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 comert 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 origair 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 deno 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 sublikened 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 somehost, 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. At present a large share of the research activities of relationships are as benign, however, and where the parasite is unusually aggressive or the host unusually my own group and that of a group of chemists cooperating with us are devoted to a search for a drug to conpassive the condition known as disease arises. trol this disease of turkeys. A solution to this problem versus an ymperfectn parexample of a Nperfectfl =itic relationship is seen in the protozoanparasite would revolutionize the turkey industry probably as of incubator hatching of ~ i nekagr&s ~ which unknown l to most ~ of us ~ much as did ~ the introduction ~ ~ has played an important role in the economy of theNew eggs. A story of the background, with some of its I believe, t England states. This parasite lives peacefully for the ramifications, leading up to this ~ r o j e cwill, mostpart 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 ~ ~ search i ~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 everythat 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. onthe hand, Shortly after sulfanilamide was introduced to human so rapidly that it keeps it in 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 includmg coccidiosis of poultry. Sulfanilamide had * Based on a paper presented a t the Eleventh Summer Conthe N.E.A.c.T., university of N~~ hi^^, some effect in this infection. Shortly after this a pharference macologist, Dr. E. K. Marshall, who was ausious to August 23, 1949. 286
MAY, 1950
apply the sulfonamides to the treatment of bacillary dysentery argued that since the bacteria causing the trouble were found within the intestine the ideal drng vould be one that stayed there rather than being too readily absorbed by the body. Studies in mice indieated that sulfaguanidine was such a dmg and it was subsequently found to be effective in the treatment of bacillary dysentery in man. This postulation attracted the attention of several investigators in veterinary medicine who thought the same reasoning should apply to coccidiosis in chickens, which is a parasitic disease of the intestine or its branches known as the ceca. When tried, sulfaguanidine nas found to be so effective that it soon appeared on the market and was widely used for many years, and still is, effecting a large reduction in the estimated ten per cent loss suffered by the poultry industry each year from coccidiosis. During the war while concentrating on malaria, the No. 1 disease problem of our troops in the tropics, particular attention was given to a study of the sulfanilamide derivatives for two reasons. The first was that me had the good fortune to be working with a group of investigators who had specialized in the chemistry of the sulfanilamide derivatives for several years; and, secondly, because it had been shown that this group of drugs did something in experimental malaria that none of the antimalarials known then, such as quinine, atebrin, or plasmochin, would do. Up to that time it had been generally accepted that the malarial parasites dwelt only in the red blood cells, but recent research had shown that they may also dvell in certain of the tissue cells and, in fact, must pass through this stage after being injected by the mosquito before they can enter the red blood cells. The sulfonamideswere shown to attack the stagesin the tissues, while the other known antimalarials were active only against the parasites in the red blood cells. If a snlfonamide was administered each day to a chicken which had been bitten by infected mosqnitoes malaria was completely prevented. Thus, it was hoped that the same thing might occur if a soldier exposed to malaria were to take the right sulfonamide in the proper amount each day. Unfortunately, the sulfonamides failed to have any practical application in malaria, but much that had been learned about them in the malaria studies has been transferred to coccidiosis where the sulfonamides have played an extremely important role. For example, my colleague, Dr. Waletzky, suspected that the premises for the activity of sulfagnanidine in coccidiosis were false. In the first place, contrary to the situation in mice and men, sulfaguanidine is quite readily absorbed into the blood and tissues of chickens and, in the second place, the coccidial parasite dwells for the most part in tissue cells of the intestinal wall rather than free in the lumen of the intestine. Dr. Waletzky suggested that the action of sulfaguanidine might actually be dependent upon the drugs being absorbed, and that if such were the case, some of the other sulfonamides should be more useful in treating this infection since
287
they result in better blood levels per unit of oral dose. After carefully standardizing the laboratory infections of coccidiosis so that quantitative comparisons of drngs could be made, Dr. Waletzky found, just as he had suspected, that the activity of the sulfonamides in coccidiosis was completely correlated with blood levels. From this he selected sulfamethazine as being the most economical of the readily available sulfonamides for the treatment of coccidiosis, and this drug was soon widely accepted in the poultry industry. Thus, the practical results confirmed the value of the laboratory observations and speculations. Even though the sulfonamides have been quite snccessful in coccidiosis, it was felt that a better dmg could be found. The methods of using the sulfonamides for controlling outbreaks of coccidiosis were somelvhat cumbersome as far as the poultry man was concerned. Also, before he realized that medication was called for, he would have already suffered some losses which continued until the medication was actually started and took effect. A drug which could be administered continuously as a preventive would seem to be the answer to this problem. Since there were no leads whatsoever to this type of dmg, it wasnecessary to resort to a technique known as screening, which is simply the testing of large numbers of chemicals in a standardized fashion until one is found which exhibits activity against the infection in question. Such a compound is known as a lead, and the success of a screening program depends in large part on what is done to follow up such a lead. Related chemical compounds are prepared by the chemists and tested by the biologist until the member of the series with the best all-around properties is discovered. Drug screening was practiced extensively in Germany between World War I and World War I1 in a search for better antimalarials and led to the development of such notable drngs as atebrin and plasmochin. During World War 11, a remarkable cooperative program in this country and England "screened" over 13,000 compounds for antimalarial activity and developed paludrin, chloroquin, and pentaquin. In addition, a number of other types of compounds were found to he active against the bird malarias used in the laboratories. When tested against human malaria they failed to be practical for one reason or another, but it can be hoped that the activity demonstrated against avian malaria may carry over to some other type of infection. Drug screening in coccidiosis led to a compound known as nitrophenide (bis-(m-nitropheny1)disulfide) which mould seem to date to possess those features necessary for a drng that is to be used continuously for prevention. It is highly active, inexpensive and safe a t the recommended doses. In fact, it seems possible that such a drng may come to be incorporated as a standard ingredient in a11 chicken feeds and will prevent coccidiosis just as vitamin D in chicken feeds now prevents rickets. Those compounds which had demonstrated activity in the malaria and coccidiosis screening programs but which had not proved practical in actual application
288
were set aside as possibilities for early trials in other infections. About 23 different structural types of compounds from this group were tested in blackhead infection 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
JOURNAL OF CHEMICAL EDUCATION
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 biologists 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.
