Biomedical subjects

H Yoshimura

Publications and source records attributed to H Yoshimura.

At least 163 records · Page 9Linked to original sources

PubMed1995

A novel metabolite, an oxepin formed from cannabidiol with guinea-pig hepatic microsomes.

The metabolic formation of an oxepin derivative, 3-pentyl-6,7,7a,8,9,11a-hexahydro-1,7-dihydroxy-7,10- dimethyldibenzo-[b,d]-oxepin, from cannabidiol was studied in-vitro using guinea-pig hepatic microsomes. The hepatic microsomes catalysed the formation of the metabolite from cannabidiol and 8S, 9-epoxycannabidiol in the presence of an NADPH-generating system and 3, 3, 3-trichloropropene-1, 2-oxide. 8S, 9-Epoxycannabidiol was thought to be an intermediate in the formation of the metabolite, which was identified by gas chromatography-mass spectrometry. The metabolite synthesized from 8S, 9-epoxycannabidiol diacetate exhibited catalepsy, hypothermia and pentobarbitone-induced sleep prolongation in mice, although the pharmacological effect was less potent than that of delta 9-tetrahydrocannabinol.

Animals↗

PubMed1995

Involvement of CYP2C in the metabolism of cannabinoids by human hepatic microsomes from an old woman.

The hepatic microsomal metabolism of cannabinoids was studied using the liver from an old woman. delta 8-Tetrahydrocannabinol, delta 9-tetrahydrocannabinol and cannabinol were biotransformed to their respective 11-hydroxy metabolites by a microsomal fraction with specific activities (pmol/min/mg protein) of 29.1, 47.1 and 27.9, respectively. In addition, both 11-oxo-delta 8-tetrahydrocannabinol and 11-oxo-delta 9-tetrahydrocannabinol were metabolized to the corresponding carboxylic acids with the microsomes. An antibody against mouse CYP2C29 almost completely inhibited 11-hydroxylation of the cannabinoids and microsomal aldehyde oxygenase (MALDO) activity for 11-oxo-delta 8-tetrahydrocannabinol and 11-oxo-delta 9-tetrahydrocannabinol, used as substrates, whereas an antibody against rat CYP3A2 conversely stimulated the 11-hydroxylation of delta 8-tetrahydrocannabinol and MALDO activity for 11-oxo-delta 8-tetrahydrocannabinol. The results indicate that a member of CYP2C is primarily responsible for the metabolism of the above cannabinoids in the human hepatic microsomes.

Aged↗

PubMed1995

Formation of carbon monoxide during mouse hepatic microsomal oxidative metabolism of cannabidiol; identification and determination.

Carbon monoxide (CO) was generated in the process of hepatic microsomal oxidative metabolism of cannabidiol (CBD). After the generated CO was reduced to methane (CH4) with a methanizer, CH4 formed was determined by gas chromatography (GC) with a flame ionization detector. After oxidation with hopcalite, CO was also identified as CO2 by gas chromatography/mass spectrometry (GC/MS). The reaction was NADPH-dependent and required molecular oxygen. It was inhibited by addition of some inhibitors of cytochrome P450-dependent monooxygenase. When CBD (191 microM) was incubated with hepatic microsomes of mice in the presence of an NADPH-generating system and oxygen, concentration of CO determined by GC was 4.7 +/- 0.5 ppm/nmol P450 in the incubation atmosphere. Pretreatment with phenobarbital (100 mg/kg, i.p. for 3d) but not 3-methylcholanthrene (80 mg/kg, i.p.) increased the CO formation 78%, while pretreatment with cobaltous chloride (40 mg/kg, i.p. for 3 d) decreased the formation 56%. When CBD was incubated under oxygen-18 gas, molecular oxygen was not incorporated into the CO molecule. 8,9-Dihydro- and 1,2,8,9-tetrahydro-CBDs also produced CO to some extent, whereas CBD monomethyl- and dimethylethers reduced the ability to produce CO. In addition, cannabidivarin and olivetol produced CO, although none of delta 9-tetrahydrocannabinol, cannabinol and d-limonene did. Thus, the resorcinol moiety of CBD is important for CO formation.

