hypothesis that chemicals, particularly dyes, act by virtue of their interference with the reproductive power of parasites. Emetine placed in cultures of B. histolytica apparently interferes with reproduction. Dale has intimated that phenylarsine oxides, known to act directly,areless useful per se than compounds from which they may be derived by intermediary action in the body (6). On the contrary, experience with cultures of E. histolytica indicates that, properly used, phenylarsine oxides may offer another adjunct to the chemotherapy of amebiasis. The uncertain action of antimony compounds against parasitic disease has been emphasized by Goodwin, as an added difficulty in the determination of mode of action (6). As indicated earlier, kala-azar in the Sudan does not respond well to therapy with antimony. Slibine oxide groupings may be the most active form against trypanosome and schistosome infections, but in leishmaniasis pentavalent compounds are more useful. After use of the latter, excretion of antimony is more rapid than after potassium antimonyl tartrate. Goodwin believes that rapidly excreted antimony may pass through the body unchanged. Whether indirect action by stimulation of phagocytosis is more important than direct toxic action on leishmania is not known. Current studies may give us the answers t o some of these vital questions. Drug Resistance Another problem of importance in chemotherapy is drug resistance. Any significant observations in this connection would influence the development of a hypothesis to explain mode of action. Reinvestigation of some of the phenomena of drug resistance has shown that a strain of trypanosomes made resistant to one member of a series of organicarsenicalsor antimonials also acquires resistance to other commonly used aromatic compounds of these metals. Strains resistant to metal-free derivatives such as Bayer 205 are not resistant to organic metallic compounds. It is believed that the phenomenon of drug resistance is due in some
cases to changes which occur in the cell membrane of trypanosomes themselves. Resistant strains do not absorb antimonials even when they are present in concentration lethal for nonresistant strains, owing presumably to frequent exposures to suitable concentrations. This acquired resistance apparently persists indefinitely. It might he well to reconsider the dosage and spacing of injections of drugs used against infections now believed to be drugresistant. In this connection, recent studies by Pak (13) are of interest. Pak has found that animals, such as rats and mice, given a dose equivalent to approximately one third of the lethal amount of an antimonial can, within 5 to 48 hours, be given a surely lethal dose of the same drug without harm. When smaller initial amounts of an antimonial are given, the animal is not usually able to survive the subsequent injection of a lethal amount. Perhaps we should reconsider our methods of administration of such compounds. As Warrington Yorke has indicated (6), drug resistance in trypanosomiasis has been extensively studied, and is known to exist in Babesia cants infections and in Plasmodium knowlesi infections of macaques, but little is known of this phenomenon in other infections. Drug resistance is an important factor in the therapy of parasitic disease. This factor might be minimized by using optimum dosage early in the course of chronic infections to avoid the production of drug-resistant strains. Alternative use of chemically unrelated compounds has proved effective against certain chronic parasitic diseases and may be a desirable approach to others. Summary In man the parasitic diseases which present chemotherapeutic problems are essentially chronic in their clinical course. It is not difficult to control the acute phase of such diseases as amebiasis and leishmaniasis, and with persistent, properly supervised therapy relapses can be eliminated, but only by vigorous, specific treatment in the early stages of the disease.
Amebiasis, helminthiasis, leishmaniasis, schistosomiasis, and trypanosomiasis may be given to or are found naturally in suitable experimental animals for laboratory study. This is not the case with onchocerciasis or filariasis, although heartworm infection in dogs and filarial infection in the Florida cotton rat offer convenient suggestive infections as a preliminary to studies in man. In vitro tests, where infected tissue slices from developing chick embryos are utilized, offer opportunities for the evaluation of new drugs which kill parasites directly or by interference with metabolism or reproduction without the intermediary action of the host's tissues. An ideal, arbitrary method of study of drug and vehicle toxicities, absorption, distribution, and excretion in various species of normal and infected animals is suggested as a prelude to critical evaluation in man. The mode of action and drug resistance of chemotherapeutic agents are discussed briefly. Literature Cited (1) Adler, S., and Tchernomoretz, I., Ann. Trop. Med. Parasil., 35, 9, No. 1 (1941). (2) Anderson, H. H., Emerson, G. A., and Leake, C. D., Univ. Calif. Publ. Pharmacol., 1, 31, No. 2 (1938). (3) Chagas, Carlos Filho, personal communication. (4) Chung, H. !»., personal communication. (5) Daniels, T. C , personal communication. (6) Findlay, G. M.( et al.t Biochem. J., 36. 1 (1942). (7) Geiling, E. M. K., Cannon, P., et at., J. Am. Med. Assoc, 109, 1531 (1937). (8) Hogue, M. J., Am. J. Trop. Med., 14, 443 (1934). ' r (9) Johnstone, H. G.t personal'communication. (10) Khaw, O. K., Proc. Soc. Exptl. Biol • Med., 32, 520 (1934). (11) Kofoid, C. A., Wood, F. D., and McNeil, E., Univ. Calif. Publ. Zool., 41, 23, No. 3(1935). (12) Leake, C. D., J. Am. Med. Assoc, 93, 1632 (1929); 98, 195 (1932). (13) Pak, C, personal communication. (14) Soong, H. Y., and Anderson, H. H., Am. J. Trop. Med., 21, 461 (1941). (15) Soong, H. Y., and Hou, E. A., personal communication.
Organometallic Compounds Used as Antiparasitic Agents C. KENNETH BANKS Parke, Davis * Co., Detroit, Mich. HEAVY metals and their compounds have been used as antiparasitic agents for several thousand years. That heavy metals should have been used by man in his first attempts at medication may be attributed to the availability of the 1368
metals and their compounds, but their continued utilization for many years is indicative of some therapeutic activity. It will probably never be ascertained whether kohl, a naturally occurring stibonite, was first a beauty aid and later found CHEMICAL
useful as a prophylactic against epidemic conjunctivitis (59), or if the reverse be true. In either event, its use dates at least to Egypt of the Middle Kingdoms (ca. 2100 B.C.) as evidenced by the contents of vanity cases unearthed by AND
ENGINEERING
NEWS
Table I.
Therapeutically Active Types of Arsenical*
GENERIC NAME RADICAL NAME TYPE FORMULA Arsonic acid Arsono R—AsOsHs Areo R—AsO* Arseno8o R—AsO or Arsine oxide R— Aa(OH)i Arseno R—As-=As—R Areeno Arsine R—AsH.
de Prorok on the Libyan plateau. Further mention of antimony ointments is to be found in the Bible (38). Similarly, ar-
timony likewise forms conjugates and esters, and can b e linked directly to benzenoid carbon atoms t o give many semistable organo derivatives. In contrast, arsenic forms few conjugates and esters, most of which are unstable in water, but does form a large number of stable organo-arsenicals. Correspondingly, bismuth compounds differ but little in pharmacological activity, antimony compounds show some specific relationships between structure and activity, while organo-
Table II.
arsenicals show a great specificity of structure t o pharmacological activity. Since bismuth compounds seem t o differ o n l y i n solubility and rate of absorption, t h e y will not be considered further. Of antimony and arsenic, the pharmacologic a l work is more definitive for arsenic. Arsenic Compounds The first arsenical containing a direct carbon-to-arsenic link was Cadet's fuming liquor, which on oxidation gave dimethyl-
Common Arsenicals
DERIVATIVES OF ARSPHENAMINE B A S E
As—-
H2N OH
XH2 OH
As
HCI.H,NLJ
n
IJNH,.HCI
OH
HfNl
OH
V,
Arsphenamine Salvarsan Ehrlich 606
Arsphenamine Base
-An l^NHCHsSOsNa
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