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Biomedical subjects

T Uematsu

Publications and source records attributed to T Uematsu.

At least 163 records · Page 9Linked to original sources
PubMed1996

The measurement of caffeine concentration in scalp hair as an indicator of liver function.

Caffeine concentration in plasma and scalp hair has been determined for subjects consuming normal daily amounts of caffeine and the results used as an indicator of individual hepatic metabolic capacity. Daily exposure to caffeine was assessed in six healthy Japanese volunteers by direct HPLC measurement of the concentrations of caffeine in aliquots of all caffeine-containing beverages consumed by the subjects. The measurements were repeated on three different occasions for each subject and caffeine consumption (mean +/- s.d.) was calculated as 178.0 +/- 84.3 mg day-1 with an intra-individual variability of 23.8 +/- 6.3% as coefficient of variation. A survey of daily caffeine consumption in 121 adult Japanese by means of a questionnaire revealed a similar value (231.8 +/- 177.8 mg day-1). Caffeine concentration in the plasma sampled during an overnight caffeine-free interval was measured by HPLC and a comparison made between healthy subjects and patients with liver disease (0.71 +/- 0.32, 0.77 +/- 0.45 and 3.92 +/- 1.91 micrograms mL-1 for healthy volunteers (n = 6), patients with hepatitis (n = 11) and those with liver cirrhosis (n = 4), respectively). Strands of scalp hair were collected from six healthy subjects and six patients with liver cirrhosis. Caffeine in hair was identified and measured by gas chromatography-mass spectrometry after digestion of the hair matrix with protease and extraction of the caffeine with chloroform. Caffeine concentration in hair collected from patients with liver cirrhosis (26.5 +/- 5.04 ng mg-1 hair) was significantly higher than that in hair sampled from healthy subjects (7.21 +/- 3.11 ng mg-1). These findings suggest that the determination of caffeine concentration in the plasma and hair of subjects consuming normal daily amounts of caffeine-containing beverages provides a practical assessment of individual liver metabolic capacity.

Adult↗
PubMed1996

Comparative study of pharmacokinetics of two new fluoroquinolones, balofloxacin and grepafloxacin, in elderly subjects.

Comparative pharmacokinetics and tolerability were studied in healthy elderly volunteers for two new fluoroquinolones, balofloxacin (Q-35) and grepafloxacin (OPC-17116), the main excretion routes being the renal and hepatic routes, respectively. Both agents were well tolerated in elderly subjects. In comparison with previously reported data from healthy younger adults, the absorption of balofloxacin was slightly delayed and urinary excretion was delayed and diminished. As a significant linear correlation was observed between renal clearance of balofloxacin and creatinine clearance, the delayed and diminished urinary recovery was attributed to the reduced renal function of the elderly subjects enrolled in the study. The absorption of grepafloxacin was also delayed, and the maximum plasma drug concentration and area under the plasma drug concentration-time curve were increased in the elderly by 31 and 48%, respectively, over those in younger adults on the basis of dose normalized to body weight. The plasma terminal elimination half-life and urinary recovery remained unchanged. Decreases in distribution volume and total body clearance in the elderly were considered to be the primary factors contributing to these differences.

Aged↗
PubMed1996

Pyruvate dehydrogenase complex-catalyzed formation of N-arylacetohydroxamic acids from nitroso aromatic compounds in rat isolated cells and perfused organs.

The formation of N-arylacetohydroxamic acid derivatives from m-nitrosobenzyl alcohol (MBNO) and a nitroso derivative of chloramphenicol, 2,2-dichloro-N-[2-hydroxy-1-(hydroxymethyl)-2-(4-nitrosophenyl) ethyl]acetamide, in the presence of pyruvate was investigated with rat isolated cells (heart, kidney, liver, small intestine, lung, bone marrow and spermatozoa) and perfused organs (liver and heart). The activity in N-(m-hydroxymethylphenyl) acetohydroxamic acid (MBHA) formation was found in all the cells tested. Measurement of the kinetic parameters revealed that K(m) values of MBNO were ca. 0.3 mM and that the order of Vmax per cell was heart > kidney > liver > small intestine. In the hepatocytes, MBHA was metabolized further and the in vitro intrinsic clearance of MBHA was 1.91 +/- 0.24 ml/min/10(8) cells. In a single-pass perfusion of rat liver with MBNO, the corresponding amino, acetylamino and azoxy derivatives and unknown materials were formed in addition to MBHA. The activity in MBHA formation was increased by the addition of both diethyl maleate and paraoxon. In a recirculating perfusion of rat liver with MBNO, however, the net MBHA formation was hardly detected, because of the disposition of MBHA formed. The hepatic clearance of MBHA was 1.15 +/- 0.06 ml/min/g of liver. In a recirculating perfusion of isolated rat heart with MBNO, MBHA was formed as a major metabolite and further biotransformation was not found. The N-arylacetohydroxamic acid derivative of 2,2-dichloro-N-[2-hydroxy-1-(hydroxymethyl)-2-(4-nitrosophenyl) ethyl]acetamide was also formed in rat bone marrow cells and the isolated perfused heart. These results indicate that the formation of N-arylacetohydroxamic acids from nitroso aromatic compounds and pyruvate catalyzed by pyruvate dehydrogenase complex proceeds in virtually all mammalian tissues.

