80 Yearbook of Agriculture 1956 tion of the magnitude of preventable search Service, He was trained as a para- loss from parasites is the chief stimulus sitologist in the Johns Hopkins University to an awakened interest. School oj Hygiene and Public Health. He received the degree of doctor oj science from AuREL O. FOSTER is head of the Para- that institution in igjj- He taught in Balti- site Treatment Section^ Animal Disease aiid more and conducted research in Panama be- Parasite Research Branchy Agricultural Re- fore entering the Department in ig^g.

Chemotherapeutic Agents for Internal Parasites

AUREL O. FOSTER

CHEMICALS are our oldest weapons significant as new drugs. Today, in for combating the parasitic infections. consequence of a better understanding They arc also the most practicable and of the nature and gravity of para- powerful weapons in modern use. sitism, the strictly curative use of anti- The Ebers Papyrus—the oldest parasitic chemicals is becoming rare. medical document, dating from about Emphasis is on prevention rather than 1550 B. C.—mentions the use of cure, and the concept of parasite pomegranate against intestinal worms. control embraces all feasible steps that Pomegranate is listed for the same minimize economic losses from para- purpose in a late edition of the United sites. States Dispensatory, an official docu- A corollary viewpoint is that anti- ment, which gives ''original informa- parasitic chemicals may attack any tion about new drugs and current vulnerable stage of a parasite and are data about drugs already in use." best and most efficiently employed as Both volumes also mention castor oil adjuncts to other control measures as a purgative. rather than as substitutes for them: Pomegranate is listed because of However necessary and useful these longevity, not because of newness or agents are for treating heavily infested because of uses that we can recom- animals, they are used most profitably mend. Castor oil is still without a peer in proved programs of systematic, in its line. preventive medication. We see this at But specific treatments ordinarily its highest development in the exten- arc products of the times and for the sive use of free-choice and low-level times. None of the treatments current- systeiTis of medication to control ly in wide use against internal para- the gastrointestinal parasites of cattle, sites was known two decades ago. sheep, and horses, and in programs of There is the probability and the hope, continuous and intermittent medica- therefore, that we shall have many tion for controlling coccidiosis and new and better ones a decade or two blackhead of chickens and turkeys. hence. Chemotherapeutic agents, or chemi- Methods of using drugs against para- cals used in treatment or control of sites also change. The effects of new parasitic infestations and infectious approaches and viewpoints are fully as diseases, ordinarily come into use only Chemotherapeutic Agents for Internal Parasites 81 after critical evaluation from stand- ship of particle size to therapeutic points of safety and efficiency. Never- efficiency of the chemical and to low- theless, the most widely used drugs are level and free-choice use of it; those about which we are constantly The versatility and mode of action learning most. Phenothiazine, for ex- of programs of systematic, preventive ample, has been in wide and increas- medication; ing use throughout the w^orld for The applicability of these programs more than 15 years, yet the scientific to parasite control in dairy cattle and literature now contains more accounts goats; of research and experience with it The economic benefits of periodic than with all other anthelmintics medication and of low-level and free- combined. In the last analysis, then, choice methods of administration for treatments, like the language, are the control of subclinical parasitism; made by use. The significance of catalytic iodine in commercial products; PHENOTHIAZINE is a synthetic organic The net longtime efifects of low-level compound prepared by the union of and free-choice medication; and diphenylamine and sulfur in the pres- The evolution and occurrence of ence of iodine as a catalyst. It has well phenothiazine-resistant strains of para- established applications in horses, cat- sites. tle, sheep, goats, swine, and poultry. New problems arise, but sound usage Against many of the damaging gastro- of the chemical depends largely on intestinal roundworms, it is the most solving the old problems. effective treatment—and for some spe- Of the remarkable anthelmintics that cies the only known treatment. have been developed—carbon tetra- Phenothiazine evolved in three pe- chloride in 1921, tetrachloroethylene riods: The discovery of its application in 1925, and hexachloroethane, sodium as a standard anthelmintic (1938- fluoride, lead arsenate, toluene, and 1940); standardization and develop- many others in later years—phenothia- ment of methods of using the drug to zine must be ranked as outstanding. achieve efifective control of parasites It combines a unique range of applica- (1941-1948); and its greatly increased tion, a high degree of efficiency, an use (from 1948 on) in cattle, particu- unusual margin of safety, an ease and larly free-choice and low-level