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Biomedical subjects

A Nakai

Publications and source records attributed to A Nakai.

At least 109 records · Page 6Linked to original sources
PubMed1994

Enantioselective pharmacokinetics of homochlorcyclizine: disposition of (+)- and (-)-homochlorcyclizine after intravenous and oral administration of racemic homochlorcyclizine to rats.

Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high-performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg-1), homochlorcyclizine was rapidly distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations. After oral administration (50 mg kg-1), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (-)-isomer. The AUC0-infinity values of the (+)- and (-)-isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (-)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by in-vitro experiments.

Administration, Oral↗
PubMed1994

Effect of first-pass metabolism on enantioselective pharmacokinetics after oral administration of (+)-, (-)- and racemic homochlorcyclizine to rats.

The enantioselective relationship between the pharmacokinetics and hepatic metabolism of homochlorcyclizine hydrochloride (HCZ) was investigated using rats. There were no significant differences in blood concentrations between the three forms after intravenous administration (5 mg/kg) of (+)-, (-)- and racemic HCZ. On the other hand, there were significant differences in the pharmacokinetics between (-)- and (+)-HCZ and between (-)- and racemic HCZ after oral administration (50 mg/kg) of these three forms. The Cmax and AUC0-infinity of (-)-HCZ were lower than those of (+)-isomer and racemate, and its CLo was clearly higher than the others. The (+)-isomer and racemate showed no significant differences in their pharmacokinetic parameters. At a lower dose (10 mg/kg), however, no enantiomeric differences were found in the pharmacokinetic parameters of (+)- and (-)-HCZ. Also examined was the cytochrome p-450-dependent-oxidative metabolism of (+)-, (-)- and racemic HCZ in vitro using rat liver 9000 x g supernatant fraction. The in vitro metabolism of (-)-HCZ was extremely fast, compared with those of the (+)-isomer and the racemate. The Vmax in vitro showed a good correlation with the CLo in vivo after oral administration (50 mg/kg) of all three forms of HCZ. In vitro study of enantiomeric inhibition of the metabolism showed that (+)-HCZ was a competitive inhibitor of (-)-HCZ metabolism, with a Ki of 6.96 microM. (-)-HCZ was also a competitive inhibitor of (+)-HCZ metabolism, with a Ki of 20.4 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Immunoreactive creatine kinase-MB and creatine kinase isozyme concentrations during treatment of hypothyroid patients.

Using a highly sensitive enzyme immunoassay (EIA) system, we determined creatine kinase isozymes, namely creatine kinase-MB and creatine kinase-MM, in sera of patients suffering from primary hypothyroidism with concomitant signs of myocardial affections before and during treatment. After oral administration of L-thyroxine, the augmented mass concentrations of serum creatine kinase-MB and creatine kinase-MM, and the increased catalytic activity concentrations of serum total creatine kinase and creatine kinase-MB gradually decreased in inverse proportion to the increased concentrations of serum triiodothyronine (T3) and thyroxine (T4). By the 6th to 8th week after treatment, the elevated levels of serum total creatine kinase and creatine kinase-MB catalytic activity concentrations (assayed by a routine method) and serum creatine kinase-MM mass concentrations (assayed by EIA) declined to normal values, while serum T3, T4, and thyroid stimulating hormone attained normal values. Serum creatine kinase-MB mass concentrations (assayed by EIA), however, still remained at the higher level, without complete recovery from myocardial damage, as shown by electrocardiogram (ECG). These data indicate that metabolic distortion still exists in the myocardium, as revealed by the high creatine kinase-MB mass concentration, especially as assayed by EIA, even though the plasma levels of thyroid hormones had returned to normal.

Aged↗
PubMed1994

Changes of calmodulin concentration and cyclic 3',5'-nucleotide phosphodiesterase activities in cardiac muscle of hyper- and hypothyroid rats.

