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S Kato T Morie K Hino T Kon S Naruto N Yoshida T Karasawa J Matsumoto 《Journal of medicinal chemistry》1990,33(5):1406-1413
With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity. 相似文献
4.
A Fujie T Iwamoto N Shigematsu M Ezaki M Hino S Hashimoto M Okuhara M Kohsaka H Imanaka 《The Journal of antibiotics》1990,43(5):449-455
FR112123 is a new oligopeptide antibiotic produced by Streptomyces viridochromogenes No. 7587. The structure of FR112123 is elucidated as N-(N6-(N2-glycyl-L-glutaminyl)-D-lysyl)-D-alanine (1) by spectroscopic and chemical evidence. It resembles a partial structure of peptidoglycan in bacteria. The compound has a superior activity against an Escherichia coli mutant sensitive to inhibitors of cell wall synthesis, although it has a weak activity against the parent strain. These suggest that FR112123 might act on the biosynthesis of bacterial cell wall. 相似文献
5.
Hirotsugu Yamada MD PhD Zoran B. Popovic MD PhD David O. Martin MD MPH Kenneth C. Civello MD MPH Don W. Wallick PhD 《Heart rhythm》2006,3(6):722-727
BACKGROUND: Coupled pacing (CP), which consists of delivering a premature electrical stimulation to the heart after the effective refractory period of ventricular activation, is a novel method for controlling ventricular rate during atrial fibrillation (AF). It also has been established that CP improves pump function by enhancing external cardiac work and myocardial efficiency. OBJECTIVE: The purpose of the present study was to determine if two time delays for CP (short and long) would result in similar improvements in ventricular function. METHODS: In a canine model, we applied CP at two time delays (CP-S and CP-L) during two stages: sinus rhythm (SR) and acute AF. The cardiac responses to CP during SR served as the nontachycardic and nondepressed control. During both rhythms, we shortened the coupling interval until we obtained maximal contractility, designated CP-S. Next, we increased the delay until we started to see a measurable secondary contraction (left ventricular pressure development of approximately 20 mmHg). These longer delays were designated CP-L. RESULTS: Our results showed that the ventricular rate of intrinsic activation (VRIA) remained decreased despite prolongation of the time delay of CP during both AF and SR. Also, both delays of CP increased left ventricular systolic pressure (LVSP) and dLVP/dt, which are indices of myocardial contractility. In contrast, CP increased external cardiac work only during AF. Prolonging this time delay did not markedly decrease the improvement in external cardiac work. Myocardial O(2) consumption (MVO(2)) did not significantly change as the result of CP during either SR or AF. Finally, myocardial efficiency improved during AF as the result of CP at both time delays. CONCLUSIONS: In conclusion, shorter time delays for CP increased contractile strength during both SR and AF. However, extending the time delay of CP had minimal effects on diminishing the improved ventricular pump function and energetics that resulted from CP during AF. Thus, the maximal enhancement of myocardial contractility via CP-S was not needed to maintain the improved ventricular function during acute AF when CP is applied. 相似文献
6.
Chemically induced forestomach papillomas in transgenic mice carry mutant human c-Ha-ras transgenes.
Forestomach papillomas and skin papillomas were induced very efficiently by a single dose administration of the chemical carcinogen methylnitrosourea (MNU) in transgenic mice (rasH2 line) carrying human hybrid c-Ha-ras genes, which encode the prototype p21 gene product. The incidence of forestomach papillomas was dose dependent; when 50 mg/kg of MNU were administered i.p., all of the transgenic mice (56 of 56) developed forestomach papillomas within 12 weeks after administration, whereas 5 and 0.5 mg/kg of MNU induced papillomas in 2 of 19 and 1 of 19 mice, respectively. Nine of 56 transgenic mice (16%) also developed skin papillomas at sites wounded by bites or scratches. Only 1 of 77 nontransgenic littermates developed forestomach papillomas after administration of 50 mg/kg of MNU, and no skin papillomas appeared within 12 weeks after MNU administration. The transgenes (integrated copy number, 5-6) in the tumors developed in 55 of 56 affected transgenic mice (98%) contained at least 1 copy of the transgene that was activated by somatic point mutation at the 12th codon, from GGC (Gly) to GAC (Asp). Because somatic point mutations at the 12th or 61st codon of transgenes have never been detected in normal tissues of transgenic mice thus far examined, these mutational activations of transgenes are tumor-specific events. RNA expression of these activated transgenes was also detected. From these results, it is suggested that somatic mutational activation of the human c-Ha-ras transgene plays a causative role in the occurrence of forestomach and skin papillomas induced by MNU administration in these transgenic mice. This transgenic mouse provides a unique screening system for chemicals that induce or suppress papillomagenesis. 相似文献
7.
