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Biomedical subjects

T Hibi

Publications and source records attributed to T Hibi.

At least 37 records · Page 2Linked to original sources
PubMed1996

Pharmacokinetics and safety of a novel, long-acting, prodrug-type potassium channel opener, Y-27152, in healthy volunteers.

The pharmacokinetics and safety of a novel, long-acting, prodrug-type K(+)-channel opener, Y-27152, were investigated in healthy male volunteers. In the first phase, single oral doses of 0.1, 0.25, 0.5, 0.75, and 1.0 mg of Y-27152 (n = 3-6 per dose) were given after overnight fasts in a dose-escalating manner. The 0.75-mg dose was given both after an overnight fast or after food to examine the effects of food intake. In the second phase, multiple doses of Y-27152 were taken after meals once daily for 7 consecutive days. In part A of this phase, either placebo (n = 3) or 0.5 mg of Y-27152 (n = 6) was taken for 7 days, and in part B of this phase 0.5-, 0.75-, and 1.0-mg doses were taken in a dose-escalating manner for 1,3, and 3 days, respectively (n = 9). In the single-dose study, peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) of main active metabolite (Y-26763; M1) increased in parallel with dosage. This dose-linearity was less obvious with Y-27152, which had an AUC approximately 6 to 10 times less than that of M1. Administration with food at 0.75 mg resulted in a small but significant decrease (approximately 10%) in the Cmax and AUC of M1. At doses of 0.5 mg or higher, participants experienced headaches and palpitations, which were probably due to the vasodilatory effects and did not require treatment. Mean diastolic blood pressure significantly decreased and pulse rate increased at doses of 0.5 mg or higher compared with predose values. Plasma renin activity was significantly elevated 4 hours after the administration of the 0.75- and 1.0-mg doses, but showed no significant change at 0.5 mg. In the multiple-dose study, the time profile of the plasma concentration of M1 approximately coincided with the simulation curves worked out using the pharmacokinetic parameters obtained in the singledose study. The incidence of headaches tended to increase with dose in part B, but drug administration was not discontinued in any case. Plasma renin activity again increased 4 hours after administration. In phase B of the multiple-dose study, diastolic blood pressure decreased and pulse rate increased compared with predose values. Y-27152 was metabolized to M1 and well tolerated in healthy volunteers, and its pharmacologic effects were likely caused by vasodilation, which could make it an effective antihypertensive agent.

Administration, Oral↗
PubMed1996

Preferential activation of CD4+V beta 5.2/5.3+ intestinal intraepithelial lymphocytes in the inflamed lesions of Crohn's disease.

To analyze the nature of intestinal intraepithelial lymphocytes (iIELs) in inflammatory intestinal disease, we established T cell lines of iIELs isolated from endoscopic biopsied ileal and colonic mucosa of Crohn's disease patients. Seven T cell lines from the inflamed terminal ileum of 13 patients, but none of 16 T cell lines from normal terminal ileum, have shown a deviation of T cell receptor variable region gene usage and were enriched in the proportion of CD4+V beta 5.2/5.3+ cells. CD4+V beta 5.2/5.3+ cells in the T cell lines were not increased after stimulation with purified protein derivatives or 65-kDa heat-shock protein but significantly increased after stimulation with staphylococcal enterotoxins C1 and D. Those cells showed increased cytolytic activity against target cells cross-linked by anti-V beta 5.2/5.3 and produced a large amount of interferon-gamma. These results indicated that CD4+V beta 5.2/5.3+ iIELs were preferentially activated in the inflamed lesions of Crohn's disease and may play a possible role in the triggering and progression of human inflammatory intestinal disease.

Adolescent↗
PubMed1996

Laparoscopically assisted ileocecal resection for Crohn's disease associated with intestinal stenosis and ileovesical fistula.

We describe a 22-year-old man with Crohn's ileocolitis accompanied by intestinal stenosis and ileovesical fistula in whom laparoscopically-assisted surgery was successfully performed after thorough nutritional therapy. Laparoscopic procedures are characterized by minimal access and minimal invasion, features which can contribute to the early recovery of patients who undergo surgery. It is suggested that laparoscopic (or laparoscopically-assisted) surgery after strict nutritional therapy can be effective in the treatment of patients with Crohn's disease who have intestinal complications.

Adult↗
PubMed1996

Deletion mapping on chromosome 1p in well-differentiated gastric cancer.

To define the region on the short arm of chromosome 1 that is thought to include one or more tumour-suppressor genes for gastric cancers, we carried out loss of heterozygosity (LOH) studies in 26 gastric adenocarcinomas, using three restriction fragment length polymorphism (RFLP) markers and nine microsatellite markers. All tumours were informative with at least one locus; three revealed replication errors (RERs) at multiple microsatellite loci, and interstitial or telomeric allelic deletions were observed in 12 cases. Deletion mapping of these tumours defined a commonly deleted region between two loci, D1S201 and D1S197, that are 13 cM apart. As two loci within the commonly deleted region, D1S57 (pYNZ2) and D1S62 (pTHI54), were mapped respectively to 1p35 and 1p34.3 by fluorescence in situ hybridisation, we conclude that a locus likely to contain a tumour-suppressor gene for gastric cancer is located within a 13 cM region encompassing two chromosomal bands.

