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Biomedical subjects

H Araki

Publications and source records attributed to H Araki.

At least 145 records · Page 8Linked to original sources
PubMed1995

Retinoid agonist activities of synthetic geranyl geranoic acid derivatives.

Micromolar concentrations of 4,5- didehydro geranyl geranoic acid (GGA) were able to induce up-regulation of retinoic acid receptor-beta gene expression in human hepatoma-derived cell line, HuH-7, to the same extent as all-trans RA. In chloramphenicol acetyl transferase (CAT) assay with retinoic acid response element-beta, GGA and 4,5-didehydro GGA were both positive, but 2,3-dihydro GGA was negative, even though these GGA derivatives have been reported to be all potent ligands for cellular retinoic-acid-binding protein(CRABP). However, 10,11,14,15- tetrahydro- 4,5- didehydro GGA, a compound without any affinity for CRABP, transactivated CAT gene expression. On the other hand, only GGA and 4,5-didehydro GGA were active to induce CAT gene expression through retinoid X response element of cellular retinol binding protein, type II gene. We show for the first time that chemically synthesized acyclic organic acids are potential agonists of natural retinoids.

Chloramphenicol O-Acetyltransferase↗
PubMed1995

Stable prostacyclin improves postischaemic microcirculatory changes in hypertensive rats.

The prostacyclin analogue TTC-909 is incorporated in lipid microspheres and is chemically very stable. We examined the efficacy of TTC-909 on cerebral microcirculation following focal cerebral ischaemia. Focal cerebral ischaemia was produced by the occlusion of the distal middle cerebral artery in stroke-prone spontaneously hypertensive rats. Intravenous administration of TTC-909 (100 ng/kg/day) or vehicle was started 30 minutes after the occlusion and repeated for 7 days. On day 7, cerebral blood flow and blood-brain barrier permeability were measured autoradiographically. Brain oedema was estimated by the gravimetric method. The size of the infarction was calculated from area measurements on serial histologic sections. Treatment with TTC-909 resulted in significant improvement in regional blood flow in the ischaemic rim (p < 0.01) and the surrounding area (p < 0.05). With TTC-909 treatment, the increased permeability was significantly reduced in the ischaemic centre (p < 0.01) and rim (p < 0.05). A decrease in specific gravity in the ischaemic region and the remote non-ischaemic regions was prevented by the treatment (p < 0.01). We assumed that the efficacy of TTC-909 maintains the blood supply in the ischaemic area, improves disruption of the blood-brain barrier and prevents development of ischaemic oedema.

Animals↗
PubMed1995

Effects of HL-004, a novel ACAT inhibitor, on cholesterol accumulation and removal in cultured smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSP).

The cholesterol metabolism of cultured smooth muscle cells (SMC) from the thoracic aorta of SMC from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) was compared. SMC from SHRSP had a higher acylCoA:cholesterol acyltransferase (ACAT) activity and accumulated more cholesterol than those from WKY. By using SMC from SHRSP, the effects of a novel ACAT inhibitor, HL-004, on the accumulation and removal of cholesterol were investigated. HL-004 inhibited microsomal ACAT activity from rabbit liver, intestine, aorta, and cultured SMC of SHRSP with 50% inhibition (IC50) values of 2.2, 1.7, 7.9, and 20 nM, respectively. HL-004 suppressed the accumulation of the intracellular cholesteryl ester (CE), but did not affect the intracellular free cholesterol (FC) content. Removal of cholesterol from the lipid-loaded SMC was accelerated by HL-004. These effects of HL-004 on cholesterol levels showed a good parallel to ACAT inhibition. It would thus appear that the suppression of cholesterol accumulation and the removal of cholesterol in SMC by HL-004 can be attributed to its ACAT inhibition in the cell, which reduces the content of intracellular CE.

Acetanilides↗
PubMed1995

Prostacyclin analogue TTC-909 reduces memory impairment in rats with cerebral embolism.

