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At least 91 records · Page 5Linked to original sources
PubMed1989

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

We observed the effects of a new thyrotropin-releasing hormone derivative, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), on behavioral changes in rats for 3 weeks after focal cerebral ischemia. Under halothane anesthesia, the left middle cerebral artery was occluded via a transretro-orbital approach. YM-14673 was administered just after the operation and once a day for 3 weeks. Neurologic deficits, including hemiplegia and abnormal posture, and disturbance of passive avoidance learning were present in solvent-treated control rats for the entire 3 weeks. YM-14673 at 0.1 or 0.3 mg/kg i.p. or 1 mg/kg p.o. significantly accelerated the recovery of neurologic deficits and ameliorated cognitive disturbance compared with the solvent-treated controls although the drug at 0.1 and 0.3 mg/kg i.p. did not influence the size of the ischemic infarct. YM-14673 mitigated the behavioral disturbances in this model of chronic focal cerebral ischemia. We also discuss the suitability of this model for the evaluation of drugs.

Animals↗
PubMed1989

Effects of a new thyrotropin-releasing hormone analogue administered in rats 1 week after middle cerebral artery occlusion.

We observed the effects of a new thyrotropin-releasing hormone analogue, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate) on behavioral changes in 26 rats subjected to middle cerebral artery occlusion. The administration of 0.1 mg/kg i.p. YM-14673 was started 1 week after occlusion and was repeated daily for 2 weeks. YM-14673 significantly accelerated the recovery of neurologic deficits and ameliorated the disturbance of passive avoidance learning. Thus, YM-14673 improved behavioral response in a model of chronic focal cerebral ischemia. The availability of a chronic middle cerebral artery occlusion model for the evaluation of drugs is also discussed.

Animals↗
PubMed1985

Pilot study of fluzinamide (N-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) in refractory partial seizures.

We conducted a pilot study of fluzinamide in 15 adults with refractory partial seizures. After a baseline period, fluzinamide was added to the existing regimen of phenytoin and carbamazepine and increased to maximum tolerated dose. Common side effects included dizziness, diplopia, ataxia, headache, nausea, and rash, resulting in patient withdrawal in six cases. Seizures became less frequent in four of the nine patients who completed the 8-week trial.

Adolescent↗
PubMed1990

Synthesis and platelet aggregation-inhibitory activities of novel 3-(2-oxopropylidene)azetidin-2-one derivatives. I.

Treatment of (E)-3-(2-hydroxypropylidene)-4-methyl-1-phenylazetidin-2-one (11) with 10% Pd/C gave (E)-(12), (Z)-3-(2-oxopropylidene)-4-methyl-1-phenylazetidin-2-one (13), 3,4-cis-(14a) and 3,4-trans-3-(2-oxopropyl)-4-methyl-1-phenylazetidin-2-one (14b). Among them, 12 and 13 were found to show potent inhibitory activities against rabbit platelet-rich plasma aggregation induced by adenosine diphosphate or collagen. Ring-expanded homologous derivatives and an acyclic analogue of 12 were also synthesized and tested for the biological activities. The azetidin-2-one skeleton bearing a 2-oxoalkylidene moiety at the 3 position was found to be essential for the platelet aggregation inhibitory activities of these compounds.

Animals↗
PubMed1989

Beneficial renal effects of CS-905, a novel dihydropyridine calcium blocker, in SHR.

CS-905 is a potent dihydropyridine calcium blocker that has a gradual and long-lasting antihypertensive action with little tachycardia in SHR. In this study, we investigated chronic and acute effects of CS-905 on renal functions in SHR. To examine the chronic effects, 23 week-old male SHR were treated with CS-905 (1 or 3 mg/kg/day, p.o.) or 0.3% CMC (carboxymethylcellulose). After the 15 week-treatment, the agent dose-relatedly lowered systolic blood pressure measured 24 hr after the final administration (184 +/- 2 and 173 +/- 3 mmHg at 1 and 3 mg/kg/day vs. 218 +/- 4 mmHg for the control group). Natriuresis and the reduction of urinary protein excretion were also observed in the CS-905 treated groups. Urinary NAG (N-acetyl-beta-D-glucosaminidase) activity tended to decrease, but not significantly. Histopathological changes observed in the SHR kidney were reduced by chronic treatment with CS-905. On a single oral administration in 38 week-old SHR, CS-905 caused natriuresis at a dose of 3 mg/kg, but did not affect urinary protein excretion and urinary NAG activity. These effects of CS-905 on renal functions may be beneficial in the treatment of hypertension.

Acetylglucosaminidase↗
PubMed1989

Antihypertensive effects of CS-905, a novel dihydropyridine Ca++ channel blocker.

CS-905 is a novel dihydropyridine calcium blocker. A single oral administration of CS-905 or nicardipine at doses of 0.3-3.0 mg/kg produced a dose-dependent reduction of blood pressure in conscious SHR. CS-905, when administered orally in conscious SHR, was more than 3 times as potent as nicardipine. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in heart rate. An intravenous administration of CS-905 also produced a hypotension with a slow onset and long duration in SHR, but CS-905 was 3 times less potent than nicardipine by intravenous administration. This difference may be attributed to the first pass effect, which was associated with nicardipine but not with CS-905. The blood pressure lowering effects of CS-905 was most potent in DOCA-salt hypertensive rats, followed by SHR, RHR and normotensive rats, in this order. CS-905 is expected to be an antihypertensive agent that is effective on a once a day regimen in clinical settings.

