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Biomedical subjects

N Okamura

Publications and source records attributed to N Okamura.

At least 37 records · Page 2Linked to original sources
PubMed2001

Molecular and pharmacokinetic properties of 222 commercially available oral drugs in humans.

This study was performed to determine the exclusion criteria that differentiate poorly absorbed drugs from good drug candidates, and to accelerate drug development by exclusion of unnecessary assessment. The molecular and pharmacokinetic properties of 222 commercially available oral drugs were tabulated and their correlations were analyzed. The exclusion criteria obtained were 1) a molecular weight of more than 500, and 2) a ClogP value of more than 5. Exceptions to molecular weight criteria were compounds with a sugar moiety, high atomic weight, and large cyclic structure. It was also suggested that being a substrate for MDRI (P-glycoprotein) does not always result in poor bioavailability, and that drug development by chemical modification of a seed or lead compound with quantitative structure activity relationship analysis can result in lower bioavailability, higher bound fraction and lower urinary excretion, which would hamper later development processes and might result in considerable drug-drug interaction. The criteria should be adjusted according to the pharmacological profiles of the agents in question and depending on the estimated profit, but ignoring these criteria may result in a significant waste of time and money during drug development.

Administration, Oral↗
PubMed2001

18F-FDG PET mapping of regional brain activity in runners.

BACKGROUND: To examine regional metabolic changes in the human brain induced by free running in upright posture. METHODS. EXPERIMENTAL DESIGN: Regional brain changes in glucose uptake induced by running were examined by comparing brain images obtained by positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG). SETTING: The study was conducted at a research institute and involved participation of healthy young volunteers. Data sampling and analysis required special imaging device and special computer hardware/software. PARTICIPANTS: Subjects were 17 healthy male volunteers. They were divided at random into two equal groups, those who ran 4-5 km and the others sat in the room. MEASURES: differences in regional cerebral glucose uptake between runners and control groups were assessed statistically. Plasma glucose level was also measured and global cerebral uptake was estimated. RESULTS: Running was associated with a relative increase of glucose uptake in the temporoparietal association cortex, occipital cortex, premotor cortex and the cerebellar vermis. The highest activity was noted in the temporoparietal association cortex. Activity of the primary sensorimotor cortex was higher in the superomedial part (leg motor area) than the lateral part (thorax and arm). CONCLUSIONS: Running augmented energy consumption in the parieto-occipital region relative to the motor area, probably due to the higher energy consumption necessary for integration of multimodal sensory information than for generation of motor output. Our results indicate that FDG PET is a useful tool for brain mapping under various physiological conditions.

Adult↗
PubMed2000

18F-fluorodopa PET study of striatal dopamine uptake in the diagnosis of dementia with Lewy bodies.

Using (18)F-fluorodopa PET and a constant 0.0062 influx rate in the putamen, dementia with Lewy bodies (n = 7) was distinguished from AD (n = 10) with a sensitivity of 86% and a specificity of 100%. A constant 0.0071 influx rate in the caudate yielded a sensitivity of 71% and a specificity of 100% for distinction of the two disorders. Despite a limited sample size, these findings suggest that assessing nigrostriatal dopaminergic function with (18)F-fluorodopa PET may be a useful diagnostic aid in cases of dementia with Lewy bodies while patients are alive.

Aged↗
PubMed2000

Activation of NADPH oxidase in Alzheimer's disease brains.

The present study is the first to show that superoxide (O(-)(2)) forming NADPH oxidase is activated in Alzheimer's disease (AD) brains by demonstrating the marked translocation of the cytosolic factors p47-phox and p67-phox to the membrane. In conjunction with a recent in vitro study showing that amyloid beta activates O(-)(2) forming NADPH oxidase in microglia, where these phox proteins are localized in this study, the present results suggest that, in AD, NADPH oxidase is activated in microglia, resulting in the formation of reactive oxygen species which can be toxic to neighboring neurons in AD.

