Biomedical subjects

T Shiga

Publications and source records attributed to T Shiga.

At least 127 records · Page 7Linked to original sources

PubMed1994

[Treatment of prostatic carcinoma with UFT and leucovorin--basic study using SRCA].

Combination effect of UFT and leucovorin against the rat prostatic carcinoma (R-3327) was evaluated by the subrenal capsular assay (SRCA) using nude mice. Anticancer effect of UFT was augmented by co-administration of both low and high dose leucovorin. These results suggest a clinical usefulness of UFT administration with leucovorin for the patients with hormonally refractory advanced prostatic carcinoma.

Animals↗

PubMed1993

Spin trapping of superoxide released by opsonized asbestos from human promyelocytic leukemia cell line, HL60.

By ESR using 5,5-dimethyl-1-pyrroline-1-oxide as a spin trap, superoxide (O2-) production was proved upon stimulation of dimethyl sulfoxide-differentiated HL60 by crocidolite opsonized with fresh or refrigerated serum, as well as by phorbol myristate acetate (PMA). Crocidolite, unopsonized or opsonized with frozen-thawed or heat-inactivated serum, did not induce O2- release. Addition of iron chelators or superoxide dismutase inhibited O2- release completely. Neither undifferentiated nor PMA-differentiated HL60 released O2- upon stimulation with opsonized crocidolite.

Asbestos↗

PubMed1993

Differential expression of neuron-glia cell adhesion molecule (Ng-CAM) on developing axons and growth cones of interneurons in the chick embryo spinal cord: an immunoelectron microscopic study.

To elucidate the role of neuron-glia cell adhesion molecule (Ng-CAM) in axonal pathway formation of avian spinal interneurons, we have examined the ultrastructural expression of Ng-CAM in the developing spinal cord, by using a preembedding immunocytochemical method. Ng-CAM immunoreactivity was punctate and was restricted to cell surfaces. In accordance with our previous light microscopic observations (Shiga et al., '90), the earliest developing spinal interneurons were Ng-CAM-positive on their cell bodies, axons, and growth cones. Axons and growth cones that were either fasciculated or in contact with each other strongly expressed Ng-CAM, thus indicating the possible involvement of Ng-CAM in fasciculation of axons and in the contact guidance of growth cones along preexisting axons. By using higher resolution immunoelectron microscopy, the present study has also revealed new information on the subcellular localization of Ng-CAM on developing spinal interneurons, neuroepithelial cells, and floor plate cells. Although Ng-CAM immunoreactivity was prominent on both axons and growth cones, these structures were Ng-CAM-negative when they contacted the basal lamina around the spinal cord. By contrast, Ng-CAM was detectable on the surface of both neuroepithelial cells and floor plate cells only when they made contact with the Ng-CAM-positive axons and growth cones of interneurons. These results suggest that the subcellular distribution of Ng-CAM is regulated differentially, depending on the apposing cell surfaces, and that such differential and developmentally regulated expression may contribute to the elongation, fasciculation, and guidance of spinal axons.

Animals↗

PubMed1993

Influence of application site of a new transdermal clonidine, M-5041T, on its pharmacokinetics and pharmacodynamics in healthy subjects.

Influence of application site of a new transdermal clonidine, M-5041T(M), on its pharmacokinetics and pharmacodynamics were evaluated in eight human subjects. One patch of M-6 mg was applied for 3 days on the right chest (first trial), on the left arm (second trial), and on the upper abdomen (third trial). Blood samples for clonidine concentration were taken, and blood pressure (BP) was measured for a 120-hour postapplication period. Plasma concentrations of clonidine increased after application of M in each trial. This parameter in the second trial was significantly greater than that of the first and third trials. The values of maximum plasma concentration and area under the plasma concentration-time curve in the second trial were greater than those of other trials, but the differences did not reach significance. The BP-lowering effect of M in the second trial was significantly greater than that of the third trial. These results suggest that the plasma concentrations of clonidine after application of M and its hypotensive effect are affected by the site of application in human subjects.

