PARASITIC DISEASES AND THE CHEMIST*

STERLING BRACKETT Stamford Research Laboratories, American Cyanamid Company, Stamford, Connecticut

ONE of the laws of nature is that living organisms ex- parasite, since it develops literally unchecked and com- ert a pressure to fill every nook and cranny in search of pletely destroys parts of the digestive tract and the food and shelter. They invade not only land, sea, and liver. Evidently this parasite and turkeys, which orig- air but also the bodies of other animals. Those forms inated in America, have been associated for such a which live on or in the bodies of other animals extracting short period of time (about 400 years) that a strain of their livelihood therefrom are known as parasites. turkeys resistant to this parasite has not yet evolved, if While the term is broadly applied to all plants and mi- one ever will. mals living a t the expense of others, the term is more The disease in turkeys caused by this parasite is frequently restricted to the parasitic protozoans and commonly known as blackhead, and i t has prevented worms. No free-living animal has yet been found turkey raising from becoming a major industry in the without its own special parasites; thus, there are a t New England states where it originated. In 1890, least as many different kinds of parasites as there are 11,000,000 turkeys were raised in the United States nonparasitic species. Most of these parasites attract while in 1920 only 3,600,000 were produced. This drop little or no attention, however, since they do little or took place in spite of an increase in population and de- no damage to their host. mand for turkeys. The reason is considered to hare

The so-called perfect parasitic relationship might be been the disease losses to which the turkey man mas sub- likened to an armed truce between the host and the par- jected, and the chief cause of these losses mas probably asite. The parasites, while living a t the expense of the blackhead disease. Even now, with the industry some- host, dare not create too much havoc or else they 6nd what recovered, the New England states raise only one themselves without food or shelter. Not all parasitic of every 60 turkeys they use each year. relationships are as benign, however, and where the At present a large share of the research activities of parasite is unusually aggressive or the host unusually my own group and that of a group of chemists cooper- passive the condition known as disease arises. ating with us are devoted to a search for a drug to con-

example of a Nperfectfl versus an ymperfectn par- trol this disease of turkeys. A solution to this problem =itic relationship is seen in the protozoan parasite would revolutionize the turkey industry probably as ~ i ~ l ~ ~ ~ ~ ~ nekagr&s which unknown to most of us much as did the introduction of incubator hatching of has played an important role in the economy of theNew eggs. A story of the background, with some of its England states. This parasite lives peacefully for the ramifications, leading up to this ~roject will, I believe, most part in chickens, probably because the fowl of to- give some notion of the general principles involved in a day, which originated in the jungles of tropical ~ ~ i ~ , search for a new drug. This story winds its way through and this parasite have heen living together for so long studies on malaria, a disease of man with which every- that natural selection has evolved strains of the two one is familiar, and coccidiosis, a parasitic disease of which are about equally matched. An individual chickens which, though of primary importance to chicken ordinarily develops a resistance to this parasite poultry men, may be unfamiliar to most persons. so rapidly that it keeps it in on the hand, Shortly after sulfanilamide was introduced to human turkeys almost invariably die when infected with this medicine with such spectacular results about 10 years

ago, it was tried in infections of domesticated animals

* Based on a paper presented a t the Eleventh Summer Con- includmg coccidiosis of poultry. Sulfanilamide had ference the N.E.A.c.T., university of N~~ hi^^, some effect in this infection. Shortly after this a phar- August 23, 1949. macologist, Dr. E. K. Marshall, who was ausious to

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apply the sulfonamides to the treatment of bacillary they result in better blood levels per unit of oral dose. dysentery argued that since the bacteria causing the After carefully standardizing the laboratory infections trouble were found within the intestine the ideal drng of coccidiosis so that quantitative comparisons of drngs vould be one that stayed there rather than being too could be made, Dr. Waletzky found, just as he had sus- readily absorbed by the body. Studies in mice indi- pected, that the activity of the sulfonamides in coccid- eated that sulfaguanidine was such a dmg and it was iosis was completely correlated with blood levels. subsequently found to be effective in the treatment of From this he selected sulfamethazine as being the most bacillary dysentery in man. economical of the readily available sulfonamides for

This postulation attracted the attention of several in- the treatment of coccidiosis, and this drug was soon vestigators in veterinary medicine who thought the widely accepted in the poultry industry. Thus, the same reasoning should apply to coccidiosis in chickens, practical results confirmed the value of the laboratory which is a parasitic disease of the intestine or its observations and speculations. branches known as the ceca. When tried, sulfaguani- Even though the sulfonamides have been quite snc- dine nas found to be so effective that it soon appeared cessful in coccidiosis, it was felt that a better dmg could on the market and was widely used for many years, and be found. The methods of using the sulfonamides for still is, effecting a large reduction in the estimated ten controlling outbreaks of coccidiosis were somelvhat per cent loss suffered by the poultry industry each year cumbersome as far as the poultry man was concerned. from coccidiosis. Also, before he realized that medication was called for,