Anesthesia↗
PubMed1990

Antihypertensive effect of CS-905, a novel dihydropyridine calcium blocker, in conscious hypertensive dogs.

CS-905, (+-)-3-(1-diphenylmethylazetidin-3-yl)5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxy lat e, is a novel dihydropyridine calcium blocker. Both CS-905 and nicardipine, when administered orally, produced a dose-dependent fall of blood pressure in conscious perinephritic hypertensive dogs. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in the heart rate and plasma renin activity (PRA). The lack of both tachycardia and increase of PRA is probably mostly due to the slow onset of antihypertensive action following CS-905.

Animals↗
PubMed1975

Antimetabolites produced by microorganisms. XII (S)-alanyl-3-[alpha-(S)-chloro-3-(S)-hydroxy 2-oxo-3-azetidinylmethyl]-(S)-alanine, a new beta-lactam containing natural product.

(S)-Alanyl-3-[alpha-(S)-chloro-3-(S)-hydroxy-2-oxo-3-azetidinylmethyl]-(S)-alanine was isolated from a fermentation broth of an unidentified Streptomyces species 372 A. The structure was determined by single crystal X-ray diffraction analysis. The substance inhibits the growth of several strains of gram-positive and gram-negative bacteria in a chemically defined medium but growth inhibition is relieved by addition of L-glutamine to the medium.

Alanine↗
PubMed1975

Incorporation of L-azetidine-2-carboxylic acid into hemoglobin in rabbit reticulocytes in vitro.

L-Azetidine-2-carboxylic acid is the naturally occurring lower homologue of L-proline. Reticulocytes from anemic rabbits incubated with DL-[14-C]azetidine-2-carboxylic acid synthesized radiolabeled hemoglobin, which when isolated from cell lysates co-chromatographed with unlabeled hemoglobin on Sephadex G-100 columns. Amino acid analysis of hemoglobin from reticulocytes incubated with DL-[14-C]-azetidine-2-carboxylic acid suggested that the homologue was incorporated into hemoglobin intact and unaltered. Alternatively, another amino acid analogue, 1-aminocyclopentane-[1-14-C]carboxylic acid, which is purported to be a valine antagonist, was not incorporated into hemoglobin under these conditions. Incubation of reticulocytes with 1, 5, and 10 mM L-azetidine-2-carboxylic acid reduced L-[U-14-C]proline (0.10 mM) incorporation into hemoglobin by 25, 58, and 72%, respectively. Conversely, 1.45 and 145 muM L-proline reduced radiolabeled azetidine-2-carboxylic acid (0.8 mM) in corporation into hemoglobin by 45 and 92%, respectively. Incorporation of L-[U-14-C]leucine and L-[U-14-C]lysine (0.1 mM each) into hemoglobin was unaffected at these concentrations of L-azetidine-2-carboxylic acid. These results suggest that L-azetidine-2-carboxylic acid is incorporated into hemoglobin without reducing the rate of globin synthesis in rabbit reticulocytes in vitro. The alpha and beta chains of hemoglobin into which [14-C]azetidine-2-carboxylic acid had been incorporated in rabbit reticulocytes in vitro were resolved electrophoretically on sodium dodecyl sulfate-polyacrylamide gels. The ratio of total radioactivity in the alpha and beta chains separately extracted from gels was in good agreement with the known 7:4 ratio of prolyl residues in the respective chains. Autoradiograms of two-dimensional tryptic peptide maps of rabbit globin into which either [14-C]azetidine-2-carboxylic acid or [14-C]proline had been incorporated showed nearly identical patterns of radioactivity. These results suggest that azetidine-2-carboxylic acid substitutes specifically for prolyl residues during in vitro hemoglobin synthesis in rabbit reticulocytes.

Amino Acids↗
PubMed1985

Structural changes of hair after incorporation of the proline analogue L-azetidine-2-carboxylic acid. A model of hair disease by alteration of primary structure.

In order to correlate biochemical changes of the hair with physical properties we present a model for the examination techniques. L-azetidine was incorporated into the hair keratin complex and the resulting mechanoelastic properties were determined using the ultramicrohardness testing system on scanning electron microscopy. Structure was investigated by X-ray diffraction and incorporation of L-azetidine was detected by thin-layer chromatography. This system could possibly be introduced for examination of hair changes in humans. 8 white mice, 3 weeks of age, were given L-azetidine-2-carboxylic acid in water (0.1 g/100 ml) as only source of fluid over a period of 5 weeks. They had free access to dry mouse cake only. 8 animals of the same strain, who had free access to tap water and mouse cake and were kept under the same conditions, served as controls. After 5 weeks, the animals were sacrificed and hair was obtained for analyses. 2 dimensional thin-layer chromatography of hair hydrolyzed with 6N HCl at 105 degrees C for 12 hours revealed 2 additional spots in the chromatographic pattern in the experimental animals in comparison with the control group. 1 of the spots was identified as L-azetidine-2-carboxylic acid, while the second spot was possibly a degradation product of L-azetidine on acid hydrolysis at a high temperature. Hair of the animals was put into Mark capillaries and subjected to X-ray diffraction, which showed a markedly disordered orientation of keratin. Impression studies using scanning electron microscopy revealed a remarkably reduced elasticity of hair with incorporated L-azetidine. These findings may be explained on the basis of qualitative or quantitative changes in the helical structure of the keratin complex of hair, which is responsible for the elastic properties, whereas the globular matrix is responsible for the firmness of the hair.

Animals↗