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Resistance of Plasmodium falciparum to pyrimethamine
94
CORRESPONDENCE
Surely what occurred in the 10 weeks in question was merely that this labile quality was partially lost by the parasite. Further, I should like to suggest that perhaps 100 mg. of pyrimethamine in a single dose does not eradicate entirely the blood forms of P. falciparum. Although such dosages will certainly clear the blood forms of P. vivax (Coatney et al., 1953), they will probably not clear the blood forms of P. cynomolgi (Schmidt and Genther, 1953). Large doses of sulphadiazine will clear the peripheral blood of all asexual forms of P. falciparum, but large numbers of gametocytes will appear some days later, indicating a continuous cryptic schizogony in the internal organs. If this alternative suggestion is considered reasonable, then the 20 per cent. susceptible fraction of Clyde and Shute becomes a 20 per cent. (or some part of it) insusceptible residuum of continuous schizogony. This residuum would be the foundation for the development of drug-resistance, being constantly treated in the same host by spaced dosages of drug. Such a regimen can be expected to produce resistance on the same swift scale as is seen in P. cynomolgi infections treated by the methods of Schmidt and Genther (1953). Obviously such a consideration would alter considerably the conclusions drawn by Clyde and Shute from their data. Lastly, though a minor point, I should like to appeal against the use of the term "variety" to describe drug-resistant strains of a parasite, unless some distinct morphological change, whicl3 is reproducible, has occurred simultaneously. In general, the nomination of varieties is not practised by protozoologists.
London School of Hygiene and Tropical Medicine, 22nd December, 1954.
I am, etc., R. S. BRAY.
REFERENCES COATNEY, G. R., MYATT,A. V., HERNANDEZ,T., JEFFERY, G. M. & COOPER, W. C. (1953). Amer. J. trop. Med. Hyg., 2, 777. SCHMIDT, L. H. & GENTHER, C. S. (1953). J. Pharm. exp. Therap., 107, 61.
" RESISTANCE OF Plasmodium falciparum TO PYRIMETHAMINE" S m , - - I t is unfortunately the case that malaria parasites can readily be induced under certain conditions to develop resistance to several antimalarial drugs. Those drugs are, as far as we know, substances which interfere at a single point in a " metabolic pathway " which is responsible for the synthesis of some particular compound or compounds essential to the well-being of the parasite. The antimalarial sulphonamides, proguanil and pyrimethamine belong to this group: pyrimethamine, and probably proguanil, interfere with the conversion of folic acid to folinic acid. Other antimalarials such as quinine and the 4- and 8-aminoquinolines are believed to interfere in several metabolic reactions and consequently resistance to these drugs can be induced only with great difficulty and to a slight degree, or not at all (Goodwin and Rollo, in press). In several carefully controlled trials, weekly doses of pyrimethamine have been shown to eliminate infection in large communities and prevent re-infection. In no case is there any
CORRESPONDENCE
95
evidence of resistance having arisen. (Canet and Farinaud, 1952 ; Giblin, 1954 ; Miller, 1954 ; Vincke, 1954). In the laboratory, pyrimethamine resistance can readily be induced in, for example, Plasmodium berghei by giving subcurative doses at suitably spaced intervals. (Rollo, 1952). The experiments of Clyde and Shute suggest that with widely spaced doses pyrimethamine resistance may arise in P. falciparum infections. It should now be obvious that when pyrimethamine is used for continual prophylaxis, doses should be spaced at intervals of not greater than one week. This interval has been recommended after pharmacological investigation and clinical trials. The results of experiments with P. berghei and P. gallinaceum suggest that pyrimethamine resistance is labile in character since it has been found when the drug is withheld, a highly resistant strain can regain its normal sensitivity. This is in accord with Clyde and Shute's observation that " resistant varieties regressed and became submerged." In criticism of the paragraph concerning the action of pyrimethamine it should be said that as far as is known, the drug acts by blocking the conversion of folic acid to folinic acid and not by blocking (the uptake of ?) folinic and p-aminobenzoic acids. Also, although p-aminobenzoic acid has been shown to be important in the metabolism of P. berghei and P. cynomolgi (Hawking, 1953), there is no evidence that folinic acid need necessarily be supplied for normal plasmodial metabolism. The authors' statement that folinic acids were shown to have no similar action to that of p-aminobenzoic acid in inhibiting the action of proguanil is incorrect. Greenberg (1953) showed that pteroylglutamic acid (folic acid) and calcium leucovorin (folinic acid) did inhibit the action of proguanil against P. gallinaceum. I am, etc., The Wellcome Laboratories of Tropical Medicine, 31st December, 1954.