During the war while concentrating on malaria, the he would have already suffered some losses which con- No. 1 disease problem of our troops in the tropics, par- tinued until the medication was actually started and ticular attention was given to a study of the sulfanila- took effect. A drug which could be administered con- mide derivatives for two reasons. The first was that tinuously as a preventive would seem to be the answer me had the good fortune to be working with a group of to this problem. Since there were no leads whatsoever investigators who had specialized in the chemistry of to this type of dmg, it wasnecessary to resort to a tech- the sulfanilamide derivatives for several years; and, nique known as screening, which is simply the testing of secondly, because it had been shown that this group of large numbers of chemicals in a standardized fashion drugs did something in experimental malaria that none until one is found which exhibits activity against the of the antimalarials known then, such as quinine, ate- infection in question. Such a compound is known as a brin, or plasmochin, would do. Up to that time it had lead, and the success of a screening program depends in been generally accepted that the malarial parasites large part on what is done to follow up such a lead. dwelt only in the red blood cells, but recent research Related chemical compounds are prepared by the chem- had shown that they may also dvell in certain of the ists and tested by the biologist until the member of the tissue cells and, in fact, must pass through this stage series with the best all-around properties is discovered. after being injected by the mosquito before they can Drug screening was practiced extensively in Germany enter the red blood cells. The sulfonamides were shown between World War I and World War I1 in a search for to attack the stagesin the tissues, while the other known better antimalarials and led to the development of such antimalarials were active only against the parasites in notable drngs as atebrin and plasmochin. During the red blood cells. If a snlfonamide was administered World War 11, a remarkable cooperative program in each day to a chicken which had been bitten by infected this country and England "screened" over 13,000 com- mosqnitoes malaria was completely prevented. Thus, pounds for antimalarial activity and developed palu- it was hoped that the same thing might occur if a soldier drin, chloroquin, and pentaquin. In addition, a number exposed to malaria were to take the right sulfonamide of other types of compounds were found to he active in the proper amount each day. against the bird malarias used in the laboratories.

Unfortunately, the sulfonamides failed to have any When tested against human malaria they failed to be practical application in malaria, but much that had practical for one reason or another, but it can be hoped been learned about them in the malaria studies has that the activity demonstrated against avian malaria been transferred to coccidiosis where the sulfonamides may carry over to some other type of infection. have played an extremely important role. Drug screening in coccidiosis led to a compound

For example, my colleague, Dr. Waletzky, suspected known as nitrophenide (bis-(m-nitropheny1)disulfide) that the premises for the activity of sulfagnanidine in which mould seem to date to possess those features nec- coccidiosis were false. In the first place, contrary to the essary for a drng that is to be used continuously for pre- situation in mice and men, sulfaguanidine is quite read- vention. It is highly active, inexpensive and safe a t the ily absorbed into the blood and tissues of chickens and, recommended doses. In fact, it seems possible that in the second place, the coccidial parasite dwells for the such a drng may come to be incorporated as a standard most part in tissue cells of the intestinal wall rather than ingredient in a11 chicken feeds and will prevent coccidi- free in the lumen of the intestine. Dr. Waletzky sug- osis just as vitamin D in chicken feeds now prevents gested that the action of sulfaguanidine might actually rickets. be dependent upon the drugs being absorbed, and that Those compounds which had demonstrated activity if such were the case, some of the other sulfonamides in the malaria and coccidiosis screening programs but should be more useful in treating this infection since which had not proved practical in actual application

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were set aside as possibilities for early trials in other in- fections. About 23 different structural types of com- pounds from this group were tested in blackhead infec- tion in turkeys. One of these proved to be su5ciently active to justify an intensive program of synthesis of related compounds. The best member of this series of compounds has been selected and subjected to extensive laboratory trials both for e5cacy in treating blackhead infections and safety of use. Enheptin-T (registered trade-mark), as this drug is called, has likewise been submitted to field trials with such promising results that

it would seem desirable to make the material available to the turkey raiser as soon as possible. Ho~rever, t,here is no reason to believe that this is the best drug that can be found for use in preventing or treating blackhead disease in turkeys. Actually, the initial success in this field simply opens up another chemotherapeutic project, which will require the closest cooperation between biol- ogists and chemists for a number of years, to bring it to its successful conclusion of providing the best and cheapest drug to control another one of the diseases confronting mankind and his domesticated animals.