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Biomedical subjects

M Tani

Publications and source records attributed to M Tani.

At least 127 records · Page 7Linked to original sources
PubMed1998

Effect of E4031, a class III antiarrhythmic drug, on ischemia- and reperfusion-induced arrhythmias in isolated rat hearts.

UNLABELLED: The delayed outward rectifier K+ channel has a role in the increase in automaticity of myocytes under pathophysiological conditions. The purpose of the present study was to clarify the effect of blockade of outward rectifier K+ channels by a class III antiarrhythmic drug, E4031, on ischemia- and reperfusion-induced arrhythmias. Ion fluxes, energy metabolites and cardiac function were measured and the epicardial electrocardiograms of Langendorff-perfused rat hearts were recorded during initial perfusion, global or regional ischemia and reperfusion. 10(-7) M of E4031 administered during the initial perfusion did not prolong the QT interval, but slowed the heart rate ( CONTROL: 222, E4031: 183 bpm, p < 0.05), increased myocardial 45Ca2+ uptake ( CONTROL: 2.1, E4031: 2.9 mumol/g dwt, p < 0.05) and attenuated the loss of intracellular K+ during ischemia ( CONTROL: 238, E4031: 248 mumol/g dwt, p < 0.05). E4031 tended to reduce ischemia-induced ventricular tachyarrhythmias ( CONTROL: 60, E4031: 30%, n.s.), but reperfusion-induced ventricular tachyarrhythmias were sustained longer by the administration of E4031 (CONTROL: 255, E4031: 623 sec, p < 0.05). Prior exposure to E4031 decreased the depletion of high energy phosphates during ischemia, but suppressed their recovery during reperfusion. These results suggest that the attenuated loss of K+ from the ischemic myocardium and the decrease in heart rate by E4031 contributed to the reduction of ischemia-induced arrhythmias. However, the increase in myocardial Ca2+ uptake and altered energy metabolism may be responsible for the increase in reperfusion-induced arrhythmias.

Animals↗
PubMed1998

Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4.

Buprenorphine (BN) is a thebaine derivative with analgesic properties. To identify and characterize the cytochrome P450 (CYP) enzyme(s) involved in BN N-dealkylation, in vitro studies using human liver microsomes and recombinant human CYP enzymes were performed. Norbuprenorphine formation from BN was measured by a simple HPLC-UV assay method, without extraction. The BN N-dealkylation activities in 10 human liver microsomal preparations were strongly correlated with microsomal CYP3A-specific metabolic reactions, i.e. triazolam 1'-hydroxylation (r = 0.954), midazolam 1'-hydroxylation (r = 0.928), and testosterone 6beta-hydroxylation (r = 0.897). Among the eight recombinant CYP enzymes studied (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), only CYP3A4 could catalyze BN N-dealkylation. The apparent KM value for recombinant CYP3A4 was similar to that for human liver microsomes (23.7 vs. 39.3 +/- 9.2 microM). The demonstration of BN N-dealkylation by recombinant CYP3A4 and the agreement in the affinities (apparent KM values) of human liver microsomes and recombinant CYP3A4 provide the most supportive evidence for BN N-dealkylation being catalyzed by CYP3A4.

Alkylation↗
PubMed1998

A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes.

The metabolism of etoposide was investigated by using human liver microsomes and nine recombinant human cytochrome P450 (CYP) isoforms to identify the CYP isoform(s) involved in the major metabolic pathway (3'-demethylation) of etoposide as well as to evaluate the possible metabolic interactions with several antitumor or supporting agents. The 3'-demethylation of etoposide followed a Michaelis-Menten one-enzyme kinetic behavior in six human liver microsomal samples. The relationships were assessed with six different human liver microsomes between the 3'-demethylation of etoposide and metabolic activities for substrate probes of the respective CYP isoforms, showing a significant correlation (r = 0. 932, P < .01) only with 6beta-hydroxylation of testosterone, a marker substrate for CYP3A4. Inhibitor/substrate probes for CYP3A4, ketoconazole, troleandomycin, verapamil and cyclosporin, or supporting agents, vincristine and prednisolone, inhibited etoposide 3'-demethylation by human liver microsomes. p-Nitrophenol, a substrate for CYP2E1, also inhibited etoposide 3'-demethylation. Among the nine recombinant human CYP isoforms, CYP3A4 exhibited the highest catalytic activity with respect to etoposide 3'-demethylation, compared with the minor activities of CYP1A2 and 2E1. Collectively, these data suggest that etoposide 3'-demethylation is mediated mainly by CYP3A4 and to a minor extent by CYP1A2 and 2E1. Furthermore, some supporting agents (vincristine and prednisolone) and the substrates of CYP3A4, which may be coadministered with etoposide during the cancer chemotherapies, inhibit the etoposide 3'-demethylation activity in vitro. The results may provide clinical implications with respect to the possible metabolic interactions between etoposide and other drugs studied herein in patients with cancer undergoing etoposide concurrently with either of them.

