It seems to work! Because of research on new drug treatments for equine protozoal myeloencephalitis (EPM), horse owners might soon be able to kill the parasite that they now only can control effectively about 60% of the time. Preliminary research at the Gluck Equine Research Center in Kentucky by David Granstrom, DVM, MSc, PhD, and Thomas Tobin, MVB, MSc, PhD, MRCVS, Diplomate American Board of Toxicology, has shown that Diclazuril has turned around three severely affected horses with repeated histories of relapse on current treatments for EPM. Horse owners from around the country are going to be champing at the bit over these words, but there are still some details that need to be worked out before the newest treatment regimen for EPM can be released to private practitioners.
Current therapy for EPM utilizes pyrimethamine and sulfadiazine. These products do not kill the Sarcocystis neurona protozoa; instead, they inhibit the parasites in the horse from dividing and causing more problems (see sidebar page 54 on the life cycle of S. neurona). It must be remembered that the horse is a dead-end host for this parasite. The horse is not meant to be a part of the life cycle of S. neurona, and the parasite cannot mature to its next phase of life in the horse. Therefore, an infected horse cannot pass the parasite to other horses or other animals.
Tobin said the researchers are "almost ready" to release the drug and current treatment regimen on an experimental basis to private practitioners for use on serious cases for which there are no other options. While there have been no toxic effects observed from using Diclazuril at the current level, he emphasized that the research team will not recommend its use on pregnant mares because no studies have been done on toxicity or long-term reproductive effects. Researchers currently are trying to set the parameters of drug use, including dose amount, time of administration, and length of treatment.
The researchers warn, however, that severely affected horses might never return to the same level of physical fitness at which they were before suffering through EPM, no matter the treatment.
"Based on what we have seen, we can kill the organism with Diclazuril, but the ultimate repair of the central nervous system is slow," said Tobin. "And the horse needs to be out as much as possible for optimal rehabilitation."
"When you lose neurons, you have the possibility of permanent neurologic damage," added Granstrom.
Diclazuril has been shown in the laboratory to be able to kill S. neurona. "What differentiates this treatment in our study and the current therapy," noted Granstrom, "is the inability of the current treatment to kill S. neurona. This failure to kill the organism is the likely reason for the significant relapse rate after therapy ceases."
It is thought that the new drug and treatment regimen will kill the parasites in the horse, thus allowing the animal a "breathing period" to build up its own antibody levels to protect it against being re-infected from the environment.
Understanding the Drug
In the benzene acetonitrile drug group there is an anti-coccidial drug called Triazine. Diclazuril is an analog of Triazine. (To drop back one step, you should understand that coccidium merely refers to the group of parasites that resemble the malaria parasite. An analog in this case refers to a chemical compound that has a structure similar to that of another compound, but some of the components are different. Therefore, when researchers say Diclazuril is an analog of Triazine, it means they are very similar, but also have some differences.) This family of drugs (benzene acetonitrile) has been reported to work against similar parasites in tissue culture in human research and in other animals.
Granstrom was looking for a better drug for the treatment of EPM. In scanning the literature for anti-protozoal drugs, he found a paper showing that Diclazuril had worked on the protozoan Neospora in tissue culture. After more research, he decided he wanted to see if Diclazuril would work against S. neurona. He also found information on another drug that looked promising against S. neurona. However, further research reports indicated that the drug might have had some unwanted side effects in laboratory animals, so he didn't proceed in trying to acquire that drug for testing in horses. Granstrom also was looking at information on drugs used in AIDS patients against Neospora and other coccidias, which often affect AIDS patients. The challenge was to find a drug that could kill the parasite, and that could get to the areas in the horse where the parasite was located without injuring the horse.
"There might be a dozen drugs that could kill the parasite," said Tobin, but the question was whether they were safe for horses."
"Most of the drugs would either be toxic to horses, or were not absorbed from the gut," noted Granstrom. "Others would cause severe diarrhea or affect the intestinal tract in horses. And some were cost-
prohibitive for horses."
Granstrom finally found a source for Diclazuril, which isn't available in this country. The source was a chicken feed additive. Diclazuril is given orally only once to poultry, since the coccidia in their bodies stay in the gut and thus are easier to kill with an oral treatment. Diclazuril is licensed for use in poultry, hogs, and chickens in other countries.
Under the auspices of the Investigational New Animal Drug (INAD) program of the FDA, the Kentucky researchers gave a treatment regimen to a severely affected mare for 21 days. (The treatment lasted for that duration because that was the end of their first supply of the drug.)
"In the literature, it (Diclazuril) is used once because the infection is intestinal in other species," said Granstrom. "In systemic infections in the horse, especially because of the central nervous system involvement, it takes repeated doses."
S. neurona is of a type known as an apicomplexan parasite. Tobin explained that there is evidence that somewhere in the evolution of this single-celled organism, it "picked up" a site that is usually found only in plants. This means that certain compounds, such as Diclazuril, can be effective in killing the parasite, yet have no adverse effects on the host animal because the host animal doesn't have the "site" that is being attacked by the drug. He said that is speculation, but it "seems reasonable."
