Biomedical subjects

Shinya Uchida

Publications and source records attributed to Shinya Uchida.

15 recordsLinked to original sources

PubMed2007

Comparative evaluation of central muscarinic receptor binding activity by oxybutynin, tolterodine and darifenacin used to treat overactive bladder.

PURPOSE: We characterized muscarinic receptor binding in the mouse cerebral cortex after oral administration of anticholinergic agents used to treat overactive bladder. MATERIALS AND METHODS: Muscarinic receptors in the mouse cerebral cortex and bladder after oral administration of anticholinergic agents were measured using [(3)H]N-methylscopolamine. RESULTS: In vitro binding affinities of tolterodine and its metabolite 5-hydroxymethyl metabolite in the mouse cerebral cortex and bladder were considerably greater than those of oxybutynin and darifenacin. Also, muscarinic receptor binding affinity of oxybutynin and its metabolite N-desethyl-oxybutynin in the cerebral cortex compared with that in the bladder was 2 to 3 times higher, whereas that of tolterodine and 5-hydroxymethyl metabolite was approximately 2 times lower. Oral administration of oxybutynin (76.1 micromol/kg), tolterodine (6.31 micromol/kg) and darifenacin (59.1 micromol/kg) showed binding activity that was approximately equal to that of bladder muscarinic receptors. Oral administration of oxybutynin (76.1 micromol/kg) showed significant binding of cerebral cortical muscarinic receptors in mice, as indicated by about a 2-fold increase in K(d) values for specific [(3)H]N-methylscopolamine binding 0.5 and 2 hours later. On the other hand, tolterodine and darifenacin given at oral doses that would exert a similar extent of bladder receptor binding activity as oxybutynin showed only a low level of binding activity of central muscarinic receptors in mice. CONCLUSIONS: Significant binding of brain muscarinic receptors in mice was observed by the oral administration of oxybutynin but not tolterodine and darifenacin.

Animals↗

PubMed2006

In vivo demonstration of M3 muscarinic receptor subtype selectivity of darifenacin in mice.

A novel muscarinic receptor antagonist, darifenacin, inhibited specific binding of [N-methyl-(3)H]scopolamine ([(3)H]NMS) in the mouse bladder, submaxillary gland and heart in a concentration-dependent manner. The inhibitory effect was most potent in the submaxillary gland, followed by the bladder and heart. In addition, darifenacin inhibited specific [(3)H]NMS binding in the membranes of CHO-K1 cell lines expressing muscarinic M(2) and M(3) receptor subtypes, and the potency was significantly (22-fold) greater at the M(3) than at the M(2) subtype. At 0.5 to 12 h after oral administration of darifenacin, a significant increase in K(d) values for specific [(3)H]NMS binding was seen in the bladder, submaxillary gland and lung of mice, compared with control values. Also, there was a sustained decrease in the B(max) values in the submaxillary gland. These data suggest that muscarinic receptor binding of oral darifenacin is rapid in onset and of a long duration. On the other hand, oral darifenacin exerted only temporary or little binding of muscarinic receptors in the heart and colon. Pilocarpine-induced salivary secretion in mice was continuously suppressed by oral darifenacin. The time-course of suppression coincided well with that for the muscarinic receptor binding in the submaxillary gland. The antagonistic effect of darifenacin against the dose-response curves for pilocarpine appeared to be insurmountable. In conclusion, the present study has shown that oral darifenacin may exert a pronounced and long-lasting binding of muscarinic receptors in tissues expressing the M(3) subtype.

Administration, Oral↗

PubMed2006

Development of dry powder inhalation system of novel vasoactive intestinal peptide (VIP) analogue for pulmonary administration.

