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Biomedical subjects

Y Tsuchiya

Publications and source records attributed to Y Tsuchiya.

At least 181 records · Page 10Linked to original sources
PubMed1990

Novel piperidine derivatives. Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives.

A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives was synthesized and evaluated for anti-acetylcholinesterase (anti-AChE) activity. Substituting the benzamide with a bulky moiety in the para position led to a substantial increase in activity. Introduction of an akyl or phenyl group at the nitrogen atom of benzamide dramatically enhanced the activity. The basic quality of the nitrogen atom of piperidine appears to play an important role in the increased activity, since the N-benzoylpiperidine derivative was almost inactive. We found that 1-benzyl-4-[2-(N-[4'-(benzylsulfonyl) benzoyl]-N-methylamino]ethyl]piperidine hydrochloride (21) (IC50 = 0.56 nM) is one of the most potent inhibitors of acetylcholinesterase. Compound 21 showed an affinity 18,000 times greater for AChE than for BuChE. At a dose of 3 mg/kg, 21 produced a marked and significant increase in acetylcholine (ACh) content in the cerebral vortex and hippocampus of rats. Compound 21 was chosen for advanced development as an antidementia agent.

Acetylcholinesterase↗
PubMed1990

Effect of lithium on deoxyribonucleic acid synthesis and iodide uptake in porcine thyroid cells in culture.

We investigated the direct effect of lithium on porcine thyroid cells in culture to exclude the secondary regulatory factors. First we have studied the effect of lithium on TSH-induced iodide uptake. Significant suppression was seen at 0.1 mmol/liter, and half-maximal suppression was obtained at the pharmacological concentration reported in patient serum. The suppression was dose dependent and reversible. Besides the suppression of cAMP production stimulated by TSH, lithium also inhibited iodide uptake stimulated by forskolin or 8-bromo-cAMP. These results demonstrated that lithium inhibits TSH-induced iodide uptake not only by reducing cAMP production, but also by acting on the steps of post-cAMP production. Next, we studied the effect of lithium on DNA synthesis of the cultured porcine thyroid cells. Lithium stimulated [3H]thymidine incorporation of the thyroid cells in the basal condition (0.5% fetal calf serum) as well as those stimulated by insulin-like growth factor-I (100 micrograms/liter). The minimal concentrations for the significant increase were 0.5 and 0.1 mmol/liter, respectively. These results suggest that lithium might contribute to the formation of the goiter directly at the cellular levels in patients treated with the agent.

Animals↗
PubMed1990

Involvement of alpha 2-adrenergic receptors in the vagal reflex-induced tracheal constriction.

The effects of clonidine on the vagal reflex-induced tracheal constriction have been investigated in anesthetized, paralyzed, and artificially ventilated mongrel dogs. The cervical trachea was transected in situ into two parts. Responses of the tracheal musculature were measured as changes in the intratracheal pressure on an air-filled balloon introduced into the rostral side of the transected trachea. Reflex tracheal constriction was induced by afferent electrical stimulation at the central cut end of the vagus nerve. Drugs were injected or infused close intraarterially (i.a.) into the bilateral cranial thyroid arteries in such a way that each drug was applied just to the rostral trachea. The reflex tracheal constriction was abolished by a close i.a. infusion of 3 microM atropine. The magnitude of the reflex tracheal constriction was slightly reduced by a close i.a. infusion of 10 microM clonidine and was significantly reduced by the infusion of clonidine at a concentration of 100 and 300 microM. The response to 100 microM clonidine was antagonized by a close i.a. infusion of 1 microM yohimbine. The tracheal constriction induced by i.a. injection of 5.5 nmol acetylcholine was unaffected by infusion of 10, 100 and 300 microM clonidine. The vagal reflex-induced tracheal constriction seems to be inhibited by stimulation of prejunctional alpha 2-adrenoceptors.

Acetylcholine↗
PubMed1990

Synthesis and biological activity of [MeTyr1,MeArg7,D-Leu8]-dynorphin A(1-9)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-dynorphin A(1-9)-NH2.

