Biomedical subjects

Y Morimoto

Publications and source records attributed to Y Morimoto.

At least 289 records · Page 16Linked to original sources

PubMed1994

The effect of different routes of administration on the metabolism of morphine: the disposition of morphine and its metabolites after topical application.

The disposition of morphine (MOR) and its metabolites in the rabbit was measured after topical administration of its hydrochloride salt (MOR.HCl), and their time course was compared with those after intravenous and oral administration. The area under the plasma concentration-time curve (AUC) ratio of metabolites/MOR after the topical application of MOR.HCl was similar to that after intravenous injection, but differed from that after oral administration. Pharmacokinetic parameters of the disposition of MOR and its metabolites were obtained by a general curve fitting of the time course of plasma concentrations of these compounds after intravenous injection of MOR.HCl and its metabolites, respectively. On the other hand, the time courses of plasma concentrations of the metabolites after intravenous, oral, and topical administration of MOR.HCl were simulated using a simple compartment model without consideration of enterohepatic circulation and the pharmacokinetic parameters obtained as above. The resulting curves of the metabolites agreed well with the observed values except for those after oral administration. These results suggest that no first-pass metabolism of MOR.HCl occurs after percutaneous administration, and that topical administration of this salt is more advantageous than oral administration in terms of bioavailability.

Administration, Oral↗

PubMed1994

Effect of low-intensity argon laser irradiation on mitochondrial respiration.

We studied influences of low-intensity argon laser irradiation at various wavelengths on mitochondrial respiration in vitro. Isolated guinea pig liver mitochondria were suspended in an isotonic buffer solution (pH 7.4, 37 degrees C). The mitochondrial suspension was introduced into a constant temperature reaction chamber in which an irradiation fiber, a thermocouple, an oxygen electrode, and a stirrer were installed. Under respiratory conditions of state 4, state 3, and uncoupled respiration, mitochondrial oxygen consumption was measured during low-intensity argon laser irradiations at 351nm, 458 nm, and 514.5 nm. The 351 nm and the 458 nm irradiations at 200 mW inhibited uncoupled respiration by 19% and 11%, respectively, and the irradiation at 351 nm inhibited state 3 respiration as well by 10%. In contrast, the 514.5 nm irradiation enhanced both state 3 and uncoupled respiration by 6-7%. Temperature reference experiments indicated that the thermal effect alone could not account for the effects of laser irradiation on mitochondrial oxygen consumption. These results suggest that the 351 nm and the 458 nm laser irradiation may injure the mitochondrial inner membrane, while the 514.5 nm laser irradiation may slightly promote the rate of ATP synthesis.

2,4-Dinitrophenol↗

PubMed1994

Effect of sodium taurodihydrofusidate on nasal drug delivery: differences in its concentration and penetrant molecular weight.

The effect of sodium taurodihydrofusidate (STDHF) on drug permeation across nasal mucosa was studied in vitro using Ussing type diffusion chamber. Disodium cromoglicate (DSCG, M.W. 512.3) and fluorescein isothiocyanate-dextran (FD) of different molecular weights (M.W. 4400-71200) were used as model drugs. Permeation profiles of DSCG and FDs showed a typical pseudo steady-state curve with short lag time. The permeability coefficient of FD (M.W. 9400) sigmodially increased with increasing STDHF concentration. It also enhanced the DSCG permeation. Interestingly the enhancement efficacy was independent of molecular weight of penetrants.

Adjuvants, Pharmaceutic↗

PubMed1994

Interaction between drugs and pressure-sensitive adhesives in transdermal therapeutic systems.