Current estimates are that cost of the drug treatment could run $500-600, which might see high, but there should be no need for additional treatment if this drug proves effective at killing the parasite.
First Round of Tests
A mare was donated for research because she had repeatedly relapsed following the end of standard treatment therapy, and her symptoms were clearly asymmetric (one-sided), differentiating her from a wobbler. She was so severely affected, in fact, that Granstrom on two occasions debated euthanasia because of delays in obtaining the Diclazuril for the study.
The mare was confined to a stall at the start of the therapy because of the severity of her symptoms. By the end of the treatment, she had improved dramatically. Now, more than six months after the end of treatment, she has not relapsed, even after being outside in an environment where she would potentially have been exposed to the organism. Tobin said this mare went from a Grade 4 (severely uncoordinated) to a Grade 0-1 based on neurologic examination.
The mare, which at one point could not get around, eat, or fend for herself outside, now has re-joined the broodmare band at pasture and is fending for herself without problem.
The second horse in the study was a 2-year-old gelding in training. He was considered almost a Grade 3 at the time of donation, then quickly deteriorated to a Grade 4-5. He became stall-bound, then got down and could not rise. Again, the decision to euthanize a horse in the study was debated, but the decision was made to let the gelding keep fighting to live.
For eight weeks (during and after treatment), this gelding was in a sling, then in a double box stall bedded deeply in shavings. He began to improve slightly, so he was put outside where the footing was better for his condition. With exercise, he improved to a Grade 2-2+, and he continues to improve, said Gran-strom. He had been off treatment only a month at the time of this interview in early March, and had only been outside his stall about a week.
The third horse in the trials was a Thoroughbred mare which had a severe asymmetry and had relapsed several times after standard treatment. In the first week of treatment, she showed dramatic improvement, then showed regression in symptoms during the latter part of treatment. She now is making gradual, steady improvement and is expected to continue to improve.
The researchers questioned the regression, and said it might be due to the "kill off" of parasites and the body's attempts to get rid of them. (In other parasitic diseases in other animals, the killing of the parasites has to be regulated be-cause the load of dead parasites can itself cause problems for the animal.)
The drug was shipped to The Ohio State University to try on two severely af-fected horses which were positive for EPM on a cerebrospinal fluid test. Both died; one of aspiration pneumonia, and the other of various complications. The second horse had been bad enough to require a sling prior to the start of therapy. At post mortem, it showed evidence of EPM.
Researchers there, Granstrom said, want to try the drug again, this time on horses not so severely compromised.
Next on the Horizon
"We would like three or four more horses to go through this treatment successfully and begin working on the pharmacokenetic (movement of drugs through the body) and toxicity studies," said Tobin. "The number of cases where you see a Grade 4 knocked back to a Grade 1 is small."
He added that Diclazuril also might be used in conjunction with current therapies or other drugs. He noted that in AIDS drug studies, often one drug will slow the progression of coccidia, but two or three drugs in combination will "knock down" the infection and be more beneficial.
"So, we might use this in combination with pyrimethamine," said Granstrom.
Currently, a horse can develop resistance to the standard therapy, which means the parasites have mutated and become able to "ignore" the drugs meant to stop them. But, when two or three drugs are used together, noted Tobin, there have to be two or three mutations happening at once for the parasite to become resistant. That is unlikely to happen.
"Right now, we can increase the dose (of pyrimethamine and sulfadiazine) and hope to overcome the resistance, which is dose-related, but that is the only alternative until this (Diclazuril) or other drugs become available," said Granstrom.
Another bright area in the search to protect and/or help horses with S. neurona infections is the ability for researchers to experimentally reproduce the disease in horses. This recently published information based on work done by Granstrom will allow great advances in studying the disease. What happens to a horse--day-by-day, hour-by-hour--when it becomes infected with S. neurona? Why do some horses "fight off" the parasite, while others become ill? How do drugs work against the parasite? Is stress a factor in causing disease in exposed horses? Can a safe and effective vaccine be developed?
"This will enable us to study drugs in uniform populations," said Granstrom. "It is expensive to do because you have to hold the horses in isolation and give them extruded feeds that haven't been contaminated (with the parasite). We can learn how to diagnose a horse from the day it is infected and discover what the parasite is doing and what host mechanisms are activated. Then perhaps we can exploit those mechanisms and help the horse help itself (with immunotherapy).
There are many questions left to be answered in regard to EPM, but researchers are making headway that hopefully will provide effective treatments, and possibly even result in ways to protect horses from this sometimes devastating disease.
About the Author
Kimberly S. Brown was the Publisher/Editor of The Horse: Your Guide To Equine Health Care from June 2008 to March 2010, and she served in various positions at Blood-Horse Publications since 1980.
POLL: University Equine Hospitals