The opioid activities of [MeTyr1]-Dyn(1-7)-NH2, [MeTyr1,D-Leu8]-Dyn(1-8)-NH2, [MeTyr1,D-Leu8]-Dyn(1-9)-NH2, [MeTyr1,D-Leu8]-Dyn(1-10)-NH2, [MeTyr1,D-Leu8]-Dyn(1-11)-NH2, and [MeTyr1,D-Leu8,12]-Dyn(1-13)-NH2 were examined in the bioassays (guinea pig ileum, mouse vas deferens and rabbit vas deferens). Because [MeTyr1,D-Leu8]-Dyn(1-9)-NH2 showed the most potent opioid activity of the peptides tested, the biological activities of two kinds of Dyn(1-9) analogues, [MeTyr1,MeArg7,D-Leu8]-Dyn(1-9)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-Dyn(1-9)-NH2 were determined and compared with those of [MeTyr1,MeArg7,D-Leu8]-Dyn(1-8)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-Dyn(1-8)-NHEt in the three bioassays, in the receptor binding assays, and in the mouse tail pinch test after subcutaneous administration. The results suggest that the extension of the C-terminal in the peptide chain of [MeArg7,D-Leu8]-Dyn(1-8)-NH2 analogues by Arg is ineffective for increasing the kappa-opioid activities, kappa-receptor selectivity and/or analgesic effects of the peptides.

Amino Acid Sequence↗
PubMed1990

Stability of a novel hexapeptide, (Me)Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt, with neurotensin activity, in aqueous solution and in the solid state.

The stability and some physicochemical properties of a novel hexapeptide, (Me)Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt (I), with neurotensin activity, were investigated. The degradation of I in aqueous solution was observed as a pseudo-first order reaction. By determining the degradation rate of I at various pH values, it was found that I was most stable at around pH 4. The activation energies of the degradation in aqueous solutions at pH 2.2, 6.1, 7.0 and 8.0 were 16.3, 22.2, 23.9 and 24.2 kcal/mol, respectively. The enzymatic hydrolysis of I was studied in vitro with a porcine liver esterase at 37 degrees C. The degradation of I in this system was observed as a pseudo-first order reaction. The degradation rate of I in the presence of the esterase was about 10000 times larger than the rate in a buffer solution. I in the solid state was stable under 65 degrees C and labilized by strong light and/or high humidity. The pKa1, pKa2 and pKa3 of I were 7.1, 10.0 and 11.3, respectively. The partition coefficients between n-octanol and the buffer solution at pH values ranging from 2 to 11 were measured. The partition coefficient increased with the increase of the pH value. But the value at pH 7.0 was 2.10 x 10(-2), which was very low. The solubility of I in aqueous solution was more than 10 mg/ml. From the results of the powder X-ray diffraction pattern, I in the solid state was found to be amorphous. The dissolution rates in the 1st and 2nd fluid of JPXI at 37 degrees C and 100 rpm were 19.4 and 9.0 mg/cm2.min, respectively.

Amino Acid Sequence↗
PubMed1990

Effects of histamine on neurally mediated contraction of canine tracheal smooth muscle.

The neuromodulatory action of histamine was investigated in isolated canine trachea. Histamine potentiated the tracheal contraction induced by electrical field stimulation (EFS). The ACh release induced by EFS was potentiated by histamine. The potentiating effect was blocked by chlorpheniramine. These findings suggest that histamine potentiates the neurally mediated tracheal contraction and the potentiating effect may be related in part to the acceleration of the prejunctional release of ACh, which may be mediated by H1-receptors.

Acetylcholine↗
PubMed1990

Influence of ouabain on the tracheal musculature of the dog.