Adult↗
PubMed1998

[Endoscopic diagnosis of early cancer in the esophagogastric junctional region].

The endoscopic diagnosis of early esophageal and gastric cancers located within 2 cm above and below the esophagogastric junction (EGJ) is discussed. We reviewed 25 cases (10 mucosal cancers and 15 submucosal cancers). Histologically, early cancers frequently appeared as type IIc lesions (16/25: 64%). There was no relationship between tumor size and the depth of invasion of cancer lesions, and most of the lesions were well or moderately differentiated carcinomas. Endoscopically, homogenous redness with a thin white coating, some granular appearance, and easy bleeding were very important factors for the diagnosis of early gastric cancer. For superficial esophageal cancer, differential diagnosis from reflux esophagitis is correctly performed with the endoscopic dye (lugol)-staining method and biopsy. In order not to overlook early cancer at the EGJ, this area should be observed with sufficient air inflation by the U-turn or J-turn method using a frontal-view panendoscope.

Adult↗
PubMed1998

Role of autologous bone marrow transplantation as consolidation therapy in acute promyelocytic leukemia patients in complete remission.

Autologous bone marrow transplantation (ABMT), which consents a low mortality rate, has been proposed as an alternative approach to maintenance chemotherapy in patients with acute promyelocytic leukemia (APL) in first complete remission irrespective of the patients' molecular status. Sixteen patients with acute APL in complete remission were submitted to ABMT and were analyzed for the presence of the PML-RARa fusion gene by reverse transcription-polymerase chain reaction (RT-PCR). Our study demonstrated that continued positivity of PCR analysis before ABMT could predict subsequent relapse in patients who undergo un-purged ABMT procedures.

Adolescent↗
PubMed1997

Changes in ischemic tolerance and effects of ischemic preconditioning in middle-aged rat hearts.

BACKGROUND: Although both clinical and animal studies have shown that ischemic tolerance is reduced in the senescent myocardium, it has not been clarified when myocardium becomes more vulnerable to ischemia. Preconditioning protects the hearts of young adult animals of various species, but its effects are not identical in human studies. We investigated whether ischemic tolerance and the effect of preconditioning decreased in isolated hearts of middle-aged rats. METHODS AND RESULTS: The hearts of young adult rats (12 weeks old: group Y, n = 44) and middle-aged rats (50 weeks old: group M, n = 44) were subjected to global ischemia for 15, 20, or 25 minutes followed by reperfusion. Hearts were also subjected to preconditioning and then to 20 (group Y, n = 22) or 15 (group M, n = 22) minutes of ischemia followed by reperfusion. Left ventricular developed pressure (LVDP) was decreased by 40% to 60%, and the level of ATP was decreased by 60% to 70% in group M compared with group Y. Preconditioning increased LVDP (% LVDP, 40.5% to 72.4%) and levels of high-energy phosphates (ATP, 11.8 to 14.1; creatine phosphate, 17.0 to 23.1 mumol/g dry wt) and reduced left ventricular end-diastolic pressure (LVEDP, 32.8 to 10.3 mm Hg), creatine kinase release (257 to 132 U/g dry wt), and ryanodine-sensitive sarcoplasmic reticulum Ca2+ release after ischemia in group Y. Preconditioning exerted opposite effects in group M (% LVDP, 45.9% to 15.8%; LVEDP, 21.0 to 28.5 mm Hg; ATP, 14.1 to 8.5 mumol/g dry wt; and CK release, 176 to 332 U/g dry wt). Preconditioning was associated with increases in the incidence of reperfusion-induced ventricular fibrillation (0% to 62.5%) and the rate of sarcoplasmic reticulum Ca2+ release in group M. CONCLUSIONS: These results indicate that hearts became more vulnerable to ischemia with age and that the beneficial effects of preconditioning were reversed in middle-aged rat hearts.