systems versatility of administration, and a of preventive medication of beef ani- variation and range of antiparasitic mals and dairy calves. The third stage actions not found in any other anthel- marks an awakening to the importance mintic. of parasitism in cattle and a recogni- But phenothiazine has some disad- tion of the benefit that may be derived vantages. It is comparatively expen- from controlling subclinical parasitism sive. Therapeutic doses are very bulky. in cattle and other livestock. A few animals, especially horses and Despite the extensive use and study swine, are rather susceptible to in- of phenothiazine and despite the well- toxication by it. Treated animals elim- marked stages in its evolution, many inate breakdown products as a red problems remain unsolved. They have dye, in the urine and feces, which is grown in importance. Among them sometimes alarming, although harm- are: less. The dye temporarily stains the The mechanism of action of pheno- wool of treated sheep, which are ani- thiazine against parasites; mals in which the drug has great over- Subjective factors that influence its all usefulness. The dye also discolors therapeutic efficiency, such as diet and the milk of dairy animals. Finally, the condition of animals requiring treat- drug is deficient in desired efficacy ment; against some important parasites, such Physical factors, such as the relation- as the trichostrongylcs of sheep and 300304"--56 7 82 Yearbook of Agriculture 1956 several gastrointestinal ncmatodes of Because of disadvantages of the cattle. These considerations make it treatment, researchers have looked to clear that there is a place for an even other chemicals, including cadmium better drug. salts and piperazine derivatives, as possible substitutes. SODIUM FLUORIDE is a very efficient chemotherapeutic agent for removing CADMIUM SALTS, the oxide and the large roundworms from swine. As de- anthranilate, showed promise of su- veloped in 1945 and later, the admin- perseding sodium fluoride as treat- istration of the chemical (technical ments to remove large roundworms grade, tinted) in dry, ground feed at from swine. Cadmium oxide was first a concentration of i percent for i day marketed in 1953. Cadmium anthrani- is a safe treatment for growing pigs. late was marketed in 1954. Both salts The treatment removes immature are administered in feed for 3 con- and mature parasites and is more ef- secutive days, the former at a con- fective than ascaricides that formerly centration of 0.015 percent and the were available. Because the round- latter at 0.044 percent. worms take about 10 weeks to mature These compounds are as effective in pigs, effective chemotherapeutic and simple as the sodium fluoride attack on it requires strategic dosing treatment; and they are also safer and at intervals just short of 10 weeks. more palatable, although they pre- For systematic control, therefore, pigs sent the similar problem of poten- should be treated when they are about tial residues in tissues. Our limited .8 weeks old, or at weaning time, and data, however, suggest that the residues again at about 16 weeks. are not dangerous to consumers. Never- The treatment is not safe unless theless, it is recommended that treated properly administered—sodium fluo- animals not be slaughtered within 30 ride is poisonous. Some pigs have been days. Retreatment is not recommended killed by incorrect dosage and by add- for hogs intended for food for people. ing the chemical to slops, garbage, Cadmium treatments are more ex- milk, water, and wet feed. Properly pensive than the sodium fluoride treat- administered, the treatment has nat- ment, but, despite their excellence and ural safeguards. Its taste is unpleasant, popularity, seem destined to be sur- and it irritates the stomach—factors passed by chemicals, such as the piper- that prevent excess consumption of azines, which have become prominent medicated feed and cause reflex vom- in the experimental field. iting if too much is taken in. Sodium fluoride has other disad- PIPERAZINE COMPOUNDS were first in- vantages. It presents the hazard of vestigated for antiparasitic action by a poisoning not only to pigs but to users, commercial company in the United children, and pets. Transient diarrhea States. A useful treatment was devel- and vomiting occur in some pigs, even oped in 1947 for Bancroft's filiariasis of when the drug is properly adminis- man, a troublesome worm infection tered. Feed intake by pigs is reduced among soldiers in the South Pacific. for a day or two at the time of medi- The drug, designated as diethylcar- cation. Ingestion of fluorine-contain- bamazine, has shown value as an ing compounds, such as sodium fluo- ascaricide in dogs and cats and has ride, results in a cumulative deposi- been described as a treatment for tion of insoluble fluorides in the ani- cerebrospinal filariasis (Setaria cervi) in mal body, but the amounts that accrue sheep, goats, and horses and for dermal in edible portions of pork from proper filariasis {Elaeophora Schneideri) in sheep. use of the treatment in question are It has been used also against heart- too small to constitute a hazard to worms, esophageal worms, and thread- consumers. worms of dogs. Chcmothcrapeutic Agents for Internal Parasites 83 