Search PubMed⌕ Search

Biomedical subjects

T Horie

Publications and source records attributed to T Horie.

At least 307 records · Page 17Linked to original sources
PubMed1994

Characterization of monkey cytochrome P450, P450 CMLd, responsible for S-mephenytoin 4-hydroxylation in hepatic microsomes of cynomolgus monkeys.

We isolated a new form of cytochrome P450 (P450) which was able to catalyze S-mephenytoin 4'-hydroxylation from hepatic microsomes of cynomolgus monkeys. The final preparation (referred to as P450 CMLd) was apparently homogenous judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and the estimated minimum molecular weight of this protein was 53 kDa. The N-terminal amino acid sequence of P450 CMLd (identified 16 residues) was identical with that of protein encoded by P450 2C9 cDNA. P450 CMLd was cross-reactive with both antibodies raised against P450 2C11 and P450 2C9 which were purified from hepatic microsomes of male rats and humans, respectively. In hepatic microsomes of cynomolgus monkeys, both antibodies recognized two proteins showing different mobilities on SDS-PAGE (50 and 53 kDa). P450 CMLd was a good catalyst for S-mephenytoin 4'-hydroxylation in a reconstituted system. Anti-P450 2C9 antibody inhibited the activity of S-mephenytoin 4'-hydroxylase, but not the activities of R-mephenytoin 4'-hydroxylase and R- and S-mephenytoin N-demethylases in liver microsomes from cynomolgus monkeys. From these lines of evidence we conclude that P450 CMLd is classified into the P450 2C subfamily and acts as one of the S-mephenytoin 4'-hydroxylases in hepatic microsomes of cynomolgus monkeys.

Amino Acid Sequence↗
PubMed1994

Age-related decreases in the reconstituting ability of hemopoietic cells and the ability of hemopoietic microenvironment to support hemopoietic reconstitution in senescence accelerated (SAM-P) mice.

The effect of the aging process on the hemopoietic system in senescence-accelerated (SAM-P) mice with respect to the reconstituting ability of hemopoietic cells and the ability of the microenvironment to support hemopoietic reconstitution was investigated by bone marrow transplantation (reconstitution assay). When the bone marrow cells, obtained from young or old mice, were transplanted to lethally irradiated young SAM-P mice no difference in the reconstituting pattern of femoral spleen colony-forming units (CFU-S), splenic CFU-S and splenic granulocyte macrophage colony-forming units (CFU-GM) was observed between the mice transplanted with young and old donor cells. However, the reconstitution of femoral CFU-GM in mice transplanted with old donor cells was delayed compared to that in mice transplanted with young donor cells. Moreover, the recovery of WBC in mice transplanted with old donor cells was noticeably delayed. When the bone marrow cells obtained from young mice were transplanted to young or old recipient mice, no difference in the reconstituting pattern of femoral CFU-S and CFU-GM as well as splenic CFU-S and CPU-GM was observed between young and old recipient mice. However, the recovery of WBC in old recipient mice was noticeably delayed. These data indicate that the functions of both the hemopoietic cells and the hemopoietic microenvironment deteriorated with age in SAM-P mice.

Aging↗
PubMed1994

Cytotoxic effect of extracellular ATP on L1210 leukemic cells and normal hemopoietic stem cells.

The cytotoxic effect of extracellular adenosine triphosphate (ATP) was examined on normal murine hemopoietic stem cells and a representative leukemic cell line (L1210). After L1210 cells were incubated with 4 mM ATP for 3 h, 3H-thymidine incorporation was almost completely inhibited. The number of viable L1210 cells was also significantly decreased and L1210 colony formation was suppressed to approximately 30% of the control level after treatment. The CFU-GM survival rate was reduced to 70%, however, CFU-S and marrow nucleated cell numbers were not changed after the same treatment with ATP. All mice that were injected with the untreated mixture of normal marrow cells (3.3 x 10(4)) and L1210 cells (3.3 x 10(3)) died of leukemia within 18 days. On the contrary, 85% of the recipients given ATP-treated grafts survived more than 70 days. These findings indicate that ATP extra vivo treatment is useful for purging the residual leukemic cells in autologous bone marrow transplantation.

Adenosine Diphosphate↗
PubMed1994

Elevation of serum soluble intercellular adhesion molecule-1 (sICAM-1) and sE-selectin levels in bronchial asthma.

