of a race in Kentucky. At the time, split sample testing had not yet been completed to confirm the finding.

Attorney Clark Brewster, who represents Medina Spirit owner Amr Zedan, revealed that the University of California-Davis performed the split sample test, which was aimed at confirming or denying the original finding of Industrial Laboratories.

Learn more about split sample testing in this May 21 feature.

Brewster told writer Joe Drape that UC-Davis did not do any further analysis on the sample to see whether it contained other substances that could give clues as to the origins of the betamethasone. (This type of additional analysis is not typically part of a split sample test.) Brewster will request further analysis be done on the post-race samples by a different laboratory.

Robertson released the following statement, which indicated DNA testing would also be done on the sample:

“In response to the inquiries, this will acknowledge that the Medina Spirit split sample confirmed the finding of betamethasone at 25 picograms. There is other testing that is being conducted, including DNA testing. We expect this additional testing to confirm that the presence of the betamethasone was from the topical ointment Otomax and not an injection. At the end of the day, we anticipate this case to be about the treatment of Medina Spirit's skin rash with Otomax. We will have nothing further to say until the additional testing is complete.”

Baffert initially told media he did not know why the horse had betamethasone in its system, and cast suspicion that he was a victim of some kind of tampering or sabotage. Two days later, he announced that Medina Spirit had been treated with a topical cream that contained betamethasone while treating a skin rash on the horse's hindquarters.

Betamethasone is a corticosteroid which is often used therapeutically to assist with reducing inflammation in equine joints, although it is also present in some topical applications like Otomax. Kentucky changed its regulations governing corticosteroid joint injections last August, pushing out the pre-race administration time to 14 days pre-race and removing the drug threshold from its code, meaning no level of the drug is acceptable in a post-race finding. (The commission said at the time that testing could not detect administrations farther than 14 days out.)

In the wake of the Santa Anita breakdowns, Kentucky was one of several states that began requiring private veterinarians to examine horses several days pre-race in addition to the traditional pre-race examination from commission veterinarians. Commission staff had expressed concern that additional pre-race veterinary exams taking place farther ahead of race time could be influenced by the anti-inflammatory effects of corticosteroids and non-steroidal anti-inflammatories.

Baffert has had multiple high-profile therapeutic drug positives in the past year and a half, including one in Kentucky for betamethasone after the rule change when Gamine tested positive following the Kentucky Oaks.