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UntitledJ. Parasitol., 94(4), 2008, pp. 934–945 䉷 American Society of Parasitologists 2008 HISTORY OF THE DISCOVERY OF SULFAQUINOXALINE AS A COCCIDIOSTAT
William C. Campbell
Research Institute for Scientists Emeriti and Department of Biology, Drew University, Madison, New Jersey 07901.
Sulfaquinoxaline played an important part in the demotion of roast chicken from vaunted Sunday-dinner status to an unrespected position on the everyday menu of the Western world. It had its origins in the chemical synthetic program thatsprang from the introduction of sulfonamide drugs into human medicine in the 1930s. The program was sustained through theyears of World War II despite declining clinical use of that chemical class. Several sulfa drugs were known to be active againstthe sporozoan parasite (Plasmodium spp.) that causes malaria, but were not satisfactory in clinical practice. A sulfonamide thathad a long plasma half-life would ipso facto be considered promising as an antimalarial drug. Sulfaquinoxaline, synthesizedduring the war, was such a compound. It proved too toxic to be used in human malaria, but was found to be a superior agentagainst another sporozoan parasite, Eimeria spp., the causative agent of coccidiosis in domestic chickens. In 1948 sulfaquinoxalinewas introduced commercially as a poultry coccidiostat. It was not the first sulfonamide found active against Eimeria spp. inpoultry, but its practical success in disease control firmly established the routine incorporation of anticoccidial drugs in poultryfeed. In this way, the drug exerted a major impact on the worldwide production of poultry meat. Although it has long beeneclipsed by other drugs in poultry management, it continues to be used in other host species. This article describes the discoveryof sulfaquinoxaline as a practical therapeutic agent, and examines the way in which the discovery arose from a partnershipbetween industry and academia.
Sulfaquinoxaline (SQ) has faded from its glory days as a DISCOVERY AND DEVELOPMENT
pioneer feed additive for controlling disease in chickens; yet byvirtue of its continuing use as a coccidiostat in special circum- During World War II the search for new antimalarial drugs stances, it continues to bring medical and financial benefit to was intense, and Merck & Co., Inc. (hereafter ‘‘Merck'') was its ingesters and investors, respectively. Patented in 1946, its among the companies engaged in that endeavor. The multicom- efficacy in poultry coccidiosis and its value as a dietary pro- pany nature of the program reflected the high priority given to phylactic were reported soon afterward. Its subsequent field malaria research by the War Production Board under the aus- success was so great that it affected management practices in pices of the National Research Council's Office of Scientific the poultry industry, and contributed to a marked reduction in Research and Development (D. F. Green, unpubl. obs.; Coatney, the price of poultry meat. In so doing, it initiated an era of 1963). In the field of medicinal chemistry the sulfonamide mol- routine use of dietary chemicals to achieve efficiency in meat ecule was all the rage, and more than 5,000 structural deriva- tives would be made by the end of the war (Bryskier, 2005).
The sulfonamide drugs (‘‘sulfas'') had been discovered as One objective of the program was to find a sulfonamide deriv- antibacterial agents in the 1930s, and before the decade was out ative that would be effective against the malaria parasite and their efficacy had been shown to extend to protozoan parasites.
would not need to be given repeatedly during the course of a Susceptible eukaryotes included 2 rather closely related para- day. At Merck, chemist Max Tishler (Fig. 1) and his associate, sites, Plasmodium sp., the agent of human malaria, and Eimeria John Weijlard (Fig. 2), synthesized the molecule 2-(4-amino- sp., the agent of poultry coccidiosis. Nevertheless, by the close of World War II in 1945 no sulfonamide was known to be 2-sulfanilamido-quinoxaline). A patent application was filed on satisfactory in either disease. Soon after the war, however, the their behalf on 8 January 1944. The compound became known superior attributes of SQ in coccidiosis were described, and by generically as sulfaquinoxaline, and SQ became both a trade- 1948 its triumph in the marketplace had begun. This had be- mark and a handy everyday diminutive.
come possible because of a collaboration between scientists at Max Tishler was then at the beginning of his rise to eminence a state-run experiment station and scientists at the industrial as a leader in pharmaceutical research and development. He had laboratory where it had been synthesized.
been an outstanding graduate student in the chemistry depart- In the context of time and place, the idea of testing SQ ment of Harvard University, earning a Ph.D. in 1934 and stay- against coccidia in chickens was not a matter of intellectual ing on as a junior faculty member. At that time, Merck was virtuosity. Yet, because of the enormous consequence of such seeking to expand its objectives beyond the manufacture of fine an experiment, the question of how it came about acquires con- chemicals. In 1937, as part of its strategy of placing high pri- siderable historical significance. It will be argued here that al- ority on research, the company recruited Tishler. He would go though it may not be possible to say precisely who first pro- on to become President of the Merck Sharp and Dohme Re- posed this line of experimentation, much can be said about the search Laboratories (a Division of Merck & Co., Inc.), a mem- people and the circumstances responsible for it. It will be sug- ber of the National Inventor's Hall of Fame, and a member of gested that discovery of the drug's efficacy in avian coccidiosis the National Academy of Sciences (Sarett and Roche, 1995).
can be traced to wartime concern about human malaria as well In 1987, the National Medal of Science was conferred on him as to everyday concern about a disease in chickens. The un- by the President of the United States (Ronald Reagan) at a derlying collaboration between public and private research in- ceremony in the White House. An application for a patent on stitutions will be given particular attention.
SQ was filed on 8 January 1944. The patent, assigned by Weij-lard and Tishler (1946) to Merck & Co. Inc., was issued on 16 Received 17 July 2007; revised 20 September 2007; accepted 6 Feb- July 1946 (U.S. Patent No. 2,404,199). As would be expected, it dealt almost entirely with the chemical structure of SQ and
CAMPBELL—SULFAQUINOXALINE AS A COCCIDIOSTAT M. Tishler. Merck & Co. Inc. photograph.