The effects of the stable prostacyclin analogue TTC-909 on memory impairment in the water maze task and on neuronal damage were studied in rats with cerebral embolism induced by injecting polyvinyl acetate (PVA) into the right internal carotid artery and the ensuing embolism extending out into the right middle cerebral artery. Areas supplied by the lenticulostriate artery were most markedly damaged. In the water maze test, the PVA-embolized rats took longer to reach the platform than did the nontreated control rats. To some extent, repeated administrations of TTC-909 (200 ng/kg, IV) overcame this impairment in water maze learning in the rats. We assume that the vasodilating effects of TTC-909 maintain this blood supply to the ischemic area and that TTC-909 prevents the development of thrombosis around the PVA particles in the arterial capillaries, as a result of antiplatelet aggregative effects. These two mechanisms are likely to be involved in memory improvement. TTC-909 may prove effective for treating subjects with stroke and other cerebrovascular disorders.

Animals↗
PubMed1995

The sigma-selective ligand NE-100 attenuates the effect of phencyclidine in a rat diving model.

1. Phencyclidine (PCP) reduces the latency of rats diving into a water-filled pool from a hidden platform, without stereotyped behavior. 2. The sigma-selective ligand, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethyl-amine monohydrochloride), attenuates the effects of PCP in this procedure. 3. The serotonin2 (5-HT2) antagonist, ritanserin, and the sigma receptor ligands, 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine HBr (Dup734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1- (cyclopropylmethyl)piperidine (XJ448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY14802) and rimcazole similarly attenuate the effects of PCP. 4. The dopamine D2/sigma ligands, haloperidol and cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4- methylaminobenzamide (YM-09151-2) completely reverse the effects of PCP, whereas the same dose ranges of these drugs produce sedation. 5. The dopamine D2-selective antagonist, sulpiride, has no apparent effect on the PCP latency to the rat dive. 6. Thus, PCP-induced diving behavior was improved by sigma ligands and the 5-HT2 antagonist. This model of negative symptoms in an experimental animal will facilitate experiments on drug treatments for schizophrenia.

Animals↗
PubMed1995

In vitro antibacterial properties of T-5575 and T-5578 novel parenteral 2-carboxypenams.

T-5575 and T-5578, novel 2-carboxypenams in which a carboxyl group has been introduced into the C-2 beta position of the nucleus, were evaluated for their in vitro antibacterial properties. The spectrum of activity of T-5575 was similar to that of aztreonam. However, it showed stronger activities than those of aztreonam against most gram-negative bacteria. T-5575 also showed potent activities against isolates of Enterobacter cloacae, Citrobacter freundii, and Pseudomonas aeruginosa resistant to ceftazidime, with MICs at which 90% of the isolates were inhibited of 0.39, 0.39, and 3.13 microgram/ml, respectively. T-5578 showed moderate levels of activity against gram-negative bacteria, compared with those of T-5575. Its activity against P. aeruginosa, however, was superior to those of T-5575 and the reference drugs tested. The most characteristic feature of T-5578 was its potent activities against ceftazidime-, imipenem-, and gentamicin-resistant P. aeruginosa isolates, with MICs at which 90% of the isolates were inhibited at 0.39, 3.13, and 3.13 microgram/ml, respectively. These two compounds were unfortunately poorly active against gram-positive bacteria, such as Staphylococcus aureus and streptococci. Both compounds were found to be stable for hydrolysis by various kinds of beta-lactamases and to have low affinities for these enzymes, with Ki values of > 100 microM. These novel penams bound most tightly to penicillin-binding protein 3 of Escherichia coli and P. aeruginosa. These results indicate that T-5575 and T-5578 can be regarded as promising 2-carboxypenams specially targeted against gram-negative pathogens.

Anti-Bacterial Agents↗
PubMed1995

Detection of proteoglycans in human posterior capsule opacification.

