Search PubMed⌕ Search

Biomedical subjects

N Nagai

Publications and source records attributed to N Nagai.

At least 109 records · Page 6Linked to original sources
PubMed1996

Pharmacokinetics and polymorphic oxidation of dextromethorphan in a Japanese population.

The plasma concentration and cumulative urinary excretion over 34 h of dextromethorphan, free and conjugated dextrorphan, and 3-hydroxymorphinan were determined in seven healthy Japanese subjects after oral administration of 30 mg dextromethorphan hydrobromide. Conjugated metabolites were extensively present, whereas no detectable dextromethorphan or free metabolites were observed in the plasma of any subject. On average, 72% of the dose was excreted in urine within 34 h. This was detected mainly as conjugated metabolites with only slight traces of dextromethorphan and free metabolites. From the time-courses of the metabolic ratio (the ratio of urinary output of dextromethorphan to dextrorphan), the metabolic ratios seemed to become constant 7.5 h after oral administration. Phenotyping was performed using metabolic ratios in 75 unrelated healthy Japanese subjects (43 males and 32 females). The logarithmic metabolic ratio was bimodally distributed and one subject (1.3%) was identified as a poor metabolizer.

Administration, Oral↗
PubMed1996

Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients.

PURPOSE: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). METHODS: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary beta2-microglobulin (BMGp and BMGu), urinary N-acetyl-beta-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. RESULTS: The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dt(max)), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. CONCLUSION: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 microg/ml in a standard continuous infusion schedule over 2 h and 4 h.

Adult↗
PubMed1996

Changes in taste responsiveness in patients with anorexia nervosa during behavior therapy.

We evaluated the changes in taste responsiveness of anorexia nervosa (AN) patients during behavior therapy. Taste responsiveness of AN patients was lower at admission when compared to controls but it improved significantly over the course of treatment (p < 0.01). Taste responsiveness improved prior to increase in body weight. No significant correlation was noted between weight gain and improvement in taste responsiveness. The period required to reach a food intake of 1600 Kcal/day and the duration of hospitalization were highly correlated (r = 0.72, p < 0.05). Those who reached 1600 Kcal/day earlier showed more rapid improvements in taste responsiveness. These results suggest that decreased taste responsiveness in AN patients can rapidly improve and such early improvement may result in better progression of treatment.

Adolescent↗
PubMed1996

Bilateral lesions of the hypothalamic suprachiasmatic nucleus eliminated sympathetic response to intracranial injection of 2-deoxy-D-glucose and VIP rescued this response.

We previously found that bilateral lesions of the suprachiasmatic nucleus abolished hyperglycemic response to intracranial injection of 2-deoxy-D-glucose in rats. Because the hyperglycemia due to 2-deoxy-D-glucose was shown to be dependent on the functions of the adrenal medulla and sympathetic nervous system, the effect of bilateral lesions of the suprachiasmatic nucleus on changes in the nervous activity of sympathetic efferents to the adrenal after intracranial injection of 2-deoxy-D-glucose was examined in rats. It was found that bilateral lesions of the nucleus eliminated the increase in neural activity of the sympathetic efferent that occurred after the injection of 2-deoxy-D-glucose. Because the suprachiasmatic nucleus possesses neurons containing a vasoactive intestinal polypeptide-like substance, the effects of vasoactive intestinal polypeptide and 2-deoxy-D-glucose, administered alone or in combination, on the sympathetic activity were examined in intact control rats and in rats with bilateral lesions of the suprachiasmatic nucleus. It was found that in the normal control rats, vasoactive intestinal polypeptide alone increased the sympathetic activity, whereas it dramatically enhanced the sympathetic response to 2-deoxy-D-glucose. However, in rats with bilateral lesions of the suprachiasmatic nucleus, vasoactive intestinal polypeptide alone elicited no increase in the nervous activity of the sympathetic efferents to the adrenal, but combined administration of vasoactive intestinal polypeptide and 2-deoxy-D-glucose caused an increase in the nervous activity of sympathetic efferents to the adrenal. These findings suggest that the suprachiasmatic nucleus is involved in the enhancement of sympathetic activity caused by intracranial injection of 2-deoxy-D-glucose, and that neurons containing a vasoactive intestinal polypeptide-like substance in the suprachiasmatic nucleus play an important role in the sympathetic enhancement that occurs after intracranial injection of 2-deoxy-D-glucose. This role might be a permissive and facilitative one.

Analysis of Variance↗
PubMed1996

The renal clearance of unchanged cisplatin during furosemide and mannitol diuresis is dependent on glomerular filtration rate in rats.