Abdomen↗

PubMed1993

Pharmacokinetics and pharmacodynamics of a new transdermal clonidine, M-5041T, in healthy subjects.

The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M-5041T (M), and its safety were evaluated after single and repeated applications. In the single-application study, one patch of M (4 mg-->6 mg-->8 mg) was applied for 3 days in eight healthy subjects. In the repeated-application study, first (0-72 hours), second (72-144 hours), and third (144-216 hours) patches of M 6 mg were applied in seven healthy subjects. In the single-application study, plasma clonidine concentration increased in a dose-dependent manner after application of M. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-dependent manner, but the difference did not reach significance. Time to maximum concentration, elimination half-life, and total and renal clearance did not differ significantly among three trials. Blood pressure (BP) decreased gradually after application of each dose of M. The BP-lowering effect of M 8 mg was greater than that of M 4 mg and 6 mg. Adverse effects such as erythema and drowsiness were reported in some subjects. No subject had to be withdrawn from the study because of the appearance of adverse effects. In the repeated-application study, plasma concentration of clonidine increased up to 48 hours after application of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ significantly among three trials. Blood pressure during an active period decreased significantly during treatment with M, whereas BP at midnight did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

PubMed1993

Effects of diltiazem and cimetidine on theophylline oxidative metabolism.

The effect of diltiazem or cimetidine pretreatment on the inhibition of theophylline oxidative metabolism was investigated in nine healthy male nonsmokers. Diltiazem 60 mg, cimetidine 400 mg, or placebo was given orally three times daily for 3 days in a randomized three-way crossover manner. Both diltiazem and cimetidine pretreatment decreased the mean theophylline clearance (0.702 on placebo versus 0.641 on diltiazem, P < .05, and 0.542 mL/minute/kg on cimetidine, P < .01), resulting in prolonged mean theophylline half-life (7.58 on placebo versus 8.59 on diltiazem, P < .05, and 10.08 hours on cimetidine, P < .01) with no change in volume of distribution. The mean metabolic clearances for three major theophylline metabolites, 1-methyluric acid (1-MU), 1,3-dimethyluric acid (1,3-DMU), and 3-methylxanthine (3-MX), were reduced significantly by cimetidine (28%; P < .05, 32%; P < .01, and 33%; P < .01, respectively). Conversely, diltiazem significantly reduced only the mean metabolic clearance of 1,3-DMU by 21% (P < .05) without changes in that of 1-MU or 3-MX. These results suggest that cimetidine inhibited both N-demethylation and 8-hydroxylation of theophylline, whereas diltiazem exerted little influence on N-demethylation in spite of inhibition in 8-hydroxylation.

Adult↗

PubMed1993

Influence of lisinopril on urinary electrolytes excretion after furosemide in healthy subjects.

It has been reported that the urinary excretions of chloride (Cl), potassium (K), and magnesium (Mg), but not sodium (Na), after furosemide, a loop diuretic, were decreased by pretreatment with lisinopril, an ACE inhibitor in hypertensive subjects. The electrolytes disturbance induced by furosemide might be ameliorated by lisinopril. The present study re-examines this potential drug interaction in healthy subjects. Lisinopril (20 mg) or its matching placebo was given orally using a double-blind, crossover design. Four hours after lisinopril administration, furosemide (20 mg) was injected intravenously and urine was collected during the following intervals: 0-0.5, 0.5-1, 1-1.5, 1.5-2, 2-3, 3-4, and 4-6 hours. Blood samples for plasma furosemide concentration were obtained at 0.5, 1, 1.5, 2, 3, 4, and 6 hours after the agent. There were no significant differences between the two trials in plasma concentrations of furosemide or urinary excretions of the agent. Urine volume and urinary excretions of electrolytes (Na, Cl, K, and Mg) after the furosemide with lisinopril administration were not significantly different from those of placebo at any observation period. These results suggest that the urinary excretions of electrolytes after furosemide administration are not influenced by pretreatment with lisinopril.