Vasoactive intestinal peptide (VIP) exerts a relaxing action on tracheal smooth muscle which is mediated through interaction with VIP receptors. The deficiency of VIP in the airways has been implicated in the pathogenesis of asthma. Thus, the administration of VIP may be useful for the therapy of pulmonary diseases. However, the therapeutic application of VIP is largely limited by its rapid degradation in addition to the systemic adverse effects due to the wide distribution of VIP receptors. To overcome these problems, we succeeded to synthesize a novel VIP derivative of VIP, [R15, 20, 21, L17]-VIP-GRR (IK312532), and to prepare its dry powder for the topical administration to the lung. The physicochemical properties of dry powder were evaluated by laser diffraction and cascade impactor. The laser diffraction analysis indicated that the carrier and fine particles had median diameter of 65.6 and 4.5 microm, respectively, and the air flow at the pressure of 0.15 MPa or higher resulted in the high dispersion and significant separation of fine particle containing peptide from the carrier molecule. The cascade impactor analysis clearly showed the high emission of dry powder from capsule and the deposition of peptide on stages 3 of the cascade impactor. The intratracheal administration of dry powder inhaler (DPI) of VIP or IK312532 brought about a significant decrease of maximal number of binding sites (Bmax) for [125I]VIP in anterior and posterior lobes of rat right lung, suggesting a significant occupancy of lung VIP receptors. This effect by IK312532-DPI compared with VIP-DPI lasted for a longer period. Thus, IK312532-DPI may be a pharmacologically useful drug delivery system for the VIP therapy of pulmonary diseases such as asthma.

Administration, Inhalation↗

PubMed2006

Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers.

This study was undertaken to clarify the influence of repeated oral administration of Ginkgo biloba extract (GBE) on CYP2C9 and CYP3A4. CYP2C9 probe (tolbutamide, 125 mg) and CYP3A4 probe (midazolam, 8 mg) were orally administered to 10 male healthy volunteers before and after GBE intake (360 mg/d) for 28 days, and they received 75 g glucose after the dosing of tolbutamide. Plasma drug concentrations and blood glucose levels were measured. The area under concentration versus time curve (AUC0-infinity) for tolbutamide after GBE intake was slightly but significantly (16%) lower than that before GBE intake. Concomitantly, GBE tended to attenuate AUC0-2 of blood glucose-lowering effect of tolbutamide. AUC0-infinity for midazolam was significantly (25%) increased by GBE intake and oral clearance was significantly (26%) decreased. Thus, it is suggested that the combination of GBE and drugs should be cautious in terms of the potential interactions, especially in elderly patients or patients treated with drugs exerting relatively narrow therapeutic windows.

Adult↗

PubMed2005

Cortical activation in the processing of passive sentences in L1 and L2: an fMRI study.

The question of whether the bilingual brain processes a first and second language (L1 and L2, respectively) differently is a central issue in many psycholinguistic and neurolinguistic studies. This study used functional magnetic resonance imaging (fMRI) to investigate whether late bilinguals process structurally complex sentences in L1 and L2 in different cortical networks. For this purpose, we directly compared brain activity during the processing of active and passive sentences in both L1 and L2. We asked 36 healthy subjects to judge whether or not a presented sentence was semantically plausible. Both L1 and L2 activated the left hemispheric language-related regions such as the left inferior frontal, superior/middle temporal, and parietal cortices. However, we found different activation patterns between L1 and L2 in the processing of passive sentences. Passive sentences elicited greater activation than their active counterparts in the left pars triangularis, the premotor area, and the superior parietal lobule in Japanese, but not in English. Furthermore, there was a significant interaction between sentence type (active versus passive) and language (Japanese versus English) in the left pars orbitalis. The results of this study indicate that late bilinguals use similar cortical regions to comprehend both L1 and L2. However, when late bilinguals are presented with structurally complex sentences, the involvement of these regions differs between L1 and L2. These results suggest that, in addition to age of L2 acquisition and L2 proficiency, differences in grammatical construction affect cortical representation during the comprehension of L1 and L2.

Adult↗

PubMed2005

Male elderly subthreshold depression patients have smaller volume of medial part of prefrontal cortex and precentral gyrus compared with age-matched normal subjects: a voxel-based morphometry.

