Structural studies of a new dihydropyridine calcium channel antagonist, nilvadipine.
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Biomedical subjects
Publications and source records attributed to Y Morimoto.
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The effect of Y-8894 on the abnormal electrocorticogram (ECoG) of alcuronium-immobilized rats, induced by destruction of the internal capsule with heat, was compared with that produced by imipramine, amantadine and Ca-hopantenate. ECoG power in the delta + theta (1-7 Hz), alpha (7.5-12.5 Hz) and beta (13-30 Hz) bands was used as an index. Delta + theta power increased following destruction of the internal capsule with heat. The increased delta + theta power (abnormal ECoG) lasted for 60 min following the injection of saline at 60 degrees C for 3 min. Y-8894 (0.1-1 mg/kg, i.v.) apparently improved the abnormal ECoG dose-dependently by significantly reducing the increased delta + theta power. Similar results were obtained with amantadine (10 mg/kg, i.v.), but its potency was weaker than that of Y-8894. Imipramine (1 mg/kg, i.v.) and Ca-hopantenate (30 mg/kg, i.v.), however, both failed to modify the abnormal ECoG. All drugs, except Ca-hopantenate, decreased the magnitudes of the alpha and beta bands. The above results suggest that Y-8894 may be effective in ameliorating cerebral dysfunction induced experimentally by the lesion of the internal capsule.
The new additional operation for the prevention of the gastric stasis after the selective gastric vagotomy with antrectomy (SV + A) was performed. Our additional operative procedure was followed: After selective gastric vagotomy and antrectomy, gastroduodenostomy was anastomosed at acute angle with the longitudinalis of the stomach. Then, both lesser and greater omentum were incised outside of the gastric vessels. After these procedure, posterior wall sided to lesser curvature was fixed with the edge of the hepatogastric ligament and posterior wall sided to greater curvature was fixed with the retroperitoneum inferior to the pancreas by several sutures. The outcome of these treatments of the additional operation on SV + A enabled to shorten the duration of drainage of gastric juice, as well as smooth intake. By fluoroscopic examination one month after operation, gastric stasis was observed on SV + A due to the contrast medium stored in the ptotic corpus, whereas, in the case of SV + A with our additional operation, smooth gastric emptying was observed without any stasis of the contrast medium, because the corpus was placed upper from the anastomosis portion. In conclusion, our additional operation to SV + A was able to perform easy and safely, and was observed the effective prevention of gastric stasis.
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Acute effects of 200 mg of orally given 4-[2-(methylamino)ethyl]-o-phenylene diisobutyrate hydrochloride (ibopamine hydrochloride) which is a new diisobutyric ester of N-methyldopamine, on hemodynamics and metabolism were evaluated in 11 patients with severe heart failure (New York Heart Association class IV). Significant effects occurred within 30 min and persisted for 6 h after dosing. Peak effects were observed at 2 h. At peak effects, cardiac index increased from 2.53 to 3.07 l/min/m2 (+20%, p less than 0.01), stroke volume index from 35 to 41 ml/beat/m2 (+18%, p less than 0.05), stroke work index from 35 to 44 g X m/beat/m2 (+26%, p less than 0.05), epinephrine from 0.05 to 0.15 ng/ml (+200%, p less than 0.05), urine volume from 50 to 81 ml/h (+61%, p less than 0.05), pulmonary capillary wedge pressure decreased from 23 to 18 mmHg (-24%, p less than 0.001), mean pulmonary arterial pressure from 33 to 27 mmHg (-19%, p less than 0.001), right atrial pressure from 10 to 7 mmHg (-27%, p less than 0.001), systemic vascular resistance from 1735 to 1546 dyne X s X cm-5 (-11%, p less than 0.1), pulmonary vascular resistance from 204 to 168 dyne X s X cm-5 (-25%, p less than 0.05), arterio-venous oxygen difference from 6.09 to 5.36 ml/dl (-12%, p less than 0.05), norepinephrine from 0.45 to 0.34 ng/ml (-24%, p less than 0.1), renin activity 1.80 to 1.26 ng/ml/h (-30%, p less than 0.05), respectively, whereas there were no significant changes in blood gases, heart rate, blood pressure, double product, aldosterone, urine Na+, K+ or lactate/pyruvate.(ABSTRACT TRUNCATED AT 250 WORDS)
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Thirty-two patients with inoperable hepatic cancer underwent intra-arterial hepatic infusion using mitomycin C (MMC) and 5-fluorouracil (5-FU) or intra-arterial hepatic chemoembolization using heated albumin microspheres containing MMC with an average diameter 45 +/- 8 micron. Nineteen of the 32 patients received the MMC microsphere treatment and another 13 received the conventional infusion treatment, lasting for 3.4 months. The administered doses of MMC microspheres were 11.7 +/- 11.1 mg as MMC in the 12 with metastatic cancer and 6.9 +/- 2.1 mg as MMC in the 7 with hepatocellular cancer (HCC). On the contrary, the 13 patients who underwent conventional infusion had average doses of MMC 34.5 +/- 17.3 mg and of 5-FU 13.4 +/- 7.7 g, over 3.4 months. An objective tumor response was obtained in 13/19 (68.4%) under MMC microsphere chemoembolization, compared to 6/13 (46.2%) under the conventional infusion. The average level of CEA in the 12 with metastatic cancer, who underwent MMC microsphere therapy, dropped from 57.7 ng/ml to 16.5 ng/ml, while that in the 10 patients on conventional infusion dropped from 24.0 ng/ml to 17.4 ng/ml; that of alpha-fetoprotein dropped in all 7 with HCC on MMC microsphere chemoembolization, compared to a fall in 1/3 on conventional infusion. With the MMC microsphere treatment, 5 patients from colorectal cancer lived for 15.6 +/- 7.6 months, 2 are alive with a long life expectancy; and 7 patients from gastric or pancreatic cancer lived for only 9.3 +/- 3.3 months. In case of conventional infusion, 6 patients from colorectal cancer survived for 8.6 +/- 3.2 months; and 4 patients from gastric or gallbladder cancer survived for 6.0 +/- 1.0 months. The MMC microsphere treatment is superior at P = 0.059 in survival duration to the conventional infusion treatment. However, much the same survival occurred in 7 on MMC microsphere chemoembolization and 3 on continuous infusion.
