Protocidal

I AM SO EXCITED! TOOK LEGS OUT IN THE LOUNGE PEN & OMG! NOT ONLY WAS HE TROTTING BETTER & HIS LOPE LOOKED LIKE THE OLD JAW DROPPING FLOATY NATURALLY COLLECTED LOPE, BUT HE WAS BREATHING BETTER!    I grabbed everybody from the barn and made them come watch and listen.  I just wanted verification that it was not me just hoping he was breathing better, but they all  agreed he was SIGNIFICANTLY BETTER! Don’t get me wrong I didn’t lope him much, it didn’t take much to start his roaring before, like about 3 strides into the lope and he  sounded like he was going to die. This time I asked to lope around each way (60 ft. round pen) twice and all though you could hear his breathing it was only about half as loud as it before. More importantly, he looked happy doing it because he could breathe so much better! I can, also, say I had forgotten how pretty he could be.  He had degenerated so slowly that it was hard to notice until now I see the improvement. I just wanted to let you know. Deborah

 

Decoquinate is protocidal

Your horse and those animals that you treat deserve a therapy that works!  There are two major reasons why Oroquin-10 is working for the treatment of equine protozoal myeloencephalitis in horses–one is decoquinate and the other is levamisole.  Decoquinate is a drug that kills pathogenic protozoa very quickly but spare the good protozoa in the cecum—beneficial protozoa in the hind gut of the horse are unaffected by treatment.  Decoquinate is a protocidal drug, unlike triazine drugs that exert static effects.  Static drugs work by slowing the growth of protozoa which allows the immune system to kill the organisms.  The cidal drugs need a functional immune system or the parasites aren’t eliminated.  Suppressed immune systems are thought to impact horses and leave horses susceptible to infections by S. neurona.   And we have previously shown that S. neurona can turn off the immune system of horses in a very (parasite specific) way that benefits the protozoa.  Levamisole is an immune modulating drug that may reverse the parasite specific down regulation of the immune system present in EPM horses among other possible effects.

The definitions of protocidal and protostatic drugs revolve around the in vitro capacity to deliver a rapid rate of microbial killing.  By convention the cidal agents are the preferable therapeutic options.  Additional issues are toxicity.  Good therapeutic agents are those that target structures or cell processes that are sufficiently unique to the invading organism than those of the host.  That means toxicity to the host is minimized. Decoquinate exerts its effect on the gametocytes (sexual stages) and is active against these stages in just 48 hours.  The action that decoquinate exerts is disrupt electron transport chains in mitochondrial cytochromes systems of coccidia.  There is no action against mammalian cells or even protozoa that are not apicomplexans. 

Triazine resistance issues

Drugs are prone to resistance issues.  Resistance to a drug by an organism is generally described as inherent resistance or developmental/acquired resistance.  The perceived resistance of S. neurona strains to triazines is not necessarily inherent or acquired but a function of the static action of the drug.  The triazines are slower acting and limit stages of parasite growth. Treatment success depends on the host’s immune system to kill parasites.  Relapses may occur if the horses aren’t treated long enough with triazine drugs—this scenario is evident in the recommendations to treat longer and with an increased dose of drug.  There are reports that there is no difference between 1, 5, and 10 mg/kg of triazines in the treatment of EPM—so it’s not dose it is duration.  And that is expected with a statically acting drug.  Periods of unusual stress would elicit relapses.  This is because all the disease-causing parasites are not removed from the nervous tissues of the horse.  Our work with Oroquin-10 has demonstrated “resistance” of S. neurona to triazine drugs.  Horses initially treated with Marquis or diclazuril can show an increase in a specific phenotype (and the horses don’t improve clinically).  Changing the therapy to the protocidal drug decoquinate elicits a rapid clinical response followed by a reduction in antibody titer.

Decoquinate is a 4-hydroxyquinolone that is highly active against Sarcocystis neurona (and N. hughesi) and decoquinate even at low concentrations accomplishes intracellular stage killing. It is an anti-protozoal that may be fed prophylatically to horses, to prevent EPM, and may be administered to horses to treat EPM. FDA clearances are for decoquinate for prevention of coccidiosis in cattle, goats, sheep and broiler chickens and the product sheet data indicate that decoquinate is non-toxic to horses.