Clonal growth of hepatitis B virus-integrated hepatocytes in cirrhotic liver nodules. 总被引:6,自引:0,他引:6
A total of 83 cirrhotic nodules (pseudolobules) individually collected from 11 cirrhotic livers of hepatitis B virus carrier patient were analyzed for the frequency and mode of hepatitis B virus integration as well as histological features. Southern blot analysis disclosed discrete bands at higher molecular weight region in 26 of 83 nodules (31.3%), indicating a clonal growth of hepatocytes with viral integration. Considerable variation (0-75%) existed in the positive rates for discrete bands in nodules among livers. Molecular cloning revealed the sequence flanking an integrated viral sequence to be host DNA and thus confirmed true integration. Histological analysis, however, did not reveal any neoplastic-appearing foci of growth within nodules, despite the fact that the detection sensitivity would predict clones of more than 10(5) cells to give rise to clonal integration patterns on Southern blot analysis. The question of whether clonal expansion of hepatocytes reflects any viral integration-associated growth advantage and/or a preneoplastic condition awaits future studies. 相似文献
8.
H Iioka I Moriyama M Kyuma M Akasaki Y Katoh K Itoh M Saitoh K Hino Y Okamura Y Itani 《Nippon Sanka Fujinka Gakkai zasshi》1987,39(5):725-730
The placental transport mechanism of glutathione (GSH) was investigated using microvillous membrane vesicles prepared from human term placenta. Using (3H-glycine)-labeled-GSH, it was clarified that GSH in the extravesicular compartment of placental microvillous membranes was rapidly degraded by gamma-GTP (gamma-glutamyltranspeptidase) and resulting amino acid, and 3H-labeled-glycine was actively transported via a sodium cotransport system. AT-125 treated microvillous membrane vesicles almost entirely lost its gamma-GTP activity, and showed intact GSH transport. Using AT-125 treated microvillous membrane vesicles, it was revealed that GSH was transported across the microvillous membrane as an anion via a membrane potential-dependent mechanism. These results indicated that gamma-GTP which existed in microvillous membrane played a role in GSH metabolism and that intracellular GSH was translocated out of the syncythiotrophoblast cell into the maternal blood space via a specific carrier in microvillous membrane because the GSH concentration was higher in intracellular than extracellular and extracellular membrane potential was positively charged. 相似文献
9.
Hirotsugu Ueshima 《Hypertension research》2006,29(11):835-836
10.
Kawashima Yoshiaki Cui Fude Takeuchi Hirofumi Niwa Toshiyuki Hino Tomoaki Kiuchi Katsumi 《Pharmaceutical research》1995,12(7):1040-1044
Purpose. Poorly compressible crystals of acebutolol hydrochloride were agglomerated by the spherical crystallization technique with a two-solvent system to improve the compressibility for direct tabletting. The mechanism of improvements in static compression behaviors and tablettabilities of the spherically agglomerated crystals were investigated.
Methods. The improvement of static compression behaviors of the agglomerated crystals was determined by measuring the stress relaxations and elastic recoveries of compressed powder of original and agglomerated crystals. The improved tablettability of agglomerated crystals was evaluated by the pressure transmission ratio upon compression, the ejection pressure for releasing the tablet from the die and the tablet strength, i.e., tensile strength required for breaking.
Results. The higher relaxation pressure and the lower elastic recovery of the agglomerated crystals than of the original crystals were found. The pressure transmission ratio data showed that the friction pressures of the two crystals were similar during the compression period. The ejection pressure of the agglomerated crystals was lower than that of the original crystals. The tensile strength of the tablet of agglomerated crystals was greater than that of the original crystals.
Conclusions. The compressibility and tablettability of the spherically agglomerated crystals prepared by the spherical crystallization technique were much improved due to their increased plastic property and reduced adhesive property compared to the original crystals. 相似文献