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A radioimmunoassay for the antidiabetic drug 3-(4-[beta-(5-methyl-isoxazol-3-carboxyamido)-ethyl]-benzenesulfonyl)-ureido-piperidine-4-carboxic acid (glisoxepide, I, Pro-Diaban) is described. Antisera were obtained by immunizing rabbits with a piperidine carboxylic acid analogue of glisoxepide coupled to bovine serum albumine. The carboxylic acid analogue coupled to [3H]-1-tyrosine methyl ester was used as the tracer. Antisera with high sensitivity were obtained. With some glisoxepide analogues the specificity of the antisera was investigated. For good binding the isoxazole and the benzene ring as well as the appropriate distance between both rings are essential. The assay can be carried out without extraction of the compound from the serum. Dextran coated charcoal is used for separation of free and bound glisoxepide.

The purpose of the study was to investigate whether the potency of effect on the beta cell differs with type of sulfonylurea (SU) and with degree of severity of diabetes. 12 maturity onset diabetics were classed according to fasting blood glucose (FBG) in three groups of 4 patients each. Each patient served as his own control. Glibenclamide, Gliquidone, Glusoxepide and placebo were administered in random order with degree dosage adjusted according to degree of severity of diabetes. All patients were given a standardized diet with 150 g carbohydrates per day. Fullday profiles of blood glucose, insulin, C-peptide and sulfonylurea level in serum were made on the third day under each preparation. Results showed that with proper nutrition and sufficient weight reduction, patients in group I (FBG 80--130 mg/dl) needed no oral medication and in fact showed a tendency towards hypoglycaemic episodes under oral therapy. In group II (FBG 130--200 mg/dl) the effect of nutrients on beta cell secretion appeared to be both enhanced and accelerated by SU administration. Satisfactory metabolic control was achieved with SU, but not with placebo. This group seems to represent the type of patient most likely to benefit from SU therapy. In spite of high dosage levels, satisfactory control was not achieved with SU in any patient in group III (FBG greater than 200 mg/dl). Depending on individual factors such as ketosis-proneness, vascular complications, age and psycho-social aspects, insulin administration should be considered for these patients. There were not differences between the individual SU preparations in the parameters studied. There was insufficient evidence for a pharmacokinetic differential diagnosis.

The oral antidiabetic agent 1-(hexahydro-1-H-azepin-1-yl)-3-(p-[2-(5-methyl-isoxazol-3-carboxamido)-ethyl]-phenylsulfonyl)-urea (glisoxepide, BS 4231, Pro-Diaban¿) was studied in a multi-centre open clinical trial comprising 4337 patients and was found to be an effective therapeutic agent for maturity-onset diabetics. About 66% of the patients had been pre-treated with oral antidiabetics. 54.7% of those 3572 patients treated with Pro-Diaban for at least 3 months achieved stabilization, which was classified according to strict criteria as "good", 73.4% achieved at least "satisfactory" stabilization. 12.5% of the cases dropped out after having received at least 12 mg/day because of inadequate efficacy of Pro-Diaban; 51.9% of these patients dropped out in the first 3 months (early failures 6.9% of the total case number). 61.9% received their daily dose in one portion, 29% in two and 10% in three portions. 98% received maximally 16 mg, 70% maximally 8 mg, and 42% 4 mg per day. Hypoglycaemic episodes led in 0.9% to a termination of the trial. In 1.22% of the cases the trial was terminated because of side effects, in 0.18% of cases they consisted of allergic or suspected allergic complaints and in 0.69% they consisted mainly of gastro-intestinal symptoms. Of the side-effects which did not lead to a termination of the trial, dizziness, headache and nausea were the relatively more frequent symptoms. An analysis of the laboratory data under consideration of pathological and normal initial and subsequent values showed that under the influence of Pro-Diaban pathological data reverted to normal more frequently than initially normal values changed to pathological ones. The analysis of laboratory and blood pressure data from 4 subgroups of patients, e.g. patients with diseases of the liver or the kidneys and hyperlipaemic or hypertensive patients, revealed that those data of special interest in each subgroup had mostly improved or remained unchanged under Pro-Diaban.