Animals↗
PubMed1995

Angiotensin AT1 receptor-mediated attenuation of cardiac hypertrophy due to volume overload: involvement of endothelin.

The role of angiotensin II via the angiotensin type 1 (AT1) receptor in the development of volume overload cardiac hypertrophy was investigated in adult male Wistar rats with aortic insufficiency. We examined the effects of specific angiotensin AT1 receptor blockade with losartan (2-n-butyl-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]-imidazole potassium) on left ventricular weight and left ventricular angiotensin II and endothelin-1 level to test the possibility that the cardiac action of angiotensin II may be mediated by endogenous endothelin-1. Moreover, to verify the possible involvement of endothelin-1, we measured left ventricular endothelin-1 levels during the hypertrophic process and evaluated the effect of the endothelin ETA receptor specific antagonist, FR139317 ((R)2-[(R)2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carbonly] amino-4-methylpentanoyl]amino-3-[3-(1-methyl-1H-indolyl) propionyl]amino-3-(2-pyridyl) propionic acid), on left ventricular weight. Two weeks after production of aortic insufficiency, left ventricular weight and left ventricular endothelin-1 concentration were markedly elevated in the rats with aortic insufficiency as compared with the sham-operated control rats, but left ventricular angiotensin II was not changed. Losartan (10 mg/kg/day p.o., 2 weeks) significantly reduced left ventricular weight and left ventricular endothelin-1 level in the rats with aortic insufficiency without affecting blood pressure and there was a significant positive correlation between left ventricular weight and left ventricular endothelin-1 content. Left ventricular endothelin-1 content correlatively increased to left ventricular weight during the development of the left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Temporal profile of nuclear DNA fragmentation in situ in gerbil hippocampus following transient forebrain ischemia.

To determine the time course of nuclear DNA damage in the gerbil hippocampus following transient ischemia, brain sections 48, 72, 96 h and 7 days following 5 min ischemia were evaluated by a specific in situ labeling method of DNA breaks. After 72 h, only the neurons located in the medial part of the CA1 sector were labeled. And then, DNA damage extended to the lateral part of the sector with time.

Animals↗
PubMed1995

The effect of high-energy shock wave therapy combined with cisplatin on mouse hepatoma.

It is well documented that high-energy shock waves (HESW) can produce antitumor effects in vivo and in vitro. Furthermore, because HESW can be focused on a limited area, this therapy is considered applicable to the treatment of localized cancer. In this study, we investigated the effects of HESW therapy combined with cisplatin (CDDP) on MH134 hepatoma in a mouse model. Tumor growth was inhibited by 1 mg/kg CDDP treatment in combination with 2,000 HESW administration, but not by 1 mg/kg CDDP treatment only. Moreover, the CDDP concentration in the tumor increased after HESW administration. The active oxygen induced by HESW was then investigated by the electron spin resonance system, and it was found that HESW generated hydroxy-radicals. As oxygen radicals have been reported to change cell membrane potential, it is supposed that active oxygen induced by HESW changes cell membrane permeability, and that CDDP is concentrated in the tumor. Therefore, the combined therapy with HESW and CDDP showed synergistic inhibitory effects on tumor growth.

Animals↗
PubMed1995

Time course of appearance of ofloxacin in human scalp hair after oral administration.

The time course of appearance of antimicrobial ofloxacin (OFLX) in human scalp hair was monitored in three healthy male volunteers after the oral administration of 100 mg OFLX three times daily for 2 consecutive days. Hair samples were collected from each subject by plucking several strands of frontal hair every day from 1 till 16 days after administration. A single hair was dissolved in 1 M NaOH to extract OFLX by chloroform, and the drug was measured by high-performance liquid chromatography and fluorescence detection. OFLX started to appear in the hair 1 to 3 days after administration and reached the maximal level approximately 4 to 9 days, remaining at almost the same level thereafter. This finding suggests the slow transfer of OFLX from hair follicle cells to hair matrix may be due to the slow dissociation of OFLX from bound melanin.

