Biomedical subjects

T Nabeshima

Publications and source records attributed to T Nabeshima.

At least 199 records · Page 11Linked to original sources

PubMed1995

Time-dependent changes in the pharmacokinetics and renal excretion of xanthine derivative enprofylline induced by bacterial endotoxin in rats.

Time-dependent changes in the pharmacokinetics and renal handling of enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250 micrograms/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 micrograms/min/kg for inulin and enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CLr) of enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CLr was slightly greater than that in GFR. LPS-induced decreases in the CLr for enprofylline and GFR continued over the testing period of 120 min. The time-dependent effect of LPS on the pharmacokinetics of enprofylline was examined by a single injection of enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24 h earlier with or without LPS. The pharmacokinetic parameters of enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for enprofylline were observed in rats pretreated 2 and 10 h earlier with LPS, but no such changes were observed in rats pretreated 24 h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of enprofylline, and suggest that LPS at a dose of 250 micrograms/kg, at least, does not induce cytotoxicity to kidney cells.

Animals↗

PubMed1995

Pharmaceutical evaluation of carbamazepine suppositories in rats.

The absorption of carbamazepine (CBZ) after rectal administration in the form of a suppository was studied in rats. CBZ suppositories were prepared with Witepsol H-15 (H-15), Witepsol S-55 (S-55) or polyethylene glycol 6000 (PEG) bases by moulding procedure. An in vitro investigation was undertaken using a dissolution apparatus. The in vitro dissolution rate of CBZ showed marked differences among the bases in the order PEG > H-15 > S-55. An in vivo study demonstrated marked differences in the time required to reach peak plasma concentration (Tmax) of CBZ after rectal and oral administration: the absorption of CBZ from PEG base was the most prolonged among these bases (in the order PEG > H-15 > S-55 > ORAL). Comparison of the area under the plasma concentration-time curve (AUC) of CBZ after rectal administration of the three different suppositories with those after intravenous and oral administration showed no significant differences in the AUC among the five preparations. These results suggest the possibility that CBZ suppositories can replace oral treatment for epilepsy.

Animals↗

PubMed1995

Pharmacokinetic model of oral levodopa and role of carbidopa in parkinsonian patients.

A pharmacokinetic model of oral levodopa is proposed to elucidate the effects of carbidopa on the pharmacokinetics of levodopa. The propriety of the model was evaluated by simultaneous computer Multi-Line fitting for the plasma concentration-time data of levodopa and dopamine-3-O-sulfate (DA-S), a major metabolite of levodopa, after oral administration of three different levodopa doses to parkinsonian patients. Plasma profiles of levodopa and DA-S were also determined in 12 parkinsonian patients during daily oral administration of Neodopaston, a levodopa preparation containing carbidopa in tablet form. We investigated the role of carbidopa by comparing the populational mean parameters calculated in the levodopa alone model with those obtained in patients coadministered levodopa and carbidopa. The results indicated that the pharmacokinetics of levodopa coadministered with carbidopa were dose-independent and that carbidopa reduces the first-pass metabolism of levodopa in the gut wall to less than 10% of the dose absorbed, and decreases the systemic clearance of levodopa by 35-39%. The proposed pharmacokinetic model and the evaluation of carbidopa in this study will provide useful information for the development of drug delivery systems for levodopa or catechol-O-methyltransferase inhibitors, for further stabilization of plasma concentrations of levodopa in parkinsonian patients.

Administration, Oral↗

PubMed1995

[Nerve growth factor strategy and preparation of animal model for Alzheimer-type senile dementia].