J. Wiejlard. Merck & Co. Inc. photograph.
synthetic processes for making it. It did note, however, that thenew compound was slowly excreted in treated animals, makingit possible to maintain antibacterial plasma levels with low dos- SQ had been tested against malaria in chickens and ducks, and age. Long before the patent was issued, the basic chemical and had been found very effective (Seeler et al., 1944; Green, 1947; biological properties of the compound had been reported in the Anonymous, 1949). According to the anonymous report of 1949, the tests were done in late 1942 or early 1943. Presum- The chemical synthesis was reported in a paper in which ably they were carried out against Plasmodium gallinaceum in Weijlard and Tishler, now joined by their colleague Erickson, chickens and Plasmodium lophurae in ducks, these being stan- noted that the compound was slowly eliminated from treated dard malaria models at that time (before nonprimate mamma- animals and was highly effective against pneumococcal infec- lian models had become available). The present writer has tions in mice when administered only once a day (Weijlard et found only 1 reference to antimalarial testing of SQ in the hu- al., 1944). Underlying the brief mention of SQ's biological man. It occurs in unattributed articles in a Merck magazine properties in that chemical report, and acknowledged by the (Anonymous, 1952a) and a poultry magazine (Anonymous, authors, was an intense study carried out by scientists in the 1952b). Both are about the success that SQ was having in the biological arm of the company (the Merck Institute for Thera- control of coccidiosis in poultry, and the latter article was based peutic Research, then under the direction of Hans Molitor).
in part on promotional material provided by Merck (Craig, The antibacterial efficacy of SQ was studied in vitro and in 1952). The poultry magazine text states (by way of background vivo; and it was shown that daily doses of SQ (given orally on SQ): ‘‘Preliminary studies in man indicated that it had some over a 5-day treatment period) were as effective against lethal effect on human malaria . . ''. The Merck Review text is iden- Diplococcus pneumoniae infections in mice as sulfadiazine or tical except that the words ‘‘in man'' are absent. These articles sulfathiazole in divided doses given 4 times a day (Smith and would have been written by and for nonscientists, some 7–9 yr Robinson, 1944). The compound thus acquired distinction after any such trial in humans had taken place. It is possible among the early sulfa drugs, most of which would become that they reflect some confusion between tests against malaria known as ‘‘short-acting sulfonamides.'' in humans and tests done in systems used as models of human Although malaria was the prime focus of the early Merck studies, little mention was made of it in the published reports— The early biological data showed that SQ met the objective probably because much of the wartime information on anti- of finding an antimalarial sulfonamide with a long plasma half- malarial testing was officially declared secret (Coatney, 1963).
life, and it seemed possible that such a drug could fill an im- Seeler et al. (1944) recorded that SQ suppressed ‘‘certain avian portant medical and strategic need. In both World War I and malaria infections'' when administered in single doses at 48 World War II the movement of quinine from the East to the hour intervals‘‘ whereas sulfadiazine and sulfapyrazine had to West was disrupted, stimulating several nations to set up re- be given 3 times daily or incorporated in the diet. The authors search programs aimed at finding a synthetic replacement for referred to ‘‘P. lophurae and another species of avian malaria'' the natural alkaloid. The urgent search for antimalarials in the without mention of host species, suggesting deliberate caution United States during World War II was 1 such program (Coat- on their part. Once the war was over, and SQ had been em- ney, 1963; Black et al., 1981; Campbell, 1986; Sneader, 2005).
ployed for other purposes, there would have been little incen- On the basis of the tests against avian malaria, it seemed pos- tive for the investigators to prepare technical reports for pub- sible that SQ could become the desired long-acting sulfonamide lication. There are passing postwar statements to the effect that for preventing and treating malaria in military personnel. That
THE JOURNAL OF PARASITOLOGY, VOL. 94, NO. 4, AUGUST 2008 P. Delaplane. RIAES photograph.
the amino-quinolines quickly eclipsed the sulfonamides as po-tential agents for the control of malaria. (Interest in the sulfon-amides would be revived decades later when resistance to chlo-roquine emerged and synergism between sulfas and dihydro-folate reductase inhibitors was appreciated.) With human application thwarted, Merck sought outside help in assessing the potential value of SQ in veterinary medicine.
This was done through the agency of 1 of its scientists, DavidF. Green (Fig. 3). In the 1930s, Green had worked half-time atMerck while pursuing his Ph.D. degree at Rutgers University.
An important fact (which seems to have been overlooked in thepresent context) is that Green, several years before the synthesisof SQ, had been senior author of a paper on the pharmacologyof sulfa drugs (Green et al., 1938). That paper reported dataobtained at Rutgers University on sulfonilamides provided byMerck (the research being financially supported by Merck).
Moreover, Green's report dealt with the renal clearance of sul-fonilamides. Sulfa drugs were a hot topic at the time and Greenhad attended at least 1 scientific meeting at which they had beendebated. By the time SQ was synthesized, Green was working D. F. Green. Merck & Co. Inc. photograph.
full-time at Merck and would have been very familiar with itsresearch on new sulfa-drug candidates. He was thus well po-sitioned to initiate efforts to exploit SQ for animal health, and would change when the Merck team investigated the toxicity, that responsibility was assigned to him as Manager of Merck's excretion rates, and urinary excretion products of SQ. The stud- Veterinary Department (Anonymous, 1949).
ies were done in rats, dogs, rabbits, and monkeys (Maccacus In 1944 or early 1945 Merck provided a sample of SQ to rhesus), and at least urine analysis seems to have been done in poultry pathologist John Paul Delaplane (Fig. 4) of Texas humans (Scudi and Silber, 1944; Seeler et al., 1944; Stevens et A&M. Presumably the initial Merck approach to Delaplane was al., 1946). Toxic effects observed at high dosage included hy- made by Green, but it has not been possible to confirm this. By pothrombinemia in rats, with resultant internal bleeding (Mush- July 1945, Delaplane had not only tested the Merck compound ett and Seeler, 1947). The most significant finding was that the in chickens, but had published his finding that SQ had prophy- relatively insoluble 3-hydroxy derivative of the compound pre- lactic activity against the bacterium Pasteurella avicida (agent cipitated in the kidneys of rat and monkey, but not dog or rabbit of enzootic fowl cholera; Delaplane, 1945). Soon thereafter (1 (Seeler et al., 1944). A later report would show that SQ was January 1946) Delaplane returned to the Rhode Island Agri- very well tolerated in poultry (Cuckler and Ott, 1955). In the cultural Experiment Station (RIAES) whence he had come, and meantime, however, the renal precipitation and kidney damage in quick succession he and his associates found SQ highly ef- in monkeys put an end to any further consideration of SQ as fective against Eimeria tenella (1 of the agents of cecal coccid- an antimalarial drug for humans.