Release experiments with four drugs using representative pressure-sensitive adhesive (PSA) matrices were performed at 37 degrees C, and drug-PSA polymer interaction was determined by the Williams, Landel, and Ferry (WLF) equation. Two acrylic-type [2-ethylhexylacrylate and acrylic acid copolymer (2EHA/AA) or acrylamide copolymer (2EHA/AAm)], one rubber-type (a mixture of high and low molecular weight polyisobutylene), and one silicone-type PSA were used, and dipropylphthalate (PP), aminopyrine (AMP), ketoprofen (KP), and lidocaine (LC) were selected as model drugs because of their molecular size and functional groups. PSA containing acrylic acid (2EHA/AA) strongly interacted with the amide LC, with the tertiary amine AMP, and with the carboxylic acid KP; PSA-containing acrylamide (2EHA/AAm), however, did not interact with LC or AMP, although it markedly interacted with KP. The rubber-type and silicone-type PSAs, composed of no or only a few polar functional groups, did not interact with any of the drugs used in this experiment. Therefore, the diffusion coefficient of the drugs through PSA was influenced by the drug-PSA polymer interaction, and the extent of this interaction can be estimated by the relationship between the drug concentrations in the PSA and their diffusion coefficients.

Acrylates↗

PubMed1994

An application of the hydrodynamic pore theory to percutaneous absorption of drugs.

Skin permeability of drugs was evaluated based on the hydrodynamic pore theory. Four polar solutes were used, with differing molecular sizes--ethylene glycol, 1,3-butylene glycol, antipyrine and sucrose--and isosorbide dinitrate was also selected as a lipophilic drug. The skin permeations of solvent (D2O) and one of these drugs were measured simultaneously under various osmotic pressures to calculate the reflection coefficient. The clearance of isosorbide dinitrate was independent of the solvent flux, whereas a linear relationship was obtained between the solvent flux and the clearance of each hydrophilic drug except for sucrose. The reflection coefficient of the hydrophilic drugs increased with increasing molecular radius. These results suggest that the convective flow contributes significantly to the total skin permeability of hydrophilic drugs and that the extent of contribution decreases with increasing molecular size of the drugs. The pore radius of the skin barrier could be estimated from the reflection coefficient of the hydrophilic drugs and the resulting value was compared with that for the other absorption sites, jejunum, rectum, and nose. The apparent water influx was also compared to assess the volume occupied by the pores. The pore radius and apparent influx of skin were lower than those for the other absorption sites, which is apparently one reason for low skin permeability of drugs, especially hydrophilic drugs.

Animals↗

PubMed1994

Analysis of the combined effect of 1-menthol and ethanol as skin permeation enhancers based on a two-layer skin model.

The combined effects of 1-menthol and ethanol as a skin permeation enhancer were evaluated with two equations describing the permeability coefficient through full-thickness skin (PFT) and the full-thickness skin/vehicle concentration ratio (CFT/CV) of drugs as a function of their octanol/vehicle partition coefficient (KOV). A two-layer model was applied for skin, which consists of a stratum corneum (SC) with lipid and porous pathways and a viable epidermis and dermis (ED). The two equations contain one variable (KOV) and nine coefficients, six of which (three diffusion coefficients, the porosity of the SC, and two terms of the linear free energy relationship) were considered different, dependent on the drug vehicle. In vitro permeation of four drugs (morphine hydrochloride, atenolol, nifedipine, and vinpocetine) was determined using excised hairless rat skin and four aqueous vehicles (water, 5% 1-menthol, 40% ethanol, and 5% 1-menthol-40% ethanol) to measure each PFT. Drug concentrations in full-thickness skin were also measured to obtain CFT/CV. A nonlinear least-squares method was employed to determine six coefficients using the two equations and experimentally obtained PFT and CFT/CV. The addition of 1-menthol to water and 40% ethanol increased the diffusion coefficient of drugs in lipid and pore pathways of SC, whereas the addition of ethanol to water and 5% 1-menthol increased the drug solubility in the vehicle, decreased the skin polarity, and increased the contribution of the pore pathway to whole-skin permeation.

Animals↗

PubMed1994

Dynamic properties of nucleic acids in biosupramolecular systems, as studied by 31P NMR.