After dicthylcarbamazine was intro- but in horses the results suggest that duced, investigators in France and toluene may be a suitable and long- England turned to simpler piperazine awaited replacement of carbon disul- derivatives, such as the hexahydrate, fide, which has been the drug of choice the citrate, and the adipate. Following against large roundworms and stomach studies on mice, piperazine citrate came bots. The use of toluene for this pur- into use in 1953 as a treatment for pose was in the experimental stage in human pinworm infection. It and re- 1956, but tests have indicated that it lated salts were found to be effective is safe and effective, although optimum also against the large round worm. dosages had not been determined and Against these parasites of men, piper- the number of trials has been too small azine has become established as the to warrant recommendations. treatment of choice. It is also effective against large roundworms in dogs and METALLIC ARSENATES are effective cats and partially active against one for removing the common broad tape- species of hookworms. worm from cattle, sheep, and goats. Piperazines, notably piperazine adi- A question is which of several active pate, are promising anthclmintics for compounds is best in safety, efficacy, horses, cattle, swine, and chickens. simplicity, and cost. Piperazine is essentially nontoxic in Workers in the Department of Agri- effective doses (about o.i to 0.2 gram culture determined in 1940 that lead of a salt, or 50 milligrams of the base, arscnate could remove tapeworms from per pound of body weight). It is easily chickens. The chemical was too toxic administered and contains no metallic for use in poultry, but the result was or other noxious ingredients. It seems noteworthy because poultry tapeworms to cause no side effects. were then regarded as resistant to drug The status of piperazines in veteri- action. nary medicine, including the proprie- Lead arsenate was tried against tape- taries known as Safersan and Parvex, worms in lambs at the State College of could not be defined exactly in 1956, Washington. Doses of one-half gram but they seemed destined for promi- of the chemical (acid, spray-grade) nent and profitable use. were given to 555 lambs. The tests were not designed to give critical in- TOLUENE, or methylbcnzene, has formation on the efficacy of the chemi- antiparasitic action in horses, swine, cal, but the doses did cause the expul- chickens, dogs, and cats. It was first sion of large numbers of tapeworms tested in 1926, but the preliminary without hurting the lambs. trials led to the wrong conclusion that A veterinarian in Texas reported in the chemical was ineffective. After re- 1944 his experience in treating 1,158 testing, the chemical was described in lambs, 2,072 kids, 131 calves, and 4 1947 as an efficient drug for removing cows. The treatments seemed to be well large roundworms and hookworms tolerated and efficient. from dogs. Doses of about o.i cubic Studies conducted by the Depart- centimeter per pound of body weight ment of Agriculture and the South are about 97 percent effective against Dakota Agricultural Experiment Sta- roundworms and 87 percent against tion in 1947 established the efficacy hookworms. (There are approximately at about 92 percent, a figure that, in 30 cc. in a fluid ounce.) Toluene has the light of later experience, might become the accepted, standard treat- have been conservative. ment against those common parasites Despite the favorable experience with of dogs. lead arsenate and its status as the Limited studies with swine and chick- standard tapeworm treatment for ru- ens have not established a superiority minants, the undesirability of its lead of toluene over newer treatments. component was recognized from the 84 Yearbook of Agriculture 1956 beginning. A few trials with arsenates which of the aforementioned drugs is of calcium, cobalt, copper, and iron superior for preventing a specific kind have indicated that lead is unnecessary of coccidiosis or arresting its course. for effective teniacidal, or tapeworm- None of them was used before 1944, killing, action. Presumably, therefore, and some questions about them have more complete data will show" that remained unanswered in the subse- dosage depends on the arsenic content quent swift march of events. of the compound and that some other Indeed, as a measure of the progress arsenatc is as efficient as lead arsenate. that has been made in the chemical We have indications that some metallic control of coccidial diseases, it should arsenates have effective action also be noted that no drug possessing anti- against stomach worms. coccidial efficacy was known before 1936, when research workers at the SuLFONAMiDES and certain newer University of Wisconsin showed that chemical agents have been beneficial elemental sulfur helped to prevent the in controlling coccidiosis, a kind of development of cecal coccidiosis in '^intestinal malaria" that affects all chicks. Other early developments, to classes of our domestic animals except which the Department of Agriculture horses. In rabbits, besides intestinal contributed, included sulfanilamide in infection, the disease often produces 1939, sulfaguanidine in 1941, and severe involvement of the liver. sodium