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PubMed1987

Effect of glipizide on hepatic fructose 2,6-bisphosphate concentration and glucose metabolism.

Glipizide raised, in a dose-dependent manner, the concentration of fructose 2,6-bisphosphate in hepatocytes isolated from 24-hour fasted rats and incubated in the presence of 10 mmol/L glucose. Simultaneously, the rate of L-lactate production, as well as the rate of 3H2O formation from (3-3H)glucose, increased markedly. The concentration of glipizide calculated as corresponding to the half-maximal effect in these metabolic parameters was 12 to 15 mumol/L. In hepatocytes isolated from fed rats, either normal or made diabetic by treatment with alloxan, glipizide inhibited the conversion of both (U-14C)pyruvate and (U-14C)lactate to (14C)glucose; an inverse correlation was established between hepatocyte fructose 2,6-bisphosphate levels and the rate of gluconeogenesis. The increase of fructose 2,6-bisphosphate concentration elicited by glipizide, which occurs without a significant modification of either 6-phospho-fructo 2-kinase activity or hepatocyte cyclic AMP levels, seems to be related to a significant accumulation of hexose 6-phosphates (glucose 6-phosphate and fructose 6-phosphate) in the hepatic cells.

Animals↗
PubMed1990

Grinspan's syndrome: a drug-induced phenomenon?

Three cases of apparently drug-induced Grinspan's syndrome involving the triad of oral lichen planus, diabetes mellitus, and hypertension are reported. Because drug therapy for diabetes mellitus and hypertension is capable of producing lichenoid reactions of the oral mucosa, the question arises as to whether Grinspan's syndrome is an iatrogenically induced syndrome.

Aged↗
PubMed2005

Low level determination of p-toluenesulfonate and benzenesulfonate esters in drug substance by high performance liquid chromatography/mass spectrometry.

GC/FID and HPLC/MS single ion monitoring methods have been evaluated for the determination of trace levels of methyl, ethyl and isopropyl esters of p-toluenesulfonic acid and methyl, ethyl, isopropyl and n-butyl esters of benzenesulfonic acid in drug substances. These sulfonate esters have been highlighted as potential genotoxins. HPLC/MS was found to be more promising and limits of quantification were between 2.5 and 5 ng/mL, which enabled detection limits in drug substance at 0.01-0.1 ppm for a 50 mg/mL solution. For one drug substance excellent recoveries of 94-95% were obtained at the 1.0 ppm level, however, with a second drug substance, a besylate salt, recoveries ranged from 86% to 100% and were dependant on the sample preparation. Limited stability of the sulfonate esters in various potential sample solutions indicated that samples may need to be prepared immediately before injection.

Benzenesulfonates↗
PubMed2006

Solubility measurement of polymorphic compounds via the pH-metric titration technique.

In drug development, the thermodynamically most stable form of a compound is preferred because metastable forms are prone to transform to the stable form during processing, formulation, or storage [Guillory, J.K., 1999. Generation of polymorphs, hydrates, solvates, and amorphous solids. In: Brittain, H.G. (Ed.), Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, pp. 183-226]. It is therefore important to discover and characterize the stable form as early as possible. One of the most important properties to determine is thermodynamic solubility. However, due to compound and time constraints this solubility value is usually not determined until late in discovery. This report explores the ability of the pH-metric titration method to measure intrinsic solubility of the stable form of compounds that exist in one or more polymorphic forms. One metastable form and the stable form of eight compounds were examined. Intrinsic solubility was measured via pH-metric titration. The technique was performed on a larger scale in order to monitor polymorphic form changes by powder X-ray diffraction. Shake-flask solubility and corresponding X-ray diffraction data of each form was also determined. The results of this study indicate that, in general, when starting with a metastable polymorph, the pH-metric titration method is able to achieve the solubility of the stable form by the third titration, while the traditional shake-flask solubility method is unable to consistently determine the stable form solubility.

Acetaminophen↗