BACKGROUND: The brain morphological changes in subthreshold depression (sD) have not been clarified. We examined the structural difference in regional gray matter volume between community-dwelling elderly subjects with sD and age-matched nondepressed normal subjects by voxel-based morphometry (VBM) based on magnetic resonance imaging (MRI). METHODS: Thirty-four community-dwelling elderly subjects with sD and 109 age-matched nondepressed normal subjects were studied by MRI. We defined subjects with sD as those who showed a Geriatric Depression Scale score of 15 or higher and a Mini Mental State Examination score of 22 or higher, and do not fulfill the criteria of major depressive disorder (MDD) in the Diagnostic and Statistical Manual for Mental Disorders IV. We collected brain magnetic resonance images of 34 subjects with sD and 109 age-matched normal subjects, and analyzed the difference in regional gray matter volume between these two groups by VBM. RESULTS: Male subjects with sD had significantly smaller volumes of the medial part of the bilateral frontal lobes and the right precentral gyrus than normal male subjects. LIMITATIONS: We have not clarified the discrepancy in the results of gender difference. CONCLUSIONS: Our study revealed that even community-dwelling elderly male subjects with sD show bilateral prefrontal gray matter volume reduction, which was reported to be observed in elderly patients with MDD, although there is no significant volume reduction in the hippocampus, which was also reported to be observed in MDD. Our study may contribute to clarifying the mechanism underlying brain pathological changes in sD.

Age of Onset↗

PubMed2005

Effects of continuous administration of paroxetine on ligand binding site and expression of serotonin transporter protein in mouse brain.

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, are utilized in the treatment of depression and anxiety disorders. Although SSRIs potently interfere with the activity of brain serotonin transporter (SERT) after acute treatment, clinical improvement of psychiatric diseases is observed only after the repeated administration for several weeks (2-6 weeks). The present study was undertaken to investigate the effects of continuous administration of paroxetine on specific [3H]paroxetine binding sites and expression of SERT protein in mouse brain. Mice continuously and subcutaneously received paroxetine at doses of 2.67 or 13.3 mumol/kg/day for 21 days by using osmotic minipumps, and the steady-state plasma drug levels were within the range of reported concentrations in the clinical therapy. Continuous administration of paroxetine at theses doses produced significant (25-46%) reduction of [3H]paroxetine binding in each brain region (cerebral cortex, striatum, hippocampus, thalamus, midbrain) of mice. In Western blot analysis, expression levels of SERT protein in the thalamus and midbrain of mice were significantly (51% and 61%, respectively) decreased on day 21 after the implantation of minipumps at the higher dose. In conclusion, this study has firstly shown that continuous administration of paroxetine induces significant reduction of not only ligand binding sites of SERT but the protein expression level in mouse brain. Such down-regulation of SERT may partly underlie the therapeutic effect of long-term treatment with SSRIs in human.

Analysis of Variance↗

PubMed2005

Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors.

1. The present study was undertaken to characterise the relationship between in vivo brain serotonin transporter (SERT) binding, plasma concentration and pharmacological effect of selective serotonin reuptake inhibitors (SSRIs) in mice. Oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at pharmacologically relevant doses exerted dose- and time-dependent binding activity of brain SERT as revealed by significant increases in KD for specific [3H]paroxetine binding, and the in vivo SERT-binding potency was in the order of paroxetine>>fluoxetine, sertraline>fluvoxamine. 2. The time courses of brain SERT binding by SSRIs in mice were mostly in parallel to those of their plasma concentrations. Also, norfluoxetine (active metabolite) has been suggested to contribute largely to the long-lasting binding activity of brain SERT after the fluoxetine administration. 3. Oral administration of each SSRI suppressed significantly the marble-burying behaviour with no change in locomotor activity in mice, and the extent and time course of suppression agreed well with those of brain SERT binding. Thus, the pharmacological potencies of SSRIs in the attenuation of marble-burying behaviour correlated significantly with their brain SERT binding activities. 4. In conclusion, the present study has provided the first in vivo evidences to support that fluvoxamine, fluoxetine, paroxetine and sertraline orally administered bind to the pharmacologically relevant brain SERT in mice and that their SERT-binding characteristics is closely associated with the pharmacokinetics and inhibition of marble-burying behaviour.