iosis) and against Eimeria necatrix (an agent of intestinal coc- Prospects for the sulfonamides in the malaria arena no longer cidiosis) in chickens (Delaplane et al., 1947).
looked good. The 1 sulfonamide with a long plasma life was The role actually played by each of the associates is not out of the picture, and the short plasma life of the other sul- evident from the scientific literature. A quarter-century after fonamides was 1 of the reasons for shelving the whole class these events, a newspaper reporter described Thomas C. Hig- (Black et al., 1981). Another reason was that the 4-amino-quin- gins as the 1 who discovered the efficacy of SQ against coc- olines were rising to the forefront as antimalarials. They had cidiosis (Sawtelle, 1971). Higgins (Fig. 5) was 1 of 2 coauthors been studied as antimalarials for a decade (Coatney, 1963), and on Delaplane's first (1947) publication on the subject, and the the leading candidate, which was to become famous as chlo- newspaper article was apparently based on an interview with roquine, had its first American trial in humans in the year that Higgins made 25 yr after his initial contribution to the discov- the SQ patent was filed. With the collapse of SQ as a contender, ery. The reporter added that Higgins ‘‘was joined in the dis-
CAMPBELL—SULFAQUINOXALINE AS A COCCIDIOSTAT notations: ‘‘First coccidiosis work with sulfaquinoxaline'' and‘‘Chas Chong Chinese student with T C Higgins.'' Despite itshistorical significance, this first trial is not mentioned in theinitial publication; nor, indeed, has the present writer been ableto find any public documentation of it. It may have providedthe impulse for a more complex and ‘‘publishable'' trial andhave been considered unworthy of or unnecessary for inclusionin the paper that announced the breakthrough discovery.
The Higgins letter does not say when the first trial was made.
Nor does the Delaplane report of 1947 give dates for the ex-periments described therein. In that Delaplane report, however,a passing reference is made to the weather in Rhode Island inthe summer of 1946, when at least some of the work was beingcarried out. Further evidence as to when the essential discoverywas made is to be found in the projection slide mentionedabove. The image (Fig. 8) shows the severely damaged cecumof a chicken infected with E. tenella lying next to the cecumof a chicken successfully protected by administration of SQ.
The inscription, probably made by Higgins, includes ‘‘Spring1946'' as well as the words ‘‘First coccidiosis work with sul-faquinoxaline.'' The slide thus clearly refers to the very firsttrial, and indicates that the discovery was made in 1946, theyear in which the patent was issued. That conclusion is in ac-cord with an unsigned article in a Merck magazine (Anony-mous, 1949).
Apparently Delaplane recalled the discovery somewhat dif- ferently. An obituary article on Delaplane appeared in a news-paper within days of his death, and its tone makes it likely thathe had himself been the direct or indirect source of the infor- mation in it. (The article, entitled ‘‘Dr. Delaplane, 50, Dead in T. C. Higgins and D. F. Green, at dedication of Delaplane Memorial Laboratory, University of Rhode Island, Kingston, Rhode Is- Texas'' was unsigned. A photocopy is in the archives of the land. From undated newspaper clipping in University of Rhode Island University of Rhode Island, but it does not reveal the date of the newspaper or the place of publication. It was probably pub-lished in Rhode Island in 1956.) The writer noted that in 1941,Delaplane found that sulfathiazole would prevent infectious Co- covery'' by Delaplane. Higgins himself, in a letter written to ryza in poultry, and added that he ‘‘had been screening sulfa his son 41 yr after the event, recalled how he ‘‘had hounded drugs for the control of the respiratory form of fowl cholera'' John [Delaplane] for weeks to test the drug'' but that he ‘‘was when 1 of them, SQ, ‘‘turned out to be highly effective.'' The always too busy'' (Higgins, 1987). Delaplane, on his return writer of the article further added ‘‘On impulse, he suggested from Texas, had become Chairman of Pathology at RIAES.
to a foreign trainee working in the department that he feed the Higgins was agricultural extension poultryman and presumably drug to some birds infected with coccidiosis. The results were had neither the drug nor the authority to initiate a trial in De- startling and further testing proved the effectiveness of treat- laplane's department. As he recalled it, he then hit upon a plan ment. Out of these tests came the principle of low-level, con- to get things moving. He needed, at that time, to come up with tinuous medication as a practical means of poultry disease con- a project for a student who had been assigned to work with trol.'' The 2 accounts, given many years after the event, are at him. He says in his letter that he had the idea of having the variance in regard to the impetus driving the crucially important student test SQ against coccidiosis under the direction of De- first experiment. We will probably never know the truth of this laplane and himself, and that he ‘‘persuaded John to cooperate matter, or be able to applaud 1 party or another for historical with me in setting up the trial.'' He goes on to describe the inerrancy. Those who spend a lifetime in science sometimes proposed ‘‘very simple . . and probably crude'' trial as con- find that modestly divergent perceptions may be driven further sisting of 2 groups of chickens that would be inoculated with apart, quite unconsciously, by the frailty of memory.
coccidial oocysts, with 1 group then being given SQ in the The contribution made by Delaplane and his colleagues at drinking water. In writing that personal letter, Higgins takes it RIAES was not confined to matters of therapeutic efficacy. Par- as understood that the experiment was carried out, for he goes ticularly important was their finding that SQ treatment did not on to say that ‘‘the results were astounding''—all untreated interfere with development of immunity (at least in the case of chickens died whereas all treated chickens survived and were E. tenella). They described the histopathological characteristics free of infection. It is clear that a student assistant did indeed of a toxic reaction that seemed to be associated with SQ treat- carry some responsibility for the conduct of the trial. The paper ment under certain conditions (Delaplane and Milliff, 1948).