Aged↗
PubMed2000

Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies.

Cerebral glucose metabolism using positron emission tomography (PET) with (18)F-fluorodeoxyglucose was examined in 11 patients with probable Alzheimer's disease (AD), 6 patients with probable, and 1 patient with autopsy-confirmed dementia with Lewy bodies (DLB) as well as in 10 age-matched normal control subjects. Among widespread cortical regions showing glucose hypometabolism in the DLB group, the metabolic reduction was most pronounced in the visual association cortex compared to that in the AD group. Using a metabolic ratio of 0.92 in the visual association cortex as a cutoff (mean-2 SD of normal control subjects), DLB could be distinguished from AD with a sensitivity of 86% and a specificity of 91%. In contrast, apolipoprotein E4 allele frequency and cerebrospinal fluid tau levels did not differ significantly between the two groups. In order to further dissect out neuropathological correlates of the dysfunctional occipital lobe, postmortem brains from 19 patients with AD and 17 with DLB as well as 11 brains from normal controls were examined. A distinct and extensive spongiform change with coexisting gliosis was variably noted throughout cerebral white matter with relative sparing of gray matter in DLB. Notably, the white matter spongiform change and gliosis was most prominently and consistently found in the occipital region of DLB, and the severity of the spongiform change in each brain region generally paralleled to the regional difference in reduced glucose metabolism between the living AD and DLB patients. These findings suggest that (1) among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the occipital cortex may be an informative diagnostic aid to distinguish DLB from AD; and (2) a pathological process that generates widespread spongiform change and gliosis in long projection fibers may contribute, at least in part, to the characteristic imaging features of DLB.

Aged↗
PubMed2000

CSF phosphorylated tau protein and mild cognitive impairment: a prospective study.

Cerebrospinal fluid (CSF) tau protein phosphorylated at both Thr231 and Ser235 sites (CSF/phospho-tau(231-235)) and total tau (CSF/total-tau) were quantified by sandwich ELISA in 20 patients with mild cognitive impairment (MCI) who eventually developed AD on follow-up as well as seven memory complainers with no objective memory loss. 13/20 (65%) of the MCI patients had high CSF/total-tau and detectable levels of CSF/phospho-tau(231-235), whereas these markers were low and under a detectable level in all of the memory complainers. Although either a total-tau, phospho-tau measurement or a combination of these can help in predicting if MCI will develop AD, our results suggest that the pathogenic steps of AD may be at the stage that finally leads to an accumulation of abnormally phosphorylated tau and neuron death, at least in some brain areas, when MCI patients present with the earliest detectable clinical symptoms of dementia.

Aged↗
PubMed2000

Circulating cytokines and hormones with immunosuppressive but neutrophil-priming potentials rise after endurance exercise in humans.

To investigate the mechanisms of exercise-induced immune perturbations, we measured promising immunomodulatory hormones and cytokines in plasma of 16 male marathon runners before and after a competitive 42.195-km race. Interleukin 1-beta (IL-1beta) and interferon gamma (IFN-gamma) concentrations remained unchanged after the marathon. The cytokines IL-12, IFN-alpha and tumour necrosis factor alpha (TNF-alpha) could not be detected even using highly sensitive specific immunoassays, indicating at least that overshooting responses of these cytokines had not occurred after exercise. As mechanisms for the small changes in these cytokines, we demonstrated for the first time a significant rise in concentrations of inhibitory cytokine IL-10 in addition to the immunosuppressive hormone cortisol, although concentrations of IL-4 and transforming growth factor-beta (TGF-beta) were unaffected by the race. Furthermore, concentrations of IL-1 receptor antagonist (IL-1ra) and IL-6, which are negative-feedback inhibitors of cytokine production, increased by more than 100 times. As for humoral mediators of neutrophil mobilization, concentrations of growth hormone (GH), cortisol and granulocyte colony-stimulating factor (G-CSF) increased significantly. In addition, concentrations of neutrophil-priming substances (IL-6, IL-8, G-CSF, GH and prolactin) also increased significantly and the induction of IL-8 and G-CSF with exercise was demonstrated for the first time in the present study. In contrast, IL-2 concentration decreased, by 32%, and this was correlated with the induction of nitric oxide (NO) production. Muscle damage, monitored using changes in concentrations of creatine kinase and myoglobin, was also observed. These results suggested that exercise-induced pathogenesis including previously reported immunosuppression and neutrophil hyper-reactivity might be attributed, at least partly, to the systemic dynamics of the above bioactive substances.