The effects of ouabain on the smooth muscles of the airway were investigated in anesthetized, paralyzed and artificially ventilated mongrel dogs. Ouabain (30 micrograms/kg, i.v.) caused a constriction of the tracheal smooth muscle which was followed by bradycardia. When ouabain was infused at a rate of 2 micrograms/kg/min (i.v.), the tracheal constriction was induced by a total dose of 45.0 +/- 5.5 micrograms/kg, while the bradycardia appeared with a total dose of 54.4 +/- 6.1 micrograms/kg. The ouabain-induced tracheal constriction was inhibited by bilateral vagotomy. The tracheal constriction induced by i.a. infusion of 10 microM ouabain into the bilateral cranial thyroid arteries was inhibited by bilateral vagotomy, but it was not completely blocked. With bilateral vagotomy, the tracheal constriction induced by i.a. infusion of ouabain was unaffected by 3 microM hexamethonium, but it was significantly inhibited by 1 microM atropine. These results suggest that ouabain may induce tracheal constriction by a neurogenic action in addition to its action via the augmentation of the vagal reflex, and the neurogenic action of ouabain may be related, in large part, to the release of acetylcholine from the presynapses of vagus nerves in dogs.

Animals↗
PubMed1990

Influence of ouabain on the cholinergic neurotransmission in the canine trachea.

The effect of ouabain on the cholinergic neurotransmission of the trachea was investigated using isolated tracheal strips in dogs. Tracheal strips without epithelium were suspended in organ chambers filled with modified Krebs-Henseleit solution. Ouabain (3 X 10(-7)-10(-5) M) concentration-dependently caused a slow sustained tracheal contraction. The contractile response was significantly inhibited by 10(-6) M atropine and was enhanced by 10(-8) M physostigmine. The ouabain-induced tracheal contraction was unaffected by 10(-7) M tetrodotoxin, but was significantly reduced by 10(-3) M hemicholinium-3. In superfusion experiments, ouabain (10(-5) M) produced an increase in the ACh release. Superfusion with Ca(++)-free solution almost eradicated the ACh release and abolished the tracheal contraction induced by ouabain. omega-Conotoxin (5 X 10(-8) M), but not nicardipine (10(-6) M), inhibited significantly the increase in ACh release induced by ouabain. These results suggest that the ouabain-induced tracheal contraction may be mainly due to acceleration of presynaptic ACh release by enhancing the influx of Ca++, and the Ca(+)+ entry may occur through the N-type Ca(+)+ channels in the canine airway presynaptic site.

Acetylcholine↗
PubMed1990

Triphasic AVP secretion in encephalopathy.

A patient with encephalopathy developed triphasic changes in the clinical course, starting with diabetes insipidus (DI), then the syndrome of inappropriate ADH secretion (SIADH), and followed by the final phase of DI. The clinical course of encephalopathy was very rapid. The patient lost consciousness completely within only one day after the onset. During the early phase, he lapsed into a condition of "brain death". We could not identify the etiology of the encephalopathy. The triphasic change referred to above is similar to previous reports of cats model after stereotactic destruction of the supraopticohypophyseal tract. We speculate that our case may have been associated with neurohypophyseal dysfunction caused by supraopticohypophyseal tract damage.

Arginine Vasopressin↗
PubMed1990

[Hepatic resection plus hepatic artery infusion with implantable port for colorectal metastases].

Hepatic resection of metastatic colorectal carcinoma offers a chance for long term survival and is being performed with increasing frequency. The aim of this study is to reduce the re relapse in the residual liver after curative hepatectomy. Nineteen patients with hepatic metastases from colorectal carcinoma who underwent hepatic resection plus hepatic artery infusion therapy using an implantable port (HR-HAI) were analyzed. As hepatic resection, lobectomies were performed in 6 patients, segmentectomies in 8 patients and wedge resection in 5 patients. As chemotherapeutic agents, adriamycin in 8 patients, mitomycin C in 7 patients and OK-432 in 4 patients were used. The drugs were administered through hepatic artery via a port every one month for one year at the out patient clinic. Eight out of 19 patients had no complication by HR-HAI therapy, but 3 patients had catheter obstruction within one year, 4 had gastrointestinal discomfort, 3 fever up and 1 liver tissue necrosis. The serious hepatotoxicity such as sclerosing cholangitis was not observed. Re-relapses were appeared in 15 patients and the sites were the residual liver in 10 patients, and 5 in the other organs. The 3-year survival rate of 19 treated patients was 40.0% higher than 33.3% of 52 patients undergone hepatic resection alone, but the difference was not statistically significant.

Antineoplastic Agents↗
PubMed1990

[Effect of lithium on iodide uptake and DNA synthesis in porcine thyroid cells in culture].

