Title: Reciprocal Cross Resistance between Cycloguanil Hydrochloride and Pyrimethamine in Plasmodium berghei Infections in Mice
Abstract: One line of Plasmodium berghei was made highly resistant to cycloguanil hydrochloride and another to pyrimethamine. The degree of cross resistance of each line was then determined to these two drugs and to four others representing diverse chemical types. This was done by testing each compound at several dose levels for suppressive action in respective groups of 10 mice following infection with the parent and resistant lines. The degree of relative cross resistance varied among the compounds. The composite results indicated that resistance induced by cycloguanil hydrochloride was broader than that induced by pyrimethamine. The data also suggested that the latter two drugs have similar but not identical modes of action. A line of Plasmodium berghei made resistant to cycloguanil hydrochloride* showed high cross resistance to pyrimethamine (Thompson et al., 1967). One might presume therefore that this line could be used in determining whether or not a new substance is likely to be active against parasites that are resistant to pyrimethamine. This would be a safe presumption if cycloguanil and pyrimethamine have identical modes of action or if resistance induced with cycloguanil is not narrower or more specific than that induced with pyrimethamine. This paper deals with these hitherto undetermined points. The approach chosen was determination of the degree of reciprocal cross resistance between these drugs by the use of two resistant lines-one that had been made resistant by exposure to cycloguanil hydrochloride and the other by exposure to pyrimethamine. Four additional compounds also were tested for information on the relative breadth of resistance induced by the two drugs. MATERIALS AND METHODS Carworth (CF-1) female mice of approximately 18 to 22 g weight range were used. The KGB-173 strain of Plasmodium berghei was used as the parent line (P), and two derivatives from it were used as the drug-resistant lines. Infections were induced by the intraperitoneal administration of 15 X 106 parasitized blood cells. Treatment was administered by feeding the drug in the ration (powdered Rockland mouse pellets) for 6 days and was started the day before parasites were injected. The medicated rations were given in food Received for publication 12 January 1968. * 4,6-diamino-1( p-chlorophenyl)-l,2-dihydro-2,2dimethyl-s-triazine hydrochloride. cups designed to minimize spillage and to permit meaningful calculations of drug intakes. The effects of treatment were assessed by comparing the percentage of parasitized cells in Giemsa-stained blood smears, prepared from treated and control mice on the 5th day after parasites had been injected. Estimates of the percentages of parasitized cells were made in the following manner. The number of erythrocytes per field (demarcated by a Howard ocular disc) were first estimated in the portion of the smear selected for study; the erythrocyte estimates in terms of 100 or 200 were made by inspection, based upon much experience in actual counting. When at least 5% of the cells were infected, parasites were counted in a sample of an estimated 200 erythrocytes. When clearly less than 5% of the cells were parasitized but at least two parasites occurred per field, parasites were counted in an estimated 1,000 erythrocytes. In fields containing less than two parasites counting was continued until 10 parasites had been seen or at least 100 fields had been examined; the number of fields examined in such instances ranged from 10 to 100. Groups of 10 mice were infected for each dose level of drug tested and a group of 10 untreated mice were infected as controls for each experiment. The percentage of parasite suppression was calculated for each treated mouse, and from this the mean percentage of suppression and its standard error were computed. These values were plotted against the drug dose (in mg/kg/day) on a logarithmic scale and the doses required for 70% suppression (sD70) were estimated from the graphs. The degree of increase in drug tolerance (resistance or cross resistance) was computed by dividing the SD7o of the resistant lines by the SD7, of the parent line in the same experiment. History of the drug-resistant lines The early history of the cycloguanil-resistant line (T) has been presented previously (Thompson et al., 1967). Briefly, it was derived from the parent KGB-173 strain by 48 weekly passages
Publication Year: 1968
Publication Date: 1968-06-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 13
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