Animals↗

PubMed1995

3,4,5-Trimethoxyphenylacetaldehyde, an intermediate metabolite of mescaline, is a substrate for microsomal aldehyde oxygenase in the mouse liver.

3,4,5-Trimethoxyphenylacetaldehyde, an intermediate metabolite of mescaline, was oxidized to 3,4,5-trimethoxyphenylacetic acid by mouse hepatic microsomes. The reaction was NADPH-dependent, and inhibited by SKF 525-A, metyrapone and disulfiram. A P450 isozyme in mouse hepatic microsomes, P450 MUT-2 (CYP2C29), catalyzed the reaction (0.96 nmol/min/nmol P450) in which NADPH and NADPH-cytochrome c reductase were essential for the catalytic activity. The reaction was confirmed to be an oxygenation since molecular oxygen was incorporated into the carboxylic acid metabolite formed under oxygen-18 gas by GC-MS analysis. By addition of antibody against CYP2C29 to the microsomes (3.2 mg/mg microsomal protein) the MALDO activity was inhibited by 35% of the control value with preimmune serum, suggesting that CYP2C29 or an immunologically-related isozyme(s) plays a major role in the NADPH-dependent oxidation of 3,4,5-trimethoxyphenylacetaldehyde to 3,4,5-trimethoxyphenylacetic acid by mouse hepatic microsomes. Pharmacological experiments on mescaline and its deaminated metabolites using mice indicated that the metabolites were much less active or were inactive in cataleptogenic effect and pentobarbital-induced sleep prolongation as compared with the parent compound.

Acetaldehyde↗

PubMed1995

Effect of cytochrome P450 inducers on liver microsomal metabolism of tetrachlorobiphenyls in rats, guinea pigs and hamsters.

Effect of cytochrome P450 (P450) inducers on liver microsomal metabolism of 3,4,3',4'-, 3,5,3',5'- and 2,5,2', 5'-tetrachlorobiphenyl (TCB) was studied using male Wistar rats, male Hartley guinea pigs and male Golden syrian hamsters. In metabolism of 3,4,3'4'- and 3,5,3',5'-TCB, liver microsomes from 3-methylcholanthrene (MC)- or 3,4,5,3',4'-pentachlorobiphenyl (PenCB)-treated hamsters showed hydroxylase activities for both TCB isomers, although the activities were much less than those of rats. In contrast, liver microsomes form untreated and phenobarbital (PB)-, MC- or PenCB-treated guinea pigs showed no hydroxylase activity. In 2,5,2',5'-TCB metabolism, 3-hydroxylase activity was observed in untreated guinea pigs and hamsters, but not in untreated rats. The activity pigs was induced by PB treatment in all three species, at rates of 324, 19 and 20 pmol/min/mg protein in rats, guinea and hamsters, respectively. This activity was not enhanced by treatment with either MC or PenCB. Only in hamsters was 4-hydroxylated metabolite formed in all microsomes used in addition to the 3-hydroxylated one, and the formation was accelerated 2.0-, 2.7- and 4.8-fold by treatment with PB, MC and PenCB, respectively. These results suggest that different P450 isoforms in hamster liver microsomes are involved in 3- and 4-hydroxylation of 2,5,2',5'-TCB. Thus, there are species differences in the basal ability to hydroxylate TCB isomers, and in the extent of effect of P450 inducers on the metabolism of these isomers among the three species.

Animals↗

PubMed1995

Synthesis and pharmacological effects in mice of halogenated cannabinol derivatives.

Eight halogenated derivatives of cannabinol (CBN) substituted on the aromatic ring at the 2 and/or 4 position were synthesized and their pharmacological effects were evaluated by intracerebroventricular injection (50 micrograms/mouse) in mice, using hypothermia, pentobarbital-induced sleep prolongation, catalepsy and anticonvulsant effect as indices. The hypothermic effects of monohalogenated derivatives of CBN were comparable to that of CBN, whereas the effects of dihalogenated derivatives of CBN except for the fluorinated derivative were attenuated. In the interaction with pentobarbital, two monochlorinated derivatives exhibited a significant prolongation of sleeping time, although other derivatives did not significantly affect the sleeping time. The cataleptogenic effects of monofluoro- and 4-bromo-CBN were stronger than that of CBN. 4-Bromo-CBN exhibited a significant prolongation of seizure latency induced by pentylenetetrazol. These data suggest that halogenation of CBN modifies the pharmacological profile of the cannabinoid.