IAN M. ROLLO.
REFERENCES CANET, J. & FARINAtlD,E. (1952). Bull. Soc. Path. exot. 45, 645. GIBLIN, W. E. (1954). Med. J. Must., 41, 9. GOODWIN,L. G. • ROLLO,I.M. Biochemistry ¢.~ Physiology of Protozoa, Vol. 2 (in the press). York : Academic Press Inc. GREENBERG,J. (1953). Exp. Parasit., 2, 271. HAWKING,F. (1953). Brit. reed. J., i, 1201. MILLER, M. J. (1954). Miner.J. trop. Med., 3, 458. RoLLo, I. M. (1952). Nature, Lond., 170, 415. VINCKE, I. H. (1954). Bull. Wld. Hlth. Org., 11, 785.
New
THE SIMILARITY OF BRAZZAVILLEENCEPHALOMYELITISVIRUS AND TYPE 1 POLIOMYELITISVIRUS SIR--The recovery of what was believed to be a hitherto undescribed encephalomyelitis virus was made in Brazzaville by Pellissier and Trinquier (1953). Immunological studies of one strain (Felix) of this virus showed that it was not related to any of the known encephalitis viruses with which it was compared (Pellissier, 1954). Dick (1954) noted that no tests had been done by Pellissier which had excluded the possibility that the Brazzaville encephalomyelitis virus might be poliomyelitis virus of Type 1 or 3. In order to test this possibility the Felix strain of the virus was tested in tissue cultures. The virus was kindly forwarded from the Pasteur Institute, Brazzaville, by Dr. R.
CORRESPONDENCE
Surely what occurred in the 10 weeks in question was merely that this labile quality was partially lost by the parasite. Further, I should like to suggest that perhaps 100 mg. of pyrimethamine in a single dose does not eradicate entirely the blood forms of P. falciparum. Although such dosages will certainly clear the blood forms of P. vivax (Coatney et al., 1953), they will probably not clear the blood forms of P. cynomolgi (Schmidt and Genther, 1953). Large doses of sulphadiazine will clear the peripheral blood of all asexual forms of P. falciparum, but large numbers of gametocytes will appear some days later, indicating a continuous cryptic schizogony in the internal organs. If this alternative suggestion is considered reasonable, then the 20 per cent. susceptible fraction of Clyde and Shute becomes a 20 per cent. (or some part of it) insusceptible residuum of continuous schizogony. This residuum would be the foundation for the development of drug-resistance, being constantly treated in the same host by spaced dosages of drug. Such a regimen can be expected to produce resistance on the same swift scale as is seen in P. cynomolgi infections treated by the methods of Schmidt and Genther (1953). Obviously such a consideration would alter considerably the conclusions drawn by Clyde and Shute from their data. Lastly, though a minor point, I should like to appeal against the use of the term "variety" to describe drug-resistant strains of a parasite, unless some distinct morphological change, whicl3 is reproducible, has occurred simultaneously. In general, the nomination of varieties is not practised by protozoologists.
London School of Hygiene and Tropical Medicine, 22nd December, 1954.
I am, etc., R. S. BRAY.
REFERENCES COATNEY, G. R., MYATT,A. V., HERNANDEZ,T., JEFFERY, G. M. & COOPER, W. C. (1953). Amer. J. trop. Med. Hyg., 2, 777. SCHMIDT, L. H. & GENTHER, C. S. (1953). J. Pharm. exp. Therap., 107, 61.