To investigate the effect of thyroid hormone on cardiac muscle dysfunction in hyper- and hypothyroid states, we evaluated cyclic 3',5'-nucleotide metabolism by measuring cyclic 3',5'-nucleotide phosphodiesterase activity and calmodulin concentrations in the cardiac muscles of hyper- and hypothyroid rats. Cyclic AMP (cAMP) concentration was significantly high in the cardiac muscle of hyperthyroid rats and low in that from hypothyroid rats compared with control rats. Cyclic AMP and cyclic GMP phosphodiesterase activities were significantly decreased in the soluble fraction of cardiac muscle from hyperthyroid rats and markedly increased in this fraction in hypothyroid rats compared with normal animals. Calmodulin concentration was high in hyperthyroid and low in hypothyroid rats. It was concluded from these findings that low cAMP-phosphodiesterase activity might, in part, bring about the high concentration of cAMP. Calmodulin was significantly high in the cardiac muscle of hyperthyroid rats and the reverse was the case in hypothyroid rats compared with normal rats. The implication is that, in hyper- and hypothyroid states, these changes may play an important role in cardiac function via their effect on cyclic nucleotide and Ca2+ metabolism.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Abnormal fatty acid composition of lymphocytes of biotin-deficient rats.

The relative proportions (% of total fatty acids) of odd-chain (15:0-29:0) and long-chain (22:0-30:0) saturated fatty acids in phospholipids of biotin-deficient rat lymphocytes were significantly increased as compared with biotin-supplemented rats, and the ratio of unsaturated fatty acids to saturated fatty acids in the former was significantly decreased mainly due to the reduced composition of polyunsaturated fatty acids in the omega-3, omega-6, and omega-9 pathway. The ratio of cis-vaccenic acid to palmitoleic acid in biotin-deficient rats was significantly lower than that in control rats, and was thought to be another important, but previously unreported indicator of biotin deficiency. These changes imply that the elongation and desaturation of unsaturated fatty acids are depressed in lymphocytes of biotin-deficient rats, and may contribute to the associated immunological dysfunction in biotin deficiency through abnormal prostaglandin metabolism and/or cell membrane functions.

Animals↗
PubMed1994

Bilateral ptosis with ophthalmoplegia in a 72-year-old woman with diabetes.

Ophthalmoplegia is common cranial neuropathy of Diabetes. In case of 3rd nerve involvement, usually unilateral extra ocular muscles are affected. However, ptosis is very rare in patients with diabetic neuropathy. In this report, we describe bilateral ptosis with ophthalmoplegia in diabetes. In ophthalmoplegia associated with diabetes, ischemic nerve infarction was reported. We treated this patient with Lipo prostaglandin (PG) E1. Since then, increased platelet aggregation activity was found in this patient. After two months, the symptoms of this patient were improved.

Aged↗
PubMed1994

[Ultrasonographic blood flow velocimetry in maternal and umbilical arteries during maternal exercise].

To see hemodynamic changes induced by exercise in pregnant women, we performed blood flow velocimetry with an ultrasonic pulsed Doppler in femoral (FA), external carotid (CA), uterine (UA) and umbilical arteries (Umb A) of pregnant women before and after aerobic dancing at an intensity of approximately 65% maximal heart rates. The subjects were 21 volunteer pregnant women at from 34 to 40 weeks of gestation without obstetrical problems. The velocimetry was done at intervals of five minutes for only one artery of the four arteries. The measurement was repeated 4 times. The following results were obtained: (1) Both pulse rates and blood pressure (BP) increased significantly five minutes after the onset of exercise (p < 0.05) and tachycardia continued for 20 minutes. The intensity of exercise was equivalent to 68.8 +/- 1.1% of the maximal heart rates (mean +/- S.E.). (2) Systolic peak velocity in the FA of the pregnant women increased by 130%, flow volume per minute jumped by 337% (p < 0.05), and the pulsatility index (PI) decreased by 80% (p < 0.05). (3) Neither the systolic peak velocity nor the PI of CA and UA changed significantly. (4) The FHR became tachycardic due to exercise from 142.2 +/- 2.5 bpm to 161.1 +/- 3.8 bpm, associated with the increase in maternal pulse rates. (5) The PI of Umb A was decreased from 0.95 +/- 0.04 to 0.80 +/- 0.03 by exercise. The PI showed a negative correlation (r = -0.37, p < 0.05) with the FHR, not different from a correlation shown without exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Structure and function of TRAP].

