Carbutamide--the first oral antidiabetic. A retrospect.

This work describes the history of the first oral antidiabetic in East and West Germany. M. Janbon and A. Loubatières reported experimental and clinical findings about a blood sugar-decreasing effect of a sulphonamide derivate, sulphoisopropyl thiodiazol (1942). These findings, however, did not prove to be useful in the treatment of diabetes. In 1952 the author found a series of hypoglycemic shocks with the sulfonamid-urea derivate carbutamdide during clinical tests of infectious diseases. These were reported to the pharmaceutical company Von Heyden in Dresden. The head chemist E. Haack went with my files from East to West Germany, to Boehringer Mannheim. Without mentioning the synthesis in Dresden, he synthesized carbutamide in Mannheim. The hypoglycemic effect was rediscovered by his friend H. Franke together with J. Fuchs. It took twenty years until the results of the author's research were officially acknowledged.

Effects of sulfonylurea compounds on Pneumocystis carinii.

Two sulfonylurea compounds, carbutamide and tolbutamide, were studied for efficacy against Pneumocystis carinii pneumonitis in the corticosteroid-treated rat model and compared with trimethoprim-sulfamethoxazole (TMP-SMZ). The chemical structures of these sulfonylureas are identical except that an amino group in carbutamide is replaced with a methyl group in tolbutamide. Carbutamide was totally effective in the prevention and treatment of P. carinii pneumonitis in dosages of 100 and 200 mg/kg per day. The carbutamide dosage of 50 mg/kg per day prevented the infection in 90% of animals, whereas tolbutamide in the same dosage permitted infection in 100% of animals. This study shows that carbutamide is at least as effective as TMP-SMZ in the treatment and prevention of murine P. carinii pneumonitis. The presence of an amino group in the para position on the benezene ring is a determinant for this activity.

[Disputable problems of the effect of sulfanilylurea derivatives in patients with diabetes mellitus and perspectives on their use]. / Spornye voprosy ob éffekte proizvodnykh sul'fanilmocheviny u bol'nykh sakharnym diabetom i perspektivy ikh primeneniia.

Critical analysis of studies, realized by the University Group on diabetes mellitus program (UGDP), involving 12 colleges of the USA, was performed. A higher death rate due to cardiovascular pathology was manifested by patients with diabetes mellitus given tolbutamide. A possible restriction and/or prohibition of drugs of this series was discussed. The literature data and the authors' findings are presented, disproving the results, obtained by this Group. A wide use of sulfanilurea derivatives is recommended in the treatment of early stages of the disease, provided a stable 24 hours' normoglycemia is attained in patients with evident diabetes. The results obtained and the literature data allow the conclusion, that sulfanilurea derivatives exert an antiatherogenic effect under conditions of diabetes mellitus compensation.

[The course of asymptomatic diabetes under varying preventive therapy--concluding report of a 5-year prospective study]. / Verlauf des asymptomatischen Diabetes bei untershiedlicher Präventivbehandlung - Abshlussbericht einer 5jährigen prospektiven Studie.

During a prospective study the course of asymptomatic diabetes in different preventive treatment (diet, additionally tolbutamide, carbutamide or buformin) was observed concerning the frequency of manifestation and the behaviour of the oral glucose tolerance. Among the 100 protodiabetics after 5 years 38 clinical manifestations could be established, which finally nearly equally were distributed to all 4 groups of treatment. Only under the influence of buformin an effect preventing manifestation limited to 2 years appeared. Patients with persisting full or partial remissions continuously and more decreased in weight than cases of manifestation. Furthermore, the course was determined by the initially existing degree of hyperglycaemia as well as by the improvement of the glucose tolerance achieved in the first year. On account of the results of the examinations and the existing literature a preventive use of oral antidiabetics cannot be recommended.

[Effect of methylpyrazole-carboxylic acid on carbohydrate and lipid metabolisms in patients with diabetes mellitus]. / Die Wirkung der Methylpyrazolcarbonsäure auf den Kohlenhydrat- und Fettstoffwechsel von Patienten mit Diabetes mellitus

The effect of 3-methylpyrazole-5-carboxylic acid (MPC) on carbohydrate and lipid metabolisms was studied in 18 patients with diabetes mellitus. In addition to diet 17 patients had basic treatment with sulfonylureas with or without biguanides, one patient was treated with insulin. In all patients carbohydrate metabolism was not well controlled, 14 patients had elevated triglycerides. Following a control period of 2 weeks the patients received increasing doses of MPC in addition to basic treatment (25825825 mg; 50,25,25 mg; 50, 50, 25 mg). Blood samples were taken in the fasting state before the first dose of MPC. Free fatty acids almost doubled under the influence of MPC. This was due to a rebound effect at night following suppression of lipolysis during the day. Blood glucose levels showed a tendency to fall, urinary glucose excretion, separately examined for day and night ,did not change consistently. Triglycerides fell markedly by 25%, but this reduction was not statistically significant. Cholesterol decreased by 5%. 40% of the patients showed an increase in urinary ketone bodies. Body weight did not change. Side effects due to MPC included flushing, gastrointestinal distress and cardiovascular complaints and were observed in 75% of the patients. Due to the high frequency of side effects it does not seem to be worthwhile to further investigate the therapeutic effect of MPC in a larger number of patients with different dosage regimens.