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Malaria: Discovery by Committee
Perhaps the best known of all recent antimalarial drugs is chloroquine. As antimalarial drugs were desperately needed during the war, it is startling to realize that chloroquine was first synthesized several years before the war and recognized at that time as having antimalarial activity. A delightfully frank account of its development shows some of the less scientific problems of discovery.
In 1934, H. Andersag, a chemist at the Bayer Laboratories in Elberfeld, prepared a compound which was first known as Resochin. It might be described as a simplified mepacrine, although it belonged to a substantially different chemical class. For 10 years few people knew anything about it. Some limited laboratory and clinical tests undertaken at Bayer led to the belief that it was slightly too toxic to be acceptable. A closely related substance, which was given the name Sontochin, was also laid aside. Under cartel agreements, both the Winthrop Chemical Company in the United States and, later, the French firm of Specia were informed about Resochin and Sontochin. By this time, 1940, the German army had overrun France, and in Europe the normal assessment of new drugs was made subordinate to military needs.
In the USA, the need for research into antimalarial drugs had naturally been foreseen. A program on the synthesis of new antimalarial drugs was initiated at the National Institutes of Health in 1939 and formed the basis of a war program organized by the Committee on Medical Research of the Office of Scientific Research and Development, National Research Council. The program involved scientists from the universities and industry, private individuals, the US Army, the Navy and the Public Health Service, and included liaison with Great Britain and Australia. It was coordinated by a group of conferences, subcommittees, and, from November 1943, by the Board for the Co-ordination of Malarial Studies. The overall search for new antimalarial agents involved the screening of some 16,000 compounds, most of them for both suppressive and prophylactic activity against several avian malarias, plus a thorough study of the toxicology and pharmacology of many of the preparations in lower animals. Finally the appraisal was undertaken of some 80 compounds against the malarias of man.
A great deal of useful information was assembled. Some people will regard such a massive exercise in organization with awe. To others it may seem like a recipe for disaster rather than for successful research. It seems that the machinery did not work very well in discovering chloroquine. Under cartel agreements, the identity and properties both of Sontochin and of Resochin had been disclosed to the Winthrop Chemical Company. The reports created sufficient interest for Sontochin to be synthesized and tested by the American company, and it was found to be active against malaria in canaries. Resochin was not pursued at that time, but both compounds were duly registered for purposes of patenting. The information very properly reached the files of the survey for antimalarial compounds under the Survey Number SN-183 and was available to various conferences, committees, and subcommittees on the Co-ordination of Malarial Studies. History does not record what the members of these committees thought about it, or whether they had time to read their papers.
Meanwhile, P. Decourt, a French clinical consultant to Specia, took samples of the drug to Tunisia for human trials. There he was helped by Jean Schneider, later a professor in the medical faculty at Paris. Schneider's trials were interrupted by the Allied invasion of North Africa in November 1942, and after the capture of Tunis, Schneider turned over his promising results and his remaining samples of Sontochin to the US Army.
In due course some of the drug reached the United States. Its chemical composition was determined at the Rockefeller Institute in New York and found to be identical with the material synthesized at the Winthrop laboratories 3 years earlier. According to Coatney, this discovery created havoc bordering on hysteria. "We had dropped the ball and in doing so had lost valuable time in the search for a reliable synthetic antimalarial". Naturally the lapse had to be covered up. The compound was given a new number and the biological data declared secret.
Further trials on Sontochin, now SN-6911, confirmed its considerable effectiveness, and also generated several ideas which resulted in the synthesis of a compound which was named SN-7618. It was made, but it was also found to be known already and to have been patented in the USA, along with Sontochin, by Winthrop. It was, in fact, a different salt of the same base as the original Bayer Resochin, and after much comparison with other related compounds it became established and was recognized formally in February 1946 under the name chloroquine. It had been synthesized and first tested in animals about 12 years earlier, and rejected, or ignored, twice. It has become the drug of choice for the American armed forces and for the World Health Organization, and has survived against the threat of resistant strains for a surprisingly long time.
Since this time much progress has been made in understanding the biology of plasmodia and new antimalarial drugs have been discovered. Primaquine, chemically in the same family as the pre-war German drug patnaquin, emerged as the most notable success of the great US wartime project. Daraprim (pyritnethatnine), a very different substance, evolved some years later from research of more general significance, to which we shall return in the next chapter. There are also more recent drugs and a radically different approach, based on advances immunology, is leading towards the development of vaccines. Much has been done to control mosquitoes too, but they, like the malaria parasites, have adapted to survive in the face of new enemies. The great hope of eradicating malaria has faded: new battles must be fought and new weapons devised if even the present level of control is to be maintained.
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