Control of a Robot Dancer for Enhancing Haptic Human-Robot Interaction in Waltz.

Haptic interaction between a human leader and a robot follower in waltz is studied in this paper. An inverted pendulum model is used to approximate the human's body dynamics. With the feedbacks from the force sensor and laser range finders, the robot is able to estimate the human leader's state by using an extended Kalman filter (EKF). To reduce interaction force, two robot controllers, namely, admittance with virtual force controller, and inverted pendulum controller, are proposed and evaluated in experiments. The former controller failed the experiment; reasons for the failure are explained. At the same time, the use of the latter controller is validated by experiment results.

Effects of tea catechin inhalation on methicillin-resistant Staphylococcus aureus in elderly patients in a hospital ward.

We investigated the effects of inhalation of tea catechin on MRSA in the 24 elderly in patients, who were known to carry MRSA in sputum. The patients in the catechin group (N=12) were administered an inhalation of tea catechin extracts (in saline/bromhexine) (3.7 g/L catechins, 43% of them are composed of epigallocatechin gallate), three times daily with hand nebulizer for four weeks. The clinical effects were compared with the control group (N=12) who were given an inhalation of saline/bromhexine alone. After a week of the course, the numbers of the patients with decreased or disappearance of MRSA in their sputum was significantly higher in the catechin group, compared with that in the control group (seven vs. no patients; P<0.05). The number of patients discharged during the study was significantly increased, and the days of hospital stay were significantly decreased in the catechin group compared with those in the control group (six vs. one patient; P<0.05, 51+/-22 vs. 85+/-50 days, mean+/-S.D.;P <0.05, respectively). No adverse effects were observed in any patients during the study. Catechin inhalation seemed to be safe, and at least temporarily effective in the reduction of MRSA and shortening of hospitalization.

Collapse of valence transition in Yb0.8Y0.2InCu4: pressure-induced weak ferromagnetism.

We investigated the magnetization of Yb0.8Y0.2InCu4 as a function of temperature down to 0.6 K, pressure up to 1.2 GPa, and magnetic field up to 9 T. The valence transition temperature of Yb0.8Y0.2InCu4 is lowered with applying pressure. At 0.8 GPa, collapse of the valence transition and ferromagnetic ordering occur almost simultaneously. The ferromagnetic phase at 1.2 GPa is characterized by a low Curie temperature of 1.7 K and an extremely small ordered moment of 0.05 micro(B) per Yb. Some effect of screening the ordered moment may play a key role in the ferromagnetism and the valence transition.

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH.

BACKGROUND: Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status. AIM: To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes. METHODS: Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On post-dose days 1 and 8, 24-h profiles of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined. RESULTS: After single and repeated doses of omeprazole, the intragastric pH values and plasma concentrations of omeprazole and its metabolites were significantly dependent on the CYP2C19 genotype. Significant differences in the same kinetic and dynamic parameters were also observed after single doses of rabeprazole. Although the plasma levels of rabeprazole differed among the different CYP2C19 genotype groups after repeated doses, no significant differences in intragastric pH values were observed. CONCLUSIONS: The acid inhibitory effects of omeprazole and rabeprazole are significantly dependent on the CYP2C19 genotype status, as well as on their intrinsic pharmacokinetic and pharmacodynamic characteristics and dosing schemes.

Partially disordered antiferromagnetic phase in Ca(3)CoRhO(6).

Neutron diffraction experiments are reported on Ca(3)CoRhO(6) which consists of ferromagnetic Ising spin chains on a triangular lattice. It was first confirmed from temperature dependence of the (110) peak intensity that Ca(3)CoRhO(6) realizes a partially disordered antiferromagnetic state, where 2/3 of the ferromagnetic chains order antiferromagnetically with each other and the remaining 1/3 are left incoherent with the other chains. The 1/3 incoherent ferromagnetic Ising chains freeze to maintain a disordered state at lower temperatures. This compound is successfully discussed as a candidate of a nonequilibrium one-dimensional Ising model.

Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status.