" RESISTANCE OF Plasmodium falciparum TO PYRIMETHAMINE" S m , - - I t is unfortunately the case that malaria parasites can readily be induced under certain conditions to develop resistance to several antimalarial drugs. Those drugs are, as far as we know, substances which interfere at a single point in a " metabolic pathway " which is responsible for the synthesis of some particular compound or compounds essential to the well-being of the parasite. The antimalarial sulphonamides, proguanil and pyrimethamine belong to this group: pyrimethamine, and probably proguanil, interfere with the conversion of folic acid to folinic acid. Other antimalarials such as quinine and the 4- and 8-aminoquinolines are believed to interfere in several metabolic reactions and consequently resistance to these drugs can be induced only with great difficulty and to a slight degree, or not at all (Goodwin and Rollo, in press). In several carefully controlled trials, weekly doses of pyrimethamine have been shown to eliminate infection in large communities and prevent re-infection. In no case is there any
CORRESPONDENCE
95
evidence of resistance having arisen. (Canet and Farinaud, 1952 ; Giblin, 1954 ; Miller, 1954 ; Vincke, 1954). In the laboratory, pyrimethamine resistance can readily be induced in, for example, Plasmodium berghei by giving subcurative doses at suitably spaced intervals. (Rollo, 1952). The experiments of Clyde and Shute suggest that with widely spaced doses pyrimethamine resistance may arise in P. falciparum infections. It should now be obvious that when pyrimethamine is used for continual prophylaxis, doses should be spaced at intervals of not greater than one week. This interval has been recommended after pharmacological investigation and clinical trials. The results of experiments with P. berghei and P. gallinaceum suggest that pyrimethamine resistance is labile in character since it has been found when the drug is withheld, a highly resistant strain can regain its normal sensitivity. This is in accord with Clyde and Shute's observation that " resistant varieties regressed and became submerged." In criticism of the paragraph concerning the action of pyrimethamine it should be said that as far as is known, the drug acts by blocking the conversion of folic acid to folinic acid and not by blocking (the uptake of ?) folinic and p-aminobenzoic acids. Also, although p-aminobenzoic acid has been shown to be important in the metabolism of P. berghei and P. cynomolgi (Hawking, 1953), there is no evidence that folinic acid need necessarily be supplied for normal plasmodial metabolism. The authors' statement that folinic acids were shown to have no similar action to that of p-aminobenzoic acid in inhibiting the action of proguanil is incorrect. Greenberg (1953) showed that pteroylglutamic acid (folic acid) and calcium leucovorin (folinic acid) did inhibit the action of proguanil against P. gallinaceum. I am, etc., The Wellcome Laboratories of Tropical Medicine, 31st December, 1954.
IAN M. ROLLO.
REFERENCES CANET, J. & FARINAtlD,E. (1952). Bull. Soc. Path. exot. 45, 645. GIBLIN, W. E. (1954). Med. J. Must., 41, 9. GOODWIN,L. G. • ROLLO,I.M. Biochemistry ¢.~ Physiology of Protozoa, Vol. 2 (in the press). York : Academic Press Inc. GREENBERG,J. (1953). Exp. Parasit., 2, 271. HAWKING,F. (1953). Brit. reed. J., i, 1201. MILLER, M. J. (1954). Miner.J. trop. Med., 3, 458. RoLLo, I. M. (1952). Nature, Lond., 170, 415. VINCKE, I. H. (1954). Bull. Wld. Hlth. Org., 11, 785.
New
THE SIMILARITY OF BRAZZAVILLEENCEPHALOMYELITISVIRUS AND TYPE 1 POLIOMYELITISVIRUS SIR--The recovery of what was believed to be a hitherto undescribed encephalomyelitis virus was made in Brazzaville by Pellissier and Trinquier (1953). Immunological studies of one strain (Felix) of this virus showed that it was not related to any of the known encephalitis viruses with which it was compared (Pellissier, 1954). Dick (1954) noted that no tests had been done by Pellissier which had excluded the possibility that the Brazzaville encephalomyelitis virus might be poliomyelitis virus of Type 1 or 3. In order to test this possibility the Felix strain of the virus was tested in tissue cultures. The virus was kindly forwarded from the Pasteur Institute, Brazzaville, by Dr. R.