Chemotherapeutic Agents for Internal Parasites

AUREL O. FOSTER.

CHEMICALS are our oldest weapons for combating the parasitic infections. They are also the most practicable and powerful weapons in modern use.

The Ebers Papyrus the oldest medical document, dating from about 1550 B. C. mentions the use of pomegranate against intestinal worms. Pomegranate is listed for the same purpose in a late edition of the United States Dispensatory, an official document, which gives "original information about new drugs and current data about drugs already in use." Both volumes also mention castor oil as a purgative.

Pomegranate is listed because of longevity, not because of newness or because of uses that we can recommend. Castor oil is still without a peer in its line.

But specific treatments ordinarily are products of the times and for the times. None of the treatments currently in wide use against internal parasites was known two decades ago. There is the probability and the hope, therefore, that we shall have many new and better ones a decade or two hence.

Methods of using drugs against parasites also change. The effects of new approaches and viewpoints are fully as significant as new drugs. Today, in consequence of a better understanding of the nature and gravity of parasitism, the strictly curative use of anti-parasitic chemicals is becoming rare. Emphasis is on prevention rather than cure, and the concept of parasite control embraces all feasible steps that minimize economic losses from parasites.

A corollary viewpoint is that anti-parasitic chemicals may attack any vulnerable stage of a parasite and are best and most efficiently employed as adjuncts to other control measures rather than as substitutes for them: However necessary and useful these agents are for treating heavily infested animals, they are used most profitably in proved programs of systematic, preventive medication. We see this at its highest development in the extensive use of free-choice and low-level systems of medication to control the gastrointestinal parasites of cattle, sheep, and horses, and in programs of continuous and intermittent medication for controlling coccidiosis and blackhead of chickens and turkeys.

Chemotherapeutic agents, or chemicals used in treatment or control of parasitic infestations and infectious diseases, ordinarily come into use only after critical evaluation from standpoints of safety and efficiency. Nevertheless, the most widely used drugs are those about which we are constantly learning most. Phenothiazine, for example, has been in wide and increasing use throughout the world for more than 15 years, yet the scientific literature now contains more accounts of research and experience with it than with all other anthelmintics combined. In the last analysis, then, treatments, like the language, are made by use.

PHENOTHIAZINE is a synthetic organic compound prepared by the union of diphenylamine and sulfur in the presence of iodine as a catalyst. It has well established applications in horses, cattle, sheep, goats, swine, and poultry. Against many of the damaging gastrointestinal roundworms, it is the most effective treatment and for some species the only known treatment.

Phenothiazine evolved in three periods: The discovery of its application as a standard anthelmintic (1938-1940); standardization and development of methods of using the drug to achieve effective control of parasites (1941-1948); and its greatly increased use (from 1948 on) in cattle, particularly free-choice and low-level systems of preventive medication of beef animals and dairy calves. The third stage marks an awakening to the importance of parasitism in cattle and a recognition of the benefit that may be derived from controlling subclinical parasitism in cattle and other livestock.

Despite the extensive use and study of phenothiazine and despite the well-marked stages in its evolution, many problems remain unsolved. They have grown in importance. Among', them are:

The mechanism of action of phenothiazine against parasites;

Subjective factors that influence its therapeutic efficiency, such as diet and condition of animals requiring treatment;

Physical factors, such as the relation-ship of particle size to therapeutic efficiency of the chemical and to low-level and free-choice use of it;

The versatility and mode of action of programs of systematic, preventive medication;

The applicability of these programs to parasite control in dairy cattle and goats;

The economic benefits of periodic medication and of low-level and free-choice methods of administration for the control of subclinical parasitism;

The significance of catalytic iodine in commercial products;

The net longtime effects of low-level and free-choice medication; and;

The evolution and occurrence of phenothiazine-resistant strains of parasites.

New problems arise, but sound usage of the chemical depends largely on solving the old problems.

Of the remarkable anthelmintics that have been developed carbon tetrachloride in 1921, tetrachloroethylene in 1925, and hexachloroethane, sodium fluoride, lead arsenate, toluene, and many others in later years phenothiazine must be ranked as outstanding. It combines a unique range of application, a high degree of efficiency, an unusual margin of safety, an ease and versatility of administration, and a variation and range of antiparasitic actions not found in any other anthelmintic.