Thyroid hormone receptor (THR) binds to specific thyroid hormone response element (TRE). Using an electrophoretic mobility shift assay (gel-shift), Murray and Towel recently found that cell nuclear extracts enhance the binding of THR to TRE. This protein has been designated T3 receptor auxiliary protein (TRAP). Retinoid X receptors (RXR alpha, beta) can function as TRAP. TRAP forms a heterodimer with THR through the ligand binding domain of both receptors. This area contains leucine zipper like heptad repeats which can form amphipathic alpha-helixes. The ligand (9-cis retinoic acid) of RXR may or may not synergistically increase T3/THR-mediated transactivation. The effects of 9-cis retinoic acid depends on the nature of the TRE. One of the functions of TRAP may be to alter the expression of T3-regulated genes.

Base Sequence↗
PubMed1993

Detection of heterozygotes for fructose-1,6-diphosphatase deficiency by measuring fructose-1,6-diphosphatase activity in monocytes cultured with calcitriol.

The increase of fructose-1,6-diphosphatase activity during culture with calcitriol, which was reported in monocytes, was found not to occur in lymphocytes. Monocytes cultured with calcitriol were accordingly used as more reliable diagnosis of heterozygotes for fructose-1,6-diphosphatase deficiency, instead of mononuclear cells (lymphocyte-fraction-containing monocytes) cultured without calcitriol by a conventional method. Variation of fructose-1,6-diphosphatase values in leukocytes from nine healthy adults was smallest in monocytes cultured with calcitriol, among four different experimental conditions: monocytes cultured with or without calcitriol and mononuclear cells cultured with or without calcitriol. Both parents of two sisters with fructose-1,6-diphosphatase deficiency were successfully confirmed as carriers of fructose-1,6-diphosphatase deficiency by this method. However, confirmation by the conventional method using mononuclear cells cultured without calcitriol was possible only in the father, not in the mother. Thus, the new method using monocytes cultured with calcitriol seems more reliable for detecting heterozygotes for fructose-1,6-diphosphatase deficiency.

Calcitriol↗
PubMed1993

Enantioselective pharmacokinetics of homochlorcyclizine. III. Simultaneous determination of (+)- and (-)- homochlorcyclizine in human urine by high-performance liquid chromatography.

A method is described for the simultaneous determination of (+)- and (-)-homochlorcyclizine (HCZ) in human urine by high-performance liquid chromatography on a chiral stationary phase of ovomucoid-bonded silica. The pH of the buffer and organic modifier in the mobile phase markedly affected the chromatographic separation. A mobile phase of methanol-0.02 M acetate buffer (pH 4.7) (25:75,v/v) at a flow-rate of 1.0 ml/min was used for the urine assays. The ultraviolet absorption was monitored at 240 nm, and diphenhydramine was employed as the internal standard for the quantitation. (+)-HCZ, (-)-HCZ and the internal standard were eluted at retention times of 15, 25 and 8 min, respectively. The limit of determination for HCZ enantiomers was ca. 50 ng/ml of urine. One of the metabolites in human urine, which was a quaternary ammonium-linked glucuronide, could also be determined in a manner similar to unchanged HCZ after beta-glucuronidase hydrolysis. A pharmacokinetic study was conducted with three healthy volunteers, who each received a single oral dose of racemic HCZ (20 mg). Distinct differences were found between the two enantiomers, particularly in the metabolic process, that is, the urinary excretion as (-)-HCZ-glucuronide within 48 h was ca. four times higher than that of the (+)-isomer. This method should be very useful for enantioselective pharmacokinetic studies of HCZ.

