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Biomedical subjects

J Semba

Publications and source records attributed to J Semba.

36 records · Page 2Linked to original sources
PubMed1993

Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: milacemide.

1. The kinetics and metabolism of milacemide have been studied in an animal model which allows the simultaneous investigation of the temporal inter-relationships of drugs and metabolites in blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) in individual freely moving rats. 2. Milacemide dose-dependently increased CSF glycine and glycinamide (intermediary metabolite) concentrations. This confirms that milacemide is a CNS glycine prodrug. 3. Pretreatment with L-deprenyl (2 mg kg-1), a specific inhibitor of monoamine oxidase type B (MAO-B), almost completely prevented the formation of glycinamide and increased milacemide accumulation in CSF. Tmax and t1/2 were significantly increased and Cmax and AUC values were decreased for glycinamide compared to controls. Pretreatment with clorgyline (5 mg kg-1), a specific inhibitor of MAO-type A, only moderately decreased glycinamide Cmax and AUC values. 4. After milacemide administration (100, 200 and 400 mg kg-1, i.p.) serum and CSF milacemide concentrations rose linearly and dose-dependently. Serum glycinamide concentrations exhibited small dose-dependent rises but these were not linearly related. In contrast, CSF glycinamide concentrations rose linearly and dose-dependently with Cmax values 2.5, 3.2 and 4.1 times greater than the corresponding values for serum glycinamide after giving 100, 200 and 400 mg kg-1 respectively of milacemide. 5. Serum glycine concentrations were unaffected but CSF concentrations increased dose-dependently and these were significant at the higher milacemide doses (200 and 400 mg kg-1). Animals given 400 mg kg-1 milacemide had glycine values which were still significantly elevated 7 h later. 6. In conclusion, serum milacemide rapidly enters and equilibrates with the CNS compartment where it is metabolised primarily by MAO-B to glycinamide and finally to glycine. Metabolism in the peripheral compartment is negligible.

Acetamides↗
PubMed1992

Measurement of glutamate, aspartate and glycine and its potential precursors in human brain using high-performance liquid chromatography by pre-column derivatization with dimethylaminoazobenzene [correction of diethylaminoazobenzene] sulphonyl chloride.

This paper describes a high-performance liquid chromatographic technique, with dimethylaminoazobenzene sulphonyl chloride derivatization, for the measurement of glutamate, aspartate and glycine and its potential precursors in human brain tissue. The derivatization procedure is simple, sensitive and highly reproducible. The derivatized amino acids are stable and can be analysed by reversed-phase chromatography with visible detection at an absorption wavelength of 436 nm. A preliminary application to the determination of the concentrations of several amino acids in several regions of the human brain is described.

Aged↗
PubMed1992

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics (cerebrospinal fluid): hematological and biochemical characterization and kinetic evaluation using carbamazepine.

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics [cerebrospinal fluid (CSF)] is described. The blood (jugular vein) and CSF (cisterna magna) catheters employed are simple, reliable, and inexpensive. The blood catheter was made of soft and flexible Silastic tubing and sealed with heparin. The CSF catheter consisted of intersliding polythene tubing and interlocking Silastic tubing, which allowed maneuverability within the cisternal magna space and thus prolonging patency for chronic studies. Both catheters were well tolerated by the animals, and the postoperative success rate was 80%-100%; after 8 days 80%-85% of catheters were still patent. Using a sampling protocol considered suitable for kinetic studies, we determined numerous biochemical and hematological parameters and compared them with those values obtained postsurgically and in control rats. The parameter changes associated with the sampling protocol did not affect the kinetics of the commonly prescribed antiepileptic drug carbamazepine and its primary pharmacologically active metabolite carbamazepine-10, 11-epoxide. Therefore, the model can be used to study the interrelationship between drug kinetics at central and peripheral sampling sites and mechanism(s) of drug action.

Animals↗
PubMed1992

Effect of milacemide on extracellular and tissue concentrations of dopamine and 5-hydroxytryptamine in rat frontal cortex.

1. Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5-hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2. Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400 mg kg-1, i.p.), peaking at 1 h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-1 milacemide). 3. Dialysate 5-HT was significantly increased only at 1.5 h after giving milacemide 400 mg kg-1. Dialysate 5-hydroxyindoleacetic acid (5-HIAA) concentration was not affected. 4. Milacemide (400 mg kg-1) at 1.5 h post-administration significantly increased frontal cortex tissue concentrations of dopamine and 5-HT; the percentage increase in dopamine being about four times that of 5-HT. Metabolite concentrations, including 5-HIAA, decreased. Changes in tissue and dialysate dopamine, DOPAC and HVA were approximately proportionate to each other. 5. The results are explicable in terms of an inhibition by milacemide of MAO-A.