But phenothiazine has some disadvantages. It is comparatively expensive. Therapeutic doses are very bulky. A few animals, especially horses and swine, are rather susceptible to intoxication by it. Treated animals eliminate breakdown products as a red dye, in the urine and feces, which is sometimes alarming, although harmless. The dye temporarily stains the wool of treated sheep, which are animals in which the drug has great overall usefulness. The dye also discolors the milk of dairy animals. Finally, the drug is deficient in desired efficacy against some important parasites, such as the trichostrongyles of sheep and several gastrointestinal nematodes of cattle. These considerations make it clear that there is a place for an even better drug.

SODIUM FLUORIDE is a very efficient chemotherapeutic agent for removing large roundworms from swine. As developed in 1945 and later, the administration of the chemical (technical grade, tinted) in dry, ground feed at a concentration of 1 percent for 1 day is a safe treatment for growing pigs.

The treatment removes immature and mature parasites and is more effective than ascaricides that formerly were available. Because the roundworms take about 10 weeks to mature in pigs, effective chemotherapeutic attack on it requires strategic dosing at intervals just short of 10 weeks. For systematic control, therefore, pigs should be treated when they are about 8 weeks old, or at weaning time, and again at about 16 weeks.

The treatment is not safe unless properly administered sodium fluoride is poisonous. Some pigs have been killed by incorrect dosage and by adding the chemical to slops, garbage, milk, water, and wet feed. Properly administered, the treatment has natural safeguards. Its taste is unpleasant, and it irritates the stomach factors that prevent excess consumption of medicated feed and cause reflex vomiting if too much is taken in.

Sodium fluoride has other disadvantages. It presents the hazard of poisoning not only to pigs but to users, children, and pets. Transient diarrhea and vomiting occur in some pigs, even when the drug is properly administered. Feed intake by pigs is reduced for a day or two at the time of medication. Ingestion of fluorine-containing compounds, such as sodium fluoride, results in a cumulative deposition of insoluble fluorides in the animal body, but the amounts that accrue in edible portions of pork from proper use of the treatment in question are too small to constitute a hazard to consumers.

Because of disadvantages of the treatment, researchers have looked to other chemicals, including cadmium salts and piperazine derivatives, as possible substitutes.

CADMIUM SALTS, the oxide and the anthranilate, showed promise of superseding sodium fluoride as treatments to remove large roundworms from swine. Cadmium oxide was first marketed in 1953. Cadmium anthranilate was marketed in 1954. Both salts are administered in feed for 3 consecutive days, the former at a concentration of 0.015 percent and the latter at 0.044 percent.

These compounds are as effective and simple as the sodium fluoride treatment; and they are also safer and more palatable, although they present the similar problem of potential residues in tissues. Our limited data, however, suggest that the residues are not dangerous to consumers. Nevertheless, it is recommended that treated animals not be slaughtered within 30 days. Retreatment is not recommended for hogs intended for food for people.

Cadmium treatments are more expensive than the sodium fluoride treatment, but, despite their excellence and popularity, seem destined to be surpassed by chemicals, such as the piperazines, which have become prominent in the experimental field.

PIPERAZINE COMPOUNDS were first investigated for antiparasitic action by a commercial company in the United States. A useful treatment was developed in 1947 for Bancroft's filiariasis of man, a troublesome worm infection among soldiers in the South Pacific.

The drug, designated as diethylcarbamazine, has shown value as an ascaricide in dogs and cats and has been described as a treatment for cerebrospinal filariasis (Setaria cervi) in sheep, goats, and horses and for dermal filariasis (Elaeophora schneideri) in sheep. It has been used also against heart-worms, esophageal worms, and thread-worms of dogs.

After diethylcarbamazine was introduced, investigators in France and England turned to simpler piperazine derivatives, such as the hexahydrate, the citrate, and the adipate. Following studies on mice, piperazine citrate came into use in 1953 as a treatment for human pinworm infection. It and related salts were found to be effective also against the large roundworm. Against these parasites of men, piperazine has become established as the treatment of choice. It is also effective against large roundworms in dogs and cats and partially active against one species of hookworms.

Piperazines, notably piperazine adipate, are promising anthelmintics for horses, cattle, swine, and chickens. Piperazine is essentially nontoxic in effective doses (about 0.1 to 0.2 gram of a salt, or 50 milligrams of the base, per pound of body weight). It is easily administered and contains no metallic or other noxious ingredients. It seems to cause no side effects.

The status of piperazines in veterinary medicine, including the proprietaries known as Safersan and Parvex, could not be defined exactly in 1956, but they seemed destined for prominent and profitable use.