We prepared biodegradable microspheres containing about 5% mitomycin C (MMC) and of 45 +/- 8 microns in diameter. These preparations were infused into the rat hepatic artery as a preclinical model of intra-arterial infusion treatment for patients with inoperable hepatic tumor. The leaked MMC levels in the hepatic vein decreased below the assay limitation 2 hours after conventional MMC injection, whereas in the case of MMC microsphere the leaked drug levels were maintained at almost the same concentration for over 2 hours after infusion. The entrapped period of MMC microspheres within the hepatic artery was at least 2 weeks, and the necrobiotic foci due to antitumor effects of the condensed MMC released from the microspheres were observed in the area fed by these entrapped arterioles. This phenomenon was never observed in the case of conventional MMC and placebo microspheres. Intra-arterial infusion of MMC microspheres may be a promising clinical treatment for patients with malignant hepatic tumor.
Biodegradable albumin microspheres containing about 5% mitomycin C (MMC) were prepared in an average diameter of 45 +/- 8 microns by heat denaturation in oil at 120 degrees C and/or cross-linking with glutaraldehyde. These MMC microspheres released, in vitro, about 20% of the contained MMC for over 3 days, and they were intra-arterially infused into albino rabbits and Wistar rats, as a preclinical model of intra-arterial infusion treatment for patients with inoperable hepatic tumor. We infused these microspheres into the femoral artery of rabbits with a VX-2 tumor implanted into the flank of the hindleg. High levels of MMC were maintained for several hours in the tumor and the entrapped MMC microspheres were detected within arterioles in the VX-2 tumors. The growth of VX-2 tumor was inhibited considerably, compared to findings in the control rabbits given conventional MMC. In the next studies, MMC microspheres were infused into the rat hepatic artery, and the levels of MMC in the hepatic vein blood were maintained at much the same concentration for over 2 hours after the infusion, in marked contrast to rapid decreases in the conventional MMC. Histologic findings revealed that MMC micro-spheres were entrapped within the hepatic arterioles for over 2 weeks and released biologically active MMC into the neighboring tissues for prolonged periods of time.
Protein complexes (photochemical reaction complex; PR complex) bound to both light-harvesting bacteriochlorophyll-1 (LH-Bchl-1) and reaction center Bchl (RC-Bchl) were purified from Rhodospirillum rubrum (wild and carotenoid-less), Rhodopseudomonas sphaeroides (wild), and Chromatium vinosum (wild). Another protein complex (LH-2 complex) bound to LH-Bchl-2 was also purified from Rps. sphaeroides. The bacteria were grown in the presence of a [14C]amino acid mixture. The purification procedure included molecular-sieve chromatography in the presence of cholate-deoxycholate, and non-equilibrated isoelectric electrophoresis with 3-[(3-cholamidopropyl)dimethylamino]-1-propanesulfonate. The purified complexes were separated into their constituent proteins by sodium dodecylsulfate-polyacrylamide gel electrophoresis. The molar ratios of the proteins were determined by comparing their radioactivities divided by their molecular weights after consideration of the molecular masses of the complexes. The PR complexes all contained per mol: 1 mol each of RC H-, M-, and L-subunits, 10-13 (probably 12) mol each of two other proteins with molecular weights of 11-12K and 8-11K, 28-32 mol Bchl, 13-15 mol carotenoids (except in the carotenoid-less mutant), 2.6-3.9 mol ubiquinone (or menaquinone in Chr. vinosum), and 53-79 mol phosphate without phospholipid. The LH-2 complex contained per mol: 1 mol 52K protein, about 13 (probably 12) mol each of 9K and 8K proteins, 30 mol Bchl, 10 mol carotenoids, and 38 mol phosphate without phospholipid. The PR complexes and LH-2 complex showed similar X-ray diffraction patterns, implying that they had similar, highly organized molecular structures.
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The effect of the percutaneous absorption enhancer, Azone, on the transport of 5-fluorouracil across hairless rat skin has been investigated by an in-vitro permeation technique using 2-chamber diffusion cells. Azone (3% w/v) emulsions were used. Azone enhanced the permeability of drug 10-100 times across the full-thickness skin although there was a lag time about 10 h. The long lag time, however, disappeared with Azone pretreatment. Azone also affected the transport across stripped skin. These results suggest that Azone mainly affects the stratum corneum. It seems to change the diffusivity of drug in that layer and is not so effective against diffusivities in the epidermis and dermis.
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