Diclazuril and the History of EPM Treatment
Diclazuril is a triazinone antiprotozoal that is effective for treating infections caused by Isospora spp., Toxoplasma gondii, and Eimeria spp. and has been used for treating coccidiosis.1 Initially, diclazuril was approved in Europe and in the U.S. for its activity against chicken Eimeria to control coccidiosis in poultry.
Currently, diclazuril is FDA-approved in the U.S. for the treatment of equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona and as a coccidiostat in broiler chickens.2 In the UK, oral diclazuril suspension is approved for the treatment and prevention of coccidial infections in lambs caused, in particular, by the more pathogenic Eimeria spp, E crandallis and E ovinoidalis and as an aid in the control of coccidiosis in calves caused by E bovis and E zuernii.2-3
Equine protozoal myeloencephalitis (EPM) in Horses
Equine protozoal myeloencephalitis is the most important infectious neurologic disease of horses in the Western Hemisphere. Equine protozoal myeloencephalitis can interfere with a horse’s ability to race, work, and perform; untreated, EPM can be lethal. Antemortem diagnosis of EPM is challenging, requiring careful evaluation of the animal’s history, clinical signs, and laboratory data, with rigorous exclusion of other causes. Therapeutic approaches to EPM are evolving. First-generation therapeutic approaches for EPM were based on the classic anti–Toxoplasma gondii pyrimethamine–sulfonamide combinations; treatment is prolonged and can be associated with a considerable relapse rate, which may be associated with the difficulty in maintaining effective CNS concentrations of pyrimethamine. Second-generation therapeutic approaches are based on diclazuril and related triazine agents.4
S. neurona is endemic to the Americas, and is only found in horses that reside in these areas. While the symptoms that would come to be known as EPM were identified in the late 1960s, it wasn’t until the 1990s that researchers definitively identified the causative agent. This led to a fairly frenzied quest for viable treatment modalities.
At first, veterinarians and researchers were scrambling to discover anything about the “new” neurologic disease that was causing such a stir in the horse industry. The disease, equine protozoal myeloencephalitis (EPM), was discovered to be caused by a one-celled protozoal parasite called Sarcocystis neurona. This parasite does not include the horse in its normal life cycle (which means horses can’t pass it to other horses). It is known to migrate into the spinal cord or brain of the horse and cause a multitude of asymmetric symptoms, ranging from hardly noticeable to life-threatening.5
History of EPM Treatments
In the 1990s, a new Western blot assay using cerebrospinal fluid was developed that was specific for S. neurona and did not react for the other sarcocystis organisms. Treatments utilizing pyrimethamine and a sulfonamide (usually trimethoprim-sulfamethoxazole or sulfadiazine) were aimed at stopping replication of the organism in the horse’s body until the horse could mount a suitable defense.
It was during this time period that the life cycle of S. neurona was discovered, and prevention in the form of farm management and animal (opossum and birds) control was added to the arsenal. Folic acid supplementation was recommended, especially for mares, because of the mode of operation of drugs used in treatment. It now is thought that folic acid supplementation is not in the best interest of the health of some horses, especially pregnant mares and unborn foals.
Looking for antibodies with a blood test revealed an incredible number of positive horses (up to half the equine population or more in some areas, which is still true today). In the beginning, it was thought that a positive blood test meant a horse had EPM. Then researchers realized that a positive blood test only meant the horse had been exposed to the protozoal parasite and had developed antibodies against it.
Ultimately, the U.S. Food and Drug Administration (FDA) approved two drugs (Diclazuril and Toltrazuril, both anti-protozoal medications) to be imported from Canada by veterinarians under a special provision of the U. S. government.3
EPM Treatment with Diclazuril
In the infected horse, diclazuril crosses the blood-brain barrier and enters the cerebrospinal fluid at levels high enough to either limit the reproduction of the S. neurona protozoa or kill them outright. At standard doses, it can take at least a few days for diclazuril to reach therapeutic levels in the cerebrospinal fluid, but researchers are working to find ways to help the drug work faster. In more severe cases, or if the disease is progressing rapidly, a veterinarian may opt to start a course of treatment with a “loading dose” (the administration of up to seven times the normal amount) before beginning the routine drug regimen. With this method, therapeutic levels in the CSF can be achieved much faster.6
Diclazuril is available in pelleted, suspension, powder and injectable forms. For treatment of EPM, manufacturers recommend using oral pellets for top dressing feed at the rate of 1 mg/kg/day for 28 days. If horse’s bodyweight is in between 2 graduations on the dosing cup, fill the cup to the higher of the 2 marks. For prevention of EPM in horses (including foals), the recommended dosage is 0.5 mg/kg daily, beginning at 4 weeks of age. 2 Dosage for injectable and other forms should be per manufacturer’s recommendations and at the direction of the veterinarian.
1Papich, M. Diclazuril. In: Saunders Handbook of Veterinary Drugs (Fourth Edition) Small and Large Animal 2016, Pages 232-233.
2Pusterla N, et al. Daily feeding of diclazuril top dress pellets in foals reduces seroconversion to Sarcocystis neurona. Vet J. 2015;206(2):236-238.
3Le Sueur C, et al. Efficacy of toltrazuril (BaycoxA (R) 5% suspension) in natural infections with pathogenic Eimeria spp. in housed lambs. Parasitol Res. 2009;104(5):1157-1162.
4Dirikolu, Levent & Foreman, Jonathan & Tobin, Thomas. (2013). Current Therapeutic Approaches to Equine Protozoal Myeloencephalitis. Journal of the American Veterinary Medical Association. 242. 482-91. 10.2460/javma.242.4.482.
5Brown, K. EPM Tests and Treatment. In: The Horse (Feb 1999) AAEP Convention, Article, Equine Protozoal Myeloencephalitis (EPM).
6Thomas, H. The continuing threat of EPM. Equus, April 2017.
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