Adult↗

PubMed1993

Differences of chronopharmacokinetic profiles between propranolol and atenolol in hypertensive subjects.

Previous studies have shown that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the night dosage than after the morning dosage in nocturnal rodents. The present study examines whether such a difference in chronopharmacokinetic profiles between lipophilic and hydrophilic agents also exists in humans. Propranolol (20 mg), a lipophilic beta-blocker, or atenolol (50 mg), a hydrophilic beta-blocker, was given orally to 13 hypertensive patients at 9:00 AM (day trial) or 9:00 PM (night trial) by a crossover design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, and atenolol were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours after treatment. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of propranolol in the day trial were significantly greater than those in the night trial. Time to maximum plasma concentration (tmax) was significantly shorter in the day trial. No significant difference was observed in the elimination half-life between the two trials. There were similar administration time-dependent changes in the Cmax for 4-hydroxypropranolol and naphthoxylactic acid. On the other hand, although the Cmax of atenolol was greater and its tmax was shorter in the day trial, the differences did not reach significance. These results suggest that propranolol, but not atenolol is absorbed more rapidly after the morning dosage than after the night dosage. Based on these findings, the authors speculate that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the morning dosage than after the night dosage in humans.

Administration, Oral↗

PubMed1993

The effect of age on diurnal variation in the pharmacokinetics of propranolol in hypertensive subjects.

There is diurnal variation in the absorption rate of propranolol in younger subjects. This study was undertaken to examine the effect of age on the chronopharmacokinetics of propranolol. We gave 20 mg of propranolol orally to 13 younger and 11 older hypertensive subjects at 09.00 h (day study) or 21.00 h (night study) in a cross-over design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 h after dosage. In the younger subjects the absorption rate constant (ka) of propranolol and its maximum plasma concentration (Cmax) were significantly higher and the time to maximum concentration (tmax) was significantly shorter in the day than at night. There were similar time-variant changes in Cmax and tmax for 4-hydroxypropranolol and naphthoxylactic acid. In contrast, there were no time-variant changes in ka, Cmax and tmax of propranolol and its metabolites in the older subjects. These results suggest that propranolol is absorbed more rapidly after morning dosing than after night-time dosing in younger but not in older subjects. Based on these findings, we speculate that the time-variance in the absorption rate or first-pass elimination, or both, of propranolol diminish with age.

Adult↗

PubMed1993

Influence of clorgyline treatment on chronopharmacology of furosemide in rats.

Circadian variations in the adrenergic nervous system have been reported to be altered by chronic treatment with clorgyline, a monoamine-oxidase inhibitor. In the present study, the influence of clorgyline on the chronopharmacology of furosemide, a loop diuretic agent, was examined in rats maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Clorgyline (4 mg/kg/day) or its vehicle alone was infused subcutaneously by osmotic minipumps for 14 days. Furosemide (30 mg/kg) was given orally at 12 am [noon (N)] or 12 pm [midnight (M)]. Urine was collected for 8 hours after the agent, and urinary excretions of sodium and furosemide were determined. Urine volume and urinary excretions of sodium and furosemide were significantly greater at 12 N than at 12 M in the vehicle-infused group of rats. However these administration time-dependent changes in the effects of furosemide and its urinary excretion disappeared in the clorgyline-infused animals. These results suggest that the mode of the diurnal variation in the effects of furosemide is altered by chronic treatment with clorgyline. As chronic clorgyline is considered to disturb the adrenergic nervous system, the present findings are compatible with the hypothesis that this system is involved in the mechanism responsible for the time-dependent change in the effects of furosemide.

Analysis of Variance↗

PubMed1993

Chronopharmacology of amlodipine in rats.