Adenosine Triphosphate↗
PubMed1997

Mutation analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human colon cancer using genomic DNA and intron primers.

Mutations in the transforming growth factor beta type II receptor (TGFbeta RII) gene have been detected in several human cancers exhibiting microsatellite instability. To extend analyses of this gene, we previously investigated the exon-intron organization of the TGFbeta RII gene and defined seven exons and flanking intron sequences. In this study, we further determined the nucleotide sequences surrounding these seven exons and designed eight sets of intron-based primers to examine the entire coding region of the TGFbeta RII gene. Using these primers, we screened genomic DNA sequences from 30 sporadic colorectal cancers for mutations of the TGFbeta RII gene. TGFbeta RII mutations were detected in two of 30 tumors and both displayed microsatellite instability. One had a deletion in a polyadenine tract in exon 3 and the other had a point mutation in the kinase domain located in exon 7. There were no mutations in exons 1, 2, 4, 5 and 6. These results further implicate the polyadenine tract and kinase domain as mutational hotspots in the TGFbeta RII gene in cells with genomic instability and suggest that TGFbeta RII gene mutations occur rarely in cells lacking genomic instability.

Base Sequence↗
PubMed1997

Isolation of a novel Sry-related gene that is expressed in high-metastatic K-1735 murine melanoma cells.

To identify genes differentially expressed in association with metastatic potential of K-1735 mouse melanoma cells, the mRNA differential display method was applied to compare mRNAs from high- and low-metastatic K-1735 cells. A novel gene was identified as being expressed in high-metastatic cells but not in low-metastatic cells. Sequence analysis revealed that this gene had an open reading frame of 538 amino acid residues containing a Sry high-mobility group (HMG) box domain, known as a DNA binding motif, particularly in the Sox family genes. This gene showed the highest homology to the human SOX9 gene, which is the responsible gene for an inherited disease, campomelic dysplasia. Thus, this gene was designated the Sox21 gene (the 21st Sox family gene). The Sox21 gene was mapped to mouse Chromosome 15, to which neither genes containing the HMG box region nor the loci of hereditary diseases similar to campomelic dysplasia have been previously mapped. This gene was highly conserved and specifically expressed in the brain. These results suggest that expression of the Sox21 gene is involved in the development of nerve systems and may function to enhance the metastatic potential of K-1735 mouse melanoma cells of nerve cell origin.

Amino Acid Sequence↗
PubMed1997

Decrease in ischemic tolerance with aging in isolated perfused Fischer 344 rat hearts: relation to increases in intracellular Na+ after ischemia.

While the ischemic tolerance of the myocardium has been reported to decrease with senescence, it is not known when and how this occurs. Our objectives were to determine whether the tolerance to myocardial ischemia in rats decreased before the onset of senescence and whether an increase in myocardial ionic imbalance was associated with an enhanced myocardial injury with aging. Hearts were isolated from Fischer 344 rats categorized as young (12 weeks old), mature adult (24 weeks), middle-aged (50 weeks) or senescent (100 weeks). Hearts were perfused isovolumically by the Langendorff procedure and subjected to 25 min of global ischemia followed by 30 min of reperfusion. In the 50- and 100-week-old rats, the recovery of ventricular function and high-energy phosphate levels was lower and there was increased incidence of ventricular fibrillation after 25 min of global ischemia followed by reperfusion. The release of creatine kinase and lactate dehydrogenase during reperfusion was greater in the 50-and 100-week-old rats than in the 12- and 24-week-old rats, indicating the irreversible myocardial damage due to ischemia-reperfusion increased by middle-age. Intracellular levels of Na+ and K+ before ischemia were higher in the 50- or 100-week-old rats than in the 12-week-old rats. The increase in intracellular Na+ at end of ischemia was greater in the older (50-week-old, 215% of the pre-ischemic value; 100-week-old, 232% of the pre-ischemic value) than in the younger rats (12-week-old, 158% of the pre-ischemic value). Results indicated that the rat heart becomes more vulnerable to ischemia in middle-age. This decrease in ischemic tolerance may be caused by an acceleration of myocardial ionic imbalance with aging.