Adhesion molecules such as ICAM-1 and E-selectin have been shown to play important roles in the production of allergic inflammation. In the present study, we measured serum soluble ICAM-1 (sICAM-1) and soluble E-selectin (sE-selectin) levels by ELISA in 42 patients with bronchial asthma (22 atopic and 20 non-atopic) during asthma attacks and in stable conditions in order to assess the state of ICAM-1 and E-selectin in allergic inflammation. Both serum sICAM-1 levels and serum sE-selectin levels in sera obtained during bronchial asthma attacks were higher than those in sera obtained in stable conditions. These findings were observed regardless of atopic status. To examine the regulatory mechanism in the elevation of serum sICAM-1 and sE-selectin levels, serum tumour necrosis factor-alpha (TNF-alpha) levels were measured by ELISA. TNF-alpha levels in sera obtained during bronchial asthma attacks were higher than those in sera obtained in stable conditions. There was a correlation between the nature of change in serum TNF-alpha levels and the nature of change in serum sICAM-1 levels or serum sE-selectin levels, though serum TNF-alpha levels did not correlate with serum sICAM-1 levels or serum sE-selectin levels. These results suggest that higher levels of sICAM-1 and sE-selectin during asthma attacks may reflect the up-regulation of ICAM-1 and E-selectin expression in allergic inflammation, and that the soluble form of these adhesion molecules may be useful markers for the presence of allergic inflammation. TNF-alpha is shown to enhance the expression and release of ICAM-1 and E-selectin in vitro, however; the regulatory mechanism in the elevation of serum sICAM-1 and sE-selectin levels remains to be clarified.

Acute Disease↗
PubMed1994

Aztreonam decreases hepatic microsomal cytochrome P450 in cynomolgus monkeys.

We examined the effect of successive administrations of aztreonam, which is used clinically as an antibiotic, on the mixed function oxidase system in non-human primates. Treatment of cynomolgus monkeys with aztreonam at doses of between 40 and 300 mg/kg for 4 weeks resulted in a significant decrease in the content of hepatic microsomal P450. On the other hand, no significant change was observed in hepatic cytochrome b5 content and NADPH-cytochrome c (P450) reductase activity following treatment with aztreonam. The activity of testosterone 6 beta-hydroxylase, but not 2 beta- and 16 alpha-hydroxylases in hepatic microsomes, was decreased following the treatment of cynomolgus monkeys with aztreonam. The content of P450 CMLc, which is classified into the 3A subfamily, was also decreased by aztreonam treatment although the content of P450 CMLb, which is a 2A enzyme in cynomolgus monkeys, was unchanged. From these results, we concluded that aztreonam decreased P450 CMLc in hepatic microsomes of cynomolgus monkeys.

Animals↗
PubMed1994

Refractoriness of eucapnic hyperventilation-induced bronchoconstriction in rabbits.

The mechanism of refractoriness in bronchoconstriction after repeated hyperventilation was investigated in 18 sensitized rabbits. Rabbits were separated into three groups: an untreated control group (n = 7), a cimetidine-treated group (n = 6), and an indomethacin-treated group (n = 5). After anesthetization, hyperventilation was performed for 15 min (120 breaths/min, 7 ml/kg tidal volume) with dry air containing 5% CO2. Total lung resistance (RL) and dynamic compliance (Cdyn) were measured before (baseline) and after hyperventilation challenge. After RL and Cdyn had returned to baseline values, the hyperventilation challenge was repeated. In the control group maximal increase in percent RL (max %RL) was 49 +/- 9% after the first challenge, but 16 +/- 4% after the second challenge, indicating refractoriness. A similar tendency was observed in percent Cdyn. In the cimetidine- and indomethacin-treated groups, max %RL were 42 +/- 3% and 60 +/- 15% after the first challenge, and 35 +/- 8% and 60 +/- 7% after the second challenge, respectively, indicating no refractoriness. These results suggest that the H2-receptor and bronchodilating prostanoids play an important role in producing the refractoriness to bronchoconstriction observed in sensitized rabbits after repeated hyperventilation.

Airway Resistance↗
PubMed1994

Lipid peroxidation and chemiluminescence during naproxen metabolism in rat liver microsomes.