We investigated the direct effect of lithium on porcine thyroid cells in culture to exclude the secondary regulatory factors. First we have studied the effect of lithium on TSH-induced iodide uptake. Significant suppression was seen at 0.1 mmol/1 and half-maximal suppression was obtained at the pharmacological concentration reported in serum of patients. The suppression was dose-dependent and reversible. Besides the suppression of cAMP production stimulated by TSH, lithium also inhibited iodide uptake stimulated by forskolin or 8 bromo-cAMP. These results demonstrated that lithium inhibits TSH-induced iodide uptake not only by reducing cAMP production but also by affecting the post cAMP production process. Next we studied the effect of lithium on DNA synthesis of the cultured porcine thyroid cells. Lithium stimulated [3H] thymidine incorporation of the thyroid cells in the basal condition (0.5% fetal calf serum), and with IGF-I (100 micrograms/l) added it stimulated incorporation further. The minimal concentration for the significant increase was 0.5 mmol/l and 0.1 mmol/l, respectively. These results suggested that lithium might contribute to the formation of the goiter directly at the cellular levels in patients treated with agent.

Animals↗
PubMed1990

[Utility of percutaneous biliary drainage in patients with hepatic hilar carcinoma in reference to prognosis and associated complication].

We investigated prognosis in 48 patients with hepatic hilar carcinoma (35 treated with percutaneous biliary drainage (PBD) and 13 without PBD) and complication associated with PBD. Survival rate in 20 patients who had no cholangitis within 1 month after PBD was significantly superior to that in 15 patients with cholangitis. The former was 51.9% at 6 months and 13.0% at 1 year. We thought that this result would be helpful in estimating prognosis in patients with hepatic hilar carcinoma treated with combined therapy. Cholangitis within 1 month after PBD was caused from inadequate drainage for separated intrahepatic bile ducts, ERC before PBD and dislodgement of drainage catheter. Survival rate in patients with PBD not accompanied by cholangitis in 1 month after was superior to that in those without PBD. So we thought that PBD could improve prognosis in patients with hepatic hilar carcinoma if they had no cholangitis within 1 month after PBD.

Aged↗
PubMed1990

[Long-term follow-up results in nonoperated patients with intrahepatic and predominant intrahepatic type of hepatolithiasis].

In order to clarify therapeutic principles of hepatolithiasis associated with a variety of pathological conditions, we studied follow-up results in a term of 5 years after diagnosis in 29 nonoperated patients with intrahepatic gallstones. The patients including 14 males and 15 females underwent direct cholangiography for making diagnosis of the disease consisting of the intrahepatic type (I) and the predominant intrahepatic (IE). Out of the patients, 21 had good results in the follow-up and no one died from the disease or cholangiocarcinoma incidentally occurred. The follow-up results were closely related with the distribution and the location of gallstones in the liver and the grade of severity in clinical symptoms at the diagnosis. The unilateral lober type of the stone distribution had better follow-up results than the bilateral (P less than 0.01), and the peripheral intrahepatic bile duct type of the stone location did better follow-up results than the major (P less than 0.01). The pathological state of mild clinical symptoms showed better follow-up results than that of severe ones (P less than 0.05). The removal of coexisted extrahepatic bile duct stones by endoscopic papillotomy was effective for improving clinical symptoms. The conservative treatment in hepatolithiasis with the type I or IE was generally good in the follow-up results. The follow-up results were various, depending on the pathological conditions at the diagnosis. Accordingly, the treatment of hepatolithiasis must be selected in consideration of pathological conditions.

Adolescent↗
PubMed1989

Structure of the rat alpha 2-macroglobulin-coding gene.

Rat alpha 2-macroglobulin (alpha 2M) is an acute-phase protein, i.e., produced upon tissue inflammation. Genomic DNA clones covering the entire sequence of the alpha 2M gene were isolated and characterized by restriction mapping. Southern blotting and (partial) DNA sequencing. The rat alpha 2M gene is approx. 50 kb in length and consists of 36 exons ranging in size from 21 to 229 bp. Two functional domains, a bait region and a thiol ester site, are encoded by the exon 18 and 24, respectively. Several possible regulatory signals such as a TPA-inducible enhancer core, an identifier sequence, purine-pyrimidine alternative stretches and viral enhancer core sequences were identified. Several genomic DNA clones which cross-hybridized with the alpha 2M cDNA probe were also identified. Sequence analysis showed that they possessed sequences identical to a part of the rat alpha 1-inhibitor III cDNA and that they had a strikingly similar exon organization to the alpha 2M gene.