The dynamic properties of nucleic acids in five different types of intact supramolecular systems, namely, chicken erythrocyte chromatin, the wild type and a deletion mutant of the lambda phage, lipid-containing phage PM2, and Alteromonas espejiana ribosomes, were investigated by means of 31P solid-state NMR. The nucleic acids in the different supramolecular systems showed unique dynamic properties, which are closely connected with their functions. The total anisotropy of the phosphorus chemical shift (delta sigma = sigma 33-sigma 11) of the ribosomes was 210 ppm at 5 degrees C. This anisotropy was much larger than those of any DNA complexes, suggesting the highly rigid structure of ribosomal RNA. In contrast, 160 ppm was the largest chemical shift anisotropy at 5 degrees C for B-form DNA in the supramolecular systems. This flexibility would be essential for DNAs to exert their functions. The involvement of a condensation protein in the PM2 phage was supported by the chemical shift anisotropy. The spin-lattice relaxation time in the proton rotating frame [T1 rho(H)] of the nucleic acids became shorter with the increase in the effective field in the rotating frame for all systems examined, showing that the motions of the nucleic acids effective for the relaxation are in the slow motional regime or in the range of omega 1 tau c = 1 at 5 degrees C. The motional state of DNA of the lambda phage was found to change at about 20 degrees C on the basis of the temperature dependence of the spin-lattice relaxation time of phosphorus (T1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Noninvasive, continuous blood pressure measurement by arterial tonometry during anesthesia in children.

BACKGROUND: The authors' previous study of arterial tonometry in children demonstrated poor agreement of tonometric blood pressure (TBP) measurements with intraarterial blood pressure (IBP) measurements. The aim of the current study is to evaluate the feasibility of TBP measurements in children aged 1-6 yr using a newly designed pediatric sensor housing, by comparing TBP values with values obtained by IBP measurements. METHODS: Thirty-four children (aged 1-6 yr, ASA physical status 1-2) were studied undergoing elective abdominal or urologic surgery under general anesthesia. A 22- or 24-G cannula was inserted into the right radial artery. A TBP sensor housing was positioned over the left radial artery. TBP and IBP were continuously monitored and data were periodically sampled during and after intubation, during surgery, and during the recovery period. RESULTS: TBP waveforms were similar to those of IBP. Limits of agreement (bias +/- 2 SD) were 12 and -13.3 mmHg for systolic, 11.6 and -10.4 mmHg for mean, and 13.2 and -10.8 mmHg for diastolic pressures for 3,400 paired points. Measurements could not be made in ten children because of insufficient pulse contour. CONCLUSIONS: When pulse contour is sufficient for analysis, TBP monitoring provides an apparently safe and accurate method for the continuous measurement of arterial blood pressure during anesthesia in children aged 1-6 yr.

Anesthesia↗

PubMed1994

The pharmacological properties of Y-23684, a benzodiazepine receptor partial agonist.

1. The pharmacological properties of a benzodiazepine receptor (BZR) partial agonist, Y-23684 were investigated in comparison with those of diazepam, a conventional BZR full agonist. 2. Y-23684 and diazepam showed high and selective affinity for the BZR with Ki values of 41 and 5.8 nM, respectively. 3. In contrast to diazepam, variability was noted in the anticonvulsive potency of Y-23684 depending on convulsants (bicuculline, pentylenetetrazol and maximal electrical shock). Y-23684 produced the most potent protective effect against bicuculline in rats and mice with ED50S of 1.3 and 1.2 mg kg-1, respectively. 4. In rat conflict models (Geller-Seifter and water-lick tests), Y-23684 produced an antipunishment action at doses 2-4 times lower than diazepam. In contrast to diazepam, Y-23684 did not affect unpunished responding up to 50 mg kg-1 in the Geller-Seifter test. 5. In other rat models of anxiety (social interaction and elevated plus-maze tests), Y-23684 was as efficacious as and ten fold more potent than diazepam. In a mouse model of anxiety (exploration (light/dark box) test), Y-23684 was as efficacious and two fold less potent as diazepam. In these paradigms, Y-23684 showed a selective anxiolytic profile over a wide dose-range without loss of efficacy and sedative action. 6. The impairment of motor coordination (rotarod) and potentiation of CNS depressants (ethanol and hexobarbitone) by Y-23684 was much weaker than that of diazepam. 7. These results suggest that Y-23684 would be a potent and selective anxiolytic agent in man with less side-effects than conventional BZ-anxiolytics.