Using cuprolinic blue staining, we histochemically examined the ultrastructural localization of proteoglycans in the fibrous-type human posterior capsule opacification. This capsule opacification contained proteoglycans that showed positive staining with cuprolinic blue. Many cuprolinic-blue-positive filaments were present within the bundles of collagen fibrils, basal lamina-like material and basal lamina of proliferated lens epithelial cells. Pretreatment with enzymes and nitrous acid revealed that the collagen fibrils contained chondroitin sulfate and dermatan sulfate, whereas the basal lamina-like material and basal lamina of epithelial cells contained heparan sulfate. These results suggest that proteoglycans are one of the components in posterior capsule opacification.

Aged↗
PubMed1995

Frontal N30 potential following a sustained voluntary movement.

With 6 male subjects we investigated whether the decreased amplitude in the frontal N30 potential of Somatosensory Evoked Potentials is related to a sustained voluntary movement or not. We concluded that the diminution of frontal N30 was also closely related to the sustained voluntary movement.

Evoked Potentials, Somatosensory↗
PubMed1995

Synthesis and pharmacological evaluation of 1,2,3,4-tetrahydro-beta-carboline derivatives.

A series of 1,2,3,4-tetrahydro-beta-carbolines has been synthesized and evaluated for cerebral protecting effects against lipid peroxidation and potassium cyanide intoxication in mice. Most of the compounds synthesized had potent effects against lipid peroxidation. Among them, 1-(3,5-dimethoxyphenyl)-2-propyl-1,2,3,4-tetrahydro-beta-carboline (22) was found to have a combination of potent effects against both lipid peroxidation and potassium cyanide intoxication. Structure-activity relationships are discussed.

Animals↗
PubMed1995

Exhibition of anti-platelet effect of isocarbacyclin methyl ester and its free acid via an increase in cAMP in platelets.

Isocarbacyclin methyl ester (CAS 88931-51-5, TEI-9090) and its free acid (CAS 88911-35-7, TEI-7165) are chemically stable analogues of prostaglandin (PG) I2. The cAMP increasing activities of TEI-9090 and TEI-7165 were investigated. TEI-9090, TEI-7165, PGI2, and PGE1 caused the accumulation of cAMP in rabbit and human platelets. The effects of TEI-9090, TEI-7165, and PGE1 were longer lasting than the effect of PGI2. Each drug concentration-dependently increased the cAMP level in rabbit and human platelets. The order of cAMP-increasing activity was PGI2 > PGE1 = TEI-9090 = TEI-7165 in rabbit platelets and PGI2 > TEI-9090 = TEI-7165 > PGE1 in human platelets. The antiplatelet aggregation activity of TEI-9090 in rabbit and human platelets was remarkably decreased by the addition of an esterase inhibitor, diisopropyl fluorophosphate (DFP). However, this activity of TEI-7165 was not affected by the inhibitor. In the presence of DFP, the cAMP accumulation by TEI-9090 in rabbit platelets was almost completely inhibited but that by TEI-7165 was not inhibited. These results suggest that TEI-9090 is deesterified to TEI-7165 and that this free acid then inhibits platelet aggregation via an increase in the cAMP level in the platelets.

Alprostadil↗
PubMed1995

Anti-platelet effects of isocarbacyclin methyl ester on human and rabbit platelets in vitro.

Anti-platelet effects of isocarbacyclin methyl ester (CAS 88931-51-5, TEI-9090) and of its free acid form, TEI-7165 (CAS 88911-35-7) were compared with those of prostaglandin (PG) I2 and PGE1. TEI-9090 and TEI-7165 dose-dependently inhibited human and rabbit platelet aggregation and human platelet adhesion in vitro. The IC50 values of TEI-9090, TEI-7165, PGI2, and PGE1 against ADP-induced human (rabbit) platelet aggregation were 22.90 (25.00) ng/ml, 2.78 (6.46) ng/ml, 1.67 (3.34) ng/ml, and 19.91 (8.32) ng/ml, respectively; and those against human platelet adhesion were 3.47 ng/ml, 0.13 ng/ml, 0.25 ng/ml, and 1.45 ng/ml, respectively. TTC-909, a product incorporating TEI-9090 in lipid microspheres, had an aggregation inhibitory effect similar to that of TEI-9090 in human platelets. The aggregation inhibitory effect of TEI-9090 and TTC-909 increased with incubation time, and reached a level similar to that of TEI-7165. In contrast, the aggregation inhibitory effect of TEI-7165 remained constant for 120 min, whereas that of PGI2 decreased with time. TEI-9090 and TEI-7165 also enhanced the disaggregation of human platelets at nearly the same concentration as they exerted their inhibitory effect on aggregation. The order of anti-platelet activities, compared at each optimum incubation point, were PGI2 approximately equal to TEI-7165 approximately equal to TEI-9090 (approximately equal to TTC-909) > PGE1 in human and rabbit platelets. These results indicate that TEI-9090 (TTC-909) and its active metabolite, TEI-7165, may be a potent anti-platelet drug.

