Oral Antidiabetic Sulfonamides

In October 1955 three reports in the Deutsche Medizinische Wochenschrift' described a new sulfonamide derivative possessing the ability when given by mouth to reduce normal blood sugar values to subnormal, and elevated blood and urine sugar values in diabetes to normal. Reduction of normoglycemia had been shown with other sulfonamide derivatives as early as 1942," but the application to therapy in diabetes mellitus wasnot made. The earlier compounds were p-amino-sulphonamido-alkyl-thiodiazoles: The current ones are aryl sulfonylureas. Those now under the most intensive investigation are Ni-sulfanilyl-Ns-n-butylcarbamide (BZ 55) and Ni-p-tolylsulfonyl-Na-n-butylurea (u 2043 or D 860). More clinical evidence is available concerning the former than the latter: The laboratory evidence on glycemia with both is similar. There is no doubt that these substances in single doses by mouth lower the blood sugar promptly and substantially in normal men, dogs and rabbits. Hypoglycemic effects are observed within an hour or two (earlier when given with alkali) and they persist for hours. Indeed, it was the hypoglycemic manifestations seen on administration to nondiabetics for antibacterial purposes which led to their trial in diabetes. There is no doubt, also, that abnormal glycosuria and hyperglycemia are reduced or eliminated by these compounds in many patients with mild and moderately severe diabetes mellitus. Franke and Fuchs showed eight examples of this, and they claim similar results in 80 per cent of fifty diabetics treated in Berlin for periods up to one year. After seven months of study in Hamburg, Bertram, Bendfeldt, and Otto reported successful control of diabetes in 25 of 28 older, mild diabetics not using insulin and replacement of insulin in 28 of 38 patients using it. In younger patients with severe forms of the disease the sulfonamide had no effect. In some cases it appears uncertain from their data whether r e striction of food or the sulfonamide was responsible for the reduction in sugar, but the evidence in favor of the drug is convincing in some of the trials. Unpublished results comparable to these are being obtained by laboratories and clinical investigators in this country. Toxic side effects appear to be negligible and LD 50 dosages in animals are high. Skin reactions have been encountered not infrequently, but hematologic, hepatic and renal effects have seldom been observed. Crystalluria seems less likely to occur than with other sulfonamides. especially when alkali is given concurrently. Therapeutically effective blood sulfonamide levels of 10 to 15 mg. per 100 ml. are obtained with about 1 gm. daily, following larger priming doses for the first day or two. Blood levels fall slowly for days after administration is stopped. There is general agreement among all investigators that the compound is totally ineffective in "pancreatectomy diabetes" and relatively so in alloxan diabetes. Fernef and others'' have seen damage to the alpha cells of the islets after its use. These considerations, together with the fact that in most diabetics with favorable responses glycosuria does not recur promptly on stopping the drug, have led to the favored hypothesis that it acts by suppressing glucagon secretion. Other mechanisms of action have not been eliminated, however, among them accelerated release of insulin from the pancreas, inhibition of insulinase, other hepatic effects, and suppression of pituitary or adrenal function. It must be borne in mind that hypoglycemia in normals and apparent improvement of diabetes in diabetics can be produced at will by administration of insulin, hepatectomy, hepatic damage, and reduction in pituitary or adrenal activity. The fact that diabetes can be ameliorated and normoglycemia reduced by artificial means does not prove that the fundamental defect in diabetes has been improved in a physiological manner. Indeed, the fact that acidosis and severe diabetes cannot be controlled with the new compounds suggests that it is not. No agent of this type is on the market yet in this country, but supplies have recently been distributed by two pharmaceutical firms for appraisal in diabetic patients in selected clinics and laboratories. Controlled experiments are being conducted, mechanisms of action explored and the effects of long continued administration watched closely. Results are being compared freely in joint conferences. Investigators feel as great an obligation to protect the diabetic public from possible exploitation and harm as to recognize and adopt a long sought therapeutically effective oral agent. The record of dependable and rational therapy in diabetes has been kept remarkably free from abuse and there is every