Choice of sulphonamides for mixture therapy.

Extensive experimental and clinical studies of the last five years have established the advantages of sulphonamide mixture therapy. 1-17 In brief the rationale for the use of mixtures is as follows: The renal toxicity of most of the newer sulphonamides, if used singly, is due primarily to over-saturation of the tubular urine with a sparingly soluble sulphonamide and/or its metabolic product, resulting in the formation and deposition of drug crystals in the urinary pathways (crystalluria). This event may be followed by haematuria, oliguria, and complete renal shutdown. If instead of a single sulphonamide a combination of partial dosages of several therapeutically equivalent sulphonamides is employed, the danger of crystal formation in the kidney from the drugs comprising the mixture is significantly reduced. In fact, it will be only as great as if each compound had been administered alone and in the partial dosage contained in the mixture, since sulphonamides of different molecular structure, even if closely related, can be dissolved simultaneously to the full extent of their individual solubilities. At the same time full therapeutic potency is retained, since the antibacterial effect of such combinations is completely additive and may in many instances even show potentiation of action in vitro as well as at the bedside.1 2 15 From the standpoint of renal protection, combinations of substantially equal partial dosages of at least three sulphonamides were considered adequate in routine therapy in the absence of alkalization.'8 Some objection has been voiced against the use of mixed sulphonamides on theoretical grounds. It was intimated that the concomitant use of several drugs may lead to the simultaneous development of allergy against more than one component of the mixture.19 Thus the incidence of allergic reactions might be increased and the possibility of "switching" a sensitized patient to another sulphonamide drug might be eliminated. This thought was based on the concept that the incidence of sensitization to sulphonamides is largely independent of the dosage used. However, this point of view is not borne out by practical experience. Critical evaluation of the vast literature on sulphonamide therapy12 demonstrated that, in the dosage range employed in human prophylaxis and therapy, the incidence of sensitization increases in direct proportion with the dosage. Table I shows that, for example, at an oral dosage of not more than 2 to 4 g. of sulphanilamide, sulphathiazole,