 At least as good recovery is expected using decoquinate as for conventional treatments. Decoquinate was a promising drug once for malaria in people.  The drug showed single digit nanomolar actions against in vitro Plasmodium falciparum parasites.  When decoquinate was tagged with carbon 14 (to follow the radioactive label) 96% disappeared from the blood in one hour in cattle, chickens, sheep, and quail.  The half-life is less than 1 day and it is gone from tissues in 14 days. 

Cows, goats, and sheep are tolerant of very high doses of decoquinate that were used in toxicity studies.  The beneficial protozoa, active in the hind-gut (cecum) of horses, are unaffected by decoquinate treatment.  The horse is a non-ruminant herbivore and the cecum is full of beneficial bacteria, fungi, and protozoa that digest insoluble carbohydrates.  When high starch and sugar are delivered to the cecum the resulting unnatural fermentation can kill the beneficial microbes and ultimately lead to the release of endotoxins.  This is most often seen in pathologic diarrhea secondary to anti-bacterial products.  Any drug that kills beneficial bacteria or protozoa in the equine cecum would also result in diarrhea and secondary release of endotoxins.

 Experimental evidence for the safety of decoquinate in animals is well described, albeit long ago in the 1970’s.  The consensus was that decoquinate was safe and was marketed as an over-the-counter product for use in calves, chickens, swine, sheep, game birds, humans, rats, rabbits, and guinea pigs.  It was given to young calves at 12.5 times the treatment dose for 120 days in sixteen calves with no clinical, gross, or histological evidence of toxicity in the animals.  Additional animals were treated for 160 days with no toxicity seen (they looked at all the tissues by histopathology).  In newborn calves the drug was found safe at 22.7 mG/100 pounds.  More decoquinate given to calves… at 20 mG/kG, 10 mG/kg for 10 days, and 6.25 mG/kG for 4 and 6 months and was not toxic.  In chickens 11g/kg did not elicit toxicity.  That wasn’t a typo…the experiment used 11 GRAMS/kG.  Eleven thousand mg/kg.  This group also used 15 mG/kG for 3 weeks and then 1000 mG/kG for 13 weeks…and then they did a 2 year experiment with 200 and 1000 ppm in feed.  None of these treatments were toxic.

In rats 5mG/kG and 62 mg/kG for 11 weeks and 2G/Kg for 16 weeks were not toxic and elicited no effects (for which they checked) on embryos.  In swine the decoquinate was added to feed and was given for 112 days at 3, 10, 30, 100, and 300 G/ton.  The same researchers reported using 6.25 mG/kG in horses with no toxicity.  Sheep got 45 mG/KG and lambs got 200 G/ton in feed (8X) and no toxicity was observed.  Game birds were tested at 5 mG/kG and goats got 5 mG/kG for 84 days.

Decoquinate exerts it’s activity on biochemical pathways that humans and animals don’t have and that’s why there is so high a safety margin.  That’s not true with other conventional treatments for EPM.

Warning!  Why you want to be careful with your sources

A warning about decoquinate is that monensin and rumensin are calcium ionophores that are highly toxic to horses but not to ruminants.  Ionophores are often added to products that are given to ruminants.  It is imperative that not only should decoquinate therapy not contain these ionophores but the products used for horses should not be produced in a facility that uses ionophores in their products.  That includes the starting products as well as the final products. 

Toxicity with other drugs

Pyrimethamine and sulfonamides are used to treat EPM, with a prolonged course of treatment (twelve weeks being about the average length of treatment time). Complications of anemia and/or leucopenia have been observed, especially for doubling the pyrimethamine dose, and in some horses diarrhea occurs.  Blood anomalies are observed after 4 weeks therapy at the recommended label doses. 

Your horse deserves a safe and effective treatment for EPM.  We are working with FDA on bringing that product to you, one that is safe and effective.  And while we’re at it we will make it cost effective.