12 metabolically healthy subjects were i.v. administered equipotent doses (ED30) of tolbutamide (7.5 mg/kg), glisoxepide (0.02 mg/kg) and glibenclamide (0.006 mg/kg). Prior to and 2, 5, 8, 10, 20, 40, 60 and 120 min after the injection the following serum parameters were determined: blood glucose, immunologically measurable insulin (IMI) with the double-antibody method (Hales and Randle) and proinsulin (IMP) enzymatically (ISP-method). The maximum level of insulin follows the injection of tolbutamide with a value of 70.5 micronU/ml after 2 min, of glisoxepide after 5 min (67.0 micronU/ml) and of glibenclamide after 20 min (32.3 micronU/ml). The proinsulin fraction of the total insulin shows a level of 12.5 micronU/ml before the test. After the administration of the three compounds proinsulin increases, too, but reaches only 20-40% of the total immunoreactive insulin. The amount of secreted insulin and proinsulin during the 120-min test is rather the same for the three substances. The average increase of insulin is nearly identical for tolbutamide and glisoxepide, whereas it is less for glibenclamide. Both the mean blood sugar depression and the highest mean increase of proinsulin is reached after glisoxepide. The significance of the one-chain precursor of insulin as a part of the sulfonylurea stimulated total insulin for glucose depression is discussed.

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Copyright of Acta Diabetologica Latina is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The reactions of 2,2-dichlorovinyl ketones with hydroxylamine hydrochloride give the corresponding oximes. The subsequent heterocyclization of the latter under the action of t-BuOK in t-BuOH results in selective formation of 5-chloro-3-alkyl- or 5-chloro-3-aryl-substituted isoxazoles in good yields. [ABSTRACT FROM AUTHOR]

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Copyright of Rechtsmedizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Melting point is a basic physical property that specifies the transition temperature between solid and liquid phases. Melting point has numerous applications in biochemical and environmental sciences due to its relationship with solubility. Sufficient aqueous solubility is essential for a compound to be transferred to the site of action within an organism. In spite of the huge number of available melting point data, few useful guidelines exist for understanding the relationship between the compound melting point and its chemical structure. Therefore, methods for estimating the melting point of organic compounds would considerably help medicinal chemists in designing new drugs within a specified range of melting point and solubility. A highly effective tool depending on quantitative structure-property relationship (QSPR) can be utilized to predict melting point for drug-like compounds with no literature values. QSPR models were developed using genetic algorithms, multiple linear regression and neural networks analyses. Predictive non-linear QSPR models were developed for the relevant descriptors. The results obtained offers excellent regression models that possesses good prediction ability. [ABSTRACT FROM AUTHOR]

Objectives: Insulin-treated patients with diabetes are at a higher risk than the general population in causing traffic accidents due to hypoglycaemias. Preceding investigations focused on insulin-treated patients and hypoglycaemia-induced accidents as "end-points". We studied the incidence of symptomatic hypoglycaemia and hypoglycaemia-induced accidents during driving and put it in relation to the different treatment modes of insulin therapy (Conventional Insulin Treatment = CT, Intensified Conventional Insulin Treatment = ICT, Continuous Subcutaneous Insulin Infusion = CSII) as well as to patients treated with oral hypoglycaemia-inducing agents and the two main types of diabetes mellitus.Design: Subjects and Setting: We investigated 450 patients (122 treated with sulphonylureas, 151 with CT, 143 with ICT and 34 with CSII) by an anonymous questionnaire at different locations to avoid bias. A total of 176 persons had type 1 diabetes, 243 persons had type 2 diabetes, 31 subjects could not be classified.Results: Symptomatic hypoglycaemias during driving were rare events with an occurrence of 0.19-8.26 (minimal and maximal mean, depending on the mode of treatment), if given as hypoglycaemias per 100 000 km on one treatment regimen, or 0.02-0.63, if given as events per year driven. Their incidence increased significantly with the degree of "strictness" between the treatment groups, except between the patients treated with ICT and CSII. Hypoglycaemia-induced accidents are rare with 0.01-0.49, if given as events per 100 000 km and 0.007-0.01, if given as events per year driven. These differences were not significant. Significant confounders influencing the traffic safety of the patients were age, duration of diabetes and concomitant antihypertensive medication. Analysing the data in accordance with the type of diabetes revealed a significantly higher rate of hypoglycaemic events in patients with type 1 diabetes. The number of hypoglycaemia-induced accidents was considerably higher in this group, but failed slightly to reach statistical significance.Conclusions: Hypoglycaemias during driving are rare events, their occurrence is significantly influenced by the treatment regimen and type of diabetes. Hypoglycaemia-induced accidents are extremely rare, presumably as a positive effect of patient education in our group. [ABSTRACT FROM AUTHOR]