Nerve growth factor (NGF) plays an important role in the survival and maintenance of cholinergic neurons in the central nervous system. In senile dementia of the Alzheimer type (SDAT), learning and memory are impaired by the loss of neurons in the magnocellular cholinergic neuronal system. It is, therefore, of interest to investigate the role of NGF in this degenerative disorder. Since NGF does not cross the blood-brain barrier and is easily metabolized by peptidases when administered peripherally, it can be used for medical treatment only when directly injected into the brain. We tried to develop drugs which could be taken orally and stimulate the NGF synthesis in the brain. In addition, we attempted to develop a SDAT animal model using osmotic minipump to infuse beta-amyloid protein into cerebral ventricle, since there are no SDAT model animals accompanied with various pathophysiological changes. We demonstrate here that the oral administration of propentofylline, idebenone and trimethylquinone derivative, potent in vitro NGF synthesis stimulators, induced the increase in NGF protein and mRNA, and in choline acetyltransferase activity, in basal forebrain-lesioned and aged rats, but not in intact young rats. These drugs also ameliorated the behavioral deficits in habituation, water maze, and passive avoidance tasks in these animals. These results suggest that these drugs stimulated NGF synthesis in vivo and ameliorated the behavioral deficits which were accompanied with the reduced choline acetyltransferase activity in the basal forebrain-lesioned and aged rats. In terms of the SDAT animal model, the performance of the water maze and passive avoidance tasks was impaired and choline acetyltransferase activity significantly decreased in beta-amyloid protein-treated rats. Histochemical results showed the deposition of beta-amyloid protein in the cortex and hippocampus and atrophy and loss of hippocampal neurons. These results suggest that the deposition of beta-amyloid protein in the brain is related to the impairment of learning and cholinergic neuronal degeneration, and that beta-amyloid protein-treated rats could be an animal model for SDAT and used for the screening of drugs for SDAT.

Alzheimer Disease↗

PubMed1995

[Trial to produce animal model of Alzheimer's disease by continuous infusion of beta-amyloid protein into the rat cerebral ventricle].

To develop an animal model of Alzheimer's disease, we investigated the toxicity of beta-amyloid protein which is a component of senile plaques in Alzheimer's disease. beta-Amyloid was infused into the cerebral ventricle of rats for 14 days using a mini-osmotic pump. The performance of habituation, water maze and passive avoidance tasks in beta-amyloid protein-treated rats was impaired. Choline acetyltransferase activity significantly decreased in the hippocampus both immediately and 2 weeks after cessation of the infusion. However, the learning impairment is recoverable 2 weeks after cessation of the infusion. Both immediately and 2 weeks after cessation of the infusion, glial fibrillary acidic protein immunoreactivity increased. Further, beta-amyloid protein altered the staining of nuclei of cells in the hippocampus only 2 weeks after cessation. These results suggest that beta-amyloid protein damages the central nervous system in vivo, and that this animal could be used as a model of Alzheimer's disease.

Aging↗

PubMed1994

SKF-10,047 reverses stress-induced motor suppression: interaction with dopaminergic system.

Mice exhibited a marked suppression of motility (conditioned suppression) when placed in the same environment in which they had previously received an electric footshock. This stress-induced motor suppression was dose dependently attenuated by (+/-)-SKF-10,047, a sigma receptor agonist, but not by its (-)-optical isomer ((-)-SKF-10,047) and the sigma receptor ligands (+)-pentazocine and 1,3-di-(2-tolyl)guanidine. This effect of (+/-)-SKF-10,047 was antagonized by BMY-14802, a sigma receptor antagonist, and by pimozide, a dopamine receptor antagonist. When dopaminergic neurons were destroyed by pretreatment with 6-hydroxydopamine, the effect of (+/-)-SKF-10,047 on the stress response was also attenuated. Furthermore, (+/-)-SKF-10,047 dose dependently reversed the decrease in striatal dopamine turnover in the conditioned suppression group. These results suggest that stress-induced motor suppression is restored by (+/-)-SKF-10,047 acting through sigma receptors, which are closely linked to the dopaminergic neuronal system.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Competitive NMDA antagonists enhance the catalepsy induced by delta 9-tetrahydrocannabinol in mice.

Competitive N-methyl-D-aspartate (NMDA) receptor antagonists, such as CPP and AP-7, dose-dependently enhanced the catalepsy induced by delta 9-tetrahydrocannabinol (THC; 5 mg/kg) in mice, but CPP failed to enhance haloperidol-induced catalepsy. The enhancing effect of CPP on THC-induced catalepsy was dose-dependently blocked by a muscarinic receptor antagonist, scopolamine, and by dopamine D1 and D2 receptor agonists such as apomorphine, SKF 38393 and quinpirole. The effect of CPP was quite opposite to that of the noncompetitive NMDA receptor antagonist MK-801. Therefore, the THC-induced catalepsy model may be useful for distinguishing between both classes of NMDA receptor antagonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Behavioral evidence for a modulating role of sigma ligands in memory processes. I. Attenuation of dizocilpine (MK-801)-induced amnesia.