Acetamides↗
PubMed1991

Simple and rapid micro-analytical procedures for the estimation of milacemide and its metabolite glycinamide in rat plasma and cerebrospinal fluid by high-performance liquid chromatography.

A high-performance liquid chromatographic technique is described for the determination of milacemide and its primary metabolite glycinamide in rat plasma and cerebrospinal fluid. Milacemide and glycinamide are derivatized with fluorescamine to form a chromophore and a fluorophore and subsequent analysis using ultraviolet and fluorescence detectors, respectively. The extraction procedures are simple with a limit of detection 2 and 0.5 micrograms/ml for milacemide in plasma and cerebrospinal fluid, respectively, and 0.5 micrograms/ml for glycinamide in plasma or cerebrospinal fluid. The within-batch coefficients of variation for both analytes were less than 3%. Since only a small amount of sample is required, these techniques are well suited for the study of milacemide pharmacokinetics in the rat.

Acetamides↗
PubMed1990

Neuroendocrinological effects of L-threo-3, 4-dihydroxyphenylserine (DOPS), a putative norepinephrine precursor, on healthy volunteers.

The effect of L-threo-3, 4-dihydroxyphenylserine (DOPS) on plasma cortisol, prolactin, thyrotropin-stimulating hormone (TSH) and growth hormone concentrations was studied in nine healthy male volunteers. The drug was administered orally (300 mg or 600 mg DOPS) using a multiple crossover placebo-controlled study design. Plasma hormone concentrations were measured at 30 minute intervals for 3 hours after dosing. Plasma DOPS peak concentrations were observed between 2 and 3 hours after dosing. DOPS, however, had no effect on plasma hormone concentrations and this may be attributed to the known low brain permeability of DOPS in healthy subjects.

Adult↗
PubMed1989

Potential antidepressant properties of subchronic GABA transaminase inhibitors in the forced swimming test in mice.

We carried out the forced swimming test in mice to investigate the antidepressant potentials of GABA transaminase (GABA-T) inhibitors including aminooxyacetic acid, ethanolamine-O-sulfate, gamma-vinyl GABA (GVG) and valproic acid (VPA). In acute experiments only GVG reduced immobility. Following chronic oral administration via drinking water containing the drugs, immobility was significantly reduced at days 5 and 10 in all of the GABA-T inhibitors examined. The tolerance of the anti-immobility effect, however, occurred at day 20. Brain GABA contents showed moderate to marked increase during the session with the exception of VPA, which did not alter GABA contents. These results suggest that subchronic GABA-T inhibitors possess antidepressant properties, though the anti-immobility effect of GABA-T inhibitors did not directly correlate with the increase in brain GABA.

4-Aminobutyrate Transaminase↗
PubMed1988

Increase in urinary beta-phenylethylamine preceding the switch from mania to depression: a "rapid cycler".

beta-Phenylethylamine (PEA), an endogenous amphetamine-like substance, is known to increase central catecholamine metabolism and has been hypothesized to have an etiological importance in affective disorders. A case of a "rapid cycler" who showed increased PEA excretion before the switch from mania into depression was reported. In order to evaluate whether the patient's cycle of moods could be prevented by modulating PEA metabolism, carbidopa (peripheral dopa decarboxylase inhibitor) and safrazine (monoamine oxidase inhibitor) were administered during the manic and depressive periods of the patient, respectively. Carbidopa exacerbated the manic symptoms, although it decreased PEA excretion. Safrazine induced the increase of PEA without any beneficial effect on the depressive symptoms. These findings may suggest that PEA plays the role of a biochemical trigger in the switch mechanism of a rapid cycler, especially in the switch from mania to depression.

Adult↗
PubMed1985

Determination of free and total 3-methoxy-4-hydroxyphenylethylene glycol in human plasma by high-performance liquid chromatography with electrochemical detection.