Animals↗
PubMed1995

Ex vivo anti-platelet effects of isocarbacyclin methyl ester incorporated in lipid microspheres in rabbits.

Effect of TTC-909, a chemically stable isocarbacyclin methyl ester (CAS 88931-51-5, TEI-9090) incorporated in lipid microspheres, on platelet aggregation was tested in conscious rabbits. TTC-909 significantly inhibited platelet aggregation induced by ADP at early times after bolus i.v. injection from the dose of 0.3 micrograms/kg in a dose-dependent manner. Similarly, TTC-909 significantly inhibited platelet aggregation induced by ADP during the venous infusion from the dose of 100 ng/kg/min, also in a dose-dependent manner. The anti-platelet effect of TTC-909 was observed at a dose lower than that inducing hypotensive effect when given as both bolus i.v. and venous infusion. On the other hand, prostaglandin (PG) E1 (LM)--PGE1 incorporated in lipid microspheres--reduced blood pressure without having an anti-platelet effect. These results indicate that TTC-909 may be a potent anti-thrombotic drug.

Alprostadil↗
PubMed1995

Vasorelaxant effect of isocarbacyclin methyl ester incorporated into lipid microspheres on isolated canine arteries.

TTC-909 is a preparation of isocarbacyclin methyl ester (CAS 88931-51-5, TEI-9090) incorporated into lipid microspheres. The characteristics of vasorelaxation induced by TTC-909 were investigated in isolated canine arteries. TTC-909 produced concentration-dependent relaxation of prostaglandin F2a(PGF2a)-induced and U-46619 (TXA2 receptor agonist)-induced contraction in basilar, coronary, renal, mesenteric, and femoral arteries. The vasorelaxant potency of TTC-909 was compared with the potencies of TEI-9090, TEI-7165 (CAS 88911-35-7, free acid of TEI-9090), prostaglandin I2 (PGI2), and prostaglandin E1 (PGE1) on PGF2a-induced contraction in basilar and femoral arteries. The relaxing potency of TTC-909 was similar to the values for TEI-9090, TEI-7165, and PGI2, and more potent than that of PGE1 in both of these arteries. An esterase inhibitor, diisopropyl fluorophosphate (DFP), reduced the vasorelaxant effect of TEI-9090, but not that of TEI-7165, on PGF2a-induced contraction in femoral arteries. These results suggest that TTC-909 has vasorelaxant potency similar to that of PGI2 and greater than that of PGE1. Further, it appears that TEI-9090 was converted to TEI-7165 by esterase and then produced its vasorelaxing effect.

Animals↗
PubMed1995

Effect of isocarbacyclin methyl ester incorporated into lipid microspheres on cutaneous blood flow in rat.

A new stable prostacyclin analogue, isocarbacyclin methyl ester (CAS 88931-51-5, TEI-9090), incorporated into lipid microspheres (TTC-909), was examined for its effects on cutaneous blood flow and mean blood pressure in rats in comparison with PGE1 (LM) (prostaglandin E1 in lipid microspheres). TTC-909 at 0.3 micrograms/kg i.v. significantly increased the sole cutaneous blood flow without changing blood pressure. A significant decrease in mean blood pressure was observed with TTC-909 above 1 microgram/kg i.v. PGE1 (LM) also showed a decrease in the blood pressure from 1 microgram/kg i.v., whereas the sole cutaneous blood flow was not affected even at 10 micrograms/kg i.v. These results suggest that TTC-909 dilates the skin vessels preferentially to other blood vessels in the rat and that effect is more potent than that of PGE1 (LM). TTC-909 may thus prove to be an effective agent for the treatment of peripheral vascular disease.