The potentiating effect of low doses of sigma ligands on the N-methyl-D-aspartate (NMDA)-induced excitation of pyramidal CA3 dorsal hippocampal neurons has recently been reported. In the present study, we investigated behavioral effects relevant to these findings in the experimental amnesia induced by the non-competitive NMDA antagonist, dizocilpine (MK-801), in mice. At doses below 1 mg/kg s.c., the sigma ligands, 1,3-di-(2-tolyl)guanidine (DTG), (+)-SKF 10,047, and (+)-pentazocine, but not their (-)-isomers, significantly decreased MK-801 (100 microgram/kg s.c.)-induced impairment of spontaneous alternation performances in 8-min sessions of a Y-maze exploration, an index of spatial working memory, without affecting the concomitant hyperlocomotion. The effect of DTG (100 micrograms/kg s.c.) was completely antagonized by the simultaneous administration of BMY 14802 (10 mg/kg i.p.) and NE-100 (1 mg/kg i.p.), two putative sigma antagonists, which had no effect by themselves. In long-term memory tests (step-down and step-through types of passive avoidance, elevated plus-maze), DTG exhibited a significant attenuation of MK-801-induced amnesia, at doses of 10 and 100 micrograms/kg s.c. In all tests of short- and long-term memory, the effects exhibited by the sigma ligands tested had a bell-shaped curve; no effect was seen at 1 mg/kg. DTG did not affect the impairment of alternation induced by CPP (5 mg/kg i.p.): the modulation may selectively target the blockade of NMDA receptor-associated ion channels. Moreover, DTG (1-1000 micrograms/kg) did not affect the impairment induced by scopolamine (1 mg/kg i.p.) or diazepam (4 mg/kg i.p.), but significantly prevented the impairment induced by mecamylamine (10 mg/kg i.p.). These results suggest that the potentiating effect of sigma ligands on NMDA receptor-mediated glutamatergic neurotransmission, already demonstrated electrophysiologically, may have some relevance to learning and memory processes in the hippocampus. A similar modulation may also affect cholinergic nicotinic systems.

Amnesia↗

PubMed1994

Behavioral evidence for a modulating role of sigma ligands in memory processes. II. Reversion of carbon monoxide-induced amnesia.

This study examined the effect of low doses of sigma ligands on amnesia induced in mice by successive carbon monoxide (CO) exposure. Mice were exposed three consecutive times to CO (10 ml/min, 30-50 s) at 38 degrees C. Spatial working memory impairment was investigated 5 days later by monitoring spontaneous alternation behavior in a Y-maze. Delayed amnesia was examined 7 days after CO exposure by using a step-down passive avoidance test. The preadministration of the sigma ligand 1,3-di-(2-tolyl)guanidine (DTG), at doses of 1 to 1000 microgram/kg, s.c., 30 min before CO exposure did not affect the resulting amnesia in either test. However, when administered 30 min before the test, i.e., 5 or 7 days after CO exposure, this agent completely reversed the CO-induced decrease in alternation performance, at doses of 10 to 100 micrograms/kg. The same effect was observed with (+)-N-allylnormetazocine ((+)-SKF 10,047), at doses of 100 to 300 micrograms/kg, but not with (-)-SKF 10,047. DTG, at the same dose range that reversed the decrease in alternation, also totally reversed the CO-induced decrease in step-down latency in the passive avoidance test. The curve for these effects was bell-shaped; the effects were not observed at the dose of 1 mg/kg. Moreover, alpha-(4-fluorophenyl-2-pyrimidinyl)-1-piperazine butanol (BMY 14802), a putative sigma antagonist (1-10 mg/kg i.p.), did not affect CO-induced amnesia, but when simultaneously administered with DTG, it completely prevented its effect in both tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia↗

PubMed1994

Effects of nefiracetam on drug-induced impairment of latent learning in mice in a water finding task.

