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Despite the mass of information on the antimalarial action of sulphonamides, proguanil, and pyrimethamine (see Goodwin and Rollo, 1955), there is as yet no complete picture of the relationship between them, although they all probably act upon the same metabolic pathway in the synthesis of nucleoprotein. Hawking (1953a) in his review of protozoal chemotherapy pointed out: " Many different lines of work appear to be converging here towards a general explanation, but it will be necessary to achieve further elucidation of the metabolism of p-aminobenzoic acid (PAB) and of folic acid by the malarial parasite before all the different facts in the jigsaw puzzle can be fitted into place." In this paper an attempt is made to fill some of the gaps in our knowledge of crossresistance, potentiation, and antagonism between antimalarial drugs, by reviewing and analysing the known facts, in the light of new data. METHODSThe parent strain of Plasmodium gallinaceum was that maintained in these laboratories for many years by blood and occasional mosquito passage in young chicks. This and the other drug-treated strains have, during the course of the experiments, been passaged solely by blood inoculation. Five-or twelve-day-old chicks (Rhode Island Red-Light Sussex cross) were inoculated intravenously with approximately 50 million parasitized red blood cells. The antimalarial drugs were given orally either in solution or, if insoluble in water, in gum tragacanth suspension. Starting a few hours after inoculation, a total of seven doses was given over 3-} days. Infection was assessed from stained blood films on the fourth day after inoculation, when in untreated controls about 70-90% of the red blood cells were infected. The infected red cells in the test animals were counted and the results were expressed as percentages of the controls. That dose which reduces parasitaemia to 50% of the mean parasitaemia of untreated controls (ED5O) was obtained from a 3-or 4-dose assay (Rollo, 1952). A group of five chicks was normally used at each dose level.Cross-resistance.-A strain of P. galinaceum (P.36), which was highly resistant to proguanil and to pyrimethamine, was obtained from Dr. D. G. Davey, of Imperial Chemical Industries. The sensitivity of this strain to sulphadiazine was tested in order to complete the picture of cross-resistance relationships reviewed by Thurston (1953). Two further strains were prepared by treating successive passages with subcurative doses of proguanil and pyrimethamine respectively. During each passage the chicks received a total of seven doses of the drug as described above. Both strains were passaged and treated in parallel and were tested periodically for cross-resistance during the early stages of the development of drug resistance.Potentiation.-The potentiating effect of pyrimethamine upon the activity of proguanil was investigated by giving the drugs both singly, and together in various proportions, to groups of infected chicks. ED50's were determined from the dose-response curves and were plotted on a ...

The purpose of the current study was to investigate the influence of ingesting a carbohydrate-electrolyte (CHO-E) beverage ad libitum or as a prescribed volume on 10-mile run performance and gastrointestinal (GI) discomfort. Nine male recreational runners completed the 10-mile run under the following 3 conditions: no drinking (ND; 0 ml, 0 g CHO), ad libitum drinking (AD; 315 ± 123 ml, 19 ± 7 g CHO), and prescribed drinking (PD; 1,055 ± 90 ml, 64 ± 5 g CHO). During the AD and PD trials, drinks were provided on completion of Miles 2, 4, 6, and 8. Running performance, speed (km/hr), and 10-mile run time were assessed using a global positioning satellite system. The runners' ratings of perceived exertion and GI comfort were recorded on completion of each lap of the 10-mile run. There was a significant difference (p < .10) in performance times for the 10-mile race for the ND, AD, and PD trials, which were 72:05 ± 3:36, 71:14 ± 3:35, and 72:12 ± 3.53 min:s, respectively (p = .094). Ratings of GI comfort were reduced during the PD trial in comparison with both AD and ND trials. In conclusion, runners unaccustomed to habitually drinking CHO-E beverages during training improved their 10-mile race performance with AD drinking a CHO-E beverage, in comparison with drinking a prescribed volume of the same beverage or no drinking.

Eight strains of Trypanosoma rhodesiense, made resistant respectively to atoxyl, butarsen, acriflavine, stilbamidine, Surfen C, suramin, and pontamine sky blue 5BX, have been examined for cross-resistance to representatives of nine structurally dissimilar groups of trypanocide. On the basis of their predominant ionic form at blood pH, these groups are considered in three main classes: (a) feebly ionized (neutral aromatic arsenicals), (b) ionized as cations (melaminyl arsenicals and antimonials, acridine derivatives, diguanidines and diamidines, 6-aminoquinoline and 6-aminocinnoline derivatives, phenanthridinium derivatives, triphenylmethane dyes), and (c) ionized as anions (carboxylated aromatic arsenicals and sulphonated naphthylamine derivatives). The results are discussed in relation to those of other workers and to possible modes of trypanocidal drug action. Cross-resistance behaviour is not wholly explicable on an ionic basis; the results suggest that stereospecific structural changes associated with initial drug uptake occur in resistant trypanosomes.