mount of a photographic projection slide in the archives of the From their various studies they concluded that SQ provided safe University of Rhode Island, bears the following hand-written and effective control of coccidiosis in chickens when the drug
THE JOURNAL OF PARASITOLOGY, VOL. 94, NO. 4, AUGUST 2008 discussion with the present writer, he disclaimed any significantrole in evaluating SQ as a coccidiostat, but that may be undulymodest. With the assistance of Ms. Christine Malanga, Cucklerdemonstrated resistance in 1 strain of Eimeria acervulina and2 strains of E. tenella after exposure to suboptimal dosages ofSQ for 15 successive passages in chickens (Cuckler and Ma-langa, 1955). With his friend and colleague, poultry physiolo-gist Walther Ott, he carried out a series of elaborate safety trialsthat showed that in-feed administration of SQ was very welltolerated by chickens, turkeys, and ducks (Cuckler and Ott,1955). They also demonstrated that SQ was lethal to the spo-rozoite and schizont stages of the life cycle, but did not fullysuppress their development (Cuckler and Ott, 1947, cited byChapman, 2003). As pointed out by Chapman, that observationwas helpful in explaining the acquisition of immunity by chick-ens in which clinical coccidiosis had been averted by SQ pro-phylaxis. Most of these studies were published after SQ wasintroduced to the marketplace. It is not known how much ofthe information was on hand when Merck sought approval fromthe Food and Drug Administration (FDA) to market SQ, butCuckler's firsthand knowledge of the drug must have contrib-uted to the success of the application. In January 1985 Cucklertold the present writer that he and Green had traveled by traintogether from Rahway, New Jersey, to Washington, D.C., tosubmit the application for FDA approval. When they left theFDA for their return journey on the same day, they had alreadybeen given informal approval of the application. Formal con-firmation arrived by mail soon afterwards. One wonders if thisis a speed record, and what feelings it might conjure up in thosecurrently responsible for applying for regulatory approval ofnew drugs. Lest the timing seem truly incredible to a modernreader, it may be pointed out that in the 1940s there was nofederal (FDA) requirement for evidence that a drug actually L. C. Grumbles. Photo by Bob Dooman.
worked. Safety was all, and it was not until the 1962 passageof the Kefauver–Harris Amendment to the Food, Drug, andCosmetic Act that proof of efficacy was demanded. According was incorporated in feed and administered continuously to Tishler (1988), Merck established that SQ was depleted from throughout the growth of the birds. Strongly supporting that poultry tissues before the birds went to slaughter. It is worth conclusion was a second efficacy paper published by the RIAESgroup (Grumbles et al., 1948). The first author of that important remembering, however, that although ‘‘additives'' in the food contribution was Leland C. Grumbles, DVM (Fig. 6) who had of meat animals have been regulated under the Act since its graduated from the veterinary college of Texas A&M in 1945, inception in 1938, it was not until the 1950s (and the creation just as Delaplane was finishing his first stint at that institution.
of a Veterinary Medicine Branch within the FDA's Bureau of He then joined Delaplane at RIAES and participated in the SQ Medicine) that serious attention was given to ‘‘tissue residues'' work before returning to Texas A&M for the remainder of his in meat. Thus the preparation of a ‘‘New Drug Application'' long academic career. The paper dealt with coccidiosis under was much less formidable in 1948 than it has since become.
field conditions, with only natural exposure to infection. Almost In 1948 SQ was introduced as a commercial product. Feed 20,000 chickens (many of them on litter on which other flocks manufacturers bought the drug from Merck and incorporated it had been raised) were fed a diet containing 0.0125% SQ, while into a feed premix for sale to poultry producers. When properly at the same time more than 3,000 control birds (all on clean mixed with feed to give a final concentration of 0.0125%, it litter) were raised on unmedicated feed. The mortality rate was provided chickens with a daily intake of SQ sufficient to pre- 1% in the treated birds and 17% in the controls. Outbreaks of vent outbreaks of coccidiosis. The drug also had the advantage such severity were by no means uncommon under the intensive of being usable therapeutically in drinking water (the compound production methods then being employed.
itself is insoluble in water, but its sodium salt is soluble). Early While these encouraging results were being obtained at reports of toxic reactions under field conditions were not easy RIAES, a program of developmental research was underway at to confirm or explain (Delaplane and Milliff, 1948; Davies and Merck & Co., Inc. Parasitologist Ashton Cuckler was hired by Kendall, 1953; Cuckler and Ott, 1955; Joyner and Davies, Merck in 1947 to work on the malaria project, but soon focused 1956; Spoo and Riviere, 2001). Because Merck sold SQ only his attention on the chemotherapy of coccidiosis, a field in to the manufacturers of commercial feeds and the producers of which he was to become a notable leader (Campbell, 2001). In veterinary therapeutic products, the use of the drug was well CAMPBELL—SULFAQUINOXALINE AS A COCCIDIOSTAT controlled and poultry producers found that the benefits of treat- From the middle of the century, vaccination was used to a ment far outweighed the risk of toxic reactions.
limited degree (Shirley and Long, 1990), but the vaccines con- Because of the importance of sulfas as antibacterial agents tained live coccidian oocysts, and under practical conditions it in humans, their mode of action had been elucidated soon after was difficult to formulate them and administer them in a way they were introduced—before SQ had even been synthesized.
that would allow infection to reach immunogenic but not path- Their essential role as inhibitors of folate synthesis had been ogenic proportion. By the end of the century, the introduction discovered in 1940 and was confirmed and amplified by others of new drugs had almost ceased, but nonliving ‘‘subunit'' vac- in subsequent decades (Woods, 1940; Northey, 1948; Petri, cines had been developed (Danforth and Augustine, 1990).