Animals↗

PubMed1995

Improvement of coronary vasomotion with eicosapentaenoic acid does not inhibit acetylcholine-induced coronary vasospasm in patients with variant angina.

Impaired function of the endothelium may be a mechanism of the coronary vasospasm induced by acetylcholine. We examined whether purified eicosapentaenoic acid (EPA), a major component of fish oil, improves the coronary vasomotion in response to acetylcholine, and the effect of purified EPA on acetylcholine (ACh)-induced coronary vasospasm in 22 patients with variant angina. ACh was infused into the coronary artery both before and after 4 months of EPA treatment (EPA 1.8 g/day, n = 12). In the control group (n = 10) that did not receive EPA, the response of the coronary diameter to ACh did not change over time. In the EPA-treated group, the cholinergic response in non-spastic sites changed from vasoconstriction to vasodilation, while ACh-induced coronary vasospasm persisted at the spastic sites. Therefore, EPA treatment improved the coronary vasomotor responsiveness to ACh, but did not inhibit ACh-induced coronary vasospasm.

Acetylcholine↗

PubMed1995

New thermoluminescent BaSO4:Eu sheet for in vivo measurement of spatial dose distribution in radiation therapy.

A new highly sensitive thermoluminescent (TL) sheet has been studied as a means of in vivo measurement of spatial dose distribution of radiation therapy. This TL sheet (40 cm x 50 cm x 0.2 mm), which is composed of teflon mixed with BaSO4:Eu doped powder, is very flexible and can be cut to the desired size. The TL sheet was found to have a linear response with a very wide dynamic range of at least 0.002 cGy to 5000 cGy absorbed dose. In addition, this sheet does not need be shielded, because of its insensitivity to room light, and therefore the sheet can detect low-energy electrons decreased by a few millimeter thick air for 3H(maximum beta-ray energy: 18 KeV). The spatial dose distribution was printed out with a newly developed digital readout system. In addition, another high-resolution dosimetry system, which exposes X-ray film with TL photons emitted from the irradiated TL sheet at constant room temperature, is reported. Clinically, the in vivo dose distribution on the surface of the rectal cancer for intracavitary radiation therapy was determined. The applicability of TL sheet for in vivo measurement of dose distribution is discussed.

Humans↗

PubMed1995

[Pharmacokinetic study of intraperitoneally administered plachitin for non-curative gastrointestinal cancer].

Plachitin is a chemical compound of cis-diammine-dichloroplatinum (CDDP) and chitin. Pharmacokinetics and adverse effects of Plachitin for intraperitoneal chemotherapy (IP) were studied in 11 patients who suffered from non-curative gastrointestinal cancers in comparison with 4 patients who underwent IP of CDDP. Five patients were given 300 mg (100 mg as CDDP) of Plachitin which was cotton type on the residual cancer mass (Group A). Six patients were given IP 300 mg of Plachitin particles (Group B). As the control group, 4 patients were given IP 100 mg of CDDP (Group C). The platinum concentrations of serum, urine and intraperitoneal discharge were observed during 3-4 weeks after the treatments and calculated as the CDDP concentration. The serum CDDP levels were below 0.1 micrograms/ml for 4 weeks in Group A and B. In Group A, urine concentrations of CDDP were significantly lower than in Group B and C at 3 and 5 days after the treatment statistically (p > 0.05). But at 14 days after treatment, the urine concentration of CDDP in Group A was higher than in Group C. In Group A and B, the CDDP concentrations of intraabdominal discharge was lower than in Group C statistically (p > 0.05). Nausea was observed only in one patient of Group B and other adverse effects which contained renal sufficiency were not recognized in the three groups. Thus, Plachitin was considered an effective and safe agent for intraperitoneal chemotherapy.