Diazepam is metabolized by CYP2C19 and CYP3A4 in the liver. CYP2C19 shows genetic polymorphism associated with the poor metabolizer (PM) and extensive metabolizer (EM) phenotypes. The aim of this study was to assess the effect of diltiazem, a CYP3A4 inhibitor, on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Thirteen healthy volunteers (eight EMs and five PMs) were given placebo or diltiazem (200 mg) orally for 3 days before and for 7 days after the oral 2-mg dose of diazepam in a double-blind, randomized, crossover manner. The pharmacokinetics and pharmacodynamics of diazepam were assessed with and without diltiazem. Plasma concentrations and area under the plasma concentration-time curves (AUCs) of diazepam and N-desmethyldiazepam were significantly greater in the PM compared with the EM group during the placebo phase. Diltiazem significantly increased AUC and prolonged elimination t(1/2) of diazepam in both the PM and EM groups. These pharmacokinetic changes, however, caused no significant difference in the pharmacodynamics between the two trial phases. Diltiazem affects the pharmacokinetics of diazepam in the PM and EM groups of CYP2C19. Inhibition of CYP3A4 by a concomitant substrate drug like diltiazem may cause a pharmacokinetic interaction with diazepam irrespective of CYP2C19 genotype status, but whether this interaction would reflect a pharmacodynamic change of diazepam remains unconfirmed by our study.

A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia.

Missense mutations in the calcium-sensing receptor (CaSR) gene have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism. We identified a newborn with hypercalcemia in our hospital by mass screening. The family members were studied, and we found a novel CaSR missense mutation with polymerase chain reaction single-strand conformational polymorphism analysis. The mother, grandmother, and aunt of the baby all had FHH. A heterozygous missense mutation in exon 6 that substitutes a glutamic acid for the glycine at codon 557 (Gly557Glu), which corresponds to the extracellular domain of CaSR, was identified and shown to cosegregate with the disease. Identification of the mutation responsible for the FHH phenotype in this family may facilitate rapid testing of individuals at risk for FHH.

Inhibitory effect of insulin on bradykinin-induced venodilation.

BACKGROUND: Excessive insulin is one of the risk factors of hypertension and arteriosclerosis despite its vasodilative properties shown in recent studies. Although many vasoactive substances contribute and interact with each other in the development of hypertension, the interactions between insulin and other vasoactive substances have yet to be elucidated. OBJECTIVE: To assess the effect of insulin on the action of bradykinin. METHODS: The vasodilating effect of bradykinin was evaluated, with or without coadministration of insulin, in human dorsal hand veins of healthy volunteers. In cultured porcine aortic endothelial cells, the bradykinin-induced increase of intracellular calcium was also investigated before and after insulin administration. RESULTS: Insulin significantly attenuated bradykinin-induced increase in intracellular calcium and venodilation in cultured endothelial cells and human dorsal hand veins, respectively. CONCLUSIONS: These findings suggest that insulin attenuates the bradykinin-induced calcium elevation in endothelial cells and may decrease the production of vasodilative substances from endothelial cells, resulting in the reduction of vasodilation. This effect may contribute to the development of hypertension in patients with hyperinsulinaemia.

Increased cytosolic Ca(2+) concentration in endothelial cells by calmodulin antagonists.

Many functions of endothelial cells are Ca(2+)/calmodulin dependent, whereas the role of calmodulin in the regulation of cytosolic Ca(2+) ([Ca(2+)](i)) remains largely unexplained. In the present study, effects of various calmodulin antagonists on [Ca(2+)](i) were investigated in cultured aortic endothelial cells loaded with the Ca(2+)-sensitive dye fura-2/AM, and were compared with those of calmodulin-dependent protein kinase II (CaM kinase II) inhibitors. The calmodulin antagonists W-7, calmidazolium and fendiline provoked dose-dependent increases in [Ca(2+)](i). However, the CaM kinase II inhibitors KN-93 and lavendustin C had no effect on [Ca(2+)](i). In the absence of extracellular Ca(2+), pretreatment of cells with bradykinin (BK) and thapsigargin completely prevented W-7-stimulated increase in [Ca(2+)](i). Alternatively, pretreatment with W-7 also completely blocked BK- and thapsigargin-stimulated increases in [Ca(2+)](i). The time course of the Ca(2+)-response in W-7 treated cells was identical to that in thapsigargin-treated cells, but not that in BK-stimulated cells, suggesting that calmodulin antagonists could share a common signaling pathway with thapsigargin to increase [Ca(2+)](i) in endothelial cells. These findings indicate that calmodulin is involved in the regulation of [Ca(2+)](i), and may play an important role in the uptake of Ca(2+) to intracellular stores.

Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans.

BACKGROUND AND PURPOSE: A triple therapy with omeprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for the eradication of Helicobacter pylori. Omeprazole and clarithromycin are metabolized by CYP2C19 and CYP3A4. This study aimed to elucidate whether clarithromycin affects the metabolism of omeprazole. METHODS: After administration of placebo or 400 mg clarithromycin twice a day for 3 days, 20 mg omeprazole and placebo or 400 mg clarithromycin were administered to 21 healthy volunteers. Plasma concentrations of omeprazole and clarithromycin and their metabolites were determined before and 1, 2, 3, 5, 7, 10, and 24 hours after dosing. CYP2C19 genotype status was determined by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Subjects were classified into three groups on the basis of PCR-RFLP analyses for CYP2C19: homozygous extensive metabolizer group (n = 6), heterozygous extensive metabolizer group (n = 11), and poor metabolizer group (n = 4). Mean area under the plasma concentration-time curves from 0 to 24 hours (AUC) of omeprazole in the homozygous extensive metabolizer, heterozygous extensive metabolizer, and poor metabolizer groups were significantly increased by clarithromycin from 383.9 to 813.1, from 1001.9 to 2110.4, and from 5589.7 to 13098.6 ng x h/mL, respectively. There were significant differences in the mean AUC values of clarithromycin among the three groups. CONCLUSION: Clarithromycin inhibits the metabolism of omeprazole. Drug interaction between clarithromycin and omeprazole may underlie high eradication rates achieved by triple therapy with omeprazole, amoxicillin, and clarithromycin.

CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans.

OBJECTIVE: Omeprazole is metabolized by genetically determined S-mephenytoin 4'-hydroxylase (CYP2C19) in the liver. This study aimed to determine whether the effect of omeprazole on intragastric pH depends on CYP2C19 genotype status. METHODS: CYP2C19 genotype status for 2 mutations associated with the poor metabolizer phenotype was determined by a polymerase chain reaction-restriction fragment length polymorphism method in 16 healthy volunteers. Helicobacterpylori status was determined by serology and the [13C]urea breath test. After a single oral administration of 20 mg omeprazole or a placebo, intragastric pH values were recorded for 24 hours. Plasma levels of omeprazole and its 2 metabolites and gastrin were measured before and 1, 2, 3, 5, 7, 10, and 24 hours after administration. RESULTS: Fifteen of the 16 subjects were H pylori negative. Five of the 15 subjects were homozygous extensive metabolizers, 4 were heterozygous extensive metabolizers, and 6 were poor metabolizers. After omeprazole administration, significant differences in mean intragastric pH values and plasma levels of gastrin, omeprazole and its metabolites were observed among the 3 groups, whereas no significant differences in these parameters were observed with the placebo administration. CONCLUSIONS: The effect of omeprazole on intragastric pH significantly depends on CYP2C19 genotype status. The genotyping test of CYP2C19 may be useful for an optimal prescription of omeprazole.

Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer.

BACKGROUND: Omeprazole is metabolized by S-mephenytoin 4'-hydroxylase (CYP2C19) in the liver. In persons with a poor-metabolizer genotype for CYP2C19, the therapeutic efficacy of omeprazole may be increased. OBJECTIVE: To investigate whether CYP2C19 genotype status is associated with cure rates for Helicobacterpylori infection and peptic ulcer achieved by using dual therapy with omeprazole and amoxicillin. DESIGN: Prospective cohort study. SETTING: University hospital and health service center in Hamamatsu, Japan. PATIENTS: 62 patients with peptic ulcer and H. pylori infection. INTERVENTION: Omeprazole and amoxicillin. MEASUREMENTS: CYP2C19 genotype status and cure rates for H. pylori infection and peptic ulcer. RESULTS: Cure rates for H. pylori infection were 28.6% (95% CI, 13.1% to 48.7%), 60% (CI, 38.6% to 83.0%), and 100% (CI, 66.4% to 100%) in the rapid-, intermediate-, and poor-metabolizer groups, respectively. Healing rates for both duodenal and gastric ulcer in the three groups were roughly parallel with cure rates for H. pylori infection. CONCLUSION: The results of the genotyping test for CYP2C19 seem to predict cure of H. pylori infection and peptic ulcer in patients who receive dual therapy with omeprazole and amoxicillin.