2006). It was natural that studies would be undertaken to see They may prove economically and environmentally (as well as if the action against protozoa would be similar. As early as 1946 biologically) attractive, in which case they may come to replace it was observed that anticoccidial efficacy was reversed when the drugs that have been central to successful poultry produc- p-aminobenzoic acid (PABA) was fed to chickens that were tion since the heyday of SQ.
receiving sulfonamide treatment (Horton-Smith and Boyland,1946). From this and subsequent studies, it became clear that THE LINKAGE OF PRIVATE AND PUBLIC LINEAGES
the antiprotozoal activity of sulfonamides, like their antibacte-rial activity, resides in the blockade of folate biosynthesis, and No one would suggest that the testing of SQ for efficacy in that this blockade results from the structural similarity of the chickens was an imaginative scientific idea. Yet it was an im- drugs to PABA, 1 of the intermediates required for the synthesis portant idea—important because of both the practical outcome of dihydrofolic acid (Adams, 2001). Competitive inhibition of and because of the blending of governmental and industrial in- folate biosynthesis in the coccidial parasite blocks the series of terests. The trials conducted by Delaplane and his associates metabolic steps leading to conversion of uracil to thymine, thus demonstrated not only the efficacy of SQ in preventing out- depriving the parasite of the DNA needed for the production of breaks of disease caused by E. tenella (Delaplane et al., 1947) proteins (Looker et al., 1986). The Therapeutic Index (safety but also the practical control of multiple coccidial species by margin) of the drug derives from the fact that mammals and means of feeding low levels of the drug in the diet (Grumbles birds ingest folic acid in their diet and are also the beneficiaries et al., 1948). This is rightly lauded as an outstanding example of the folic acid produced by enteric bacteria (Zhu et al., 2005).
of the research accomplishments of the experiment stations in Chickens therefore can make DNA without having to synthe- general and of the Rhode Island station in particular (Chapman, size folic acid intracellularly. To put these events in a broader 2003). It would be misleading, however, to characterize that historical context, it may be noted that SQ was brought to mar- achievement only in reference to academia or academic exten- ket at a time when the chemical composition of DNA was sions such as governmental experiment stations. The case of known but its physical structure was not, and at a time when it SQ stands as an early example of successful collaboration be- was unusual to understand the biochemical mechanism of a tween American industry and state governments as represented drug when first introduced.
by agricultural experiment stations. More specifically, the dis- The use of sulfonamides against bacterial infections in hu- covery and development of this important agricultural tool can mans was limited by drug resistance in the pathogens and in- be said to be a joint effort on the part of Merck and RIAES.
complete spectrum of efficacy against significant pathogen spe- The customary recital of authorship and titles of papers pub- cies. The same proved true for SQ in the control of coccidiosis lished in the scientific literature tends to give a deficient picture in poultry (Geary et al., 1986; McDougald, 1986). In the second of this partnership. The same can be said (with the imbalance half of the 20th century, many other drugs were brought to being in the other direction) for the promotional literature is- market to control coccidiosis, especially in the increasingly sued in support of the marketing of the compound. The adver- large, sophisticated, and lucrative production of ‘broiler'' chick- tising of commercial compounds, however, recedes from his- ens (McDougald, 1990). More than a dozen distinct chemical torical view as the products themselves disappear from the entities had been brought to market by 1984. Their trade names, shelves. The scientific literature enjoys the advantage of being characteristics, and introduction dates were tabulated by more weighty and more enduring than the commercial ephem- McDougald (1986), and their chemical structures were itemized era. The collaboration between the parties might be described, by Chabala and Miller (1986). Under the ‘‘selection pressure'' to borrow a term from biology, as mutualism. The actual con- of dietary medication and intensive production, drug resistance tribution of each of the 2 parties deserves some consideration.
invariably emerged; but a spirited competition among chemical The discovery of SQ as a coccidiostat can be seen as an and pharmaceutical companies resulted in a more-or-less steady outgrowth of the discovery that earlier sulfonamides were ac- supply of effective new drugs. The competition also resulted in tive against coccidia in chickens. The first sulfonamide report, a raising of the acceptable standard for efficacy, with a new in this context, was Levine's (1939) article on the efficacy of candidate being expected to be effective against 7 or 8 species sulfanilamide against E. tenella. It had been preceded by aware- of avian coccidia. Synthetic chemicals were used more or less ness that sulfur was coccidiostatic (Herrick and Holmes, 1936), exclusively until an ionophorous metabolite of a filamentous but this is not mentioned by Levine and was evidently not a bacterium was found active against coccidia (Shumard and Cal- factor in his decision to test sulfanilamide. He may have be- lendar, 1967) and by the 1980s antibiotic ionophores had come come aware of the efficacy of sulfur at about this time, because to dominate the market. Throughout these years of competition he described his own studies with sulfur at a meeting in 1941 the use of SQ declined, and in the United States it had been (Chapman, 2003). Levine wrote that he was unaware of any relegated to use only in cattle, sheep, and rabbits by the end of ‘‘well substantiated reports'' on the effect of sulfonamides on the century (Lindsay and Blagburn, 2001).
