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Orale Antidiabetica vom Sulfonylsemicarbazid-Typ wie Tolazamid (1) und Glisoxepid (2) wurden unter milden nitrosierenden Bedingungen, auch annahernd physiologischen in vitro Bedingungen, nach einem neuartigen Reaktionsverlauf in Sulfonyltriazene 3a, b umgewandelt. Modellverbindungen mit N4-Acyl-semicarbazidstruktur 4 zeigen abweichendes Reaktionsverhalten, wobei Saureamide 5 neben Nitrosaminen 6 gebildet werden. Nitrosations with Hydrazine Derivatives, VI: Novel Reaction of Oral Antidiabetics of the Sulfonylsemicarbazide Type under Nitrosating Conditions Oral antidiabetics of the sulfonylsemicarbazide type like Tolazamide (1) and Glisoxepide (2) were transformed under mild nitrosating conditions, even nearly physiological in vitro conditions, to sulfonyl triazenes 3a, b by a novel reaction pathway. Model compounds with N4-Acyl-semicarbazide structure 4 showed different reaction behaviour yielding carbonamides 5 and nitrosamines 6.

Patterns of blood glucose, serum insulin and non-esterified fatty acids (NEFA) were measured over a period of eight-and-a-half hours in eleven maturity-onset diabetics receiving 8 mg glisoxepide in the morning and 4 mg in the evening (while on a standard diet). The effects of administering the tablets in the morning with breakfast were compared to those on administering the drug half-an-hour (five patients) or one hour (six patients) before breakfast. Although there was a slightly earlier increase in serum insulin when tablets were taken half-an-hour or an hour before breakfast, different times of administration did not significantly affect the blood glucose or NEFA pattern. In particular, the extreme rise in blood glucose levels after the first breakfast could not be avoided.

Pharmacodynamic studies were performed using tolbutamide, glibenclamide, glibornuride (Ro 6-4563) and glisoxepide (BS 4231). The four compounds were administered intravenously, and exact dose-response relations were established, calculating the ED 30 of the decrease in blood glucose in healthy volunteers. Accordingly, the dose corresponding to the ED 30 was given twice with a three hour interval to maturity-onset diabetics. Different dynamics of insulin response were observed after tolbutamide, glibornuride and glisoxepide on the one hand, and glibenclamide on the other. In contrast to other reports in the literature, an obvious uniformly weaker degree of insulin secretion was seen after each of the different sulphonylurea compounds when given repeatedly.

α-Glucosidase inhibition is a new principle in the treatment of diabetes mellitus. To compare this new principle with the well-established sulfonylurea therapy of type II diabetes, we treated 20 type II diabetics with the α-glucosidase inhibitor acarbose or the sulfonylurea glisoxepide in a double-dummy, double-blind, crossover study with 4-week drug-free pretreatment, 2 treatment periods of 8 weeks, with 4 weeks of washout. Dosage per day was acarbose 3 × 50 mg in week 1, 3 × 100 mg in week 2, 3 × 200 mg in weeks 3–8, glisoxepide 2 × 4 mg. Nine male and 11 female patients treated solely by means of diet (6665 ± 1217 kJ/day) were included (age, 62 ± 9 years; Broca index, 1.05 ± 0.07; median duration of diabetes, 6 years).

The efficacy of a 4-week treatment with acarbose compared to that with glisoxepide was studied in a controlled group comparison in 40 diabetics treated with diet alone. The median age of the patients was 70 (minimum 40, maximum 85), and the Broca index was 0.97 (0.69–1.74). The median history of diabetes was 54 months (minimum 0, maximum 24 months). The median daily acarbose dose throughout the treatment period was 300 mg (minimum 150 mg, maximum 600 mg). The median daily glisoxepide dose was 1 tablet (1st week) and 2 tablets (2nd–4th weeks). The two groups were not comparable. Patients in the acarbose group were significantly younger (p < 0.04) and had a longer history of diabetes (p < 0.05).

The authors conclude that administered i.v. in the normal conscious dog, glibenclamide and glisoxepide are considerably more active on glycemia than tolbutamide. Administered p.o., glibenclamide acts less rapidly on the glycemia than tolbutamide and glisoxepide. Thedynamic study of the insulin secretion shows that the secretion of insulin begins more slowly and lasts longer with glibenclamide than with the two other products. On the isolated and perfused rat pancreas, glisoxepide and tolbutamide more rapidly stimulate the secretion of insulin than glibenclamide; with the latter substance the duration of the secretion of insulin is longer and the total quantity of insulin secreted is greater. As far as thebeta-cytotrophic action is concerned, all three sulfonamides stimulate the neogenesis of the islets of Langerhans in Swiss mice.