Administration, Oral↗
PubMed1995

Enhancement of the antitumor effect by combined use of high-energy shock waves and ATX-70.

The antitumor effects of high-energy shock waves (HESW) in combination with ATX-70 [a gallium-porphyrin complex, 2,4-bis(1-decyloxyethyl)-Ga(III)-1,3,5,8-tetramethylporphyrin++ +-6, 7-dipropionyl diaspartic acid [sequence: see text] were investigated. In vitro, the cell damage to mouse MH134 hepatoma after HESW treatment was enhanced by adding ATX-70. In vivo, HESW and ATX-70 combination therapy inhibited cell growth. However, neither HESW treatment alone nor ATX-70 treatment alone inhibited cell growth. These results imply that the antitumor effects of HESW and ATX-70 combined therapy are caused by activation of ATX-70 by HESW.

Animals↗
PubMed1995

Pharmacokinetic and pharmacodynamic analysis of a novel leukotriene biosynthesis inhibitor, MK-0591, in healthy volunteers.

1. The pharmacokinetic and pharmacodynamic properties of a novel 2-indolealkanoic acid derivative (MK-0591), a potent inhibitor of leukotriene biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days were administered. 2. After the single-dose administration following overnight fasting, Cmax and AUC of MK-0591 in plasma increased in a dose-dependent manner, while elimination half-life remained constant (11.2-13.2 h) irrespective of dose. Food intake decreased Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple-dose administration before meals, there were no significant differences in the pharmacokinetic parameters between the first and last days, indicating a lack of significant accumulation of MK-0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the study. 3. Ionophore-stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single-dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore-stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK-0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

The axial distribution of nicotine content along hair shaft as an indicator of changes in smoking behaviour: evaluation in a smoking-cessation programme with or without the aid of nicotine chewing gum.

1. Hair samples were obtained from subjects at the end of a 6 month smoking-cessation programme carried out with (n = 16) or without (n = 10) the aid of nicotine chewing gum. The axial distribution of nicotine along the hair shaft was determined and compared both with the self-report of smoking behavior and with the concentration of carbon monoxide (CO) in expired air measured at 1 month intervals. 2. A gradual decrease in nicotine content along the hair shaft corresponded to the decrease in self-reported number of cigarettes smoked daily in both the nicotine chewing-gum treated and untreated subjects and with the clinical assessment of abstinence. 3. There was reasonable agreement between the CO content of expired air, the self-reported number of cigarettes smoked daily and the axial distribution of nicotine in 22 of 26 subjects. In the other four subjects there was an apparent disagreement between the CO content of expired air and the other parameters. 4. This study showed that, as a routine marker of smoking status, hair analysis may be preferable to repeated CO measurements since only a single sample at the end of an abstinence programme might be sufficient. However, one problem is that nicotine may dissociate slowly from melanin to limit the ability to mark a sudden cessation of smoking. Also, some nicotine in hair might be attributable to nicotine adsorbed to the outside of hair.

Adult↗
PubMed1995

Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers.

The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation.

Administration, Oral↗
PubMed1995

Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans.

The pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, was examined in healthy male volunteers after the oral administration of a single dose of 100, 200, 400, or 600 mg and multiple doses of 300 mg twice daily for 6.5 days (13 total doses). Throughout the whole study period, AM-1155 was well tolerated in every subject. In the single-dose study, the concentrations in serum reached a peak between 1 and 2 h, and the peak concentrations were 0.873, 1.71, 3.35, and 5.41 micrograms/ml at the doses of 100, 200, 400, and 600 mg, respectively. The elimination half-life was 7 to 8 h, independently of the doses. The unchanged drug was excreted mainly in the urine, with 82 to 88% of the doses appearing for 72 h. The fecal recovery of the unchanged drug amounted to 5.7% for 72 h after a single oral administration of a 400-mg dose. Urinary excretion of metabolites was minimal. The serum protein binding was 20%, independently of the concentrations in serum. The concentrations in saliva were approximately 80% of those in serum. The intake of food had no effect on the pharmacokinetic parameters and urinary excretion of AM-1155 except the slight decrease in area under the concentration-time curve. The concurrent administration of probenecid prolonged the elimination half-life, increased the area under the concentration-time curve, and decreased the apparent total body clearance, renal clearance, urinary recovery of unchanged drug, and the excretion ratio (intrinsic renal clearance of AM-1155/creatinine clearance). This indicated that the tubular secretion contributed to the renal excretion of AM-1155. In the multiple-dose study, the concentrations of AM-1155 in serum and urine reached a steady state within 2 to 3 days. The measured concentrations in serum fitted well the simulation curve, which reflected the persistence of linear pharmacokinetics of AM-1155. In conclusion, AM-1155 is expected to be clinically useful because of its potent antibacterial activity and favorable pharmacokinetics.