We investigated the effects of nefiracetam (DM-9384), a pyrrolidone derivative, on chlordiazepoxide-, apomorphine-, and methamphetamine-induced impairment of latent learning in a water finding test in mice. Pretreatment with nefiracetam reversed the inhibitory effects of chlordiazepoxide and apomorphine, but not those of methamphetamine, on latent learning. The ameliorative effects of nefiracetam on apomorphine-induced, but not chlordiazepoxide-induced impairment of latent learning were antagonized by scopolamine. These results provide further evidence that nefiracetam has anti-amnesic effects. Further, it is suggested that the cholinergic neuronal system may be involved in the ameliorative effects exerted by nefiracetam on apomorphine-induced impairment of latent learning.

Animals↗

PubMed1994

beta-Amyloid protein-induced Alzheimer's disease animal model.

To investigate the toxicity of beta-amyloid protein which consisted of senile plaques of Alzheimer's disease (AD), this was infused into cerebral ventricle for 14 days by using mini-osmotic pump. The performance of the water maze task in beta-amyloid protein-treated rats was impaired. Choline acetyltransferase activity significantly decreased in the frontal cortex and hippocampus. These results suggest that the deposition of beta-amyloid protein in the brain is related to the impairment of learning and cholinergic neuronal degeneration, and that beta-amyloid protein-treated rats could be used as an animal model for AD.

Alzheimer Disease↗

PubMed1994

Omega-conotoxin GVIA inhibits the methylphenidate-induced but not methamphetamine-induced behavior.

We investigated the effects of antagonists for omega-conotoxin GVIA (omega-CTX)-sensitive N-type voltage-sensitive calcium channels (N-channels) on methylphenidate- and methamphetamine-induced behavior. I.c.v. injection of omega-CTX or neomycin, both N-channel antagonists, caused a dose-dependent inhibition of methylphenidate-induced hypermotility in mice but failed to inhibit methamphetamine-induced hyperactivity. Further, omega-CTX inhibited the circling behavior induced by methylphenidate in rats that had kainic acid-induced unilateral striatal lesions. These results suggest that calcium influx through omega-CTX-sensitive N-channels plays an important role in methylphenidate-induced behavior.

Animals↗

PubMed1994

Oral administration of idebenone induces nerve growth factor in the brain and improves learning and memory in basal forebrain-lesioned rats.

Nerve growth factor plays an important role in the survival and maintenance of cholinergic neurons in the central neuronal system. In senile dementia of the Alzheimer type, learning and memory are impaired by the loss of neurons in the magnocellular cholinergic neuronal system. It is therefore, of interest to investigate the role of nerve growth factor in this degenerative disorder. Since nerve growth factor does not cross the blood-brain barrier and is easily metabolized by peptidases when administered peripherally, it can be used for medical treatment only when directly injected into the brain. We demonstrate here that the oral administration of idebenone, a potent in vitro nerve growth factors synthesis stimulator, induced an increase in nerve growth factor protein and mRNA, and in choline acetyltransferase activity, in basal forebrain lesioned rats, but not in intact rats. Idebenone also ameliorated the behavioral deficits in habituation, water maze, and passive avoidance tasks in these animals. These results suggest that idebenone stimulated nerve growth factor synthesis in vivo and ameliorates the behavioral deficits which were accompanied with the recovery of the reduced choline acetyltransferase activity in the basal forebrain-lesioned rats.

Animals↗

PubMed1994

Kinetic interaction between theophylline and a newly developed anti-allergic drug, pemirolast potassium.

The effect of a newly developed anti-allergic drug, pemirolast potassium (TBX), on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in seven healthy male volunteers. A sustained-release theophylline formulation (100 mg twice daily at 12 h intervals) was given as monotherapy and coadministered with TBX (10 mg twice daily at 12 h). Plasma concentration-time curves and the urinary excretion of theophylline and its major metabolites after administration of theophylline alone and after coadministration with TBX were compared. No significant adverse effects from this study were observed. There were no significant differences in the total body clearance, renal clearance and maximum concentration of theophylline between the two treatments, although coadministration of TBX significantly delayed the time to reach maximum concentration of theophylline. In the case of urinary excretion, no significant changes in the fraction of urinary excretion of theophylline and its metabolites were observed. These results indicate that TBX has little or no effect on the pharmacokinetics and metabolism of theophylline and suggest that TBX is safe for asthma patients receiving theophylline therapy for treatment of chronic obstructive airway diseases.