Adult↗
PubMed1993

Modulation of the phosphorylation of glucose-regulated protein, GRP78, by transformation and inhibition of glycosylation.

The phosphorylation of glucose-regulated protein, GRP78, is thought to be involved in the regulation of the binding function of GRP78 to immunoglobulin heavy chains. The phosphorylation of GRP78 proceeded faster in transformed cells than in normal cells, whereas the levels of GRP78 synthesis and accumulation were similar in both cells. Treatment of the cells with tunicamycin caused a rapid decrease in GRP78 phosphorylation within 2 to 4 h in both cell types prior to GRP78 induction. Following a longer period of tunicamycin treatment, GRP78 phosphorylation recovered gradually in parallel with the accumulation of newly synthesized GRP78. The half-life of GRP78 was over 24 h and similar in both normal and transformed cells either with or without tunicamycin treatment. In contrast, the half-life of phosphate groups incorporated into GRP78 was about 120 min in both types of cells in the absence of tunicamycin treatment. When the cells were treated with tunicamycin, the half-life of the phosphate groups was shortened (-30 min) only in transformed cells, while it remained at untreated control levels in normal cells. These results suggest that GRP78 phosphorylation is important in functional regulation, and that the cells may carry out particular requirements such as increasing or decreasing secretory proteins by modulating GRP78 phosphorylation rather than GRP78 synthesis.

3T3 Cells↗
PubMed1993

Urinary sugar phosphates and related organic acids in fructose-1,6-diphosphatase deficiency.

Two sisters with fructose-1,6-diphosphatase deficiency are reported. They presented with ketonuria, elevated plasma transaminase activity and severe metabolic acidosis during hypoglycaemic crises, which resembled Reye syndrome. Intravenous fructose tolerance tests provoked severe hypoglycaemia and metabolic acidosis. Fructose-1,6-diphosphatase activities in both peripheral leukocytes and cultured lymphocytes were below the limit of detection. Urinary organic acid analysis during crises revealed markedly increased excretion of lactate, ketone bodies, glycerol and glycerol-3-phosphate. We newly identified other glycolytic intermediates, glyceraldehyde, 3-phosphoglycerate and fructose-1,6-diphosphate, in the urine during hypoglycaemic attacks or after fructose tolerance tests. Identification of such compounds may be useful in the early diagnosis of this disease.

Female↗
PubMed1993

The effects of biotin deficiency on organic acid metabolism: increase in propionyl coenzyme A-related organic acids in biotin-deficient rats.

Volatile organic acid levels in plasma and tissues and nonvolatile organic acid levels in urine of biotin-deficient (BD) rats were measured and compared with other factors of biotin deficiency. Biotin levels and the activities of propionyl coenzyme A (CoA) carboxylase (PCC) in the livers of these rats were decreased, respectively, to 22% +/- 3% and 3.6% +/- 0.3% of the average values of pair-fed controls. Plasma concentrations of propionate were higher (15 to 223 micrograms/mL) than those of controls (5 to 7 micrograms/mL), whereas plasma levels of 3-methylcrotonate were only minimally increased as compared with those of controls. Concentrations of these volatile acids in the tissues were similarly increased, although those in brain showed less remarkable increases as compared with levels in other tissues. In the urine of BD rats, large amounts of organic acids derived from propionyl CoA, as well as those from 3-methylcrotonyl CoA, were excreted. Plasma propionate levels were not apparently related to the severity of clinical symptoms, biotin levels, or carboxylase activities, but were related to the amounts of urinary ketone bodies, lactate, and some of the organic acids derived from branched-chain amino acids, including those from propionyl CoA.