The disposition of unchanged cisplatin (CDDP) in plasma and urine after bolus injection of CDDP (5 mg/kg) was compared in rats treated with furosemide (25 mg/kg as a 40-min iv infusion) and mannitol (2 g/kg as a 40-min iv infusion). Forced diuresis significantly increased renal clearance (Clr) of unchanged CDDP in the first 10-min period after CDDP administration, compared to that in the rats given CDDP alone. Compared with furosemide, mannitol showed greater modification in Clr of unchanged CDDP in the early phase and more accelerated urinary excretion of unchanged CDDP during the study. Furosemide increased plasma concentration and reduced urinary excretion of unchanged CDDP in the terminal phase. Clr of unchanged CDDP was found to be dependent of glomerular filtration rate (GFR) during diuretic coadministration. Linear relationships among urine flow rate, GFR, and Clr of unchanged CDDP were observed only in diuretic-treated rats. Although the relationships between GFR and Clr were almost identical, there was a difference in the GFR-urine flow rate relationship between furosemide- and mannitol-treated rats. GFR was gradually reduced during diuretic treatment, and furosemide induced greater GFR reduction than mannitol. This resulted in a modification of unchanged CDDP disposition by furosemide in the terminal phase. The present study suggests that careful monitoring and maintaining of GFR during coadministration of diuretic may be useful for predicting the urinary excretion behavior of unchanged CDDP in CDDP chemotherapy.

Animals↗
PubMed1996

Decomposition kinetics of cisplatin in human biological fluids.

Cisplatin is metabolized to high- and low-molecular mass complexes by exchanging of one or both chloride ligands with nucleophilic species. The decomposition of cisplatin and the formation of its metabolites in human biological fluids was investigated in-vitro. In nucleophile-free medium, cisplatin was decomposed by a reversible chloride ligand exchange reaction, which was dependent upon both chloride ion concentration and medium pH. The effect of pH was observed in the second-order rate constant for cisplatin re-formation, which was far smaller in neutral and alkaline media than in acidic media. In the medium containing nucleophilic species (glutathione, human albumin and globulin), cisplatin was irreversibly decomposed according to apparent first-order kinetics. The linear relationship between apparent decomposition rate constant and concentration of nucleophilic species suggested that nucleophilic species in biological fluids might react with cisplatin directly. Both high- and low-molecular mass metabolites were formed in human plasma and ascites; however, only a low-molecular mass metabolite was produced in urine. The faster decomposition of cisplatin and the greater ratio of fixed and mobile metabolites formed in plasma were mainly attributed to higher albumin concentration in plasma than in ascites and urine. The in-vitro decomposition of unchanged cisplatin and formation of high- and low-molecular mass metabolites in human biological fluids were simultaneously evaluated according to the kinetic model which combined both pathways via hydrolysis and by the direct reaction process with nucleophilic species.

Antineoplastic Agents↗
PubMed1996

Roles of the suprachiasmatic nucleus and vasoactive intestinal peptide in the response of plasma arginine vasopressin to osmotic challenge.

To clarify the role of neurons containing a vasoactive intestinal peptide (VIP)-like substance (VIP neurons) in the hypothalamic suprachiasmatic nucleus (SCN) in regulation of the plasma arginine vasopressin (AVP) concentration, we examined the effects of bilateral lesions of the SCN and intracranial injection of VIP on the increase in the plasma AVP concentration caused by ip injection of hypertonic (3.6%) saline in rats. The increase in the plasma AVP concentration after ip injection of hypertonic saline was significantly suppressed in rats with bilateral lesions of the SCN. Furthermore, the increase in the plasma AVP concentration elicited by ip injection of hypertonic saline was enhanced by intracerebro-ventricular injection of VIP and suppressed by a VIP antagonist, [Lys1,Pro2,5,Arg3.4,Tyr6]VIP. However, the same dose of VIP injected into the heart had no effect on the increase in the plasma AVP concentration caused by ip injection of hypertonic saline. These results suggest that the SCN and intracranial VIP play important roles in the regulation of the plasma AVP concentration and support the possibility that VIP neurons in the SCN enhance the response of plasma AVP to osmotic challenge.

Animals↗
PubMed1996

[Evaluation of prognostic factors in gynecological cancer examined by molecular biological study].