Animals↗

PubMed1994

Effects of inhaled ceramic fibres on macrophage function of rat lungs.

To evaluate the biological effect of ceramic fibres on the clearance function of alveolar macrophages (AMs) morphological changes and phagocytic activity of AMs were assessed. Rats were exposed to respirable ceramic fibres with a mass median aerodynamic diameter of 4.4 microns and a concentration of 20.1 mg/m3 in an exposure chamber. They were killed after one week (group A) and two weeks (group B) of exposure, and four weeks (group C) and 12 weeks (group D) after exposure for two weeks. The AMs recovered by bronchoalveolar lavage (BAL) from each test group were incubated with yeast and phagocytic activity was determined by counting the number of yeast cells in AMs. Morphological features of AMs were assessed by scanning electron microscopy and quantified according to morphological changes. Total cell counts in BAL fluid from exposed rats in group A were higher than in control rats. Phagocytic activity of exposed AMs in group B and C exceeded that of control AMs. Morphological changes of the exposed AMs in groups A, B, and C were greater than those of control AMs. These findings suggest that ceramic fibres induced the phagocytic activity and morphological changes in AMs, and that the clearance function of AMs was stimulated by the inhaled ceramic fibres.

Animals↗

PubMed1994

Retention and clearance of inhaled ceramic fibres in rat lungs and development of a dissolution model.

Male Wistar rats were exposed to aluminium silicate ceramic fibres by inhalation to study pulmonary deposition, clearance, and dissolution of the fibres. Rats were killed at one day, one month, three months, and six months after the termination of exposure. After exposure, fibres greater than 50 microns in length were seen with a scanning electron microscope in the alveolar region of the lung. Fibres were recovered from the lungs with a low temperature ashing technique and their number, diameter, and length were measured by scanning electron microscopy. The number of fibres remaining in the lungs declined exponentially with time after exposure and their silicon content also fell. The geometric median diameter of fibres decreased linearly with time. By six months after exposure, the surface of fibres recovered from the lungs had an eroded appearance. The results suggest that ceramic fibres are physically cleared from the lung and that they show signs of dissolution. Finally, the results were used to develop a theoretical model of fibre dissolution that gives a satisfactory fit to the experimental data.

Aluminum Silicates↗

PubMed1994

Effect of skin surface lipid on the skin permeation of lidocaine from pressure sensitive adhesives.

Pressure sensitive adhesives (PSA) tapes containing different concentrations of lidocaine were prepared by a general casting method using styrene-isoprene-styrene block copolymer, and the in vitro skin permeation of lidocaine from each tape was evaluated using diffusion cell and excised hairless rat skin. The skin permeation was proportionally increased by up to 40% lidocaine in the PSA tape and did not change after this concentration. Although the bending point of the steady-state flux via skin concentration curve was found at 40%, saturated concentration or solubility of lidocaine in the tape was estimated to be about 20% by differential scanning calorimetry (DSC) measurement. In addition, the steady-state flux of lidocaine through skin from water or silicone fluid suspension (92 or 120 micrograms/cm2.h, respectively) was very similar to those of 40, 50 and 60% tapes (105, 101 and 112 micrograms/cm2.h, respectively). Decrease in the concentration in tapes during the permeation experiment explained only part of these phenomena. To analyze them further, the drug free PSA tape with or without (control) skin surface lipid was affixed to 50% lidocaine PSA tape for 48 h, and the amount of lidocaine crystal in the layered tapes was measured by DSC. The amount was found to be lower in the lipid-containing tape than in the lipid-free tape, suggesting that skin surface lipid can dissolve lidocaine crystal or solid in PSA tape to decrease its thermodynamic activity. Thus it is important to follow the concentration and thermodynamic activity of lidocaine in PSA tape, skin and the interface between the two layers to exactly assess its skin permeation flux.