Acyl Coenzyme A↗
PubMed1993

Enhancement of DNA polymerase beta activity in the pituitary gland by hormonal feedback.

The activity of DNA polymerase beta (beta-enzyme) in bovine and rat pituitary glands was remarkably higher in the anterior than in the posterior lobe. In sucrose gradient centrifugation, the activity in the anterior lobe of the bovine pituitary gland appeared at the sedimentation constant, 3.3 S, while that of rat pituitary gland appeared at 3.3 S, 7.3 S and 12 S, respectively. The activity in each fraction increased in the anterior lobes of rat pituitaries that were stimulated to release TSH by decreased thyroid hormone levels induced by an antithyroid drug. These results suggest that the activity of the beta-enzyme is high in the cells of the anterior lobe which are hyperfunctioned to produce pituitary thyreotrophic hormone and may be controlled by hormonal feedback regulation.

Animals↗
PubMed1993

Characterization of a novel chicken heat shock transcription factor, heat shock factor 3, suggests a new regulatory pathway.

We have cloned three avian heat shock transcription factor (HSF) genes corresponding to a novel factor, HSF3, and the avian homologs of mammalian HSF1 and HSF2. The predicted amino acid sequence of HSF3 is approximately 40% related to the sequence of HSF1 and HSF2. The sequences for all three factors exhibit extensive identify in the DNA binding motifs and the heptad repeats of hydrophobic amino acids which are common to all eukaryotic HSFs. Despite these overall similarities, each avian HSF exhibits distinct DNA binding properties. HSF2 when expressed in vitro binds constitutively to the heat shock element promoter sequence, whereas neither HSF1 nor HSF3 expressed in vitro binds to DNA. HSF1 DNA binding is induced upon heat shock or treatment with nonionic detergents, whereas the DNA binding properties of HSF3 are not induced by these conditions in vitro. These results suggest that HSF3 activation may involve an induction pathway distinct from the traditional forms of heat shock gene induction. HSF3 DNA binding activity, however, is obtained when the carboxyl-terminal region including the distal heptad repeat is deleted, indicating the presence of negative cis-regulatory sequences. The HSF3 message, like HSF1 and HSF2 messages, is coexpressed during development and in most tissues, which suggests a general role for the regulatory pathway involving HSF3.

Age Factors↗
PubMed1993

Localization of Cu/Zn and Mn superoxide dismutase in various thyroid disorders.

The intracellular localization of Cu/Zn- and Mn-superoxide dismutase (SOD), which catalyze the dismutation of superoxide radicals (O2-) to O2 and H2O2, was studied in the thyroid tissue of various thyroid disorders by an immunohistochemical technique. The concentrations of both SODs in those tissues were measured also by a sandwich enzyme immunoassay technique. Copper/zinc-SOD in thyroid tissues were identified by immunocytochemical staining in most cases of papillary carcinoma and in some cases of other thyroid disorders. In normal follicular cells this enzyme is localized in the perinuclear cytoplasm, whereas in thyroid tumor or hyperplastic follicular cells it exists homogeneously in cytoplasm. Manganese-SOD stained strongly in papillary carcinoma and papillary-growing cells in the thyroid tissue of adenoma and Graves' disease. The concentrations of Cu/Zn-and Mn-SOD in thyroid tumor tissues and hyperplastic follicular disorders were significantly higher than those in normal thyroid tissue when they were compared as a function of protein or deoxyribonucleic acid contents. The ratio of Mn-SOD to Cu/Zn-SOD was significantly higher only in papillary carcinoma, except for other thyroid disorders as compared with that in the normal thyroid. In conclusion, SOD seems to be related to cell proliferation and differentiation in the thyroid follicular cell because Cu/Zn-SOD changes its localization in tumor and hyperplastic follicular cells and because the Mn-SOD concentration is increased in papillary carcinoma or papillary-growing cells.

Humans↗