First Symposium on Chemical-Biological Correlation, May 26-27, 1950 (1951) / Chapter Skim
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Panel Discussion on Antimalarials
Panel Discussion on Antimalarials
Pages 165-208
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From page 165... ...
C Elderfield, Moderator Columbia University New York, New York
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From page 166... ...
More important than this, however, we must indicate the stage of development of a particular malaria, for, unlike the bacteria, viruses, rickettsiae and most of the protozoa, the malarial parasites have an exceedingly complex life-cycle, a cycle involving several stages of development which differ from one another both microscopically and physiologically. We shall be dealing with at least three kinds of antimalarial activity - prophylactic, suppressive and curative.
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From page 167... ...
In the primate malarias there is indirect evidence that this does not occur. The final stage in the vertebrate host is the gametocyte, a sexual parasite arising in red blood cells from erythrozoites and perhaps also from phanerozoites.
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In the human infections suppressive activity is studied in tests imitating the clinical treatment of acute malaria. Effective drugs ameliorate or cure the malarial attack.
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An extreme case is seen in the esters of para-guanyl benzoic acid, which are partially prophylactic in avian malarias yet have no detectable suppressive activity. There are indications that common physiological actions are involved in prophylactic, curative and gametocidal effects, but the number of kinds of drugs known to have such actions is still too small to warrant more than a supposition.
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From page 171... ...
The fact that a drug exerts antimalarial action in small dosage does not necessarily mean that it is a superior drug. Further, it should be realized that the figure represents a summation of the various factors involved in absorption, localization, metabolic alteration, excretion and specific antiparasitic actions of the compound.
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3 a. Gallinaceum quinine equivalents b.
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The data on Plasmodium gallmaceum in Table II are less clear, although they do not disagree with the above generalizations. Table III shows a few of the many compounds in the survey tables illustrating the effects of various ring substitutions.
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GALLINACEUM QUININE EQUIVALENTS CHLOROQUINE ANALOGS CAMOQUIN ANALOGS 7 Cl 15 7 Cl 20 7 Br 15 7 Br 15 7 I 10 7 CH3 10 5,7 Cl 4 7 1 8 3CH3 7C1 4 6 OCH3 8 6 Cl 2 7 OCH3 6 6 OCH3 2 3CH3 7 Cl 6 7 OCH3 2 6,7CH3 6 7 CH3 1 (None)
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From page 175... ...
They show what should be obvious on a priori grounds, that the superficial comparison of structural formulae has very little possibility for fundamental conclusions. It is clear that chemical as well as spatial effects determine antimalarial action.
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1946 - A Survey of Antimalarial Drugs, 1941-1945.
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The significance of the results will be briefly discussed in terms of the structure-activity relationships within each suppressive series. Although no new series showing curative activity has yet been discovered in this program, the wide structural variations among suppressive drugs strongly suggests that other curative types eventually will be found.
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Of the more than two hundred members of the group known to be active in the avian malarias, eleven have been tried in man, and four (chloroquine, SN 10, 751 . sontochin, and oxychloroquine)
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I thought our demonstration that in the naphthoquinone series biological potency can be correlated with chemical structure only when allowance is made for varying distribution characteristics of the compounds concerned might suggest useful developments in the study of other series of antimalarials and might have some impact on chemotherapeutic research in general. I did indeed have some very able cooperation at the time from such individuals as A
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180 to deliver the thermos the next day to the steward of an Arabian-American Oil Co. plane just about to leave for Saudi-Arabia.
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H SCHMIDT The Christ Hospital Institute of Medical Research Cincinnati, Ohio Some of the members of this audience may wonder why a dissertation on pharmacology, and more specifically on toxicology, should be included in tonight's panel discussion on the relations between chemical structure and biological activity.
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182 the same quinoline nucleus, with a methoxyl group substituted at position 6 and an amino group at position 8. The side chains of the compounds have the same terminal grouping, diethyl amine.