Adhesives↗

PubMed1994

Evaluation of enhancers to increase nasal absorption using Ussing chamber technique.

The effects of eight prospective absorption enhancers on the nasal mucosa in rabbit have been assessed using an in vitro Ussing chamber technique. Sodium taurodihydrofusidate (STDHF), sodium deoxycholate (DC), polyoxyethylene-9-lauryl ether (BL-9), lysophosphatidylcholine (LPC) and sodium dodecyl sulfate (SDS) were found to possess relatively high protein leaching activity, while sodium glycocholate (GC), sodium taurocholate (TC) and EDTA had relatively low activity. The permeation of fluorescein isothiocyanate-labeled dextran (FD, M.W. 9400) as a model drug across the nasal mucosa was found to be greater in the presence of these enhancers. Their enhancement ratio was found to be in the order of BL-9 > STDHF > SDS > LPC > DC > EDTA > GC > TC, which correlated with the protein leaching activity. The differences in protein leaching and enhancement ratio dependent on the magnitude of change of membrane resistance (delta Rm), indicating that these enhancers damaged the membrane and increased FD permeation. delta Rm thus appears to be a useful indicator by which one can estimate nasal mucosa damage by the enhancers.

Absorption↗

PubMed1994

In vitro-in vivo correlation of percutaneous absorption: isosorbide dinitrate and morphine hydrochloride.

The potential of an in vitro skin preparation as a model for predicting in vivo percutaneous absorption of drugs was examined. In vitro and in vivo skin permeation data for two model drugs with different lipophilicity, isosorbide dinitrate (ISDN) and morphine hydrochloride (MPH), were compared using pharmacokinetic techniques. In vitro permeation data published previously were analyzed based on a single pathway model, and permeation parameters were obtained. The disposition parameters were estimated from the plasma concentration profiles after i.v. administration. The plasma concentrations after topical application were then simulated using the obtained permeation and disposition parameters, and the values were compared with the corresponding observed ones. Although the simulated plasma concentration curves were not greatly different from those observed, there were some differences in the time course-pattern. Causes for these in vitro-in vivo differences were discussed.

Animals↗

PubMed1994

ESR study of membrane perturbation and the lysis of liposomes induced by chlorpromazine.

The mechanism of interaction between chlorpromazine (CPZ) and artificial lipid membranes, negatively or positively charged liposomes was studied by an electron spin resonance (ESR) technique. Analysis by a 5-doxyl stearic acid (DS) spin probe indicated that regardless of the electric charge of liposomes, CPZ disordered the hydrophobic region near the surface of lipid membranes at CPZ/lipid > 1. In the same CPZ/lipid range, the lysis of liposomes was observed, and it was considered that the formation of the CPZ/lipid mixed micelles as a consequence of this collapse of liposomes would probably lead to the disordering of the 5-DS reporting region. As to the middle portion of the fatty acyl chains reported by the 12-DS spin probe, the membrane disordering action of CPZ was only detected with the negatively charged liposomes at a ratio of CPZ/lipid < 1, but no membrane alteration was observed with the positively charged liposomes, regardless of the concentration range of CPZ used. In comparing these two opposite results, it is conceivable that the disordering at the 12-DS reporting region was probably induced by the cationized CPZ which would enter into the hydrocarbon-polar interface, leading to an expansion of the space between the hydrocarbon chains at this area. Also, a strong influence of CPZ on the innermost portion of the lipid bilayers was observed with both the negatively and positively charged liposomes, as reported by the 16-DS probe. This perturbing action presumably occurred when undissociated CPZ molecules penetrated into the center of the bilayers (lipid core), which could have resulted in a reduction of hydrophobic interactions of the lipid molecules.

Chemical Phenomena↗

PubMed1994

Protective effect of glycine against liposome membrane-perturbation and lysis induced by chlorpromazine.

