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October 12, 2007

New NSAID Equioxx Takes A More Selective Approach

The Food And Drug Administration and The U.S. Equestrian Federation sign off on the first COX-2 inhibitor for fighting pain and inflammation in horses.

In the quest to keep our horses comfortable, there are some double-edged swords in the world of medicine.
   
One classic example is the use of traditional non-steroidal anti-inflammatory drugs, such as phenylbutazone (Bute) and flunixin meglamine (Banamine), which are commonly used to fight pain and inflammation associated with osteoarthritis and degenerative joint disease. But long-term or high-dose use of these drugs can also cause gastric ulcers and other gastrointestinal problems, as well as kidney damage.

Last June, Duluth, Ga.-based animal health company, Merial, launched Equioxx, a new NSAID that may become a valuable tool in relieving equine joint pain with the potential for fewer adverse side effects. Based on the compound firocoxib, available in chewable tablet form as Previcox for dogs since 2005, Equioxx is the first FDA-approved equine NSAID that targets the cyclooxygenase-2 enzyme for inhibition, while sparing COX-1.

Cyclooxygenase is important because different forms of the enzyme convert the arachidonic acid found in cell membranes into prostaglandins that mediate an array of physiological processes. COX-1 gets the ball rolling when it comes to many beneficial functions such as providing a nice mucous lining to protect the stomach from its acidic digestive juices. COX-2 is involved with potentiating pain and inflammation.

Traditional NSAIDs inhibit both COX-1 and COX-2, so while they are effective at controlling unwanted pain and inflammation, they also shut down the desirable functions of the COX-1 pathways.

“We’ve been able to put together some really nice figures that show how products like phenylbutazone and flunixin are potentially non-selective, perhaps even slightly COX-1 selective. In pretty much any concentration, you’re inhibiting both enzymes, so that’s why they work really well, but it’s also one potential explanation for why you see some of the GI, particularly, and some of the renal, side effects,” explained Peter Hanson, DVM, PhD, the executive director of Merial’s project development group and Equioxx’s research and development project leader.

“With firocoxib, across the therapeutic range and even at a fairly high overdose, we don’t inhibit COX-1 at all,” he added.

With a recommended dose of 0.045 mg/lb (0.1 mg/kg) of body weight once daily for up to 14 days, Equioxx underwent safety studies with dosages up to 12.5 times that amount for 92 days. At higher doses, there was an increased incidence of oral ulcers, but GI tract ulcers were held at bay.

“If you look at horses and their grazing habits, you’ll find little nicks and cuts around their mouths. At the higher dose levels, we inhibit COX-2 all of the time, and COX-2 is important in some self-signaling activities for wound healing. At lower doses we hit the high levels of inhibition but not all day; it would drop back down to allow the healing processes to occur,” said Hanson.

“What was really interesting was that in those studies, even at those high levels where we’re hitting COX-2 100 percent, we weren’t seeing an increase in stomach ulcers or an increase in intestinal ulcers, which I think comes back to the fact that we’re COX-1 sparing,” he continued. “At very high doses above the therapeutic dose for a long period of time, we did see some changes in the kidney, just as you do with Bute or with flunixin. In the kidney, you have both COX-1 and COX-2 acting, so even though we spare the COX-1, we do inhibit COX-2, so long-term, high dose [92 days and 12.5x in the study], you might still have some impact there.”

But Does It Work?

While it may have fewer side effects, how does Equioxx compare to other medicine cabinet staples when it comes to helping the symptoms of OA?

There is currently a 500-horse trial on-going at clinics throughout the country from which Merial will be compiling and reporting data in coming months. So far, it’s getting a thumbs-up, earning the 2006 best new equine veterinary product award from Animal Pharm, an animal health industry news service.

“Horses can have a very strong response to this product, so it can be very beneficial,” said Hanson. “Absorption reaches its peak between four to six hours after the first dose. The drug has a fairly long half-life, which means it’s eliminated slowly, so there is some slight accumulation over the first week. So even though we get a quick effect up front, there’s even some potential for greater effect as you get out three or four days.”

A July 5, 2007, article in The Horse reported: “According to FDA documents, a field trial directly compared the lameness, pain on manipulation, swelling and range of motion of more than 250 horses with naturally occurring osteoarthritis treated with phenylbutazone or firocoxib for two weeks. Veterinarians examining client-owned horses reported improvement more frequently in the firocoxib group than in the phenylbutazone group in all categories except lameness (after 14 days, veterinarians replied that 83.6 percent of horses in the firocoxib group had improved in the lameness category, compared to 85.6 percent of the horses on Bute).

‘It seems every bit as effective, if not more so, than more commonly used NSAIDs,’ said Rick Mitchell, DVM, of Fairfield Equine Associates in Newtown, Conn., who has clients’ horses on Equioxx as part of an efficacy field trial for horses with osteoarthritis,” continued the article. “ ‘The advantage for me, as a practitioner, is that we have so much less concern of ulcer potential.’”

The term “COX-2 inhibitor” may send off some alarms for horse owners, as that is the modus operandi of human drugs such as Vioxx, which was recalled after negative cardiovascular side effects became evident. Hanson explained that the inherent differences between humans and animals like horses and dogs mitigate similar risks with firocoxib.

How To Use
• Equioxx is available by prescription.

• It comes in an oral paste syringe, similar to that of many commonly used deworming products.

• A single daily dose purchased from your vet costs approximately $10-$15.

• The syringe is marked in 250-lb. body weight increments and can treat a horse up to 1,250 lbs., and the plunger is notched at 50-lb. increments to fine-tune the dose.

• The once-daily dose is intended to provide pain relief for 24 hours.

• Visit www.equioxx.com for more information



“In both dogs and horses, cardiac disease is quite a bit different than in humans. Human concerns involve things like arteriosclerosis and all the risk factors we have because of smoking and eating [habits], and we just don’t see that in a horse,” he said. “Heart disease in the horse is more often arrhythmia and things of that sort, and it’s not typically things that lead to vessel obstruction and ultimately a heart attack or stroke. We haven’t seen any problem in the millions of dogs treated or in the horses we’ve studied.”

Talk To Your Vet

As with any medication, you should discuss with your horse’s veterinarian how or if it should be incorporated into an overall management and treatment plan for OA. Equioxx doesn’t specifically treat the cartilage or other degenerative changes that are on-going in the disease process so is not a cure, but it can control the pain and inflammation associated with it and improve mobility.

“A lot of times horses with chronic osteoarthritis or chronic degenerative joint disease or navicular disease—because we also included horses with navicular in our studies—they have flare-ups. That’s probably where most of this will get used,” said Hanson, providing examples such as before or after strenuous activities as times when having some Equioxx on board may prove beneficial.

The U.S. Equestrian Federation approved the use of Equioxx before their competitions as of Aug. 1, establishing a restrictive quantitative limit for blood plasma concentrations that provides a 12-hour window between a horse’s last dose and its ability to show.

“We worked with USEF and got approved a 12-hour withdrawal after last dose. This is beneficial to horse owners because they don’t have to worry about which product it is, the timing is the same,” said Hanson.

He and other Equioxx officials are still working with some of the various racing authorities to approve the product and its limits. “If it’s an organization that typically doesn’t allow any detection of product, we’re recommending closer to a week until we get definitive guidelines established for those organizations.”

Until they establish guidelines, a 30-day withdrawal period is being recommended before FEI-sanctioned events.

 
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