1. Rat liver microsomal suspension containing NADPH and MgCl2 was incubated at 37 degrees C with naproxen, a non-steroidal anti-inflammatory drug. Thiobarbituric acid reactive substances (TBA-RS), high molecular weight protein aggregates and fluorescent substances were formed in the microsomal suspension. 2. Chemiluminescence was produced from the microsomal suspension. This chemiluminescence production was well correlated to the TBA-RS formation, indicating that the chemiluminescence production was closely associated with the lipid peroxidation. 3. The addition of SKF-525A to the microsomal suspension inhibited the production of TBA-RS, chemiluminescence and 6-demethylnaproxen (6-DMN), the oxidative product of naproxen. Further, the antioxidant, alpha-tocopherol and singlet oxygen quenchers like histidine, dimethylfuran and 1,4-diazabicyclo[2,2,2]octane strikingly inhibited the productions of chemiluminescence and TBA-RS. 4. Neither naproxen nor 6-DMN caused lipid peroxidation in the absence of NADPH. Thus, lipid peroxidation and chemiluminescence during the oxidation of naproxen in liver microsomes was suggested to be provoked by reactive oxygen species and an origin of chemiluminescence was shown to be singlet oxygen.

Animals↗
PubMed1994

Suicide in patients with systemic lupus erythematosus: a clinical analysis of seven suicidal patients.

Despite many suicidal cases in patients with systemic lupus erythematosus (SLE), literature on this subject is lacking. To elucidate and prevent this phenomenon, we re-evaluated the clinical records of seven suicidal patients with SLE. Six patients had photosensitivity and insomnia. At the time of the suicide attempt, hypocomplementemia was observed in five of six patients. Diffuse slowing on electroencephalograms were observed in four of five patients. One patient successfully committed suicide while on no therapy while five patients made their attempts under the tapering courses of steroids. Five patients manifested psychoses whereas two patients displayed no psychotic findings. All patients attempted suicide shortly after admission (mean time 20 days). The subsequent courses of the survivors who received more medication were favorable. Therefore, it appears that disease activity was not fully controlled in these patients. Furthermore, signs of an imminent suicide attempt were missed in some cases. Psychosis, insomnia, history of photosensitivity, an incompletely controlled disease state, receiving tapering steroid dose, diffuse slowings on electroencephalograms and the presence of hypocomplementemia appeared to be risks for attempting suicide in SLE. We would recommend that such patients be under psychiatric care for at least 2 months to prevent suicide. When the patient is still psychotic or unstable, further medical care will be required.

Adolescent↗
PubMed1994

Purification and characterization of cytochrome P450 3A enzyme from hepatic microsomes of untreated doguera baboons.

We isolated a form of cytochrome P450 (P450) from hepatic microsomes of untreated doguera baboons. The final preparation (referred to as P450 BLa) was apparently homogenous, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The estimated minimum molecular weight of P450 BLa was 50 kDa. The N-terminal amino acid sequence of P450 BLa (identified 10 residues) was identical with that of P450 3A8 purified from cynomolgus monkeys. This protein was cross-reactive with antibodies raised against P450 3A4 and P450 CMLc which were P450 3A enzymes purified from hepatic microsomes of humans and cynomolgus monkeys, respectively. P450 BLa was capable of catalyzing testosterone 6 beta-hydroxylation and zonisamide reduction. P450 BLa antibody inhibited the activity of testosterone 6 beta-hydroxylase, but not the activities of testosterone 16 alpha- and 16 beta-hydroxylases in liver microsomes of doguera baboons. From these lines of evidence we conclude that P450 BLa can be classified as part of the P450 3A subfamily and acts as a constitutive testosterone 6 beta-hydroxylase in hepatic microsomes of doguera baboons.

Amino Acid Sequence↗
PubMed1994

Effect of E-5110, a novel non-steroidal anti-inflammatory drug, on trimethadione metabolism as an indicator of hepatic drug-oxidizing capacity in beagle dog.

1. We examined the effects of N-methoxy-3-(3,5-di-tert-butyl-4- hydroxybenzylidene pyrrolidin-2-one (E-5110), a novel non-steroidal anti-inflammatory drug, on the pharmacokinetics of trimethadione (TMO) and characterized the P450 isozymes involved in the metabolism of TMO in beagle dog. 2. In the E-5110-treated dog (50 mg/kg/day for 7 days: oral) the plasma half-life (t1/2) and the area under the curve (AUC) of TMO (4 mg/kg, i.v.) in vivo were decreased, and total body clearance (CL) was increased; the apparent volume of distribution (Vd) was relatively unchanged. 3. Contents of P450 and b5, and the activity of p-nitroanisole O-demethylase and benzphetamine N-demethylase in vitro were significantly increased compared with controls by repeated E-5110 treatment in dog. 4. Contents of CYP2B and 3A were increased by E-5110 pretreatment in dog. 5. TMO N-demethylation was inhibited by the anti-CYP2B and 3A IgG fractions in liver microsomes obtained from the E-5110-treated dog. 6. Results of both the in vivo and in vitro studies of the effects of E-5110 treatment in dog on TMO indicate that these effects may be attributed to the induction of CYP2B and 3A.