A new assay method for the determination of free and total 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) in human plasma is described. MHPG was purified with a Bond Elut PH column followed by ethyl acetate extraction. High-performance liquid chromatography (HPLC) with electrochemical detection was used for separation and detection of MHPG. Total MHPG was measured after enzymatic hydrolysis with sulfatase type H-5. 3-Hydroxy-4-methoxyphenylethylene glycol (iso-MHPG) was used as an internal standard to correct the recovery of extraction. One assay could be completed within 20 min with a short reverse-phase column. This technique is sensitive, reliable and less time-consuming than other HPLC methods. With this method, the plasma values of MHPG in healthy controls were in good agreement with those using gas chromatography-mass spectrometry.

Acetates↗
PubMed1985

The effects of L-threo-dihydroxyphenylserine on norepinephrine metabolism in rat brain.

The effects of L-threo-3,4-dihydroxyphenylserine (DOPS), an artificial precursor of norepinephrine (NE), on NE metabolism in rat brain were investigated. DOPS administration resulted in a significant elevation in cerebral NE and 3-methoxy-4-hydroxyphenylglycol contents, while carbidopa pretreatment completely blocked these increases. After brain NE was depleted by either alpha-methyl-p-tyrosine (AMPT), fusaric acid, FLA-63, or reserpine, NE restoration by DOPS was observed in rats treated with either fusaric acid or chronic reserpine. No NE restoration was observed after pretreatment with AMPT, FLA-63, or acute reserpine. The results suggest that NE formed after DOPS administration is mainly localized in the brain capillaries. In some NE-depleting conditions, however, DOPS can penetrate the brain parenchyma.

Animals↗
PubMed1984

Twenty-four hour rhythms of norepinephrine and serotonin in nucleus suprachiasmaticus, raphe nuclei, and locus coeruleus in the rat.

Twenty-four hour rhythms, at 4 h intervals, of norepinephrine (NE) and serotonin (5-HT) contents were investigated in the rat brain regions where sleep-wakefulness regulation is believed to occur: Nucleus suprachiasmaticus (SC), n. raphe dorsalis (RD) and medialis (RM), and locus coeruleus. Cosinor method of Halberg was applied to evaluate sinusoidal rhythmicity of the measured values. In the SC only NE showed a significant rhythm with a peak value at the beginning of the light period, which suggests that a NE mechanism may be involved in oscillating biological rhythms in rats. In the RD and RM, 5-HT and 5-hydroxyindoleacetic acid increased significantly during the light period. Moreover, 5-HT rhythm in the RD was maintained even under constant dark conditions, which suggests that 5-HT rhythm in the RD may be endogenous.

Animals↗
PubMed1983

[Effect of beta-phenylethylamine on locomotor activity and brain catecholamine metabolism in mice].

beta-Phenylethylamine (PEA) is a naturally occurring compound and its structure is close to amphetamine. The effects of PEA on locomotor activity and brain catecholamine metabolism in mice were investigated. Mice were injected with PEA 50 mg/kg intraperitoneally. PEA produced increased locomotor activity between 3 and 6 min, then a decline to 20 min after the injection. There was decreased activity with a slight stereotyped behavior consisted of sniffing and head bobbing between 15 and 20 min. 3-Methoxy-4-hydroxy-phenylethyleneglycol (MHPG), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the whole brain were examined. MHPG levels showed no remarkable changes at 5 min after PEA, then increase at 30 and 60 min. HVA level was increased but DOPAC level was decreased at 60 min. Type B monoamine oxidase activity showed no remarkable changes in discrete regions of the brain at 5 and 30 min. These results suggest that PEA may not only release catecholamines but inhibit the reuptake of neurogenically released dopamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Effect of systemic dexamethasone on extracellular amino acids, GABA and acetylcholine release in rat hippocampus using in vivo microdialysis.

In order to elucidate the mechanism of the cytotoxic effect of glucocorticoid on the rat hippocampus, we studied the effects of dexamethasone, a synthetic glucocorticoid, on neurotransmitter release from the hippocampus by in vivo microdialysis. Dexamethasone (10 mg/kg) was administered i.p. and the extracellular concentrations of the amino acids (glutamate, aspartate, glycine), GABA and acetylcholine were determined in the hippocampus of freely moving rats. Glutamate concentration increased by 20-25% after dexamethasone administration and this effect continued for 1 hour. The extracellular concentration of the other neurotransmitters, however, did not show any significant changes. From these results, we concluded that increased extracellular glutamate may be involved, at least in part, in the cytotoxic effect of glucocorticoid on hippocampal neurons.

Acetylcholine↗