Baycox / Toltrazuril

“EPM” means equine protozoal myelitis or equine protozoal myeloencephalitis or a disease which manifests as symptoms of either equine protozoal myelitis or equine protozoal myeloencephalitis, or closely related apicomplexan-based neurological diseases of horses.

Actions:In some areas of North America, Equine Protozoal Myeloencephalitis (EPM) is one of the most important neurologic diseases in horses. The disease may be frustrating to owners and veterinarians to diagnose and treat. The signs in individual horses range in severity and may include incoordination, weakness, spasticity and muscle loss. EPM can look like other equine neurologic diseases, including Wobbler syndrome, the neurological form of herpes virus infection, rabies, West Nile virus or other equine viral encephalitis diseases, e.g., Eastern and Western equine encephalitis. Refer to the information sheet, Equine Viral Encephalitis for further information, http://www.omafra.gov.on.ca/english/livestock/horses/facts/info_equv.htm
The primary parasite that causes the disease is the single-celled protozoal organism Sarcocystis neurona. Although identified as a protozoal disease in 1974, the specific disease-causing agent, S. neurona, was not named until 1991. The closely related parasite, Neospora hughesi, has been isolated as the cause in a few cases (1). These organisms have a predilection for the central nervous system in horses.
Generally Sarcocystis species have a life cycle that involves predator and prey animals. In this disease, the life cycle involves the final or definitive host, the opossum (Didelphis virginiana). The opossum excretes oocysts in the stool, which develop into infective sporocysts in the environment. Intermediate hosts ingest the sporocysts where they in turn develop into sarcocysts in muscle tissue (2). The life cycle is complete when opossums eat infected dead intermediary hosts. Currently, the armadillo, domestic cat, skunk and raccoon have been identified as intermediary hosts pertinent to the life cycle of the disease. The opossum is a nocturnal animal, a scavenger by nature and eats anything, including carrion. The large number of road-killed animals in some areas may contribute to the spread of the disease.
Horses are infected incidentally when they eat feed contaminated with the feces of opossum, which contain infective sporocysts. Once the sporocysts have been ingested, they migrate from the intestinal tract into the blood stream, cross the blood/brain barrier and attack the central nervous system. The horse is considered a dead-end host for S. neurona since it cannot transmit the disease to other horses. EPM will be found most commonly in horses that reside in areas inhabited by opossums. Horses staying for short-terms in endemic areas may become infected and show disease symptoms later while resident in non-endemic areas.