Animals↗

PubMed2005

Interaction between amlodipine and simvastatin in patients with hypercholesterolemia and hypertension.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are often prescribed in association with antihypertensive agents, including calcium antagonists. Simvastatin is an HMG-CoA reductase inhibitor that is metabolized by the cytochrome P450 (CYP) 3A4. The calcium antagonist amlodipine is also metabolized by CYP3A4. The purpose of this study was to investigate drug interactions between amlodipine and simvastatin. Eight patients with hypercholesterolemia and hypertension were enrolled. They were given 4 weeks of oral simvastatin (5 mg/day), followed by 4 weeks of oral amlodipine (5 mg/day) co-administered with simvastatin (5 mg/day). Combined treatment with simvastatin and amlodipine increased the peak concentration (C(max)) of HMG-CoA reductase inhibitors from 9.6 +/- 3.7 ng/ml to 13.7 +/- 4.7 ng/ml (p < 0.05) and the area under the concentration-time curve (AUC) from 34.3 +/- 16.5 ng h/ml to 43.9 +/- 16.6 ng h/ml (p < 0.05) without affecting the cholesterol-lowering effect of simvastatin. This study is the first to determine prospectively the pharmacokinetic and pharmacodynamic interaction between amlodipine and simvastatin.

Administration, Oral↗

PubMed2004

Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension.

Pharmacokinetic and pharmacodynamic interactions between simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and diltiazem, a calcium antagonist, were investigated in 7 male and 4 female patients with hypercholesterolemia and hypertension. The patients were given, for one in a three consecutive 4-week periods, oral simvastatin (5 mg/day), oral simvastatin (5 mg/day) combined with diltiazem (90 mg/day), and then oral diltiazem (90 mg/day), respectively. The area under the plasma concentration versus time curve up to 6 hours post-dose (AUC0-6h) and maximum plasma concentrations (Cmax) of the drugs, serum lipid profiles, blood pressures and liver functions were assessed on the last day of each of the three 4-week periods. After the combined treatment period, Cmax of HMG-CoA reductase inhibitor was elevated from 7.8 +/- 2.6 ng/ml to 15.4 +/- 7.9 ng/ml (P < 0.01) and AUC0-6h from 21.7 +/- 4.9 ng x hr/ml to 43.3 +/- 23.4 ng x hr/ml (P < 0.01), while Cmax of diltiazem was decreased from 74.2 +/- 36.4 ng/ml to 58.6 +/- 18.9 ng/ml (P < 0.05) and its AUC0-6h from 365 +/- 153 ng x hr/ml to 287 +/- 113 ng x hr/ml (P < 0.01). Compared to simvastatin monotherapy, combined treatment further reduced LDL-cholesterol levels by 9%, from 129 +/- 16 mg/dl to 119 +/- 17 mg/dl (P < 0.05). No adverse events were observed throughout the study. These apparent pharmacokinetic interactions, namely the increase of HMG-CoA reductase inhibitor concentration by diltiazem and the decrease of diltiazem concentration by simvastatin, enhance the cholesterol-lowering effects of simvastatin during combined treatment.

Administration, Oral↗

PubMed2004

Effects of oral administration of extracts of Hypericum perforatum (St John's wort) on brain serotonin transporter, serotonin uptake and behaviour in mice.