Aging↗
PubMed1997

Enhancement of tumor cell susceptibility to tumor-infiltrating lymphocytes by cisplatin.

Some means of enhancing the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TIL) are required in adoptive immunotherapy. This study was designed to investigate whether or not tumor cell lysis by TIL was enhanced by treatment of the tumor cells with cisplatin, and also to clarify the mechanism of cisplatin's action on tumor cells. Autologous tumor cells and established cancer cell lines, including KATO-III and MKN-28, were used. Cytotoxic activities of TIL, the surface antigens of tumor cells, conjugation of TIL and tumor cells, and the production of TNF alpha from TIL were analyzed. Tumor cells treated with 2 micrograms/ml cisplatin for 12 h in vitro were more susceptible to bulk-cultured TIL and TIL clones. The surface antigens of tumor cells were not altered by the treatment with cisplatin. Cisplatin-treated tumor cells showed a higher binding ratio to TIL than did non-treated tumor cells. The anti-(tumor necrosis factor) (anti-TNF) or anti-TNF receptor antibody blocked the enhancement of cytotoxic activity by cisplatin. Thus, it was clarified that cisplatin enhanced the susceptibility of tumor cells to bulk-cultured TIL and TIL clones. Furthermore, the enhancement of cytotoxic activity by TIL in cisplatin-treated tumor cells was caused by a higher binding ratio to TIL and higher susceptibility to the TNF produced by TIL.

Antigens, Neoplasm↗
PubMed1997

Treatment of primary multiple early gastric cancer: from the viewpoint of clinicopathologic features.

The treatment of multiple early gastric cancer was investigated through the clinicopathologic assessment of 61 cases of primary multiple early gastric cancer (82 accessory lesions) treated by surgical resection over a 15-year period. These cases accounted for 11.7% of all cases of early gastric cancer resected during the same period. The 61 patients included 48 men (mean age 64 years) and 13 women (61 years). Of the 82 accessory lesions, 41 (50%) were located in the same region as the main lesion. The most frequent combination of macroscopic types of the main lesion and the accessory lesion was depressed type/depressed type (28 cases). The main lesion was of the well differentiated type in 39 (64%) of the 61 cases; the accessory lesion was also well differentiated in 37 of the 39 cases. Of the 82 accessory lesions, 29 (35%) had been overlooked preoperatively; most of them were located in the middle third of the stomach and included 17 depressed and 10 flat lesions, most of which measured no more than 1 cm. Cases of multiple early gastric cancer are characterized by the predominance of male patients of advanced age (> 60 years), a combination of the same macroscopic type of the main and accessory lesions, and well differentiated carcinoma. Lymph node metastasis and vascular invasion are equally or less frequent than in cases of solitary early gastric cancer. The postoperative crude survival rate in patients with multiple gastric cancer is similar to that in those with solitary gastric cancer. Therefore we believe that multiple early gastric cancer does not require extended operative procedures. Endoscopic treatment may be indicated if each lesion fits the criteria for treatment and careful follow-up is ensured.

Adult↗
PubMed1997

Proximal gastrectomy and jejunal pouch interposition for the treatment of early cancer in the upper third of the stomach: surgical techniques and evaluation of postoperative function.

