Determination of "extractables" on polymer materials by means of HPLC-MS.

In biopharmaceutical processes, in the area of food and medical technology a variety of devices is used. These devices consist of various polymers. The detection and identification of potential extractables from these polymers during application are requested by the regulatory bodies. For risk and toxicity assessment, both identification and quantification of extractables are necessary. This article describes the development of a LS-MS methodology transfered from an established HPLC-UV-VIS method for full extractables analysis of sterile-grade filtration cartridges.

Glucose-induced insulin secretion is potentiated by a new imidazoline compound.

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration. This can lead to hypoglycaemia in type 2 diabetic patients. Over the last years a number of imidazoline derivatives have been identified that stimulate insulin secretion in a more glucose-dependent way. In agreement with this, our aim was to generate imidazoline derivatives with a potential for the treatment of type 2 diabetic patients. We developed the compound 2-[4-(4-chlorophenyl)-3-(2-methoxyethoxy)-2-naphthalenyl]-4,5-dihydro-1-H-imidazole monohydrochloride (LY389382) with an imidazoline moiety and investigated its effects on glucose-dependent insulin secretion in a beta-cell line, isolated rat islets and in vivo. We could demonstrate that LY389382 induces insulin secretion in MIN6 cells and rat islets in a glucose-dependent manner (EC50=1.1 microM and 0.3 microM, respectively). Furthermore during hyperglycaemia LY389382 increased insulin secretion in a dose-dependent manner in healthy rats, whereas the compound had no effect at euglycemia in a tenfold higher dosage. After 7 days of treatment of Zucker Diabetic Fatty [ZDF/ (Gmi/fa)] rats with LY389382 with a dose of 15 mg/kg twice daily the blood glucose concentration was reduced from 22.7 +/- 1.7 mM to 16.6 +/- 2.3 mM. During the same time period the glucose concentration increased from 21.7+/-1.7 mM to 28.9 +/- 1.3 mM in the vehicle-treated group (P<0.05). The drop of the insulin level was also inhibited by LY389382 in ZDF rats. In contrast to other well-characterised imidazolines that have been shown to induce a glucose-dependent insulin secretion only within a limited range of concentrations, LY389382 stimulates insulin secretion over a concentration range of at least two log units in a glucose-dependent manner. These data suggest that this imidazoline compound has a potential for the treatment of type 2 diabetes.

Fused bicyclic Gly-Asp beta-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere.

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.

Synthesis and applicability of photolabile 7,7-azo analogues of natural bile salt precursors.

In an approach to the identification of proteins involved in the side chain degradation of bile salt biosynthesis, the photolabile 7,7-azo derivatives of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,26-tetrol and 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oate were synthesized. All 7,7-azo derivatives were metabolized by intact rat liver and freshly isolated rat hepatocytes in the same manner as the nonphotolabile physiological intermediates, resulting in the formation of the 7,7-azo analogues of cholyltaurine and cholylglycine. Photolysis of all three photolabile derivatives, using a light source with a maximum emission at 350 nm, occurred with a half-life of 2.1 min; their efficacy for photoaffinity labeling was demonstrated by incorporation into rat serum albumin.

Absorption and distribution of ibuprofen from a cream formulation after dermal administration to guinea pigs.

Objective of this experimental study is the investigation of the absorption and distribution of ibuprofen in skin and muscle tissue in guinea pigs after dermal administration of Dolgit Creme. After administration of the test substance the following blood sampling intervals were applied: 10, 20, 40, 60, 90 and 120 min. Skin and muscle tissue of the application area were also sampled at the same time intervals. In blood and plasma only 90 and 120 min after administration of the test substance concentrations of radioactivity were found which were above the limit of detection. In the skin of the application area most of the radioactivity applied was found. High concentrations of radioactivity were found in the hair follicles. In muscle tissue below the application area, dependent on the depth, concentrations between 228 micrograms and 13 micrograms of parent compound/g (tissue) were found. This indicates that after dermal administration of ibuprofen cream therapeutically relevant levels were reached even in deeper tissue.

[Measurement of kidney concentrating ability in children with nonrenal glycosuria]. / Die Messung des Konzentrationsvermögens der Nieren bei Kindern mit nichtrenaler Glukosurie

In non-renal (diabetic) glucosuria we did not find any statistically real relations between the concentration of glucose in the urine and cryoscopically measured osmolality in children with healthy kidneys. The close negative correlation of the conductance of the urine to the concentration of glucose is not only to be explained by changes of the viscosity, but is an expression of an increased re-absorption of sodium as a result of a compensatory hyperaldosteronism. In renal insufficiency the electrolytic conductibility of the urine is lower than the borderline area of the normal, even when under influence of the glucose excretion the osmolality of the urine is still to be found normal. Thus also on the conditions of a considerable glucosuria we can further judge the concentrating ability of the kidney in diabetes mellitus with the help of the measurement of the conductance of the urine.