The pharmacological effects of extracts of Hypericum perforatum (St John's wort) were characterized in-vitro and ex-vivo, in relation to its behavioural effects. In in-vitro experiments, St John's wort inhibited brain synaptosomal [(3)H]serotonin uptake in mice with little effect on specific [(3)H]paroxetine binding. For selective serotonin-reuptake inhibitors (SSRIs), the IC50 value for [(3)H]serotonin uptake (molar concentration of unlabelled drug necessary to displace 50% of specific uptake) correlated well with the inhibition constant K(i) value for [(3)H]paroxetine binding in mouse brain. Oral administration of St John's wort (900 mg kg(-1)), paroxetine (1 mg kg(-1)) and sertraline (10 mg kg(-1)) brought about significant increases in the K(m) value for [(3)H]serotonin uptake into brain synaptosomes 4 h later, and only SSRIs suppressed specific [(3)H]paroxetine binding in mouse brain. St John's wort and SSRIs significantly inhibited marble-burying behaviour in mice and the time-course of attenuation of this behaviour by St John's wort was similar to that of [(3)H]serotonin uptake inhibition. In the forced swimming test, St John's wort, but not SSRIs, suppressed the immobility time of mice after oral administration. These results provide the first in-vivo evidence to suggest that the mode of antidepressant action of St John's wort differs from that of SSRIs. Thus, this study may have a significant impact on phytotherapy with St John's wort.

Administration, Oral↗

PubMed2003

Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C91/3 genotype.

An 89-year-old man with severe hypertension (190/82 mm Hg) and chronic heart failure (New York Heart Association class II) despite treatment with benidipine, doxazosin mesylate (INN, doxazosin), and furosemide was given oral candesartan cilexetil (4 mg/d), an angiotensin II type 1 receptor blocker metabolized via cytochrome p450 (CYP) 2C9. Two days later, he started to have severe dizziness and returned to the hospital on the fourth day without taking any of his medications. The blood pressure 30 hours after the last dose of candesartan was 126/64 mm Hg. Polymorphism analysis revealed the heterozygous poor metabolizer genotype CYP2C9*1/*3. The area under the concentration-time curve and the mean residence time of candesartan were both increased 2.5-fold, and the oral clearance of candesartan was 48% lower than that of the average elderly Japanese patient with hypertension. These results suggest that the CYP2C9*1/*3 genotype could be associated with decreased clearance and increased plasma concentration of candesartan, potentially enhancing its hypotensive effect.

Aged↗

PubMed2003

Blood-brain permeability of [3H]-(3-methyl-His2)thyrotropin-releasing hormone (MeTRH) in mice: effects of TRH and its analogues.

The present study was undertaken to characterize the transport of (3-methyl-His(2)) thyrotropin-releasing hormone ([(3)H]MeTRH) across the blood-brain barrier in mice and the effects of thyrotropin-releasing hormone (TRH) and its analogues (taltirelin and montirelin) on the transport and brain distribution. Integration plot analysis was used to calculate the influx clearance (CL(in)) of [(3)H]MeTRH after intravenous (i.v.) injection in mice. Furthermore, the capillary depletion method was performed to determine whether [(3)H]MeTRH crossed the blood-brain barrier. The effects of TRH and its analogues on the brain distribution of [(3)H]MeTRH were also examined by co-injection with the radioligand. The brain distribution of [(3)H]MeTRH and [(14)C]sucrose increased with the time after i.v. injection in mice, and the level of [(3)H]MeTRH was significantly higher than that of [(14)C]sucrose 5 min after the injection. The CL(in) value of [(3)H]MeTRH was significantly higher than that of [(14)C]sucrose, and the value of [(3)H]MeTRH was reduced by co-injection with unlabeled MeTRH. Also, capillary depletion showed that [(3)H]MeTRH was distributed largely in the brain parenchyma and this distribution was significantly inhibited by co-injection of TRH and montirelin but not taltirelin. The present study indicates that the transport of [(3)H]MeTRH into the brain may be via a saturable process.

Journal Article↗

PubMed2002

In vivo receptor binding of benidipine and amlodipine in mesenteric arteries and other tissues of spontaneously hypertensive rats.