Animals↗
PubMed1995

Effect of isocarbacyclin methyl ester incorporated in lipid microspheres on experimental models of peripheral obstructive disease.

The effect of TTC-909 (isocarbacyclin methyl ester (CAS 88931-51-5, TEI-9090) incorporated into lipid microspheres) on obstruction of the peripheral artery was studied in two different animal models. The first was a peripheral occlusion model induced by intra-arterial injection of sodium laurate in rats. The second was a tail gangrene model induced by subcutaneous injection of both ergotamine and epinephrine in rats. Intravenous bolus-administered TTC-909 at 1.0 microgram/kg resulted in the inhibition of both progression of lesions induced by sodium laurate and the extension of tail gangrene by ergotamine and epinephrine. Moreover, the inhibitory effect of TTC-909 was more potent than that of PGE1 (LM) (prostaglandin E1 incorporated into lipid microspheres). These findings suggested that TTC-909 may be clinically useful for the therapy of peripheral vascular disorders such as thromboangiitis obliterans (TAO) and atherosclerosis obliterans (ASO).

Alprostadil↗
PubMed1995

[Evaluation of compression radiotherapy in pelvic treatment].

In pelvic irradiation, the volume of irradiated small intestine is one of the major factors responsible for both acute and late gastrointestinal complications. In this study, exclusion of the small intestine from the pelvic radiation field was attempted with lower abdominal wall compression and bladder distention in the prone position. The mobility of intrapelvic and several problems associated with this technique were investigated. In our results, the small intestine was effectively moved outside of the whole pelvic radiation field in all but two patients. Treatment interruption of 2 days was observed in only two patients. With the AP/PA opposing field method the abdominal skin dose near the compression pillow was revealed to be higher and the dose at the isocenter was inhomogeneous; thus, a three- or four-field technique is recommended if abdominal wall compression is used.

Adult↗
PubMed1995

Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis.

The CA1 pyramidal neurons in the hippocampus are selectively vulnerable to transient ischemic damage. In experimental animals, the CA1 pyramidal neurons undergo cell death several days after brief forebrain ischemia. It remains, however, unknown whether this delayed neuronal death is necrosis or apoptosis. To investigate the degenerating processes of the CA1 pyramidal neurons in gerbil hippocampus after brief ischemia, lysosomal and nuclear alterations in the cells were examined using immunocytochemistry, in situ nick-end labeling, and Southern blotting. By light and electron microscopy, immunoreactivity for cathepsins B, H, and L, representative lysosomal cysteine proteinases, increased in the CA1 pyramidal neurons 3 d after ischemic insult, which showed cell shrinkage. By morphometric analysis, the volume density of cathepsin B-positive lysosomes markedly increased 3 d after ischemic insult, while that of autophagic vacuole-like structures also increased at this stage, suggesting that cathepsin B-immunopositive lysosomes increasing in the neurons after ischemic insult are mostly autolysosomes. Nuclei of the CA1 neurons were nick-end labeled by biotinylated dUTP mediated by terminal deoxytransferase 3 and 4 d after ischemic insult, but not in the prior stages. Simultaneously, dense chromatin masses appeared in nuclei of the neurons. By Southern blotting, laddering of DNA occurred only in CA1 hippocampal tissues obtained 4 d after ischemic insult. Confocal laser scanning microscopy demonstrated that the fragmented DNA in the CA1 pyramidal layer was phagocytosed by microglial cells. The results suggest that delayed death of the CA1 pyramidal neurons after brief ischemia is not necrotic but apoptotic.

Animals↗