(17) Cohen et al.. J. Chem. Soc, 1931, 3043. (18) Das, Indian J. Med. Research, 7, 44 (1920). (19) Day, Lancet, I, 525 (1921). (20) de Rezende, Report Pan-American Congress, July 1935. (21) Di Christina and Caronia, Pediatria, 23, 81 (1915). (22) Eagle et al., J. Am. Chem. Soc, 65, 1236 (1943). (23) Ehrlich. *'Experimental Researches of Specific Therapeutics", New York, Hoeber, 1909. (24) Ehrlich and Bertheim. Ber.. 40, 3292 (1907). (25) Ehrlich and Hata, "Die experi men telle Chemotherapie der Spirilloseir\ Berlin, Julius Springer. 1910. (26) Fan and Scott, China Med. J., 48, 1046 (1934). (27) Faust, Science, 99, 71 (1944). (28) Findlay, ''Recent Advances in Chemotherapy", 1st and 2nd éd., Philadelphia, P. Blakiston's Son and Co., 1930, 1939. (29) Fischl and Schlossberger, "Handbuch der Chemotherapie", 2nd vol., Leipzig, Fishers Medizinische Buchhandlung, 1934; also English edition containing nearly the same material, "Handbook of Chemotherapy", 3rd vol., Baltimore, H . G. Roebuck and Son. 1936. (30) Fisher, Dent. med. wochschr., 59, 1151 (1933). (31) Fourneau et al., Ann. inst. Pasteur, 37, 51 (1923); Bull. sac. chim., (4) 41, 499 (1927). (32) Friedheim, Schweiz. med. Wochschr., 5, 116 (1941). (33) Goddard, "Friend's Textbook of Inorganic Chemistry**, Vol. X I , Parts I, II, and III, Philadelphia, J. B. Lippincott Co., 1928-36. (34) Gough and King, J. Chem. Soc, 1930, 669.
(35) Gruheit, Arch. derm, syph., 32, 848 (1935). (36) Kérendal, Bull. soc. path, exotique, 3, 642 (1910). (37> Kikuth, unpublished. (38) Kings II, Chap. IX, 30. (39) Knoclcs, "Essay Review, Kala-azar", p . 15 (supplement to Annual Report of Calcutta School of Tropical Medicine, 1933). (40) Kopko, Commun, présentée au 1er Congr. med. trop. Africa Occid., Loanda, 1923. (41) Kulis and Tatum, J. Pharmacol., 61, 451 (1937). (42) League of Nations, Health Organization, Quarterly Bull., 4, 787 (1935). (43) Loreiu, U. S. S aval Med. Bull., 42, 560 (1944). (44) McFayden. China Med. J.. 43, 1053 (1929); 52, 339 (1937). (45) Manson, Ann. 4trop, med., 2, 49 (1908). (46) Manson-Bahr. *\lanson*s Tropical Diseases*', 10th éd., Baltimore, William Wood & Co.. 1936. (47) Mawa, Reun. soc. argent, patol. reg. del norte, 449 (1930); 513 (1931); 907(1933); Arch. Schiffs -»«. Tropenhyg., 583 (1931). (48) Massa et al., Univ. Buenos Aires, elision Estudios Pat. Reg. Argentina, Pub. 6 1 (1942). (49) Morgan, "Organic Compounds of Arsenic and Antimony**, New York, Longmans, Green and Co., 1918. (50) Napier, Indian J. Λfed. Research, 19, 705, 719 (1932). (51) Napier, **Kala-azar**, London, Oxford University Press, 1927. (52) National Research Council, "Summary of Recent Literature on Anthiornaline**, Washington, Office of ^Medical Information, 1943. (53) Parke, Davis & Co., D e p \ of Clinical In vestigation, private communication. (54) Peter, unpublished.