The present study was undertaken to examine whether plasma concentrations of amlodipine, a calcium antagonist, and its diuretic effects vary with the time of dosage. Pharmacokinetic study; 20 mg/kg of amlodipine was given orally to rats at 10 am (day trial) or 10 pm (night trial), and blood samples were obtained during a 24-hour period. Pharmacodynamic study; two doses (10 and 20 mg/kg) of amlodipine were given orally at 10 am or 10 pm by a cross-over design, and urine was collected for 12 hours after dosage. Rats were maintained under condition of light from 7 am to 7 pm. The following results were obtained; The tmax of amlodipine was shorter and the Cmax was greater in the night trial than in the day trial. Its diuretic effects were greater in the night trial. These results suggest that the pharmacokinetic and pharmacodynamic profiles of amlodipine vary with its time of dosage.

Amlodipine↗

PubMed1993

Measurement of redox states of mitochondrial cytochrome aa3 in regions of liver lobule by reflectance microspectroscopy.

To evaluate the sublobular distribution of oxygen tension, the redox states of mitochondrial cytochrome aa3 were assessed in local regions of the liver lobule by reflectance microspectroscopy. The reflected light from two focused microspots (20 microns in diam) on the surface of the perfused liver, placed on the stage of microscope, was conducted to the spectrophotometer with two separate light guides, giving the reflectance spectra. The redox state of cytochrome aa3 was calculated from the difference in reflectance between 603 and 630 nm. The degree of cytochrome reduction increased with the stepwise decline of the influent or effluent oxygen concentrations. The local oxygen concentration in periportal region for the half-maximal reduction of cytochrome aa3 was higher than that in pericentral region. In addition, the degree of cytochrome aa3 reduction increased with the distance from the periportal region, reflecting a physiological gradient of oxygen tension along the sinusoidal flow, although with an intersinusoidal heterogeneity within liver lobule.

Animals↗

PubMed1993

Chronopharmacokinetic study of a new immunosuppressive agent, FK 506, in mice.

Chronopharmacokinetic profiles of a new immunosuppressive agent, FK 506, were examined in mice. FK 506 (1 mg/kg) was given orally at 10 AM (day trial) or 10 PM (night trial) once a day for 7 days. Blood samples for measurement of FK 506 concentration in whole blood were obtained just before and at 1, 2, 3, 4, 6, 8 and 12 hr after the final dosage. The time to maximum concentration was shorter and the maximum concentration was greater in the night trial than in the day trial. These findings suggest that absorption of FK 506 is faster and its blood concentrations is higher in the night trial.

Animals↗

PubMed1993

Influence of alpha-receptor blockade on the time-dependent change in the effect of furosemide.

Influence of alpha-receptor blockade on the time-dependent change in the effect of furosemide (a loop diuretic agent) was examined. Furosemide (30 mg/kg) was given orally to the doxazosin (an alpha 1-blocker)- or vehicle-treated rats at 12 AM or 12 PM. Urine volume and urinary excretions of of sodium and furosemide for 8 hr were significantly greater at 12 AM than at 12 PM in the vehicle-treated animals. However, such time-dependent changes in these parameters disappeared in the doxazosin-treated rats. These results suggest that the alpha 1-receptor-mediated stimuli are involved in the mechanism of the time-dependent change in the effect of furosemide.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1993

Spin trapping study of superoxide production in ferrous ion oxidation.