Diagnosis and Clinical Signs
The clinical signs of EPM are a result of direct neuronal damage early in the disease and the secondary inflammatory reaction. The signs will vary depending on the location of the lesions in the nervous system.
EPM can cripple a horse slowly or very quickly. In fact, the clinical signs may appear in weeks or up to five years or more after infection. The signs in mild cases may be limited to mild ataxia. In the most severe cases, horses may be unable to swallow or stand. If undiagnosed and untreated, the disease can cause serious and lasting neurological deficits. The disease can mimic other important neurologic diseases making diagnosis challenging, particularly in cases that develop over long periods of time.
A veterinarian should examine any horse showing neurological signs as soon as possible. The veterinarian will perform a physical examination that will include gait evaluation and neurological assessment. Other diagnostic tests, such as radiographs of the ne ck, may be necessary to rule out problems such as Wobbler syndrome. Refer to the OMAF information sheet Wobbler Syndrome or Cervical Vertebral Stenotic Myelopathy for more information, http://www.omafra.gov.on.ca/english/livestock/horses/facts/info_wobbler.htm
In making the diagnosis of EPM, the veterinarian will consider the risk factors identified by researchers over the past decade, including (3):
1. Age of horse – young horses (1-6 years of age) appear to be more susceptible.
2. Occupation of horse – horses of highest risk are involved in racing or showing.
3. Season of year – there is an increased risk in the fall of the year.
4. Presence of woods on the premises.
5. Presence of opossums.
6. Inadequate feed security.
7. Health events before diagnosis – injury or accidents that lead to mmunosuppression increase risk.
8. Horses on farms where previous cases of EPM have been diagnosed are at an increased risk.
Laboratory Diagnosis
Other neurologic diseases must be ruled out. Diagnosis of EPM is based on the presence of neurological signs plus a positive Western Blot analysis performed on cerebrospinal fluid or CSF (the fluid that bathes the brain and spinal cord). The Western Blot detects antibodies to S. neurona. A positive Western Blot performed on serum merely means that the horse has been exposed to the agent and has developed antibodies to S. neurona (4). It does not necessarily mean that the horse has the disease. False positives and false negatives can also occur when using CSF. Contamination of the CSF with as few as eight red blood cells per microliter of CSF can result in a false positive (5). The Western Blot has been used on serum to estimate the seroprevalence (rate of exposure) in normal horses to S. neurona. Studies in the United States have shown seroprevalence rates (number of horses exposed to the agent) to be between 22 and 65% (6).
Treatment
Clearly, early detection means more successful treatment and prevention of further damage. However, horses can suffer permanent damage. The common treatments to date have included broad-spectrum antimicrobials (e.g., sulfonamides and pyrimethamine), anti-protozoal medications (diclazuril, toltrazuril), NSAIDS (non-steroidal anti-inflammatory drugs such as phenylbutazone and flunixin meglumine), corticosteroids, dimethy-sulfoxide (DMSO), vitamin E, and folinic acid. Horse owners have tried many other compounds as well as complementary and alternative therapies, such as acupuncture. Treatment can be a long process that includes the administration of medications for several weeks to months. With quick aggressive treatment, reports indicate that 60-70% of horses make a significant or complete recovery. The following are some of the common treatments currently in use against this disease:
· Pyrimethamine and sulfonamides have been combined and commonly used for up to 90 days. Folinic acid in the form of Brewers yeast is fed at the same time to prevent anemia during treatments with pyrimethamine (1). The oral administration of folic acid potentiates pyrimethamine-induced congenital defects (7). Therefore, be certain to use ‘folinic’, not ‘folic’, acid supplementation when using pyrimethamine solely or in combination.
· Baycox (toltrazuril) by Bayer is a coccidiostat used to treat coccidiosis in neonatal swine. It is marketed as a 5% suspension, in 250-ml vials for oral administration. Baycox has limited registration and is only sold to swine veterinarians under an investigational permit. However, it has been used off-label in horses to treat EPM.

Prevention
Prevention of EPM is difficult. Research is currently aimed at identifying the risk factors associated with development of the disease. In this way, horse owners can take the necessary steps to reduce a horse’s exposure to the organism. A preventive program consists of wildlife management in the stable and on the farm property, especially for opossums. Opossums maintain several nest sites, including hollow trees and burrows, usually near woodlands. They do not hibernate and have a lack of tolerance for cold weather. Therefore, colder winters and deep snow will limit their range. Horse owners should:
· Remove opossums humanely from pastures and woodlands;
· Prevent exposure of horses to opossum feces (much easier for stabled horses);
· Prevent opossums from entering barns, hay and grain storage areas;
High-pressure wash or scrub all infected areas. Disinfectants alone are ineffective for cleaning contaminated areas.
Simple oral formulations may also be made using available Clinacox, oats and molasses, or Clinacox, oats, sweet feed, bran and water, for example. Moreover, any formulation which comprises a triazine-based anti-coccidial and prior EPM treatment methods is considered within the scope of the present invention. For example, sulfonamides, trimethoprim and pyrimethamine (Daraprim) added to the above formulations are within the purview of the present invention. Of course, the formulation would have to be adjusted for the appropriate pharmaceutically-acceptable percentage of final concentration of all ingredients.

Moreover, since paste formulations are the generally preferred mode of administration of orally-bioavailable compounds, a paste formulation acceptable to horses is hereby provided. Any carriers or excipients, preferably those which enhance absorption, can also be included in the present formulations. One such absorption-enhancing carrier is lactose. Other carriers known in the art may also be used. Sweetners or other flavor-enhancers may be used as well.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl-and propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations may be made so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
In a horse that is severely affected unable to get up, or nearly so Bertone will also give DMSO, since this acts as an anti-inflammatory and reduces some of the swelling in the spinal cord which is causing the problem.
“One of the things to expect, with treatment for EPM, is it may be up to 3 to 6 months before you see substantial improvement,” he says. “Although some horses improve much faster, my usual rule is that if after 3 months of treatment there’s no improvement, the prognosis is poor. The drug has killed the organism but the damage is too severe, or it was an incorrect diagnosis.”