Attenuation by ACE inhibitor drugs of alpha-adrenoceptor sensitivity in human vessels: possible differences related to drug lipophilicity.

AIMS: We investigated the effect of angiotensin converting enzyme inhibitors (ACEIs) on postsynaptic adrenoceptor sensitivity and compared the effect of the lipophilic ACEI, quinapril, and that of hydrophilic agent, enalapril in human vessels. METHODS: Alpha-adrenoceptor sensitivity was evaluated using the dorsal hand vein compliance technique. The dose-response curves of vasoconstriction to phenylephrine and prostaglandin F2alpha were obtained in healthy male volunteers. RESULTS: The ACEIs shifted the dose-response curve of phenylephrine to the right and raised the median effective dose (ED50; 189.3 (57.6 ng min(-1)) of phenylephrine. Following quinapril administration, ED50 increased to 481.1 (101.8 ngmin(-1) compared with 266.8 (55.8 ngmin(-1) after enalapril (95% CI for differences; 31.1-397.5 ng min(-1)). Quinapril administration had no effect on the dose-response curve of PGF2alpha. CONCLUSIONS: ACE inhibition attenuates alpha-adrenoceptor sensitivity in human vessels. The effect of quinapril, a lipophilic ACEI, was greater than that of enalapril, a hydrophilic ACEI. Lipophilic ACEIs may be more potent in vasodilating effect than hydrophilic ACEIs. Angiotensin II concentration in tissue rather than that in plasma may contribute to the alpha-adrenoceptor sensitivity of the vessels.

Comparison of class II and class III activity of dl-sotalol in healthy volunteers.

Racemic sotalol has demonstrated anti-arrhythmic properties which include Class II (beta blockade) and Class III (potassium channel blockade) activity. The Class II activity is demonstrated primarily in l-sotalol, and Class III activity is almost equipotent in each isomer. Class II and Class III activity of dl-sotalol was investigated following repeated oral administration (80 mg b.i.d.) for 7 days. Class II activity was evaluated according to the low frequency spectral power obtained by fast Fourier analysis of the R-R interval variation. Class III activity was evaluated according to the change in the QTc interval of the surface electrocardiogram. The low frequency spectral power decreased after administration of the first dose on day 1 and this trend continued throughout the duration of the study. The QTc interval did not change with dl-sotalol administration. These findings may suggest that Class II activity is more potent than Class III activity.

Comparative dispositions of ofloxacin in human head, axillary, and pubic hairs.

The distribution of ofloxacin (OFLX) along the shaft of each of three hair types, i.e., head, axillary and pubic, was investigated and compared among five healthy male volunteers 1 to 4 months after ingestion of OFLX for 1 or 2 days (total dose, 200 or 600 mg). Five strands of each hair type were sectioned together into successive 0.5-cm lengths starting from the dermal end, over a length of < or = 6 cm, and the OFLX concentration in each hair section was measured by high-pressure liquid chromatography with fluorescence detection. The distribution of OFLX along the head hair shaft was narrow, having a single peak even 3 to 4 months after administration, suggesting a rather uniform growth rate among hair strands. On the other hand, the OFLX distribution along axillary or pubic hair shafts tended to be broad, even having two apparent peaks, and the growth rate did not seem uniform. Since axillary hair seemed to stop growing after having gained a length of < or = 4 to 5 cm, it was suggested to enter a resting stage after the growth of < or = 3 cm over the 2 to 4 months after OFLX incorporation. These findings indicate that head hair is the most suitable for analysis of individual drug use and the larger growth rate and cycle stage variabilities of strands of the other types of hair should be taken into account.

Enhanced effect of triazolam with diltiazem.

