(Revised 12/5/03) Horse owners have a new option for treating equine protozoal myeloencephalitis (EPM) following the Nov. 19 U.S. Food and Drug Administration's (FDA) approval of nitazoxanide. This medication has been under development as an EPM treatment for more than six years.

IDEXX Laboratories of Westbrook, Maine, received approval for the product, called Navigator, which is a 32% nitazoxanide antiprotozoal oral paste designed to kill the single-celled protozoan parasite Sarcocystis neurona, which infests the horse and causes EPM. (Read more on EPM at www.TheHorse.com/epm.)

Navigator is the second FDA-approved treatment to hit the equine market--Bayer's Marquis (active ingredient ponazuril), another antiprotozoal oral paste, was the first FDA-approved EPM drug to be launched (August 2001). An additional type of treatment, diclazuril, awaits FDA approval.

Also in November 2003, Dorsey Kordick, PhD, of IDEXX laboratories based in Greensboro, N.C., gave a scientific presentation on Navigator's safety and efficacy studies at the University of Kentucky Gluck Equine Research Center in Lexington, Ky. She explained that the treatment regimen lasts 28 days, and it begins with five days of half-strength doses, providing "a more gradual kill" of the parasite to allow intestinal microflora to adjust to the drug, and minimize the transient neurological worsening sometimes seen with extreme immune system stimulation (by numerous dead parasites). The horse should receive the dose once daily, just before he receives his grain concentrate.

Navigator's mechanism of action shuts down cellular respiration of S. Neurona and works with the horse's immune system to eliminate the parasite. Its cost to veterinarians should be comparable to other EPM treatments available.

Field Studies for Efficacy and Safety
To be considered a success in two nitazoxanide field studies, a horse with EPM (positive on a cerebrospinal fluid, or CSF, test) had to show at least one grade level of improvement in his neurologic signs and/or test negative for EPM on CSF. In the first field study of 49 horses, which had not received prior EPM treatments, 28 (57%) of the horses improved, and seven (14%) were negative on CSF analysis eight weeks after the treatment period.

A second field study group of 416 horses included those with chronic clinical signs and horses which had been previously treated for EPM. Of the 416 total, 250 were evaluated for efficacy. There was an 81% success rate in those horses, and 20% had negative CSF at the post-treatment follow-up. Of note, 44% of the horses returned to normal function.

So, why such a huge jump in efficacy in the second field study? The first field study lasted only eight months, while the second took place over the course of 28 months. "We learned a lot about using Navigator to treat EPM during the second study, and suggested practitioners recommend to owners to exercise these horses and perform physical therapy on them to help their muscles recover and get them back in condition," said Kordick. "We had a longer interval in many cases between pre-treatment and post-treatment exams in the second study, and therefore the horse had longer to recover."

John Hunt, DVM, of Heritage Farm, an equine veterinary practice in Carthage, Ind., has treated more than 50 horses with nitazoxanide during field studies and pilot development studies. "My experience with nitazoxanide has been very positive with at least 70% of my cases returning to their previous levels of performance," he said.

Adverse Reactions
"When you conduct field studies, you have to consider all adverse reactions," said Kordick. In safety trials in the first field study, 27% of horse owners reported one or more suspicious adverse reaction. The most commonly experienced adverse effects in the first field study were fever, reduced appetite, and lethargy/depression. "What we're seeing is the immune system responding to the dying organism," said Kordick. "It's not really unexpected to see (these reactions) clustered together." Some of the horses experienced edematous limbs (stocking up) when kept in a box stall without turnout. "Once we started to suggest hand-walking or turnout, we didn't see this as much," said Kordick. Other, less-reported side effects included worsening of neurologic signs, anorexia, diarrhea, stiffness, and colic.

Four horses in the first field study were euthanized, but for reasons deemed unrelated to the treatment. In the second field study, adverse effects were comparable to those in the first study, although the FDA said 5 horses that died or were euthanized might have been attributable to the nitazoxanide treatment. Kordick explained in detail each of these five horses' situations--a probable Potomac horse fever case; a nosocomial (acquired in a hospital) salmonellosis case; a gastric ulcer in a colt which was too young for enrollment in the study; a pneumonia; and a laminitic stallion which had abrupt changes in his feeding regimen and whose semen collection was continued against the recommendation of the treating veterinarian.

As with some antibiotics, administration of Navigator can disrupt the normal microbial flora of the gastrointestinal tract and lead to enterocolitis and even death.

Hunt said his patients have displayed minimal side effects and speculates that many of the adverse events that occurred during the studies were due to larger-than-desired amounts of nitazoxanide reaching the hindgut.

"Veterinarians forever have had concerns about putting antimicrobials into the gastrointestinal tract," said Hunt. "If we enhance absorption of nitazoxanide in the foregut, much less will reach the hindgut to produce changes in the microflora." If absorption is increased, more of the medication is reaching the central nervous system and thus, the insulting parasite, S. neurona.

Hunt believes that his patients have benefited from the administration of fat (4 oz. of corn oil) given with Navigator treatment.

"Nitazoxanide is fat-soluble and my conjecture is that if nitazoxanide is administered with a significant amount of fat, then its absorption is going to be enhanced, and we know that high fat in the diet slows the rate of passage through the small bowel (providing more time for absorption)."

Hunt also recommends Saccharomyces cerevisiae yeast culture supplementation to his clients with horses undergoing nitazoxanide treatment. He said, "It provides bacteria in the hindgut with readily available nutrients so they are better able to withstand the antimicrobial entering the hindgut.

Dosing and Monitoring
Kordick explained that the horse owner must dial a locking dose ring back to the graduated notch marked with the horse's weight (like one would with a dewormer paste tube), and this should prevent accidental overdosing or discharging the medication when preparing to dose the horse. The company has included a weight tape and a treatment diary so horse owners can be exact in their dosing (they should check their horse's weight weekly) and keep track of any observations they make in their horse's health or behavior.

"Nitazoxanide is excreted in the feces, urine, and sweat," she explained. "You might see pale yellow, discolored urine, and sweat in some cases." Kordick said not to be alarmed if you notice these signs in your horses. It is an indication that the drug is being absorbed.

IDEXX performed dose-tolerance studies at five and 10 times the standard dose to predict problems in case a horse is overdosed. What the scientists found is important: "This is a potent antimicrobial drug," said Kordick. "Chronic overdosing could be problematic, so always read and follow label directions, and accurate weight measurements are very important.”

Navigator overdosing can lead to problems such as loose stools, decreased appetite, and lethargy. It is important to keep a close eye on the horse for any unusual reactions to the medication.

The treatment will not be labeled for breeding animals, although nine pregnant mares were a part of the second field trial, two of which conceived while on Navigator, and all nine gave birth to full-term, healthy foals.

About the Author

Stephanie L. Church, Editor-in-Chief

Stephanie L. Church, Editor-in-Chief, received a B.A. in Journalism and Equestrian Studies from Averett College in Danville, Virginia. A Pony Club and 4-H graduate, her background is in eventing, and she is schooling her recently retired Thoroughbred racehorse, Happy, toward a career in that discipline. She also enjoys traveling, photography, cycling, and cooking in her free time.

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