‘‘intestinal protozoa.'' He makes no reference to blood-borne THE JOURNAL OF PARASITOLOGY, VOL. 94, NO. 4, AUGUST 2008 protozoa. Had his work been prompted by reports of the effi- or even centuries, before their medicinal value was realized, cacy of sulfonamides on malarial parasites he probably would and they could be exploited commercially only through use- (and certainly should) have said so. Instead, he records that he patents of limited geographical availability, or through molec- was 1 of a number of scientists trying to extend the successful ular modification, specialized formulation, marketing expertise, use of sulfas in human (bacterial) infections into utility in an- imal health. This is supported by the fact that Levine's publi- In his publications, Delaplane acknowledged Merck as pro- cation was soon followed by reports on the efficacy of other vider of the compound, and as provider of the funding that sulfas (reviewed in Chapman, 2003). In any case, the RIAES made his initial studies on SQ possible. What we may never studies do not seem to have arisen from an awareness of Lev- know is whether Merck gave the drug (and the funding) to ine's report on sulfanilamide. Delaplane does not cite Levine's Delaplane for the express purpose of having it tested against work, but cites Seeger's informal 1945 report (Seeger, 1946) on coccidia. Both Green and Delaplane were fully qualified to ar- the efficacy of sulfaguanidine against E. tenella and his 1946 rive independently at the conclusion that SQ should be tested report on the efficacy of sulfamethazine against the same spe- against coccidia in chickens. In giving this particular new sul- cies (Delaplane et al., 1947). It is possible that Delaplane's fonamide to Delaplane, Green clearly intended that it be tested work was prompted, at least in part, by awareness of Seeger's in chickens; Delaplane, after all, was a poultry specialist and even had sulfa-drug experience (apparently finding sulfamera- Alternatively, the testing of SQ as coccidiostat can be seen zine and sulfathiazole active but not useful against the Pasteu- as an extension of earlier reports of the efficacy of sulfonamides rella of fowl cholera; Delaplane, 1945). Indeed, Delaplane spe- against bacterial infections, not in humans, but in poultry. The cifically acknowledged that SQ had been called to his attention earlier studies, however, had been distinctly unpromising (see ‘‘through the courtesy of Merck and Company . . as having for example, Wernicoff and Goldhaf, 1944). The exceptional possible use in poultry'' (Delaplane, 1945). Green was very promise of the slow-clearance SQ molecule had been shown by much attuned to research on sulfa drugs and, as mentioned, had Delaplane himself. Before testing SQ against coccidia, he had studied the pharmacokinetics of sulfanilamide as early as 1938.
found it prophylactically effective against P. avicida (agent of It would be natural for him to suggest a therapeutic target for endemic fowl cholera) in chickens (Delaplane, 1945).
Delaplane's studies on the new compound, and it would be Yet again, the discovery can be seen as an extension of work equally natural for him to propose a target of importance in in the 1930s that showed sulfonamides to have antimalarial ac- poultry husbandry (why else offer the drug?). The target, be- tivity. Both the Plasmodium spp. of malaria and the Eimeria cause what he was offering was a new sulfa drug, would surely spp. of coccidiosis are members of the Apicomplexa. Within have been a bacterium such as Pasteurella avicida, or a coc- that phylum, both pathogens belong to the class Conoidasida, cidial pathogen such as E. tenella, or both. Delaplane and his although belonging to different orders, namely, the Haemo- colleagues in fact tested the new drug against both.
sporidora and Eucoccidiorida, respectively (Roberts and Jan- In a Memorandum of Agreement between Merck and RIAES, ovy, 2005). The 2 pathogens would be expected to share some dated 27 November 1946 (Anonymous, 1946), Merck pledged chemotherapeutic sensitivities, and if a drug showed even mar- a grant of $5,000 to RIAES ‘‘for the purpose of developing ginal efficacy against malaria, it would be sensible to test it in knowledge on the therapeutic activities of Sulfaquinoxaline in coccidiosis. The activity of the sulfonamide molecule against controlling diseases of poultry.'' Specific diseases were not Plasmodium was more than merely marginal. Between 1938 mentioned. The research was to be planned ‘‘in consultation and 1945 sulfanilamide proved to be potent but species-specific with Dr. D.F. Green of the Veterinary Medical Department of against P. knowlesi in monkeys; and sulfadiazine and sulfapyr- Merck.'' The date of the Memorandum is curious because, as idine were effective to a greater or lesser extent against various mentioned, there is some evidence that the first work with SQ stages of P. gallinaceum in chickens and P. vivax, P. falcipa- in coccidiosis was done in the spring or summer of 1946. De- rum, P. malariae in humans. The results of those studies were laplane had been hired by RIAES (for the second time) as of 1 summarized by Northey (1948). Delaplane and his colleagues January 1946. He would have brought from Texas A&M his make no reference to the reported tests of sulfas against malaria.
unique knowledge of SQ's antibacterial efficacy in poultry, and This is not surprising in view of the comparative rarity and perhaps his sample of the drug. The November 1946 memo- obscurity of such tests, accentuated by wartime constraints on randum may thus have been a regularization and extension of publication. However, the Merck scientists, because of their an ongoing project. Writing informally 41 yr later, Higgins, as own wartime research on malaria (and perhaps the permissible mentioned above, recalled the first trial as having been done in sharing of unpublished data between laboratories), were cer- the spring of 1946, after he had ‘‘hounded'' Delaplane for tainly aware of the efficacy of sulfonamides in malaria when weeks to get him to test SQ in coccidiosis. The collaboration they gave SQ to Delaplane.
between Merck and RIAES seems to have been mutually sat- The intellectual lineage of SQ at the Rhode Island field sta- isfactory, as evidenced by its continuation in subsequent years.
tion is thus open to interpretation, but there is no doubt of the A further agreement between the 2 parties was signed in May importance of the work, and no doubt that it was made possible 1948; RIAES director Mason H. Campbell wrote to Green ex- by the synthesis at Merck of the molecule known as sulfaqui- pressing his ‘‘appreciation to you and your Company for the noxaline. Had the compound not been synthesized, it could not help and interest which you have shown in our research pro- have been tested. Had it not been chemically novel, and thus gram'' (Anonymous, 1948).
patentable as new ‘‘composition of matter,'' it probably would Delaplane did not include Green as a co-author, nor did his not have been developed as a commercial product. (Compounds acknowledgments indicate whether he was indebted to Green such as sulfuric ether, DDT, and sulfanilamide were made years, for any scientific idea. In introducing their first report on SQ
CAMPBELL—SULFAQUINOXALINE AS A COCCIDIOSTAT ord has been found to support that idea, nor would it find sup-port in the later personal recollections of Delaplane and Higgins(above). The record does indicate that Merck provided Dela-plane with data on the correlation between dietary concentra-tions of SQ and subsequent concentrations of the drug in theblood of treated chickens (Delaplane, 1945). Depending on thedetails of the actual exchange between the 2 parties, it mightor might not have been appropriate for Delaplane to includeGreen among the authors of the article announcing the efficacyof SQ against coccidia. There was a hint of disappointment onthis score in a 1988 communication from Green to the presentwriter, in which Green surmised that his absence from the listof authors reflected a then-common attitude of academic sci-entists toward industrial research (D. F. Green, unpubl. obs.).
