The interaction of digitonin with membrane cholesterol was studied by using various digitonin analogs, and radioactive desglucodigitonin. The following results were obtained concerning the effect of digitonin on erythrocytes, granulocytes and liposomes. Digitonin and its analogs showed activity to induce hemolysis, granulocyte activation and liposomal membrane damage. The activity was affected by change of the carbohydrate residue of the molecule; the order of hemolytic activity was digitonin greater than or equal to desglucodigitonin much greater than glucosyl-galactosyl-digitogenin greater than galactosyl-digitogenin, digitogenin. The relative activities of these compounds to induce granulocyte activation and liposomal membrane damage were similar to those observed in the hemolysis. [3H]Desglucodigitonin could bind to cholesterol in liposomes. The binding was stoichiometric and the ratio of desglucodigitonin bound to liposomes/cholesterol in liposomes was close to 1, irrespective of the cholesterol content in liposome. Damage to liposomes was, however, induced by desglucodigitonin only when they contained more than 0.2 molar ratio of cholesterol to phospholipid. Addition of digitonin as well as desglucodigitonin to preformed liposomes deprived of cholesterol affected the anisotropic molecular motion of spin-labeled phosphatidylcholine incorporated into the liposomes, suggesting that the molecules could be inserted into the lipid bilayer free of cholesterol. Molecules of desglucodigitonin in the lipid phase may, however, be equilibrated with those in the aqueous phase, unless they form a complex with cholesterol, since no appreciable amount of [3H]desglucodigitonin could be detected in the liposome fraction after separation by column chromatography. Digitonin decreased the order parameter of spin-labeled phosphatidylcholine when liposomes contained equimolar cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)
A series of analogues of N-(cyclohexylcarbonyl)-D-phenylalanine (5) have been synthesized and evaluated for their hypoglycemic activity. Relationships were studied between the activity and the three-dimensional structure of the acyl moiety, which was characterized by high-resolution 1H NMR spectroscopy and MNDO calculations. The role of the carboxyl group of the phenylalanine moiety was also studied by comparing the activities of the enantiomers, the decarboxyl derivative, the esters, and the amides of the phenylalanine derivatives. Thus, the structural requirements for possessing hypoglycemic activity was elucidated and a highly active compound, N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine (13) was obtained, which showed a 20% blood glucose decrease at an oral dose of 1.6 mg/kg in fasted normal mice.
With the intention that annulation of carbo‐ or heteroaromatic rings at the 1,2‐positions can activate 3‐cyanoindolizines as 1,3‐dipolar species, 6‐cyanobenz[a]indolizines, pyridazino[4,5‐a]indolizines and 5‐cyano‐1,3‐diphenylthiopheno[3,4‐a]indolizine were prepared. 6‐Cyanobenz[a]indolizines smoothly ‐underwent 1,3‐dipolar cycloaddition on to dibenzoylacetylene and diacetylacetylene to afford the corresponding indolizino[3,4,5‐ab]isoindoles, whereas 5‐cyano‐1,4‐diphenylpyridazino[4,5‐a]indolizine reacted with dimethyl acetylenedicarboxylate to give the 1:2 adduct. Only a 3% yield of 5‐cyano‐1,3‐diphenylthiopheno[3,4‐a]indolizine formed upon phosphorus pentasulfide treatment of 1,2‐dibenzoyl‐3‐cyanoindolizine.
Journal of Liquid ChromatographyPublication details, including instructions for authors and subscription information:ABSTRACT An HPLC procedure for the detection and quantitation of a new antidiabetic agent, N-(frans4-isopropylcyclohexylcarbonyl)-Dphenylalanine (A41 66), in dog plasma was developed. The drug and internal standard were extracted from plasma using a reversed phase cl8 extraction column (Sep-pak). Separation was accomplished on a ERC-ODs-1161 reversed-phase column with a mobile phase of acetonitrile / 0.1M phosphate buffer, pH 6.6 (30 / 70). Quantitation was achieved by monitoring the ultraviolet absorbance at 21 0 nm. A linear relationship between concentration and peak height ratio (A41 66 / internal standard) was obtained. The method has been successfully used for analysis of plasma samples from beagle dogs following oral administration of A4166.
Currently, the only available evidence for the efficacy of once-weekly 17.5 mg risedronate in preventing vertebral fractures was obtained in a 48-week study in Japan. We performed a 156-week prospective, longitudinal, observational study to determine the efficacy of the 17.5 mg risedronate in preventing vertebral fractures. We included Japanese patients with established osteoporosis who were older than 50 years and had radiographically confirmed vertebral fractures. The primary endpoint was the incidence of vertebral fractures every 24 weeks, with the final interval spanning 36 weeks. We also calculated the change in bone mineral density of the lumbar spine (L BMD) and urinary N-telopeptide of type I collagen (u-NTX), and assessed the incidence of adverse drug reactions and the drug adherence rate. Data from 241 patients were available for analysis of vertebral fracture prevention. The incidence rate of vertebral fractures decreased in a time-dependent manner (P = 0.0006; Poisson regression analysis). The risk ratio (fracture incidence per 100 person-years in the final 36 weeks versus that in the first 24 weeks) was 0.21 (95 % confidence interval 0.08-0.55). Compared to baseline values, L BMD increased by 6.41 % at 156 weeks, while u-NTX decreased by 36 % at 24 weeks and was maintained thereafter (P < 0.0001). The incidence rate of adverse drug reactions was 9.18 %. Drug adherence rates assessed every 4 weeks were over 90 %. Our results indicate that 156 weeks of treatment with once-weekly 17.5 mg risedronate effectively reduced the risk of vertebral fracture in Japanese patients with established osteoporosis older than 50 years.
A prospective observational study to test the effects of risedronate 17.5 mg/week treatment on quality of life (QOL) of 1,363 Japanese female patients with osteoporosis showed QOL improvement after 12 weeks of administration. Comorbid factors such as ischemic heart disease, hip osteoarthritis, and higher values of FRAX blunted the effects of QOL of the treatment. Few studies have investigated the effect of osteoporosis treatment on QOL in relationship to comorbid factors other than osteoporosis and fracture. Efficacy was determined by changes over time in EQ-5D at baseline, at 12 and 24 weeks, and at the final assessment. Factors affecting changes in EQ-5D were evaluated with a multivariate analysis. Safety was determined by assessing the incident rate of adverse events. The improvement of EQ-5D compared to baseline was observed as significant after 12 weeks of treatment (p < 0.001). The greatest improvement was observed in the dimension of "pain/discomfort" by the multivariate analysis (p < 0.001). Factors affecting QOL improvement were FRAX value without BMD, age, glucocorticoid use, ischemic heart disease, hip osteoarthritis, and pain. The incidence rate of drug-related adverse events was 4.72 % (95 % confidence interval 3.63-6.02 %). Risedronate at 17.5 mg/week improved the QOL in patients with osteoporosis among Japanese women, and comorbidity factors decreased the effects.
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