factors affecting drug sensitivity

122 TRYPANOSOMIASIS SEMINAR Factors affecting drug sensitivity BY P. J. WALKER Zoology Department, Exeter University This programme sets out to investigate the factors affecting drug sensitivity in trypanosomes and is recognized as being a long-term aim. The questions it is hoped to answer are: where is the site of drug resistance (membrane, nuclear membrane, nucleus, mitochondria, etc.)? What mechanism is involved (permeability change, alternative pathway, etc.)? How stable is each type of resistance to altered physico- chemical environment ? How are cross resistances related to chemical structure and mode of action ? Two immediate requirements are being studied. These are the generation of resistant mutants and the development of accurate methods of analysis (population analysis) of strains resistant to drugs other than the aromatic arsenicals. The first steps taken this year were to establish some of the basic facilities necessary and to begin development of a microbeam microscope. The results of the latter in terms of resolution were shown in the demonstration. Analysis of drug resistance requires the use of pure compounds. Two-dimensional thin-layer chromatography has revealed that some work is necessary to Clean up compounds previously considered pure on one-dimensional paper chromatography. Studies on the effect of prolonged blood-passage on the drug-sensitivity, viru- lence and morphology of trypanosomes of the T. bruce/sub-group BY K. C. WILLETT Department of Tropical Medicine, London School of Hygiene and Tropical Medicine The investigations were carried out on strain EATRO 134 which was obtained from the National Institute for Medical Research in a capillary of blood from a mouse infected from the macerated salivary glands of a Glossina pallidipes from Lngala, S.E. Uganda. After 2 passages through rats to obtain sufficient material for initial drug-sensitivity tests the strain was passaged through mice and is now (October 1965) at its 45th passage. The table summarizes the results of drug-sensitivity tests: Drug Dose range Increase in sensitivity (mg. per kg.) of EATRO 134 by 32nd passage Suramin 2.5-10 None Tryparsamide 125-2000 At least 4 times Quinapyramine 1.25-10 At least twice Homidium 2- 5-40 About 16 times Berenil 1-8 Little or no change Pentamidine 1-8 About 4 times Iso-metamidium 0.125-1 About 4 times Prothidium 1.25-10 About twice Results with quinapyramine in particular, and also with suramin, are greatly in- fluenced by the degree of parasitaemia at the time of treatment. Prothidium proved

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122 TRYPANOSOMIASIS SEMINAR

Factors affecting drug sensitivity

P. J. WALKER

Zoology Department, Exeter University

This programme sets out to investigate the factors affecting drug sensitivity in trypanosomes and is recognized as being a long-term aim. The questions it is hoped to answer are: where is the site of drug resistance (membrane, nuclear membrane, nucleus, mitochondria, etc.)? What mechanism is involved (permeability change, alternative pathway, etc.)? How stable is each type of resistance to altered physico- chemical environment ? How are cross resistances related to chemical structure and mode of action ?

Two immediate requirements are being studied. These are the generation of resistant mutants and the development of accurate methods of analysis (population analysis) of strains resistant to drugs other than the aromatic arsenicals.

The first steps taken this year were to establish some of the basic facilities necessary and to begin development of a microbeam microscope. The results of the latter in terms of resolution were shown in the demonstration.

Analysis of drug resistance requires the use of pure compounds. Two-dimensional thin-layer chromatography has revealed that some work is necessary to Clean up compounds previously considered pure on one-dimensional paper chromatography.

Studies on the effect of prolonged blood-passage on the drug-sensitivity, viru- lence and morphology of trypanosomes of the T. bruce/sub-group

K. C. W I L L E T T

Department of Tropical Medicine, London School of Hygiene and Tropical Medicine

The investigations were carried out on strain EATRO 134 which was obtained from the National Institute for Medical Research in a capillary of blood from a mouse infected from the macerated salivary glands of a Glossina pallidipes from Lngala, S.E. Uganda.

After 2 passages through rats to obtain sufficient material for initial drug-sensitivity tests the strain was passaged through mice and is now (October 1965) at its 45th passage.

The table summarizes the results of drug-sensitivity tests: Drug Dose range Increase in sensitivity

(mg. per kg.) of EATRO 134 by 32nd passage

S uramin 2.5-10 None Tryparsamide 125-2000 At least 4 times Quinapyramine 1.25-10 At least twice Homidium 2- 5-40 About 16 times Berenil 1-8 Little or no change Pentamidine 1-8 About 4 times Iso-metamidium 0.125-1 About 4 times Prothidium 1.25-10 About twice

Results with quinapyramine in particular, and also with suramin, are greatly in- fluenced by the degree of parasitaemia at the time of treatment. Prothidium proved

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