borate in 1944, none of which Coccidiosis is a general term for a came into wide use although, like number of related diseases, all caused sulfur, they were noteworthy pre- by protozoan organisms known as cursors of better drugs. coccidia but differing in their occur- rence, pathobiology, treatment, and ANTIBIOTICS have no established ap- coQtrol. plications in the control of livestock In calves, kids, lambs, and rabbits, parasites, but they are of special perti- sulfamethazine effectively arrests the nence because of their potentialities. disease in individual animals and Chlortetracycline (Aureomycin) and checks an outbreak. Many other drugs oxytetracycline (Terramycin) exhibit of its class, however, have been used suppressive and sometimes curative ac- with variable and uncertain success. tion in bovine anaplasmosis. The for- Among them are sulfaquinoxaline mer is said also to influence the course (which appears, however, to lack of piroplasmosis, or tick fever, in horses efficacy against one of the injurious and cats and has been described as an bovine species, Eimeria bovis), sulfa- efficient treatment in dog coccidiosis. merazine, sulfadiazine, phthalylsulfa- Some antibiotics at times have ap- thiazole, succinylsulfathiazole, and sul- peared to reduce the mortality from fapyrazine. cecal coccidiosis of poultry. Some have Many sulfonamides are reliable shown specific action on amebic infec- agents also in controlling poultry tion in man and animals, pinworms of coccidiosis. Sulfamethazine is one of man and mice, and large roundworms the best. Other drugs, however, such of cats. as Nicarbazin, furazolidone, nitro- Many other antibiotics, besides those furazone, nitrophenide, 3-nitro-4-hy- we have named, also influence certain droxyphenylarsonic acid, and 2,2'- protozoan and helminthic infections of methylene-¿>u (4-chlorophenol), have man, laboratory animals, dogs, and all come into competitive prominence cats. They include puromycin, eryth- since 1944. Certain antibiotics, such as romycin, tetracycline, chloramphcn- chlortetracycline and chlorampheni- icol, bacitracin, carbomycin, fumagi- col, may be superior to sulfonamides in lin, trichocidin, neomycin, penicillin, treating coccidiosis in dogs and cats. streptomycin, streptocin, octidionc, We are not able to assert positively and progidiosin. Chemoihürapeutic Agents for External Parasites 85 Because some antibiotics have proved for bovine venereal trichomoniasis; active in certain parasitic infections, antimony potassium tartrate (tartar there appears to be good prospect that emetic), for dermal filariasis of sheep; this rapidly growing and meagerly emetine hydrochloride, a promising tested class of chemotherapeutic agents drug against certain lungworms (Pro- (there are already some 4,000 known tostrongylus and Muellerius) of sheep; antibiotics!) will some day provide thiacetarsamide, for heartworm infec- efficient treatments for some of the tion of dogs; Anthelin, against canine parasitic diseases of livestock and tapeworms; Phthalofyne, against ca- poultry. nine whipworms; and di-N-butyl tin Antibiotics are especially useful for dilaurate, for the removal of some combating bacterial infections that species of tapeworms from chickens. commonly occur in animals suffering These and many other agents are from parasitic diseases. examples of the developments that are Certain chemotherapeutic agents of rapidly taking place. The job ahead comparatively recent introduction have is a challenging one, however, because received prompt verification and ac- present treatments fall far short of ceptance. A few have been mentioned. the ideal, and no chemotherapeutic Others of note include 2-amino-5- agents are yet available for use against nitrothiazole (Enheptin) for control- the majority of helminthic species and ling blackhead, hexamitiasis, and many of the protozoan species that trichomoniasis of poultry; quinacrine cause loss and damage in livestock. hydrochloride, for curing giardiasis and removing tapeworms of dogs, AuREL O. FOSTER is head^ Parasite man, and certain other host animals; Treatment Section, Animal Disease and acriflavine, soluble iodides, and hydro- Parasite Research Branchy Agricultural Re- gen peroxide as treatments of a sort search Service,

Chemotherapeutic Agents for External Parasites

E. F. KNIPLING

INSECTICIDES employed for many DDT, methoxychlor, toxaphene, BHC, years to control ticks, mites, lice, and lindane, and chlordane, have come other arthropod parasites affecting ani- into prominence for controlling many mals were chiefly dips, sprays, or pests. But we still rely heaviJy on pyre- dusts containing arsenicals, nicotine, thrum and rotenone, which have been sulfur, cresols, rotenone, or pyrethrum. used for many years and are of proved To them have been added a long list safety. of synthetic organic chemicals, which A major concern in the development provide more effective materials than of new chemotherapeutic agents for those formerly used to control certain external parasites is that they be safe. external parasites and make it possible We must be certain that the materials to control a wider range of species. will not harm the animal. It is equally These newer insecticides, including imperative that their use wdll not lead