The student who worked with Higgins was not accorded au- thorship; nor was he even mentioned in published accounts ofthe work. Any surprise that this might evoke today may beattributed to a shift in attitude toward authorship over the past60 yr. We have, however, no way of knowing how much Mr.
Chong actually contributed. In the personal letter that Higginswrote long after the event, he made it clear that he and Dela-plane did not share with their student their own sense that thefirst trial of SQ in coccidiosis had yielded an important discov-ery. It would seem that Chong was treated as technician rather Decline in price of poultry meat following introduction of coccidiostats in 1948. Annual average of monthly live-weight price than as junior collaborator. He may indeed have been hired as of chicken per pound received by farmers (expressed in 2003 dollars a student laborer, but the tone of Higgins' letter suggests that calculated from data of the Federal Reserve Bank of Minneapolis, Min- some degree of research training would have been an objective, nesota, 2006). The decline reflects an increase in the use of intensive and this is supported by reference to a ‘‘foreign trainee'' in the production methods, which were made practicable by the introductionof the drugs. No attempt is made to disentangle the causative contri- obituary article on Delaplane (above). The remaining author of butions of the methods and the drugs.
the key 1947 article was veterinarian R. M. Batchelder. Therecord appears to be silent on his contribution to the discoveryof the efficacy of SQ in the prevention of poultry coccidiosis.
and coccidiosis, authors Delaplane, Batchelder, and Higgins Eight months before he died at 82 yr of age, Tishler remi- pointed out that SQ was effective against bacterial respiratory nisced about the invention of SQ (Tishler, 1988). He and Weij- infections of poultry at levels lower than those required for lard had made the original synthesis of SQ as early as 1942 other sulfas (Delaplane et al., 1947). Then, turning to the sub- (Anonymous, 1949) and more efficient industrial syntheses ject of coccidiosis, they added that ‘‘it was logical to expect were devised soon afterward (Stevens et al., 1946), so Tishler that sulfaquinoxaline would possess a similar activity at the low was remembering events of more than 40 yr in the past. He levels mentioned,'' referring to the low levels of SQ that De- recalled that following the abandonment of SQ as an antima- laplane had used against the bacterium P. avicida. Considering larial, he and Green had independently become interested in that the protozoon, like the bacterium, was already known to looking for other uses for the compound. Tishler's group of be susceptible to sulfonamides, and that the prolonged plasma chemists provided the compound to Green, who then ‘‘found levels of SQ could be expected to permit the use of low dos- that it was active as a coccidiostat.'' Apparently Tishler (in old ages, the logic of the idea would be evident to anyone familiar age, and perhaps all along) regarded the SQ research at Texas with the situation, including David Green. Any new sulfa, es- A&M and RIAES as a contracted service. In that view, Merck pecially 1 known to have slow renal clearance, should be tested had simply given grant monies to outside workers to enable against coccidia (and bacteria) in poultry. (The utility of the them to find another kind of biological activity and then to sulfas previously tested in poultry had been limited by the need evaluate practical prophylactic and therapeutic regimens for it.
to administer intermittent bouts of treatment at maximal dos- The company was simply outsourcing work that it did not (yet) age.) There seems to be nothing in the record to suggest that have the capacity to do in-house. The success of the venture Delaplane sought new sulfas from Merck. Indeed, his first ar- was valuable to both sides; and evidently each side viewed the ticle makes it clear that the initial contact was made by a Merck accomplishment through the lens of its own contribution.
representative (unnamed by Delaplane). We know from Dela-plane's words that the representative (Green) conveyed not only REFLECTIONS AND CONCLUSIONS
a material sample, but also knowledge that the material hadparticular promise for use in poultry. SQ held that promise by Following the commercial introduction of SQ in 1948, the virtue of being a sulfonamide with slow renal clearance and price of broiler chickens in the United States declined sharply, with proven efficacy against a protozoan pathogen in chickens and continued to decline over many years, during which SQ and ducks. It seems likely that Green would have presented that was succeeded by other coccidiostats (Fig. 7). Over the same rationale to Delaplane when seeking his collaboration. No rec- time period, the raising of chickens became more intensive (Na-
THE JOURNAL OF PARASITOLOGY, VOL. 94, NO. 4, AUGUST 2008 CAMPBELL—SULFAQUINOXALINE AS A COCCIDIOSTAT via, 2000) and therefore more vulnerable to the ravages of in- infections. Fortunately, there are written accounts, popular as fectious disease. It is unlikely that the raising of chickens in well as scholarly, in which the story of the sulfa drugs in human densely populated ‘‘broiler houses'' would have been successful medicine is told (see, for example, Silverman, 1942; Ryan, if coccidiosis had not been controlled. In this context Navia 1992; Sneader, 2005; Hagar, 2006). The history of SQ in chick- (2000) states that ‘‘sulfaquinoxaline enabled a revolution in the ens, in contrast, has been neglected (Campbell, 2001).
practice of poultry production.'' It was a revolution that would Considering the speed with which the Food and Drug Ad- spread throughout much of the world. It was a revolution that ministration (FDA) approved the use of SQ in poultry, there is was by no means inevitable, for the drugs were expensive and some irony in the fact that the FDA had been strengthened by their widespread use in a veterinary context depended on post- a great scandal in which a sulfonamide was involved. In 1937 war reductions in chemical costs (McDougald, 1982). On the about 100 patients, mostly children, died after ingesting a com- other hand, once the economic problems were solved there was mercial preparation of sulfanilamide (Hager, 2006). But it was no going back. Chapman (2003) cites a statement made by the the excipient diethylene glycol, not the drug, that was lethal.