(55) Raiziss and Gavron, "Organic Arsenical Compounds**, New York, Chemical Catalog Co., 1923. (56) Rodgers, Lancet, II, 604 (1919); Brit. Med. J., I, 596 (1920). (57) Roy and Β ose, Indian Med. Gaz., 57, 281 (1922). (58) Salaberry, Prensa med. argent., 2427 (1936). (59) Schmidt and Peter, *'Advances in Therapeutics of Antimony'*, English éd., Leipzig, Georg Thieme, 1938; German éd., Leipzig, Georg Thieme, 1937. (60) Sherwani, Ituiian Med. Gaz., 67, 83 (1932). (61) Sice, Bull. soc. path, exotique, 17, 179 (1924). (62) Stitt, "Diagnosis, Prevention and Treatment cf Tropical Diseases**, 6th ed. t ed. by R. P. Strong, Philadelphia, Blakiston Co., 1942. (63) Stratman-Thomas and Loevenhart, J. Pharmacol., 31, 217 (1927). (64) Struthers, China Med. J., 41, 755 ( 1927) ; 45, 1 (1931); 47, 1421 (1933); 52, 335 (1937). (65) Sweet and Gruhzit, unpublished. (66) Tatum et al., J. Pharmacol., 50, 198 (1934). (67) Tatum, Pfeiffer, and Kuhs, Ibid., 59, 241 (1937). (68) Thomas and Breinl, Liverpool School Trop. Med. Mem., 16 (1905). (69) Uhlenhuth and Seiffert, Klin. Wochschr., 10, 175 (1931). (70) Vaccarezza, Dia Med., 7, 751 (1935). (71) Van Slype, Ann. soc. belge med. trop., 13, 87 (1933). (72) Voegtlin et al., J. Pharmacol., 15, 475 (1920); 16, 199, 449 (1920-1); 17, 357 (1921); 20, 85 (1923). (73) Voegtlin and Smith, Ibid., 15. 475 (1920). (74) Yates, China Med. J., 43, 1053 (1929); 52. 339 (1937).
Nonmetallic Compounds Used as A n t i parasitic Agents against Tropical Diseases Other Than Malaria C. R. A D D I N A L L , Research Laboratory, Merck & Co., Inc., Rahway, N . J. IN HIS account of the history of the discovery of the vitamins, R. R. Williams commented that although the incentive held forth to monarch and adventurer alike during the era of exploration initiated by Columbus was the lure of the gold and gems of India, Cathay, and the Americas, such material benefits as have accrued from this exploration and subsequent colonization were mutual, and resulted from the necessary exchange of products, problems, and ideas between Europe and these newly discovered lands. From such exchanges the art of medicine benefited predominantly, both by the introduction into Europe of remarkably effective native drugs and, later, by the opportunity afforded of studying many diseases of tropical origin. Among the various primitive drugs thus introduced was the Indian remedy Kurchi, 1374
the bark and seeds of Holarrhena antidysentenca, a plant which originated, according to the Sanskrit legend, from sprinklings of the sacred elixir of life dropped to earth by the god Indra to resurrect the ape, Ramas. The drug was widely used in native Hindu medicine and
was introduced into Europe by 1563, through the agency of the court physician of the Portuguese Viceroy of Goa. Today, the total Kurchi alkaloids, or the main alkaloid conessine, are used similarly to emetine in the treatment of amebic dysentery, because of their lethal action on the
9e* Utii fatf&l 4>ΐ4*>α*φ of nonmetcMic antifXQ*aéitic αψοηίά, αψΛίηΰ,έ Uapdcal diéeaéeè, ajte* α ραά44ηψ mention. o£ tUe êtatuàalùf occu*,*l*Êf dmpé. o£ tUié, type* édded οψα4ηάί ameaiGè4é, tUe development o£ tUe. eclvtiedd éiàea, derivative*, the anil and êitfupl ^tUnoUneé, and tn\e pltenantÂàidinm camponndd jo* nAe in biypanoéomiaéié, «4 iAetclnd tvUejlu. /I jullm* account 44. fives* oj tUa cltemical and cAemûilteJiapeutical development oj tUe atonuUic. diamidined iv/ucA ko4*e> heen inÙuuUtced necentln 4s* tUe treatment oj t*f/panoéam4adid aeuL UuAntaniadié, CHEMICAL
AND
ENGINEERING
NEWS
Kurchi end Ipecac Alkaloids Holarrhena antidysenterica Cephaelis ipecacuanha Conessine contains four hydroMeO.'V'N genated, carbocylic rings with an attached ring containing a OMe nitrogen atom.