AIMS: Triazolam, a triazolobenzodiazepine hypnotic agent, is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme. The aim of this study was to determine if diltiazem affects plasma concentrations of triazolam in humans. METHODS: We investigated the interaction between triazolam and diltiazem in a randomized, three-phase crossover study. Seven healthy male volunteers received orally either a single 0.25 mg dose of triazolam, a 0.25 mg dose of triazolam after a 3-day treatment of diltiazem (180 mg day-1), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24 h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8 h. RESULTS: Diltiazem pretreatment significantly increased the area under the triazolam concentration-time curve (8.0 +/- 2.4 to 18.2 +/- 3.1 ng ml-1 h; P < 0.001; mean +/- s.d.). Peak triazolam concentration was increased (2.1 +/- 0.7 to 3.6 +/- 1.0 ng ml-1, P < 0.05) and the elimination half-life prolonged (4.1 +/- 2.1 to 7.6 +/- 1.9 h; P < 0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group. CONCLUSIONS: Diltiazem markedly affects the pharmacokinetics of triazolam and increases the intensity of its sedative effects. Inhibition of CYP3A isozyme by diltiazem may explain the observed pharmacokinetic interaction. Therefore, triazolam should be avoided when patients are using diltiazem.

Pharmacokinetics and pharmacodynamics of (+/-)-sotalol in healthy male volunteers.

1. We investigated the pharmacokinetics and pharmacodynamics of (+/-)-sotalol administered orally to healthy male volunteers in single doses of 40, 80 and 160 mg and in multiple doses of 80 mg twice daily for 7 consecutive days. 2. In the single dose studies, the half-life of (-)-sotalol (7.2-8.5 h) was significantly (P < 0.01) shorter than that of (+)-sotalol (9.1-11.4 h) while the renal clearance of (-)-sotalol (110.6-126.4 ml min-1) was significantly (P < 0.01) faster than that of (+)-sotalol (102.2-110.1 ml min-1). In the multiple dose studies, similar differences in the pharmacokinetics of (+)- and (-)-sotalol were observed. In addition, the pharmacokinetics of both (+)- and (-)-sotalol on day 4 were shown to be essentially the same as those on day 7. 3. In pharmacodynamic examinations, (+/-)-sotalol prolonged QTc intervals on electrocardiograms dose-dependently after single doses of 80 and 160 mg (3.81 +/- 2.96%, 13.23 +/- 5.66%). The correlation between the plasma concentration of (+/-)-sotalol and prolongation of QTc intervals was nearly linear, and showed no hysteresis. 4. In conclusion, we demonstrated that QTc interval was prolonged with a linear correlation to the plasma concentration of (+/-)-sotalol. In addition, our study suggested that differences in the pharmacokinetics of (+)- and (-)-sotalol may be attributable to faster urinary excretion of (-)-sotalol.

[Influence of multiple-dose administration of cefetamet pivoxil on blood and urinary concentrations of carnitine and effects of simultaneous administration of carnitine with cefetamet pivoxil].

Cefetamet pivoxil (CEMT-PI), a drug of pivaloyloxymethyl group, was investigated for its impact on the carnitine blood homeostasis and renal excretion upon administering CEMT-PI alone, and CEMT-PI simultaneously with carnitine. 500 mg of CEMT-PI (group A) and 500 mg of CEMT-PI and an equimolar amount (200 mg of carnitine) of levocarnitine chloride (group B) were administered twice a day for 7 and 1/2 consecutive days to 5 healthy volunteers (group A) and 3 healthy volunteers (group B). No serious side effects nor abnormal values in physical and laboratory tests were observed throughout the study in both groups. During the treatment period, plasma total carnitine decreased slowly down to 25.5 microM (group A) and 38.8 microM (group B) and plasma free carnitine reached steady state levels at 17.7 microM (group A) and 29.2 microM (group B) on day 5. These concentrations represent 45 and 37% in group A, 66 and 58% in group B of the average pre-treatment baseline levels. Plasma pivaloylcarnitine quickly reached plateau levels of 6.12 microM (group A) and 4.05 microM (group B) on day 4. After treatment stop, plasma total and free carnitine returned to the pretreatment baseline level within 5 days (group A) and 3 days (group B), and plasma pivaloylcarnitine was detectable until day 7 of the treatment-free follow up in both groups. Although carnitine was given concurrently at a dose equimolar to the ingested amount of pivalic acid in group B, the plasma total and free carnitine exhibited a decrease. This was considered attributable to the fact that the bioavailability of carnitine is as low as 16% when administered orally, which is considerably less compared to the 55% bioavailability of cefetamet pivoxil.