Animals↗
PubMed1994

Application of pharmacokinetic studies to a novel antidepressant, E2011.

1. The original drug tested here, (5R)-3-[2-(3-cyanopropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxaz olidinone (ER-4539), exhibited strong MAO-A inhibitory activity in vitro, but its bioavailability in rat was very low. After ER-4539 was administered orally to dog, a metabolite was found in plasma. 2. The metabolite was isolated by hplc after incubation with dog liver microsomal preparations. Its structure, determined by ms and nmr analysis, was alpha-hydroxy-ER-4539. The configuration of the alpha-hydroxy metabolite was (S), determined in comparison with the authentic sample of (R) and (S) by hplc. The isolated metabolite had potent MAO-A inhibitory action in vitro, indicating that it would have antidepressant action. 3. (5R)-3-[2-((1S)-3-Cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011), the synthesized metabolite, has been improved in regard to biopharmaceutical characteristics in rat and dog.

Animals↗
PubMed1994

Dual effects of a novel thienodiazepine platelet-activating factor antagonist, on drug-oxidizing enzymes in beagle dog.

1. We have examined the effects of (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8, 11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3, 2-f][1, 2, 4]triazolo[4, 3-a][1, 4]diazepine (E-6123), a novel thienodiazepine platelet-activating factor antagonist, on drug-oxidizing capacity in beagle dog, using antipyrine (AP) and trimethadione (TMO) as two model substrates. 2. The plasma half-life (t1/2) and area under the curve (AUC) of AP (0.5 mg/kg, i.v. injection) increased in a dose-dependent manner after a single oral dose of E-6123 (0.2, 1 or 10 mg/kg), whereas the total body clearance (Cl) of AP was decreased, and the apparent volume of distribution (Vd) was unchanged. 3. The pharmacokinetic parameters (t1/2, Cl and AUC) of the metabolism of TMO (4 mg/kg, i.v.) after repeated oral administration of E-6123 (10 mg/kg for 7 days) were not significantly changed in comparison with findings in control dog. The ratio of dimethadione (DMO), being the only TMO metabolite, to TMO in plasma after i.v. administration of TMO in E-6123-treated dog was increased only 5 and 15 min after the final dose, but was not changed at other sampling times (0.5, 1, 2 4, 6, 8 and 12 h). 4. The content of b5, the activity of p-nitroanisole O-demethylase and benzphetamine N-demethylase were significantly increased, compared with controls, by repeated E-6123 treatment. However, aniline hydroxylase activity was not significantly changed. 5. Content of P450 2B was significantly increased in E-6123 treated dog, while that of 3A was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Virological features of hepatitis C virus infection in patients with liver diseases in the inshore area of the Yangtze River.

The prevalence, genotypes, coinfection and putative core gene sequence of hepatitis C virus (HCV) were investigated in the inshore area of the Yangtze River, where hepatocellular carcinoma (HCC) is thought to be very common. Most patients with liver diseases were infected with hepatitis B virus (HBV), but the incidence of anti-HCV was very low, being 3.4% in patients with acute hepatitis, and approximately 7% in those with chronic liver diseases. The rate of coinfection with HBV and HCV in patients with HCC was 4.5%, which was similar to that in Shanghai (5.6%), but lower than that in Yangzhou (31.2%), Beijing (26.8%) and Zhejiang (28.6%). Of 124 patients with non-A, non-B (NANB) liver disease, 15 (12.1%) were positive for anti-HCV. HCV genotype analysis in 41 HCV-RNA-positive patients with liver diseases showed that genotype II was dominant (85.4%), followed by genotype III (7.3%) and II+III (7.3%). No genotype I or IV was found. The genome sequences of the HCV putative core gene from two patients with chronic hepatitis were more closely similar to those of previous isolates from Japan and China, than to that of an American isolate. These results suggest that HCV infection is not an important etiological factor for liver diseases, and that the HCV isolates in China are from the same subgroup as those in Japan.

Adult↗
PubMed1994

Prevalence of HCV-antibodies and HCV-RNA in donor blood in Tokushima Prefecture.