Adult↗
PubMed2000

Histamine H(1) receptors in patients with Alzheimer's disease assessed by positron emission tomography.

Cerebral histamine H(1) receptor binding was measured in vivo in 11 normal subjects (six young and five old) and 10 patients with Alzheimer's disease by positron emission tomography and [11C]doxepin, a radioligand for H(1) receptors. The parametric images describing the tracer kinetics were generated by either compartmental or graphical analysis, and were examined statistically on region-of-interest and voxel-by-voxel bases. The binding potential of H(1) receptors showed a significant decrease particularly in the frontal and temporal areas of the Alzheimer's disease brain compared to the old, normal subjects. In addition, the receptor binding correlated closely to the severity of Alzheimer's disease assessed by the Mini-Mental State Examination score within several brain areas. The ratio of K1 values between the brain areas and the cerebellum was used as a relative measure of regional cerebral blood flow which decreased in the frontal and temporal areas of the Alzheimer's disease brain. However, the difference in the binding potential (total concentration of receptor/equilibrium dissociation constant) between the Alzheimer's disease patients and the old, normal subjects was greater than that in the cerebral blood flow, and the rate of decrease in the binding potential with the progression of Alzheimer's disease was greater than the rate of decrease in the cerebral blood flow. This study reveals the predominant disruption of the histaminergic neurotransmission in the neurodegenerative processes of Alzheimer's disease. This study suggests that the decline of the histamine receptor binding might play a substantial role in the cognitive deficits of Alzheimer's disease patients.

Adult↗
PubMed2000

Functional neuroimaging of cognition impaired by a classical antihistamine, d-chlorpheniramine.

Antihistamine induced cognitive decline was evaluated using positron emission tomography (PET) measurement of histamine H1 receptor (H1R) occupancy and regional cerebral blood flow (rCBF). Cognitive performance in attention-demanding task deteriorated dose-dependently and the effects were statistically significant after the treatment of 2 mg of d-chlorpheniramine. There was no significant change in subjective sleepiness in the same dose. The regional blockade of H1R was observed mainly in the frontal, temporal and anterior cingulate cortices, and the intravenous administration of d-chlorpheniramine as a therapeutic dose (2 mg) blocked over 60% of H1R in the frontal cortices. The results from activation study using visual discrimination tasks demonstrated that enhanced activity in the right prefrontal and anterior cingulate cortices as well as a decreased activity in the left temporal and frontal cortices and midbrain after the treatment of d-chlorpheniramine. There were no changes in global CBF for the subjects treated with 2 mg d-chlorpheniramine (pre; 44.8+/-3.3 ml dl(-1) min(-1) vs post; 44.4+/-4.7 ml dl(-1) min(-1)). The results indicated that the attention system of human brain could be altered by therapeutic doses of H1R antagonists. These findings provide the information as to the potential risk of antihistamines in our daily activities. British Journal of Pharmacology (2000) 129, 115 - 123

Adult↗
PubMed2000

The complete DNA sequence of the O antigen gene region of Plesiomonas shigelloides serotype O17 which is identical to Shigella sonnei form I antigen.