Adult↗
PubMed1995

Effects of losartan, an angiotensin II antagonist, on the development of cardiac hypertrophy due to volume overload.

To investigate the contribution of a cardiac renin-angiotensin system to cardiac hypertrophy due to volume overload, the effects of losartan, a non-peptide angiotensin (Ang) II type 1 (AT1) receptor antagonist on left ventricular hypertrophy (LVH) was studied. LVH was produced in male Wistar rats by volume overload secondary to aortic insufficiency (AI). Losartan (10 mg/kg/d) was orally administered for 2 weeks after surgery to both AI and sham-operated (control) rats. Two weeks after surgery, aortic pulse pressure and left ventricular (LV) weight were markedly increased in the AI rats as compared with the control group, whereas cardiac angiotensin converting enzyme (ACE) activity remained unchanged. The effects of the chronic administration of losartan an AT1 receptors were verified by the blockade of Ang II pressor response. Losartan treatment produced a significant reduction in LVH in AI rats without affecting the systolic blood pressure. In separate groups of rats, to elucidate the mechanisms of the attenuation of LVH by treatment with losartan, we determined plasma and LV immunoreactive Ang II content and plasma renin activity (PRA). LV Ang II content increased in AI rats, while plasma Ang II content, PRA and II concentration were increased by the treatment. There was a significant positive correlation between LV weight and LV Ang II content. These results suggest that cardiac Ang II, rather than circulating Ang II, plays an important role in the LVH due to volume overload via the AT1 receptor.

Angiotensin II↗
PubMed1995

An experimental myocardial infarction model in the rat and its properties.

The photochemical reaction between rose bengal and light (540 nm) produces thrombotic occlusion in rat coronary artery. We have now developed an experimental myocardial infarction (MI) model by photochemically induced thrombosis (PIT) in rats and investigated the mechanisms responsible for the induction of MI. PIT in the coronary artery induced myocardial ischemia, which was determined by tissue oxygen tension (tpO2), and resulted in MI. Pretreatment with a thromboxane (TX) A2-receptor antagonist, vapiprost, prevented a decrease in myocardial tpO2 and markedly reduced the MI area, although vapiprost inhibited collagen-induced platelet aggregation by 30% ex vivo. An ADP-induced platelet aggregation inhibitor, clopidogrel, also reduced the MI area. In contrast to vapiprost, clopidogrel inhibited collagen-induced platelet aggregation by 90% ex vivo. Pretreatment with a 5-HT2-receptor antagonist, ketanserin, which did not inhibit collagen-induced platelet aggregation ex vivo, prevented the decrease in myocardial tpO2 and reduced the MI area. These results suggest that TXA2, 5-HT and ADP play a role in the induction of MI and that platelet aggregation and other factors induce ischemia in this model.

Animals↗
PubMed1994

Enhancement of thrombolytic efficacy of tissue-type plasminogen activator by adjuvants in the guinea pig thrombosis model.

Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). We investigated the effects of vapiprost ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-7-(5-((1,1'-biphenyl)-4-yl-methoxy)- 3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, a thromboxane A2 receptor antagonist); argatroban ((2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfon yl] - L-arginyl)]-2-piperidine-carboxylic acid, a specific thrombin inhibitor) and MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid, a specific leukotriene biosynthesis inhibitor) on the thrombolytic efficacy of rt-PA. The guinea pig femoral artery was thrombotically occluded by photochemical reaction between rose bengal and green light. Thirty min after the occlusion, rt-PA was administered and the time (T1) for reopening of the vessel and the frequency of reocclusion (Fro) 24 h after thrombolysis were monitored. With rt-PA alone, T1 was 28 +/- 7 min (n = 10) and Fro was 70%. T1 was reduced to 9 and 20 min by a combination of rt-PA with vapiprost and argatroban respectively. Fro was reduced by all three adjuvants. Histological observations revealed extensive adherence of polymorphonuclear leucocytes to the damaged endothelium at the site of thrombolysis. It is concluded that thromboxane A2, thrombin and leucocytes are involved in reocclusion after thrombolysis.

Adjuvants, Pharmaceutic↗