Antineoplastic Agents↗

PubMed1995

Long-term results of operation for carcinoma of the stomach in T1/T2 stages: critical evaluation of the concept of early carcinoma of the stomach.

BACKGROUND: The significance of nodal metastasis in patients with early gastric cancer (ECG) (T1) is unknown. It has been suggested that patients with T2, N0 carcinoma of the stomach have a comparable survival rate to patients with T1 carcinoma of the stomach. STUDY DESIGN: A retrospective review and survival analysis of 321 patients with T1/T2 adenocarcinoma of the stomach treated between 1979 to 1991 were performed. RESULTS: Patients were divided into four groups: group 1, 214 patients with node-negative EGC (T1, N0); group 2, 13 patients with node-positive EGC (T1, N+); group 3, 49 patients with node-negative T2 disease (T2, N0); and group 4, 45 patients with node-positive T2 disease (T2, N+). Excluding deaths from causes other than recurrence, the survival rate for patients in groups 1 and 3 was 100 percent, in contrast to the ten-year survival rate of 72.7 percent for group 2 and 62.5 percent for group 4 patients (p < 0.001, groups 1 versus 2, groups 3 versus 4). The ten-year survival rate for patients with node-negative T2 disease (group 3, 100 percent) was significantly better than that of patients with node-positive EGC (group 2, 72.7 percent) (p < 0.001). Although differences in the survival rates were noted according to lymphatic or venous invasion and whether or not patients had EGC or T2 carcinoma, the most significant factor was lymph node invasion. CONCLUSIONS: The postoperative survival rate for patients with node-positive EGC was poorer than that for those with node-negative T2 carcinomas. Reevaluation of the concept of EGC may be necessary. Post-operative chemotherapy does not appear necessary in patients with T2, N0 disease.

Adenocarcinoma↗

PubMed1995

[Effect of a coplanar PCB on lipid metabolism: the remarkable difference between rats and guinea pigs].

We studied the effect of 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB) on lipid metabolism by determining the level of triacylglycerol and total cholesterol in rats and guinea pigs. Male Wistar rats and male Hartley guinea pigs received PenCB in corn oil one at a dose of 25 mg/kg i.p. and 0.5 mg/kg i.p., respectively. Pair-fed control group of both species were treated with the vehicle and given the amount of chow matched with that taken by the PenCB-treated animals. Free-fed control group was treated with vehicle and was given the chow ad libitum. The plasma was collected on the day 5 after the treatment and the liver was removed. The plasma triacylglycerol level in guinea pigs treated with PenCB was significantly higher than those in free- and pair-fed controls, whereas no significant difference was observed in PenCB-treated rats from both control groups. The plasma cholesterol level was also higher in PenCB-treated guinea pigs than in the two control groups, though the level in rats was significantly lower than the corresponding control values. The hepatic triacylglycerol and cholesterol levels were increased significantly in both species by the PenCB treatment. Although lipid metabolism was disordered in both animals by treatment with PenCB, the responsiveness was remarkably different between guinea pigs and rats. These differences could be associated with species difference in susceptibility toward toxic chlorinated aromatic hydrocarbons.

Animals↗

PubMed1995

[Extended operation for lung cancer: concomitant resection of the heart or the great vessels with the lung].

We have analysed our experience in 43 patients with lung cancer invading the heart or great vessels who underwent surgical resection of the invaded portion of the mediastinal organs as well as the primary tumor, and have reviewed the literature on the subject of the extended operation for lung cancer invading the heart or great vessels. Among our experience of those 43 patients, a single mediastinal organ was resected in 32 patients (the left atrium in 20, the main pulmonary artery in 7, superior vena cava in 3 and the adventitia of the aorta in 2), and more than two mediastinal organ were resected in 11 patients (the main pulmonary artery and the other in 8, and the left atrium and esophagus or trachea in 3). There were 34 squamous cell carcinomas, 4 adenocarcinomas, 3 large cell carcinomas and 3 other cell types. Pathology disclosed 6 patients had pT 3 tumor (Group 1, 24 patients had pT 4 tumor that had invaded to a single mediastinal organ (Group 2) and 11 patients had pT 4 tumor that had invaded to more than two mediastinal organs (Group 3). The 5 year survival rate in patients of Group 1, 2 and 3 were 80%, 32.2% and 0%, respectively. There were statistical differences among the survivals of those three groups. We conclude that extended resection for lung cancer invading the heart or great vessels is justified if the invasion is limited to a single mediastinal organ. Several problems on such extended resection were discussed.