We cloned and determined the sequence of a DNA region of approximately 15-kb containing the cluster of genes required for O17 antigen expression in the Escherichia coli K-12 strain from the chromosome of Plesiomonas shigelloides serotype O17:H2 strain. The sequencing analysis revealed that the minimum essential region of the P. shigelloides O17 antigen gene cluster had a size of approximately 11.5-kb and contained 9 contiguous open reading frames (ORFs), which were almost identical to the corresponding ORFs of Shigella sonnei form I antigen gene region, except for IS630 sequence, at the DNA as well as amino acid levels. The putative function of most of the ORFs could be determined on the basis of amino acid sequence similarities and characteristics. In addition, the G+C content of the P. shigelloides O17 antigen genes was lower than that of the chromosomal DNA of P. shigelloides and S. sonnei, suggesting that both P. shigelloides O17 and S. sonnei form I antigen genes had been derived from the same origin with a low G+C content.

Amino Acid Sequence↗
PubMed2000

Properties of NADPH oxidase in specific granule-rich fraction prepared from guinea pig neutrophils.

Both the plasma membrane-rich fraction and specific granule-rich fraction prepared from human neutrophil lysate by Percoll centrifugation have been reported to contain cytochrome b558, a membrane activation factor for NADPH oxidase. In this study, the plasma membrane-rich fraction and specific granule-rich fraction of guinea pig neutrophils were prepared, and the abilities of both fractions to activate NADPH oxidase in a cell-free system consisting of either fraction, cytosol and arachidonate were compared. There was no difference in the Km value for NADPH between NADPH oxidase activated by specific granules or by plasma membranes. Optimum concentrations of arachidonate for the activation of NADPH oxidase in both the fractions were also the same. However, after freeze-thawing, the specific granules markedly lost the ability, compared to plasma membranes. Such instability of specific granules was also observed on hypotonic- or deoxycholate-treatment. The inactivation by freeze-thawing was not suppressed by proteinase inhibitors, and gp91-phox, a large subunit of cytochrome b558, was not degraded by freeze-thawing. Freeze-thawed specific granules did not affect the ability in plasma membranes, indicating the absence of an inactivating factor in specific granules. The increase in the amount of cytosol in the cell-free assay mixture did not compensate for the markedly decreased ability of freeze-thawed specific granules. Translocation of p47-phox, one of the cytosolic activation factors, to specific granules was not affected by freeze-thawing. We found that the ability of specific granules to activate NADPH oxidase was fragile, though it is unclear what is responsible for the instability, at present.

Animals↗
PubMed2000

Dissolution profiles of principal ingredients in Kampo medicinal powders by high-performance liquid chromatography.

We describe here a method using HPLC for the simultaneous determination of albiflorin, paeoniflorin, glycyrrhizin and six flavanone glycosides (liquiritin, liquiritin apioside, naringin, neohesperidin, hesperidin and narirutin) in the Kampo medicines, Shigyaku-san and Haino-san. All nine components were separated in less than 40 min by linear gradient elution using a mobile phase containing aqueous phosphoric acid and acetonitrile. The dissolution of these components from powders of Shigyaku-san in aqueous solution at pH 1.80, 4.08 and 6.89 was examined. All of the components except glycyrrhizin were dissolved entirely within 5 min regardless of pH. Dissolution of glycyrrhizin was dependent on the pH of the aqueous solution, and increased with increasing pH.

Chromatography, High Pressure Liquid↗
PubMed2000

Relationship between effects of alcohol on psychomotor performances and blood alcohol concentrations.

Ethanol is a social drug and has been generally known to be a CNS depressant. A large fluctuation of blood alcohol concentration (BAC) is well-known to occur due to main factors such as the genetic polymorphism of the main alcohol metabolizing enzymes and the effect of blood. Few studies have substantially discussed the relationship between impaired CNS activities and BAC. In this study, focusing on the correlation of BAC, we investigated the acute effects of alcohol intake on cognitive performance in humans by objective evaluation methods consisting of the attention-demanding cognitive tasks. Tasks were administered to ten healthy male volunteers before and after ingesting established amounts of alcohol. With increased BAC, we observed prolongation of reaction time performances and lowering of a coordination performance. From the results, we concluded that cognitive performance deteriorates with an increase of BAC. Additionally, the BAC threshold that causes significant impairment of cognitive performance was estimated to be approximately 50 mg/dl (ca. 10 mM).