The formulations are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to 10% active ingredient by weight, more usually about 0.25 to 5% of the active ingredient. The term “unit dosage form” refers to physically discrete unites suitable as unitary dosages for mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.

Formulations of the present invention could therefore also contain acceptable amounts of the following ingredients: grain products, molasses products, plant protein products, soybean oil, calcium carbonate, salt, attapulgite clay, dicalcium phosphate, sodium selenite, propionic acid, choline chloride, tetrasodium pyrophosphate, calcium pantothenate, vitamin E supplement, riboflavin supplement, vitamin B-12 supplement, niacin supplement, vitamin A supplement, vitamin D-3 supplement, ferrous carbonate, manganous oxide, zinc oxide, copper sulfate, magnesium oxide, calcium iodate and cobalt carbonate.

These compounds may be administered in any formulation which allows EPM to be treated. For feed formulations, it is important to give enough feed to the animal to ensure ingestion of the required dose. For example, it is necessary to take into account wasted feed that is left in the feeding area and inaccessible to the animal. Moreover, the compounds and/or formulations may be administered via any acceptable method or route. For example, the compounds and/or formulations may be administered in the feed, through formulation with the feed, or via liquid or solid (ie. powder) added at the time of feeding. The compounds and/or formulations can also be administered intravenously, transdermally, sublingually, transmucosally, via tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft or hard gelatin capsule, suppository, sterile injectable solution, sterile packaged powder and transdermal patch.

The dosage for treatment of EPM will preferably vary according to the weight of the horse (ie. 3-15 mg/kg/day, preferably 5-10 mg/kg/day), for from 20-40 days or longer if required, but can be administered in the following common dosage range: 1.5-10 grams of drug per day. However, any EPM-effective dose or duration of treatment is within the scope of the invention. Moreover, the dosage can be time release, which can be any of the above, except that it is formulated so as to release a certain dose continuously or intermittently over a period of time. It is also a preferred embodiment to administer the drug as an injection, one or more times per day, at the same dose as above.

The dosage for prophylaxis of EPM can be less than that necessary for treating EPM, but may be the same, depending on the need of the individual horse. A typical preventative dose of the triazine-based anti-coccidials herein disclosed would be 0.3-0.15 mg/kg/day, preferably 0.5-0.1 mg/kg/day, however, it can be administered via a feed formulation of 0.0002%-0.002% active ingredient, or 1 mg/kg-1 in feed or 200 g of 0.5% Clinacox pre-mix per ton of feed as well. Horses can be fed formulations herein described on a schedule consistent with their needs.

The Disposition And Pharmacokinetics Of Toltrazuril.

The following were initial studies to determine the bioavailability of toltrazuril in non-EPM infected horses. Five horses were given 5 grams/1000 lbs body weight toltrazuril by stomach tube and blood levels were determined at various time periods after administration.

Toltrazuril was very well-absorbed after administration, with peak plasma concentrations occurring at 24 hours after drug administration. Additionally, this agent was shown to have a long plasma half-life (54 hours). The long plasma half life facilitated maintainenance of plasma concentrations at consistently high (µg/ml) concentrations for weeks. Under these conditions of continuous high plasma concentrations, the opportunity for the drug to enter the CNS was maximized. Pharmacokinetic projections based on these kinetics were that single daily doses of 5 gms/horse will yield plasma concentrations of about 30 µg/ml of toltrazuril after 15 days. Administered every second day, this same dose yields steady state plasma concentrations of about 15 µg/ml.

Form:
Oral Liquid / Powder (Pure Toltrazuril)

Presentation:
200mL Single Dose Container / 10 Grams Powder

Storage:
Store below 30° C (Air Conditioning).