Adult↗

PubMed1994

Pharmacokinetics of doxorubicin and its active metabolite in patients with normal renal function and in patients on hemodialysis.

The comparative pharmacokinetics of doxorubicin (DOX) were investigated in five hemodialysis (HD) and eight non-hemodialysis (non-HD) patients who were infused with a 40- to 60-mg dose of DOX at a constant rate over 30 min. A significant difference was observed in the total body clearance (Cl tot) of DOX between HD and non-HD patients. The area under the curve (AUC) for both DOX and doxorubicinol (DOXol), an active metabolite, showed increases of approximately 1.5 and 3 times in HD patients as compared with non-HD patients. Although these differences were not statistically significant (P < 0.1), the mean residence time (MRT) of DOX and DOXol in HD patients showed a 2-fold increase in comparison with those in non-HD patients. Compartmental analysis indicated that the greater AUC values and longer MRT of DOX and DOXol in HD patients resulted from the lesser DOXol formation and disappearance of rate constants. As a consequence of the decrease in Cl tot for DOX and the marginal hemodialysis clearance of both DOX and DOXol, the present study suggests that the exposure to DOX and DOXol obtained in HD patients greater than achieved in non-HD patients. Careful attention should therefore be paid to HD patients receiving DOX.

Aged↗

PubMed1994

Effect of dizocilpine (MK-801) on the catalepsy induced by delta 9-tetrahydrocannabinol in mice.

Mice treated with delta 9-tetrahydrocannabinol (THC; 5 and 10 mg/kg i.v.) showed the catalepsy in high bar test, and median descent latencies of catalepsy were about 150 sec. Dizocilpine (MK-801, 0.05 and 0.1 mg/kg), non-competitive N-methyl-D-aspartate (NMDA) antagonist, significantly attenuated THC-induced catalepsy. Furthermore, the anticataleptic effect of MK-801 on THC-induced catalepsy was blocked by acetylcholine agonist oxotremorine (0.005 mg/kg) and dopamine antagonist haloperidol (0.01 mg/kg), but not by NMDA. Oxotremorine, haloperidol, and NMDA themselves did not affect THC-induced catalepsy at the doses used. These results suggest that the anticataleptic effect of MK-801 on THC-induced catalepsy may be developed through dopaminergic and acetylcholinergic neuronal systems.

Acetylcholine↗

PubMed1994

Inhibitory effects of salmon calcitonin on the tail-biting and scratching behavior induced by substance P and three excitatory amino acids.

We have examined the effects of salmon calcitonin (SCT), injected into the cerebral ventricle (i.c.v.), on the tail-biting and scratching behavior induced by the intrathecal injection of different types of nociceptive agents, i.e., substance P, N-methyl-D-aspartate (NMDA), kainate (KA), and quisqualate (Quis). Tail-biting and scratching behavior induced by the 4 substances was significantly inhibited by SCT (i.c.v.) in the same manner: the dose-response curves were U-shaped, and the most effective dose was 0.1 IU/mouse in all cases. SCT did not, however, completely inhibit tail-biting and scratching behavior. At its most effective dose, the percent inhibition of substance P-, NMDA-, KA- and Quis-induced behavior were 77.9%, 40.2%, 49.4%, and 52.9%, respectively. These results suggest that SCT has the inhibitory effects of substance P- and glutamate receptor agonists-induced nociceptive response in vivo.

Afferent Pathways↗

PubMed1994

Effects of subacute administration of methamphetamine and nicotine on locomotor activity in transgenic mice expressing the human tyrosine hydroxylase gene.

We produced transgenic (Tg) mice carrying the human tyrosine hydroxylase (TH) gene. To investigate differences in the dopaminergic (DAergic) neuronal activity between the Tg and nTg mice, we examined changes in the locomotor activity induced by methamphetamine (MAP) and nicotine (NIC), which enhances DA release and induces TH enzyme activation, respectively. Surprisingly, however, the intensity of MAP (2.5 mg/kg, once a day for 14 days)-induced hyperlocomotion in the nTg mice was greater than that in the Tg mice, and, furthermore, the Tg mice were less sensitive to subacute administration of NIC (0.5 mg/kg, once a day for 14 days) than the nTg mice. These results suggest that DAergic neuronal function is suppressed in Tg mice to compensate for the overexpression of TH.

Animals↗