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183 CHART III LEUCOPENIA AND NEUTROPENIA INDUCED BY PAMAQUINE Day of Treatment WBC per cmm. x 1000 Distribution of Leucocytes - Per Cent Neutrophils Lymphocytes Monocytes Eosinophils Basophils 0 18.5 54 38 4 2 2 5 2.6 9 81 4 1 5 9 1.35 3 91 5 1 0 13 1.
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184 CHART IV (Cont.
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185 CHART V (Cont.
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In all cases, a subacute method of studying toxicity has been employed, divided daily doses being administered for periods up to fourteen days. The results which have emerged from these studies have demonstrated remarkable, wholly unexpected and completely unexplained relations between chemical structure and pharmacological activity.
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187 CHART VII GENERAL DISTRIBUTION OF 8-AMINOQUINOLINES EXAMINED FOR THEIR EFFECTS ON THE RHESUS MONKEY No. Compounds Studied Type of 8-amino-substituent 10 -(CH2)
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188 CHART VIII (Cont.
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189 CHART IX (Cont.
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HN(CH2) 2 \\/ HNCH2CHOHCH2-N \ y N -- V CHoUO ^ CH /n ^^ Toxic reactions involve CNS Toxic reactions involve CNS It would be satisfying if in concluding this report information could be presented would explain the radically different types of reactions evoked by 8-aminoquinolines of such slightly differing chemical structures.
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From page 191... ...
-- ' These investigations were, in part, supported by a grant-in-aid from the United States Public Health Service and, in part, carried out under contract between the Office of the Surgeon General of the United States Army and the University of Chicago. The clinical studies were also aided by the participation of Army Medical Officers assigned to the project.
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All primary cases treated were characterized by having an incubation period of less than fifteen days. A limited number of patients that had relapsed after treatment with a heterogeneous group of drugs have also been included in this report, but only subjects who relapsed within thirty days after end of therapy were chosen.
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* Drug administered in six divided doses daily for two weeks Abd.
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* Drug administered in six divided doses daily for two weeks Abd.
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389 None 10.3 4 * Both drugs administered in six divided doses daily for two weeks *
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+ 7.5 6 * Both drugs were administered in six divided doses daily for two weeks *
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TABLE VI TOXICITY STUDIES OF PRIMAQUINE (SN 13,272) Days Rx Case Age Weight Symptoms Laboratory Findings MET*
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TABLE VII TOXICITY STUDIES OF PRIMAQUINE (SN 13.272) Days Rx Case Age Weight Symptoms Laboratory Findings MET*
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* given in six divided doses for two wecKs + this is equal to 133 mgm.
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200 REFERENCES Alving, A
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For example (Figure I) 2, 4 -diamino-5-p-chlorophenoxypyrimidine had been found in the screening test to have a strong antifolic acid activity.
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Others, like diaminopurine, are reversed very little by folic acid but readily by a purine, and all gradations between these two extremes can be found. In the course of our work a number of commercially available substances had been tested, and among these, both paludrine and quinine have effects in the Lactobacillus casei test which resemble those of the diaminopyrimidines.
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The 6-alkyl derivatives are prepared from acyl acetic esters (illustrated on Figure V by acetoacetic ester) by way of the o-aryloxyacylacetic ester and then by the above route to the diaminopy rimidine.
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204 "" Figure IV Figure V
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Boyd. At just about the time our work began, Plasmodium berghei infection in the mouse became available through the courtesy of Professor Shortt of the London School of Tropical Medicine and Goodwin5 studied the action of several antimalarial drugs in parallel against P_.
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The activity in the L casei system is given as the amount causing 5U per cent inhibition in the usual folic acid growth medium and the figures given, therefore, are inversely proportional to the activity.
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From page 207... ...
Thus their action appears to be similar, but not identical to that of chlorguanide. Figure VIII Before concluding, I should point out that no work with our pyrimidines in the human malarias has been reported yet, and very little work with sporozoite transmitted infections has been carried out.
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From page 208... ...
208 REFERENCES 1. Hitchings, G
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