Aorta, Thoracic↗

PubMed1995

[Pharmacokinetics of 123I-iomazenil, a benzodiazepine receptor seeker].

The biodistribution, metabolism and excretion of 123I-iomazenil have been studied in rats, rabbits and humans following i.v. administration. In all the species, 123I-iomazenil was rapidly metabolized and more than 90% of the administrated radioactivity was excreted within the first 24 hr. Dominant metabolites were acid metabolite (R-COOH), glucuronide of the acid (R-COOH-Glc) and free iodide (I-) in rats and humans. On the other hand, R-COOH, oxidative metabolite (R'-CH2COOH) and I- were found in rabbits. Thus, the possible metabolic pathways of iomazenil were hydrolysis, oxidation, conjugation and deiodination. The radioactivity was excreted into both urine and feces in rats, while primary route of excretion in rabbits and humans was from the kidneys. At 3 hr after injection, more than 97% of the radioactivity in rat brain was found in the form of the parent compound. This result indicates that metabolites of 123I-iomazenil do not cross the blood-brain barrier.

Animals↗

PubMed1994

[A five-year follow-up of two different 131I treatment methods for Graves' disease and the factors affecting the outcome].

We employed two different methods of 131I treatment for Graves' disease in 285 patients and compared the results between the two. (We also analyzed the factors affecting the treatment outcome.) A single dose of 131I adjusted to the patients' thyroid weight was administered to 180 patients in group 1, while a relatively lower dose of 131I (approximately 30Gy) was given repeatedly to 105 patients in group 2. A 5-year follow-up showed that in group 1, 34% of the patients were euthyroid, 11% hypothyroid, 11% subclinical hypothyroid and 44% still remained hyperthyroid. In group 2, 43% of the patients were euthyroid, 5% hypothyroid, 35% subclinical hypothyroid and 17% hyperthyroid. The factors affecting the outcome of the treatment in group 1 patients were their thyroid weight, the duration of the disease and TRAb levels. No significant correlation was observed between the efficacy of 131I treatment and the patients' sex, age, 24hr 131I-uptake, effective half life of administered 131I or titers of antithyroid antibodies. We conclude that the repeated low dose administration of 131I provides the best outcome in a 5-year follow-up. However, we suggest that an adjusted dose of 131I in relation to the patients' thyroid weight should be employed to obtain a faster therapeutic response.

Adult↗

PubMed1994

Protection by prosaposin against ischemia-induced learning disability and neuronal loss.

Prosaposin, the protein precursor of saposins A, B, C, and D which activate sphingolipid hydrolases, is abundant in several brain regions including the hippocampus. We infused prosaposin continuously for 7 days into the lateral ventricle of gerbils starting 3 hours before 3-min of forebrain ischemia. Using the step-down passive avoidance task, we demonstrated that ischemia-induced learning disability is prevented almost completely by prosaposin infusion. Subsequent light and electron microscopic examinations showed that pyramidal neurons in the CA1 field of the hippocampus as well as synapses within the strata moleculare, lacunosum/radiatum and oriens of the field were significantly more numerous in gerbils infused with prosaposin infusion than in those receiving saline infusion. These findings suggest that prosaposin possesses neurotrotrophic activity to protect hippocampal CA1 neurons from lethal ischemic damage.

Animals↗

PubMed1994

Effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on N-nitrosobis(2-oxopropyl)amine (BOP)-initiated carcinogenesis in hamsters.

The effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) administration during the post-initiation phase of carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Female Syrian golden hamsters were given a single s.c. injection of BOP at a dose of 10 mg/kg and then administered 3 ppm (H) or 1 ppm (L) NNK in their drinking water for the following 87 weeks. Additional groups of animals received the BOP injection alone, or only the 3 or 1 ppm NNK treatments as BOP-negative controls. At week 88 of the experiment, all surviving animals were sacrificed and development of proliferative lesions was assessed histopathologically. The results showed no statistically significant influence on pancreatic adenocarcinomas or dysplastic lesions, although the incidence and the number of atypical hyperplasias in the pancreas head in the BOP/NNK (L) group was significantly increased as compared to BOP alone group values (P < 0.05). Similarly, the NNK treatments did not affect the incidences or multiplicities of neoplastic or hyperplastic lesions in the endocrine pancreas, lung, liver or kidney. Thus, the present experiment demonstrates that the tobacco-specific carcinogen NNK does not enhance BOP-induced hamster tumorigenesis when given in the promotion phase.

Animals↗

PubMed1994

[Studies on patients with a discrepancy between free thyroid hormones and thyrotropin values].

Thyroid function has been almost exactly evaluated by the measurement of serum free thyroxine (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) concentrations. However, we occasionally experience patients who show a discrepancy between free thyroid hormones and TSH values, and the assessment of thyroid function in such cases is extremely difficult. Thyroid hormone autoantibodies (THAA) interfere with radioimmunoassay (RIA) of FT4 and FT3 by giving inappropriate values. To investigate the incidence of THAA, immune precipitation of patients' sera after incubation with labelled T4 (125I-T4) or T3 (125I-T3) analog tracer was done in 394 patients with thyroid diseases. 9 patients (2.3%) showed an increased binding of 125I-T4 or 125I-T3 analog. Heterophilic antimouse antibodies in a patient's serum (human antimouse immunoglobulin antibodies: HAMA) can interfere in two-site immunometric assays (IMA) using mouse monoclonal antibodies and result in spuriously increased serum TSH concentrations. Manufacturers now customarily add nonspecific mouse immunoglobulins into their assay kits to absorb HAMA and prevent such interference. This approach may not always be enough to prevent HAMA interference in all samples. In 14 thyrotoxic patients with inappropriately high TSH measured by an IMA kit, we measured the levels of TSH by the further addition of mouse serum into this kit. Their serum TSH levels were fully suppressed except for 2 patients with a syndrome of inappropriate secretion of TSH (SITSH). The presence of abnormal albumin in the serum also interferes with RIA of FT4 and FT3. We experienced a female case of Graves' disease treated with methimazole who showed an inappropriately high serum FT3 measured by an analog tracer RIA kit, whose serum FT4, FT3 and TSH were 1.31 ng/dl, 19.3 pg/ml and 1.9 mu U/ml respectively. Although the anti-T3 autoantibody was considered to be present initially, immune precipitation of her serum with 125I-T3 analog tracer gave a negative result. In order to elucidate this finding, Sephadex-G200 chromatography of her serum after incubation with 125I-T3 analog tracer was done. Radioactivity of her serum in albumin fraction was significantly higher than that of normal control serum to indicate the presence of abnormal albumin in the serum. In conclusion, to assess the thyroid function of a patient with a discrepancy between free thyroid hormones and TSH values, it is important to consider the presence of THAA, HAMA, or rarely, an abnormal albumin.

Adult↗

PubMed1994

cDNA cloning and sequence of CYP2C29 encoding P-450 MUT-2, a microsomal aldehyde oxygenase.

A cDNA clone encoding a cytochrome P-450 (P-450) isozyme was isolated from a mouse liver cDNA library. This P-450, designated CYP2C29, the first member of the mouse CYP2C subfamily to be reported, contained the complete coding region of 490 amino acid residues. The deduced amino acid sequence of CYP2C29 exhibited 83% identity with that of the rat CYP2C7 and had an N-terminal sequence identical to that of P-450 MUT-2, a microsomal aldehyde oxygenase. Two peptides, derived from BrCN cleavage of P-450 MUT-2, were also identical to the cDNA deduced protein of CYP2C29. These results indicate that CYP2C29 cDNA encodes P-450 MUT-2.

Amino Acid Sequence↗