The oxidation of Fe2+ was investigated by electron paramagnetic resonance (EPR) spin trapping techniques with N-t-butyl-alpha-phenylnitrone (PBN) and dimethyl sulfoxide. Under pure oxygen, the spin adduct PBN/.OCH3 was rapidly generated by the addition of Fe2+ (0.2-1.2 mM) into phosphate buffer containing ethylenediaminetetraacetate (EDTA), dimethyl sulfoxide and PBN at pH 7.4, but it decayed. The decay process of PBN/.OCH3 consists of two components. The fast decay was dependent on Fe2+ concentration. Another was due to destruction of the spin adduct by superoxide anion (.O2-), because superoxide dismutase (SOD) markedly prevented the decay. Catalase decreased the yield of PBN/.OCH3. When Fe(3+)-EDTA and ascorbate were used instead of Fe(2+)-EDTA, similar phenomena were detected. These results demonstrate that Fe2+ reacts with O2 to generate .O2-, then H2O2, which produces .CH3 by the reaction with Fe2+ and dimethyl sulfoxide. The .OCH3 radical results from the reaction between .CH3 and O2. The adduct PBN/.OCH3 decays by the reaction with Fe2+ and .O2-.

Ascorbic Acid↗

PubMed1993

The rate of oxygen release from single sinusoid of rat liver, determined by microspectroscopy.

The rate of oxygen release from single hepatic sinusoid of rat was determined. A scanning spectrophotometer, equipped with a grating and two photoncounters, was connected to a microscope with light-guides, and absorption spectra (450-650 nm) were obtained simultaneously at two microspots (10 microns diameter) on single sinusoid. The concentration ([Hb]) and oxygen saturation (SO2) of hemoglobin were calculated from the spectra. Reference transmittance was obtained at neighbouring hepatocytes. The erythrocyte velocity was measured by dual-spots cross-correlation method using two photomultipliers connected to the microscope with two light-guides. The gradient in SO2 was observed along each sinusoid, due to oxygen release from flowing erythrocytes to hepatocytes. The rate of oxygen release per unit surface area was 0.24 +/- 0.14(n = 14)nmoles O2/cm2/sec, which was calculated from [Hb], difference in SO2 between the spots at up- and down-stream, erythrocyte velocity, two spot's distance and sinusoidal diameter. The rates of O2 release depended on sinusoidal diameter and sinusoidal blood flow.

Animals↗

PubMed1993

Mechanisms of axonal guidance used by interneurons in the chick embryo spinal cord.

Axonal guidance mechanisms involved in pathway formation by avian spinal interneurons have been studied using a variety of different approaches. The earliest developing spinal interneurons can be divided into two groups on the basis of the initial direction of axonal outgrowth: circumferential cells (C-cells) and primitive longitudinal cells. Perturbation studies suggest that a chemotropic-like mechanism plays a role in the guidance of the C-cell axons toward the floor plate. The shape of floor plate cells is polarized mediolaterally (direction of axon growth) and only in this region do growth cones express integrin and contact the basement membrane. Pathway formation following dorsal to ventral spinal cord rotation indicates that the ventrolateral region of the neural tube may provide a permissive substrate for longitudinally advancing growth cones. In addition, following rostrocaudal rotation of three segments of the neural tube, the axons of dorsolateral border cells in the rotated segments modified their directionality according to the general rostrocaudal polarity of the embryo. Changes in cell adhesion molecule expression by the C-cell growth cones and axons is region and age specific. These observations suggest that a variety of mechanisms and cues are working in the guidance of spinal interneurons in each region of the pathway.

Animals↗

PubMed1992

Synergistic stimulation of nitric oxide hemoglobin production in rats by recombinant interleukin 1 and tumor necrosis factor.

Nitric oxide (NO) is formed from arginine in Escherichia coli lipopolysaccharide (LPS) treated rat; however, none of specific cytokine inducing NO generation is yet determined. We studied the effect of interleukin 1 (IL-1) and tumor necrosis factor (TNF) on NO production in rats by detecting NO-hemoglobin in their blood, using electron spin resonance. Either IL-1 or TNF alone stimulated NO-hemoglobin formation. Combined administration of IL-1 and TNF markedly enhanced NO-hemoglobin generation, demonstrating the synergistic character of both stimuli on NO production. Further, LPS and TNF in combination were more potent stimulator of NO-hemoglobin production in rats than each alone.

Animals↗