Q
ApMe )
Emetine (Staub, 1927)M e \ A (
\Ar H
Conessine C]i,Ha(NMe)(XMei) Kurchine Holarrhenine CMHMN^) Norconessine C23H&sN2 motile forms of Endamoeba histolytica, the pathogenic organisms causing amebiasis. It was also from India that knowledge was gained of the efficiency of chaulmoogra oil against the tropical disease, leprosy. This oil, from the seeds of Taraktogenos kurzii and Hydnocarpus wightiana (or H. anthelmintica) has been used since ancient times in India and Burma for the treatment of this affliction. Everyone is aware that the Spanish conquistadores introduced South American cinchona into Europe, but it is not so well known that it was from the Brazilian Indians that the civilized world learned the use of ipecac in the treatment of tropical dysentery. Large amounts of the Brazilian dysentery root, ipecacuanha, were brought to France by the Jesuits and by the end of the 17th century, the use of the root in a decoction or powder was known throughout Europe. It was not until 1894 that the main alkaloids of ipecac, emetine, cephaline, and psychotrine were isolated in a pure state. About 1912, Rogers developed the use of emetine in the treatment of tropical dysentery, and today emetine hydrochloride is regarded by many physicians as the standard drug for the treatment of acute amebic dysentery. The structure of emetine is not definitely established but the presence of two hydrogenated isoquinoline rings is assumed. Similarly, the molecule of conessine is supposed to contain four carbocyclic rings to which a heterocyclic ring containing nitrogen is attached. The activity of alkaloids against parasitic disease is not altogether unexpected in the light of modern findings concerning the activity of compounds containing long carbon chains (or corresponding aromatic nuclei) with terminal amino groups, although the present limited knowledge of the relationship between chemical structure and physiological activity affords little comfort or aid to the chemotherapeutic investigator. Apart from scattered references to the use of ipecac alkaloids in the treatment of leishmaniasis, schistosomiasis, and trypVOLUME
2 2, N O .
16
Emetine Cephaline Psychotrine Emet amine
C2»H4oNa04 C28H38N2O4 CsgHaeNjO* C2.H3.N2O4
anosomiasis; and of the employment of the drugs aspidium, hyocyamus, and buchu in schistosomiasis, there is little of importance to relate concerning the use of other naturally occurring drugs in the treatment of parasitic disease. Threat of Sleeping Sickness The colonization of West Africa by Europeans around the turn of the last century was hindered by the spread of sleeping sickness, familiar among West African natives, into the Congo Free State, Uganda, and elsewhere in Central Africa, which caused great mortality, many Europeans dying of the disease. In 1903, Castelani found the trypanosoma in the cerebrospinal fluid of sleeping sickness victims. In 1907, an international conference was held in London for the purpose of organizing research on the pathology of sleeping sickness, a conference that was an outstanding landmark in the history of the application of state effort in the advancement of science. The cause of the disease and the vector were already known, and it had further been ascertained, experimentally in animals and therapeutically in man, that the
infection once acquired could be controlled, to some extent, by arsenicals and dyestuffs. For the further study of the various problems involved in this campaign to control sleeping sickness, the British Government invited the cooperation of all the powers interested in th« colonization of tropical Africa. Ehriich in Germany, Thomas in England, Fourneau in France, and other workers in the world's scientific laboratories were then hard at work on the synthesis and testing of trypanocidal agents and by 1905 Thomas had demonstrated t o Ehriich that atoxyl was definitely trypanocidal in experimental animals. The race for an effective trypanocide was on, and the prize of victory was Empire, the control of successful colonization by Europeans of Central Africa. Dyes in Chemotherapy. Chemotherapy had developed from histological techniques and was primarily a dye therapy, pure and simple. It was found that many vital staining dyestuffs were trypanocidal, including the benzidine azo dyestuffs, chrysoidine, trypan red, and Afridol violet,. Ehriich later introduced the acridines into the therapy of trypanosomiasis. He found trypaflavine to be extremely effective i n experimental animals, but the clinical results were disappointing. Shortly afterwards, Browning called attention to the bactericidal properties of the acridines, and various derivatives were employed extensively as wound disinfectants b y the opposing armies during World War I. Morgenroth, who had studied tbe acridines used by the Central Powers, in 1921 introduced Rivanol, another strong bactericidal derivative of the acridine series, which has been used since then a s an agent for the treatment of amebic dysentery. Colorless Urea Derivatives. The trypanocidal properties of Afridol violet had
Dyes in Chemotherapy Benzidine Azo Dyes SO,Na .N=N
N=N.
-N-N..NH.
VNH* NaO,S.\ Chrysoidine Acridine Dyes
» » AUGUST
H 2 N.
J.SOaNa
NaOaS.
SOaNa
Trypan Red NH 2 C2H60./ NH«
Trypaflavine 2 5,
1944
Rivanol 1575
The Colorless Urea Derivatives
on XH, -X=-X - ^ NaO,i
y -XH—CO
i
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