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1. The binding of [3H]-P1075, a potent opener of adenosine-5'-triphosphate-(ATP)-sensitive K+ channels, was studied in a crude heart membrane preparation of the rat, at 37 degrees C. 2. Binding required MgATP. In the presence of an ATP-regenerating system, MgATP supported [3H]-P1075 binding with an EC50 value of 100 microM and a Hill coefficient of 1.4. 3. In saturation experiments [3H]-P1075 binding was homogeneous with a KD value of 6+/-1 nM and a binding capacity (Bmax) of 33+/-3 fmol mg(-1) protein. 4. Upon addition of an excess of unlabelled P1075, the [3H]-P1075-receptor complex dissociated in a mono-exponential manner with a dissociation rate constant of 0.13+/-0.01 min(-1). If a bi-molecular association mechanism was assumed, the dependence of the association kinetics on label concentration gave an association rate constant of 0.030+/-0.003 nM(-1) min(-1). From the kinetic experiments the KD value was calculated as 4.7+/-0.6 nM. 5. Openers of the ATP-sensitive K+ channel belonging to different structural classes inhibited specific [3H]-P1075 binding in a monophasic manner to completion; an exception was minoxidil sulphate where maximum inhibition was 68%. The potencies of the openers in this assay agree with published values obtained in rat cardiocytes and are on average 3.5 times lower than those determined in rat aorta. 6. Sulphonylureas, such as glibenclamide and glibornuride and the sulphonylurea-related carboxylate, AZ-DF 265, inhibited [3H]-P1075 binding with biphasic inhibition curves. The high affinity component comprised about 60% of the curves with the IC50 value of glibenclamide being approximately 90 nM; affinities for the low affinity component were in the microM concentration range. The fluorescein derivative, phloxine B, showed a monophasic inhibition curve with an IC50 value of 6 microM, a maximum inhibition of 94% and a Hill coefficient of 1.5. 7. It is concluded that binding studies with [3H]-P1075 are feasible in rat heart membranes in the presence of MgATP and of an ATP-regenerating system. The pharmacological profile of the [3H]-P1075 binding sites in the cardiac preparation, which probably contains sulphonylurea receptors (SURs) from cardiac myocytes (SUR2A) and vascular smooth muscle cells (SUR2B), differs from that expected for SUR2A and SUR2B.

Bei den Photolysen der Pharmaka 1a-h fielen als Reaktionsprodukte die Verbindungen 2,3,5,6 an. In bestimmten Fallen wurden noch weitere Produkte isoliert. Die Photofragmentierung kann sowohl auf eine α′-, als auch auf eine α-Spaltung zuruckgefuhrt werden. In mechanistischen Untersuchungen konnte gezeigt werden, das die α′- und die α-Spaltung aus einem angeregten 1S-Zustand erfolgen durfte. Die Bedeutung dieser Studien im Zusammenhang mit dem Problem der Lichtdermatosen wird kurz behandelt. Photochemical Model Studies on Photosensitizing Drugs: Sulfonamides and Sulfonylureas Photolysis of the drugs 1a-h affords the products 2, 3, 5 and 6. In some photolyses additional photofragmentation products were obtained. α′- or α-cleavage of 1 explains the nature of the products. Mechanistic studies demonstrate that most probably an excited S1-state is involved. The relevance of this work to “photosensitization” is briefly discussed.

The pharmacokinetics of glibornuride (25 mg i.v.) and the accompanying insulin and glucose responses were characterized in eight human subjects in the presence and absence of steady-state tenoxicam (20 mg p.o./day for 2 weeks). Tenoxicam affected neither the pharmacokinetic parameters of glibornuride (systemic clearance, volume of distribution and biological half-life) nor the responses of plasma insulin and blood glucose to glibornuride. The single i.v. dose of glibornuride had no detectable effect on the kinetics of tenoxicam.

Treatment with any of the sulphonylurea group of oral hypoglycaemic agents may cause hypoglycaemia, usually in situations where there may be restriction of carbohydrate intake at times of anorexia and where a potentiating drug such as salicylates, warfarin or co-trimoxazole is given (Ref 1). There is particular risk of this occurring in the elderly and in those with impaired renal function, as many of the commonly used sulphonylureas (tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide and glibornuride) are primarily excreted by the kidney. Gliquidone is a recently introduced sulphonylurea to the UK, with a short plasma half-life of 1.4h and which is excreted in the bile and does not accumulate with renal impairment. We describe a case of gliquidone-induced hypoglycaemia occurring in a female diabetic with chronic renal failure.