The usefulness of prognostic factors in gynecological cancer was evaluated using the oncogenes, tumor suppressor genes and DNA viruses detected with the molecular biological technique. In uterine cervical cancer, HPV types 16 and 18 are considered to have a high oncogenic risk, and are commonly associated with high grade CIN and invasive cancer under persistent HPV infection. C-myc overexpression in advanced stage and p53 mutation in HPV negative case are associated with poor survival. In endometrial cancer, oncogene activation and expression are less frequent than in cervical and ovarian cancer. K-ras point mutation (codon 12) tumors are more aggressive and c-erbB-2 overexpression are associated with metastasis and poor survival. In ovarian cancer, there are numerous abnormalities of oncogenes and tumor suppressor genes. Especially, EGF-R and PDGF-R alpha expression are associated with decreased survival. p53 mutation also decreases survival and response to chemotherapy. Recently. MSH2 (Lynch II syndrome) and BRCA1 gene are known to relate with familial ovarian cancer.

Female↗
PubMed1995

Suppressive effect of vasopressin on the hyperglycemic response to intracranial injection of 2-deoxy-D-glucose.

Vasopressin (VP) is a peptide consisting of 9 amino acids which acts as a neurotransmitter or neuromodulator in the central nervous system. Neurons containing VP project to some nuclei in the hypothalamus that have a role in energy metabolism. To clarify the possible role of VP on glucose metabolism in the brain, we examined the effect of intracranial injection of VP on the hyperglycemia induced by 2-deoxy-D-glucose (2DG) and obtained the following results. The hyperglycemic and hyperglucagonemic responses induced by 2DG were significantly suppressed and enhanced by co-injections of VP and a VP-antagonist with 2DG, respectively. However, co-injections of either VP or a VP-antagonist with 2DG had no effect on the change in plasma insulin concentration. These findings suggest that central VP plays a suppressive role in the hyperglycemic and hyperglucagonemic responses to 2DG.

Animals↗
PubMed1995

Quercetin suppresses heat shock response by down regulation of HSF1.

A bioflavonoid quercetin suppressed the stress response in heat-shocked cells and we have investigated the inhibitory mechanism in this report. After treatment of cells with nonlethal concentrations of quercetin, the binding of heat shock factor (HSF) to the heat shock element (HSE) was inhibited as detected by gel shift assay. We examined whether quercetin inhibits heat shock response by inhibiting HSF trimer-formation and found it was not the case. Instead, pretreatment of the cells with quercetin caused a decrease in the level of HSF1, especially of the constitutively phosphorylated form. This decrease was more prominent in heat-shocked cells than in control cells. These data suggest that (1) quercetin does not affect the trimer formation of HSF1, and (2) the decline of the HSF1-HSE complex might be linked to the decrease of HSF1 levels caused by quercetin.

Blotting, Western↗
PubMed1995

Quantitative determination of unchanged cisplatin in rat kidney and liver by high-performance liquid chromatography.

A quantitative analytical method for measuring unchanged cisplatin (CDDP) and high- and low-molecular-mass metabolites (fixed and mobile metabolites) in rat kidney and liver was developed. Unchanged CDDP, separated from fixed and mobile metabolites in tissue homogenates by consecutive procedures of fractionation and ultrafiltration, was determined by high-performance liquid chromatography (HPLC) with post-column derivatization. Although unchanged CDDP was found to be partly metabolized to fixed metabolites during the preparation of cytosolic ultrafiltrates, the recovery of unchanged CDDP gave a constant value (about 70%), which was independent of tissue type and CDDP concentration (from 1 to 10 micrograms/ml). The detection limit for unchanged CDDP in the cytosolic ultrafiltrate was 20 ng/ml, corresponding to a concentration detection limit of 65 ng Pt per g of tissue in the kidney and liver. The concentrations of fixed and mobile metabolites were determined as platinum concentrations in the tissue homogenate and in the cytosolic ultrafiltrate using atomic absorption spectrometry after correcting for transformation of unchanged CDDP to fixed metabolites. The distribution of unchanged CDDP, mobile metabolites and fixed metabolites in rat kidney and liver, after bolus injection of CDDP (5 mg/kg), was determined using this method.

Animals↗
PubMed1995

Effects of sodium thiosulfate on the pharmacokinetics of unchanged cisplatin and on the distribution of platinum species in rat kidney: protective mechanism against cisplatin nephrotoxicity.