Animals↗
PubMed1989

Identification of secretin diastereoisomers produced during synthesis.

The byproducts P-1 and P-2, which were produced during the synthesis of porcine secretin, were isolated in pure form from the crude secretin by HPLC. These were identified by a combination of amino acid analysis, enzymatic digestion, and isocratic or linear gradient reversed-phase (RP)-HPLC. The amino acid compositions of P1 and P2, determined by amino acid analysis after acid hydrolysis, were found to be the same as those of porcine secretin without distinction between L-and D-amino acids. But, HPLC of their digestive fragments with trypsin and alpha-chymotrypsin differed from that of secretin. The fragments, S7-12 of P-1 and S13-21 of P-2 were determined to be different from the corresponding fragments obtained from secretin by HPLC analysis of their digestive fragments. The amino acid composition of each acid hydrolysate, following digestion with D-amino acid oxidase, was found to have less leucine or alanine content than secretin. The HPLC analysis of the fragments from P-1 and P-2 by tryptic and alpha-chymotryptic digestion showed that they are the same as those from synthetic D-Leu10 secretin or D-Ala17 secretin, respectively. Consequently, P-1 and P-2 are concluded to be the secretin diastereoisomers, D-Leu10 and D-Ala17 secretin, respectively.

Amino Acids↗
PubMed1989

A new potential prodrug to improve the duration of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine.

L-3-(3-Hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355) is a novel L-dopa prodrug. After oral administration with carbidopa in rats, 1 demonstrated 2.3 times longer duration (MRT) and 1.4 times larger bioavailability (AUC) on plasma L-dopa concentrations than those of L-dopa itself. Similar results were obtained in dogs. The prolonged profile of L-dopa was parallel to that of carbidopa, and the intact ester was undetectable in rat plasma. After intravenous administration in rats, 1 was converted quickly and completely to L-dopa in the systemic circulation. It was also noted that the oral LD50 value of 1 was greater than 6 g/kg in mice. These data suggest that 1 will offer long-lasting L-dopa therapy for the treatment of Parkinson's disease with little concern about toxicity.

Animals↗
PubMed1989

On-off phenomenon in a child with tetrahydrobiopterin deficiency due to 6-pyruvoyl tetrahydropterin synthase deficiency (BH4 deficiency).

Marked fluctuations in mobility, known as the on-off phenomenon, frequently emerge during the course of chronic treatment with levodopa in patients with Parkinson's disease. Similar fluctuations in mobility and mental status have been observed in a 10-year-old Japanese girl with tetrahydrobiopterin deficiency (BH4 deficiency) while receiving neurotransmitter and biopterin supplement. In order to define the underlying mechanisms for the phenomenon in our patient, we studied the temporal relationship between plasma levodopa levels and clinical status during oral (2.0 mg/kg per day) and continuous intravenous (2.0 mg/kg per 12 h) administration of the drug. Following each oral levodopa dose, the plasma concentration of levodopa peaked at 60-90 ng/ml within 60 min and fell to 5-15 ng/ml within 2 h. The clinical state of the patient varied acutely in parallel with the plasma levodopa concentrations. The clinical swings completely disappeared when the plasma levodopa concentrations were stabilized between 120-150 ng/ml by continuous infusion. Paradoxically, on awakening from sleep, she was invariably ambulatory despite very low plasma levodopa levels (less than 10 ng/ml). These observations indicate that the on-off phenomenon in our patient reflect the fluctuations of plasma levodopa levels as demonstrated in Parkinson's disease, but there may be substantial differences in levodopa transport across the blood-brain barrier and/or striatal dopamine-receptor interaction between Parkinson's disease and BH4 deficiency.

Administration, Oral↗