The present study was undertaken to characterize the in vivo 1,4-dihydropyridine (DHP) receptor binding of long-acting 1,4-DHP calcium channel antagonists in the mesenteric artery and other tissues of SHR. In vivo specific binding of (+)-[3H]PN 200-110 in the SHR mesenteric artery was significantly (36.6-49.7 %) reduced 1-8 h after oral administration of benidipine (1.84 micromol/kg). A greater reduction in (+)-[3H]PN 200-110 binding in the mesenteric artery was observed at a higher dose (5.53 micromol/kg) of this drug. This dose of benidipine also reduced significantly the in vivo specific (+)-[3H]PN 200-110 binding in the aorta but not in the myocardium and cerebral cortex. Following oral administration of amlodipine (17.6 micromol/kg), a significant (51.7-94.2 %) reduction in (+)-[3H]PN 200-110 binding was seen at 1-18 h in the mesenteric artery and at 1-12 h in the aorta. Only a slight reduction in myocardial and cerebral cortical (+)-[3H]PN 200-110 binding was seen following amlodipine administration. In contrast, oral administration of nifedipine (28.9 micromol/kg) reduced markedly in vivo (+)-[3H]PN 200-110 binding in all the tissues of SHR at 1-6 h, and the degree and time-course of the reduction did not differ significantly among the tissues. The area under the curve (AUC) for the receptor occupancy vs time was calculated from the reduction rate (%) of in vivo specific (+)-[3H]PN 200-110 binding. The ratios of the AUCmesenteric artery to AUCaorta or AUCmesenteric artery to AUCmyocardium after oral administration of benidipine and amlodipine were greater than the corresponding value for nifedipine. The degree and time-course of arterial receptor occupancy by benidipine and amlodipine agreed well with those of their hypotensive effects in the conscious SHR. In conclusion, the present study demonstrates that benidipine and amlodipine may occupy, in a more selective and sustained manner, 1,4-DHP receptors in arterial tissues than in other tissues of SHR, and thus, such receptor binding specificity may be responsible for the long-lasting hypotensive effects of these drugs.

Amlodipine↗

PubMed2002

In vivo measurement of 1,4-dihydropyridine receptors in mesenteric arteries of spontaneously hypertensive rats and effect of nifedipine and cilnidipine.

The present study was undertaken to measure 1,4-dihydropyridine (DHP) receptor binding sites in vivo in the mesenteric artery and other tissues of spontaneously hypertensive rats (SHR) and to examine the effect of nifedipine and cilnidipine. Specific in vivo binding of (+)-[3H]PN 200-110 in the SHR mesenteric artery was dose dependently reduced by oral administration of nifedipine at relatively low doses. Oral administration of cilnidipine (6.09 micromol/kg) significantly reduced the specific in vivo binding of (+)-[3H]PN 200-110 in the mesenteric artery, aorta, and myocardium. A significant reduction in (+)-[3H]PN 200-110 binding was seen at 1-12 h in the mesenteric artery and at 1-7 h in the aorta and myocardium. In contrast, oral administration of nifedipine (28.9 micromol/kg) markedly reduced in vivo (+)-[3H]PN 200-110 binding in all tissues of SHR at 1-6 h, and the degree and time course of the reduction did not differ much among the tissues. The area under the curve (AUC) for receptor occupancy vs. time was calculated from the reduction rate (%) of specific in vivo (+)-[3H]PN 200-110 binding. The ratio (1.4 or 1.7) of the AUC(mesenteric artery) to AUCaorta or AUCmyocardium after oral administration of cilnidipine was greater than the corresponding value (1.1) for nifedipine. In conclusion, the present study demonstrates that cilnidipine, but not nifedipine, may occupy 1,4-DHP receptors in the small artery in a more selective and sustained manner than in other tissues of SHR, and thus such receptor binding specificity may be responsible for the long-lasting hypotensive effect of this drug.

Animals↗