Adult↗
PubMed2000

Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat.

In this study, the inhibiting action of theanine on the excitation by caffeine at the concentration regularly associated with drinking tea was investigated using electroencephalography (EEG) in rats. First, the stimulatory action by caffeine i.v. administration at a level higher than 5 micromol/kg (0.970 mg/kg) b.w. was shown by means of brain wave analysis, and this level was suggested as the minimum dose of caffeine as a stimulant. Next, the stimulatory effects of caffeine were inhibited by an i.v. administration of theanine at a level higher than 5 micromol/kg (0.781 mg/kg) b.w., and the results suggested that theanine has an antagonistic effect on caffeine's stimulatory action at an almost equivalent molar concentration. On the other hand, the excitatory effects were shown in the rat i.v. administered 1 and 2 micromol/kg (0.174 and 0.348 mg/kg) b.w. of theanine alone. These results suggested two effects of theanine, depending on its concentration.

Animals↗
PubMed2000

[Prediction of progression in patients with mild cognitive impairment using IMP-SPECT].

To examine the difference in functional brain imaging between mild cognitive impairment (MCI) and normal aging, we measured rCBF on functional brain imaging using 123I-IMP single photon emission computed tomography (IMP-SPECT) in 19 MCI patients who progressed to develop AD on follow-up and 23 probable Alzheimer's disease (AD) patients as well as 15 age-matched normal subjects. Baseline MMSE score was 25.3 (SD 1.2) in the MCI group and 17.5 (SD 3.3) in the AD group. The regions of interest (ROI) in the posterior cingulate gyrus, frontal, temporal and parietal cortices were drawn on the image of IMP-SPECT with reference to an individual MRI image. The rCBF ratio was calculated using ROI value in the cerebellum as a reference. Voxel-based analysis was also preformed using statistical parametric mapping (SPM). The rCBF ratio in the posterior cingulate gyrus was significantly reduced in the MCI group (mean 0.956, SD 0.080) and the AD group (mean 0.833, SD 0.118) compared to that in the normal group (mean 1.083, SD 0.084). In the frontal, temporal and parietal cortices, the rCBF ratio was significantly reduced only in the AD group compared to the normal group. At a fixed specificity of 80%, the diagnostic sensitivity in the discrimination between MCI patients and normal subjects was 80.5% when using rCBF ratio in posterior cingulate gyrus. In the SPM analysis, significant reduction of the rCBF in MCI group was observed only in the posterior cingulate gyrus, compared with normal subject group. Our results suggest that MCI patients presenting with a posterior cingulate hypoperfusion are at higher risk for transition from MCI to clinically recognizable AD.

Aged↗
PubMed1999

Cerebrospinal fluid levels of amyloid beta-peptide1-42, but not tau have positive correlation with brain glucose metabolism in humans.

To address the question of whether assay for cerebrospinal fluid (CSF) levels of amyloid beta-peptide 1-42 (A(beta)1-42) and tau allow us to monitor the neurodegenerative processes that lead to a progressive and massive death of neurons in Alzheimer's disease (AD) and non-AD patients, cerebral glucose metabolism using 2-[18F] fluoro-2-deoxy-glucose was quantified by positron emission tomography in fifteen AD patients and nine non-AD patients with defined levels of CSF-A(beta)1-42 and CSF-tau. The CSF-A(beta)1-42 levels, but not the CSF-tau levels, in both AD and non-AD patients consistently and significantly correlated with global and, in particular, temporal lobe glucose metabolism. Results from our study suggest that the CSF-A(beta)1-42 levels may reflect residual brain function and help monitoring progression of dementing disorders.

Aged↗