To investigate the mechanism underlying the protective effect against cisplatin (CDDP) nephrotoxicity of its antidote, sodium thiosulfate (STS), the effects of STS on the pharmacokinetics of unchanged CDDP and on the distribution of unchanged CDDP and high and low molecular mass metabolites (fixed and mobile metabolites) in the kidney 1 min after a bolus injection of CDDP (5 mg/kg) to rats were studied. A decrease in the plasma concentration of unchanged CDDP and an increase in the plasma concentration of mobile metabolites were observed in the rats after the bolus injection of CDDP in combination with STS infusion for 30 min (1200 mg/kg). Although STS accelerated platinum excretion during the first 10 min after CDDP injection, unchanged CDDP was not excreted in the urine in the STS-treated rats. Total kidney platinum 1 min after the bolus injection of CDDP was detected mainly as unchanged CDDP (86% of the total platinum) in the rats given CDDP alone. However, in the STS-treated rats, the total kidney platinum was decreased to 62% of the level in the rats given CDDP alone, and the platinum species detected in the kidney were mainly mobile metabolites. Only 24% of the total kidney platinum was detected as unchanged CDDP in the STS-treated rats. The loss of body weight and increases in BUN and serum creatinine levels usually observed after a bolus injection of CDDP were completely prevented by STS coadministration. The present study provides information about unchanged CDDP pharmacokinetics and the distribution of unchanged CDDP and some of its generic metabolites in the kidney when STS is coadministered as an antidote. These results show that the protective effect of STS against CDDP nephrotoxicity can be attributed to the formation of inactive mobile metabolites by a direct reaction between unchanged CDDP and STS in the systemic circulation, resulting in a reduction in the amount of unchanged CDDP in the kidney.

Analysis of Variance↗
PubMed1995

Clinical features of patients with anorexia nervosa: assessment of factors influencing the duration of in-patient treatment.

We investigated that factors affecting the duration of in-patient treatment of patients with anorexia nervosa by comparing pretreatment clinical features with the length of hospitalization in 55 patients. Only patients who had completed the entire course of treatment were included in our analysis. Longer hospitalization was correlated with: poor social adaptation; anxiety and/or personality disorders before onset; older age at onset; older age at admission to our hospital; lower minimum body weight after onset; lower body weight at admission; longer duration of illness; frequent previous hospital treatment and/or history of in-patient treatment for anorexia nervosa or other somatic disorders after onset; habitual stimulant (alcohol, coffee and/or cigarettes) abuse; and a history of stealing after onset. Step-wise regression analysis revealed that minimum body weight after onset and age at admission explained 47% of the variance in the duration of in-patient treatment. We also describe the nature of in patient treatment typically offered to patients with anorexia nervosa in Japan.

Adolescent↗
PubMed1995

Comparison of regional cerebral blood flow in patients with eating disorders.

We used single photon emission computed tomography (SPECT) with Tc-99m-HMPAO to examine the characteristics of regional cerebral blood flow (rCBF) in five patients with bulimia nervosa (BN), eight patients with anorexia nervosa (AN), and in nine healthy controls. The SPECT examinations were performed before and after food intake stimulus, and the values of the corrected ratio (R) for rCBF in 10 cerebral cortical regions before (Rbefore) and after eating (Rafter) were calculated. The asymmetry indices (AI) of the R values for the left and right side of each cortical region and the percent change from Rbefore to Rafter (%change) were computed. In comparison with the other two groups, BN patients showed significantly higher Rbefore values in the bilateral inferior frontal and left temporal regions. The AN patients showed significantly lower Rbefore values in the left parietal region than the control group. There were no significant differences in Rafter values among the three groups. The %change values in the AN group showed the greatest increase in 9 out of the 10 regions. In contrast to the positive values obtained from the 10 regions observed in the AN group, 5 out of the 10 regions in the BN group showed negative values. Among the three groups, significant differences in %change were observed on both sides of the inferior frontal, temporal, parietal, and occipital regions. These findings indicate that differences in cerebral function of BN and AN patients can be characterized through SPECT imaging.

Analysis of Variance↗
PubMed1995

Comparison of casual blood pressure and twenty-four-hour ambulatory blood pressure in high school students.

OBJECTIVE: To perform ambulatory blood pressure monitoring (ABPM) in high school students and to compare the 24-hour values with casual blood pressure (BP). METHODS: Ambulatory BP monitoring was carried out in 190 high school students, 15 or 16 years of age, with elevated casual BP during the first examination at school for hypertension; 66 had elevated casual BP at both the first and the second examinations (group H1), and 124 students were normotensive at the second examination (group H2). Sixty-two students who were consistently normotensive served as control subjects (group N). Average BPs for the 24-hour period, the awake period (10 AM to 10 PM), and the sleeping period (1 AM to 6 AM) were calculated. RESULTS: Average BP for each period was significantly higher in group H1 than in group N. Average BP in group H2 for these periods was intermediate between those of group H1 and of group N. The casual BP had a significant positive correlation with the average BP during the awake period (r = 0.55, p < 0.01 for systolic BP; r = 0.37, p < 0.01 for diastolic BP). In most subjects the casual BP readings were higher than BP during ABPM. CONCLUSIONS: Casual BP measurements correlated with 24-hour BP, but they tended to be higher than the measurements obtained during 24-hour ABPM.

Adolescent↗