The protective effect of glycine against the perturbing action of chlorpromazine (CPZ) on liposome membranes was investigated by an electron spin resonance (ESR) technique. Analysis using a 5-doxyl stearic acid (DS) spin probe indicated that the hydrophobic region near the surface of the liposomes containing glycine was restricted in motion by the addition of CPZ. This result suggested that the spaces between hydrocarbons in this portion would be narrowed by the penetrance of cationized CPZ molecules into the polar-hydrocarbon interface of the liposomes, in which the surface region may be tightly packed by glycine. The presence of glycine caused no difference in the disordering action of CPZ in the 12-DS reporting portion, suggesting that glycine could not influence the depth of the penetrance of cationized CPZ into the hydrocarbon phase near the surface of liposomes. The perturbing action of CPZ on the 16-DS-labeled liposomes was weakened by the presence of glycine, suggesting the reduced penetrance of undissociated CPZ molecules into the center of the bilayers (lipid core). Thus, glycine presumably prevented CPZ molecules incorporated into the liposome surface from transferring into the lipid core by its packing effect. It was shown that glycine could reduce the liposome lytic action of CPZ, without decreasing its surface activating action. This observed anti-lytic effect could be explained as a result of the above-described inhibition of the penetrance of CPZ into the lipid core.

Chlorpromazine↗

PubMed1994

4-Methoxyphenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazineacetate monofumarate monohydrate (KB-5492), a new anti-ulcer agent with a selective affinity for the sigma receptor, prevents cysteamine-induced duodenal ulcers in rats by a mechanism different from that of cimetidine.

Both KB-5492, a new anti-ulcer agent, and cimetidine, administered orally at 25-200 mg/kg, dose-dependently prevented cysteamine (400 mg/kg, s.c.)-induced duodenal ulcers in rats with ED50 values of 63 and 40 mg/kg, respectively. Anti-ulcer doses of cimetidine, but not KB-5492, inhibited gastric acid hypersecretion induced by cysteamine (400 mg/kg, s.c.). In contrast, anti-ulcer doses of KB-5492, but not cimetidine, increased duodenal HCO3- secretion in normal anesthetized rats. These findings suggest that KB-5492 prevents cysteamine-induced duodenal ulcers by stimulating duodenal HCO3- secretion, whereas cimetidine does so by inhibiting cysteamine-induced gastric acid hypersecretion.

Animals↗

PubMed1994

Effects of KB-5492, a new anti-ulcer agent, on ethanol- and acidified aspirin-induced gastric mucosal damage in vivo and in vitro.

The effects of KB-5492, a new anti-ulcer agent with selective affinity for the sigma receptor, on ethanol- and acidified aspirin-induced gastric mucosal damage were studied in vivo and in vitro and compared with those of 16,16-dimethyl prostaglandin E2 (dmPGE2). In the in vivo study, KB-5492 (200 mg/kg, p.o.) as well as dmPGE2 (0.01 mg/kg, p.o.) significantly prevented the acute macroscopic lesions in rat gastric mucosa induced by oral administration of either absolute ethanol or 80 mM aspirin in 150 mM HCl. The light microscopic examination revealed that KB-5492 almost completely prevented the deep mucosal lesions induced by these necrotizing agents. KB-5492 also prevented the exfoliation of surface epithelial cells, but its preventive effect was incomplete. In the in vitro study, gastric epithelial cells, isolated from the rat stomach, were cultured for 6 days until they reached confluency. Subsequently, 51Cr was incorporated into the cells. Both 10 mM aspirin (at pH 5.0) and 12.5% ethanol (at pH 7.4) induced damage to the cells and markedly increased 51Cr release from the cells. KB-5492 at 0.3 and 1 mM and dmPGE2 at 0.3 and 1 microM significantly, but not completely, prevented both the aspirin- and ethanol-induced increases in 51Cr release from the cells. These findings indicate that KB-5492 as well as dmPGE2 may exert a direct but limited protective effect on the surface epithelial cells in vivo.

16,16-Dimethylprostaglandin E2↗