The incidence of C100-3 among the blood specimens qualified for transfusion according to the conventional criteria was 1.1%. The incidence of C100-3 in donor blood in Tokushima Prefecture is not significantly different from that reported for all Japan. Of the donors positive for the conventional screening test and C100-3, 73.6% showed high ALT levels. For all antibodies, the incidence of HCV-RNA was very low in the donors positive for a single antibody, but was high in those positive for multiple antibodies. All of the donors showing the 3 antibodies were positive for HCV-RNA. While a test for multiple antibodies is thought to be effective for the screening of HCV, more blood needs to be discarded, having a serious cost-performance problem. The O.D. value for C100-3 and the 2nd antibody seem to be useful reference value for antibody titers.

Adolescent↗
PubMed1994

[Organ failure due to hypoxemia, and effects of oxygen therapy--effects of hypoxemia on pulmonary hemodynamics, and improvement with oxygenation].

To investigate pulmonary hemodynamics in patients with chronic respiratory failure, we performed right heart catheterization and also examined the effects of oxygen inhalation. Thirty-three patients were studied. Their mean age was 65 +/- 10 years, and FEV1.0% and PaO2 on room air were 47 +/- 16% and 63 +/- 14 mmHg, respectively. mPAP was 27 +/- 10 mmHg, and 26 (78%) had pulmonary hypertension. Although PVR was abnormally high, CI and PCWP were within normal limits. PaO2 was significant Significantly correlated with mPAP and PVR. Although oxygen inhalation (28%) for 30 minutes significantly changed PaO2, PaCO2, and PvO2, it did not significantly affect mPAP, PVR, CI, or PCWP. These results suggest that short-term oxygen inhalation does not affect pulmonary hemodynamics in patients with chronic respiratory failure. Radionuclid ventriculography was also done to evaluate cardiac function in 16 patients before and after home oxygen therapy (HOT). Both right ventricular ejection fraction (RVEP) and left ventricular ejection fraction (LVEF) were significantly increased by HOT, and the significant correlation between RVEF and LVEF that had been observed before HOT disappeared. These results suggest cardiac function improved and that the interdependence between the right and left ventricle was eliminated by HOT.

Aged↗
PubMed1994

[Capsaicin-induced cough. Tachyphylaxis and the effect of anaesthesia on the pharynx].

We examined the reproducibility of capsaicin-induced cough thresholds and the influence of pharynx anaesthesia used to treat the cough. We performed cough threshold tests on ten patients with bronchial asthma and ten patients with chronic cough. The lowest level of capsaicin-induced cough threshold was defined as ten coughs. Tachyphylaxis in cough thresholds was examined three times at intervals of 30 minutes and 120 minutes after the initial test. We measured cough thresholds before and after pharynx anaesthesia with xylocainbiscus. There was no change in cough thresholds among the three times; nor was them any change in the thresholds before and after pharynx anaesthesia. But in five patients with acute pharyngitis, the cough thresholds after pharynx anaesthesia were greater than before. It was suggested that cough threshold tests had reproducibility 30 minutes and 120 minutes after indicating that tachyphylaxis did not exist. Furthermore it was suggested that pharynx anaesthesia influenced the cough threshold in patients with acute inflammation of the pharynx, but anesthesia had no influence on cough thresholds in patients without acute inflammation of the pharynx.

Adult↗
PubMed1994

[Initial myocardial uptake and myocardial clearance of 123I-metaiodobenzylguanidine in patients with ischemic heart disease of left ventricular dysfunction and dilated cardiomyopathy].

We studied initial myocardial uptake and myocardial clearance of 123I-metaiodobenzylguanidine (MIBG) in patients with ischemic heart disease of left ventricular dysfunction and dilated cardiomyopathy. Eleven patients with ischemic heart disease of left ventricular dysfunction (IHD group), 6 patients with dilated cardiomyopathy (DCM group) and 7 control cases (control group) were studied. Heart to mediastinum activity ratio (H/M) of early and delayed image was significantly lower in the IHD and DCM groups than in the control group. Although initial myocardial uptake of MIBG showed no significant difference among three groups, myocardial clearance of MIBG was significantly higher in the IHD (35 +/- 11%) and DCM (48 +/- 13%) groups than that in the control group (19 +/- 10%). H/M of delayed image was related to the left ventricular size, initial MIBG uptake and MIBG myocardial clearance. Negative correlation was observed between MIBG myocardial clearance and left ventricular ejection fraction in all cases. In conclusion, initial myocardial uptake of MIBG were not decreased in patients with IHD and DCM. Enhanced myocardial clearance of MIBG was observed not only in patients with DCM but also in patients with IHD.

3-Iodobenzylguanidine↗