veterinary parasitologist Philip Hawkins as early as 1949: ‘‘In Spurred by the tragedy, the Food and Drug Act of 1906 was sulfaquinoxaline, we now have the most satisfactory sulfon- replaced by the much more demanding Federal Food, Drug and amide for the prevention of coccidiosis in poultry. Whether we Cosmetic Act of 1938. A decade later the safely data required like the idea of medicated feed or not, we have no choice in for a veterinary drug were apparently so limited in scope that the matter; it is here to stay. Although we may object to the they could be evaluated in only a few hours. Still, a new era adulteration of feedstuffs with medicine, we must remember in the regulatory control of medicines had begun.
that our unnatural methods of livestock and poultry production As a proprietary product (Figs. 8–11) SQ was a commercial have forced us to this extreme.'' Godley and Williams (2007) success and a trendsetter, to be followed by many other coccid- have recently provided a detailed comparison of the industri- iostats over the succeeding decades. For better and for worse, alization of poultry production in Britain and the United States.
it helped turn poultry raising into a poultry industry. It was In recent years, further doubts have been raised about the added to chicken feed but, commercially and metaphorically ethical and ecological rectitude of intensive livestock produc- speaking, it was not mere chicken feed. The scientific literature tion and its associated chemical dependency. Use of the same would lead one to believe that the phenomenon that was SQ or similar antimicrobial agents in the treatment of human dis- was the achievement of researchers at the Rhode Island Agri- ease and in the enhancement of livestock production has been cultural Experiment Station. To read the literature of commerce much criticized. The associated hazard has been stated by is to conclude that the credit belongs instead to researchers at Drews (2000b), who postulated that the use of sulfonamides in Merck. For once, the truth does not lie somewhere in between.
coccidiosis control may have accelerated the emergence of drug It is to be found, rather, by adding the 2 together.
resistance in certain strains of bacteria in humans. Important asthese issues are, they are beyond the scope of this historical examination. In the middle of the 20th century those engaged For locating and providing access to relevant documents, the author in the development of SQ were caught up in the euphoria of is particularly indebted to Emily Brown of the Archives and Special doing well (scientifically, medically, economically) while at the Collections Department, University of Rhode Island Library, Kingston, same time doing good (improving agricultural productivity).
Rhode Island; to Joseph Ciccone of the archives of Merck; and to Cath- Drews (2000a) has noted that structural derivatization of the erine Ryan, of the Drew University Library. The author is also gratefulto Dr. Michael A. Rice, University of Rhode Island; Susan Vath of sulfonamide molecule led to the development of new diuretic, Merck Research Laboratories; Dr. Jeffrey L. Sturchio, Merck; and Dr.
antidiabetic, and antihypertensive medicines for human use.
Thomas Craig, Texas A&M University, for valuable assistance.
Nevertheless, the triumph of SQ in animal husbandry is of im-portance in its own right. Navia (2000) refers to the benefits that SQ conferred on humankind in the form of plentiful andinexpensive dietary protein, and suggests that these benefits ADAMS, H. R. 2001. Veterinary pharmacology and therapeutics. Black- well, Ames, Iowa, 1,201 p.
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J. Parasitol., 94(4), 2008, p. 945 䉷 American Society of Parasitologists 2008 Outwitting College Professors: A Practical Guide to Secrets of the
paragraph of this chapter is about as good as you can get when it comes System, John Janovy, Jr. Pearson Custom Publishing, Boston, Massa-
to advanced outwitting. He says, ‘‘Academia serves as a home for some chusetts. 149 p. ISBN 0536418500.
really dangerous types, profs that can have a major negative impact onyour entire college career and perhaps even your chances of a good job Over the years, I have enjoyed reading John Janovy's popular books.
afterwards. Learn to recognize these types and avoid them if possible.
Outwitting College Professors was no different! This book was written Academia also provides a haven for some truly wonderful profs who for beginning students. It is a primer designed to serve as a guide for are happy, intelligent, and excited about their jobs and interactions withstudents. Learn to recognize these kinds, too, and cultivate them.'' students through the ‘‘minefield'' created by professors and administra- Throughout the book, John describes techniques by which the student tors in our system of higher education. But it is more than that, too. As can present herself/himself to the prof as a way of playing by the un- I read it, all of my ‘‘long ago'' experiences in the classrooms of Col- written rules of learning in the academy. These rules refer to the dress orado College emerged. For me, this means that the book rates as a code, how to verbally interact with the prof without making a fool of good read for the new/old professor as well as the new/old student.
yourself, what to expect from tests, and how, and how not, to complete There are 11 chapters and an appendix (the latter entitled ‘‘How to a good project and write a good paper. He even has a chapter dealing Be a Good College Student If You Really Want To''). In the first chap- with letters of recommendation and how to be sure that the student has ter, John explains why one needs to outwit the ‘‘prof'' and then how to a good idea about what to expect in the given prof's letter.
do it. In the second chapter, he attempts to distinguish between what Whether you are a ‘‘wet behind the ears'' freshman, a beginning he calls a normal prof and those he calls ‘‘terminally insecure, or the graduate student, a junior professor, or a seasoned teaching veteran, this feminist female/lecherous male, or the really incompetent prof with no is an interesting read, make no mistake about it. Considering the com- interpersonal skills (and burnt out cases).'' He then provides a checklist, bination of John's enthusiasm for teaching and his forty years of ex- which he describes as his ‘‘Outwittability Profile,'' that is recommended perience, I can see why he would/could write such a book. I heartily to the new student as a way to categorize the prof and create what is recommend it.
called an ‘‘outwitting plan.'' Since most profs are normal, the planshould work. For the abnormal types, he has written a special chapter Gerald W. Esch, Department of Biology, Wake Forest University, Win-
called ‘‘Advanced Outwitting.'' I think the advice he gives in the last ston-Salem, North Carolina 27109.
The Extraction of Native Giardia lamblia Actin Through Differential Detergent Treatment Nicholas Barker Stoler Submitted in fulfillment of the Senior Thesis requirement in the Department of Biology, Georgetown University, Washington, D.C., May 2008 NICHOLAS B. STOLER The Extraction of Native Giardia lamblia Actin Through Differential Detergent