BACKGROUND: Limited surgery for the treatment of early gastric cancer located in the upper third of the stomach should be based on a well-balanced reduction in the extent of lymph node dissection and gastric resection while assuring a favorable quality of life and prognosis after operation. METHODS: We have used interposition of a double jejunal pouch between the esophagus and the remnant stomach after performing proximal gastrectomy. To assure anastomosis and hemostasis during this operation, we currently use a surgical stapler with a vaginoscope and our new edge clamps. This method has been used in 12 patients to date. RESULTS: On histopathologic examination the 12 cases comprised 11 early cancers (seven mucosal and four submucosal cancers) and one subserosal cancer. There was no evidence of lymph node metastasis of postoperative complications such as anastomotic leakages or hemorrhage, demonstrating the low-risk nature of this procedure. CONCLUSIONS: The evaluation of postoperative quality of life, in terms of clinical signs and symptoms and dietary status, yielded favorable results. Thus our method has the important advantage of allowing good organ preservation.

Adult↗
PubMed1997

Infrequent mutations of the transforming growth factor beta-type II receptor gene at chromosome 3p22 in human lung cancers with chromosome 3p deletions.

Mutations in the transforming growth factor beta-type II receptor (TGFbeta RII) gene have been detected in several types of human cancers that represent the phenotype of genomic instability. The TGFbeta RII gene has been mapped to chromosome 3p, on which loss of heterozygosity (LOH) was frequently detected in both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). To investigate whether the TGFbeta RII gene on 3p22 is inactivated in lung cancers, we examined 35 sporadic lung cancers (15 SCLC and 20 NSCLC) with LOH on 3p for mutations of the TGFbeta RII gene. We previously produced eight intron based primer pairs for mutational analysis of the entire coding region of the TGFbeta RII gene. Using these primers, we screened for mutations of the TGFbeta RII gene by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis. A mutation was detected in a case of SCLC: one base insertion in the polyadenine tract of exon 3. This tumor showed the replication error (RER) phenotype. There were no mutations in exons 1, 2, 4, 5, 6 and 7. These results indicate that the polyadenine tract is a mutational hot spot in the TGFbeta RII gene in RER positive tumors, and that TGFbeta RII mutations occur rarely in lung cancers with LOH on chromosome 3p.

Carcinoma, Non-Small-Cell Lung↗
PubMed1997

Electrophysiologic effects of SD-3212, a new class I antiarrhythmic drug, on canine atrial flutter and atrial action-potential characteristics.

SD-3212 (levo-semotiadil fumarate) is a newly developed compound that exhibits potent antiarrhythmic activity because of its inhibitory action on sodium and calcium channels. In animal models, SD-3212 suppressed ventricular tachyarrhythmias, but the effects of this drug on atrial tachyarrhythmias have not been reported. We investigated the electrophysiologic effects of SD-3212 on canine atrial flutter induced after placement of the intercaval obstacle and on atrial action-potential characteristics. In all seven dogs, SD-3212 (1.9 +/- 0.3 mg/kg) terminated atrial flutter after significant increase in atrial flutter cycle length from 126 +/- 5 to 166 +/- 14 ms (increase, 31 +/- 8%; p < 0.005). SD-3212 increased right atrial effective refractory period (RAERP) significantly from 126 +/- 7 to 149 +/- 11 ms at a basic cycle length of 300 ms. The increases in RAERP after SD-3212 at basic cycle lengths of 300, 200, and 150 ms did not differ (increase, 18 +/- 4%, 17 +/- 3%, and 19 +/- 3%, respectively). Interatrial conduction time (IACT) was prolonged after SD-3212 from 63 +/- 4 to 81 +/- 6 ms (increase, 31 +/- 6%) at a basic cycle length of 150 ms. Prolongation of IACT was frequency dependent. The plasma concentration of SD-3212 after the termination of atrial flutter was 187 +/- 56 ng/ml in four dogs tested. In vitro study by using standard microelectrode techniques showed SD-3212 at concentrations of 1-3 microM significantly prolonged action-potential duration at 90% repolarization. Vmax was decreased by SD-3212 in a concentration-dependent manner (0.3-3 microM), and the inhibitory effect on Vmax was greatest at the highest stimulation frequency of 3.3 Hz. These results indicate that a new antiarrhythmic drug, SD-3212, is effective in interrupting canine atrial flutter, possibly by suppressing atrial conduction, and might be effective for the treatment of clinical atrial tachyarrhythmias.

Action Potentials↗