Chromosome Deletion↗
PubMed1996

Microvascular disturbances in the colonic mucosa in antibiotic-associated haemorrhagic colitis: involvement of platelet aggregation.

An ultrastructural study of the colonic mucosa was performed in four patients with antibiotic-associated haemorrhagic colitis and new findings are reported. Colonoscopy was performed and biopsy specimens were obtained within 24 h of the onset of bloody diarrhoea. Colonoscopy demonstrated diffuse oedematous and haemorrhagic mucosa with erosions and white coat. Light microscopy revealed mucosal haemorrhage and inflammatory cell infiltration. Ultrastructurally, platelet aggregation was frequently present in the lumina of colonic mucosal capillaries, causing engorgement of red blood cells in adjacent microvessels. Mild to severe damage was observed in capillary endothelial cells, including discontinuity of basement membranes, gaps between endothelial cells and the destruction of capillaries. There was no evidence of microvascular spasm. In conclusion, our findings suggest that antibiotics directly or indirectly cause microcirculatory disturbances, which result in tissue damage and haemorrhage, in the colonic mucosa.

Adult↗
PubMed1996

[Immunoglobulin heavy chain variable region(VH) genes in B cell clones producing anti-colon antibodies in ulcerative colitis].

We have established anti-colon antibodies producing B cell clones from the patient with ulcerative colitis, and analyzed the immunoglobulin heavy chain variable region (VH) gene segments of these clones using RT-PCR with VH family specific primers. VH3 family was used by all ten clones from ulcerative colitis that produced anti-colon antibodies, while various VH gene families were used by eight clones from normal controls. By nucleotide sequence analysis, two LPL clones were thought to be derived from a germ line gene segment, VH26. However, other three PBL clones were derived from 22-2B, 9-1 and 1.9-III, respectively. These results suggest the heterogeneity of the colonic antigens that autoantibodies in ulcerative colitis recognize.

Antibody-Producing Cells↗
PubMed1995

Use of the double-stapling technique in esophageal surgery.

This study was conducted to examine the effectiveness of the double-stapling technique (DST) for performing esophageal anastomoses. A total of 17 patients, 10 with esophageal cancer and 7 with gastric cancer, underwent esophageal anastomosis employing this technique. Of the ten patients who underwent esophageal operations, eight received esophageal-gastric tube anastomosis, one esophageal-colon and colon-residual stomach anastomosis, and one pharyngeal-gastric tube anastomosis, while all seven of the patients who underwent operations for gastric cancer received esophagojejunostomy. Thus, a total of 18 anastomoses were performed. No problems were encountered during the anastomoses, and no leakage occurred in any of the patients. Thus, we conclude that DST is a safe and easy technique for performing esophageal anastomosis, especially intrathoracic or intramediastinal anastomoses.

Anastomosis, Surgical↗
PubMed1995

Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes.

The interaction of mucosal lymphocytes and intestinal epithelial cells is thought to be important in regulating immune response in the intestinal mucosa, but conclusive evidence is limited. Here we demonstrate the expression of IL-7 mRNA in human intestinal mucosa by combined reverse transcription PCR and Southern blot hybridization. Immunohistochemistry and in situ hybridization confirm the presence of IL-7 in intestinal epithelial cells, especially in epithelial goblet cells. Moreover, IL-7 receptor expression in mucosal lymphocytes is demonstrated by immunohistochemistry and in situ hybridization, as well as by Southern blot and flow cytometric analysis of freshly isolated lamina propria lymphocytes. In contrast, IL-7 receptor could not be detected in the cell surface of freshly isolated PBLs. The functional activity of IL-7 receptor is demonstrated by the utility of recombinant IL-7 to stimulate the growth of lamina propria lymphocytes, and conversely inhibit CD3-dependent proliferation of these cells. In contrast, IL-7 caused no significant increase in DNA synthesis and cell numbers when added to PBLs. These findings suggest that human intestinal epithelial cells and epithelial goblet cells produce IL-7, and locally produced IL-7 may serve as a potent regulatory factor for intestinal mucosal lymphocytes.

Adult↗
PubMed1995

Immunosuppressive agents in the treatment of Crohn's disease and ulcerative colitis.

Low doses of 6-mercaptopurine (6MP) were used for the treatment of inflammatory bowel disease, and 20-30 mg/day was found to be effective for patients with ulcerative colitis who were corticosteroid-dependent or corticosteroid-resistant. Corticosteroid was tapered in 20 of 21 patients with ulcerative colitis. Of 15 patients who were refractory to conventional therapy, 11 responded to 6MP treatment. The same doses of 6MP were given to patients with Crohn's disease who were corticosteroid-dependent or who had associated fistula. Treatment with 6MP did not influence the changes in colonic or ileac lesions in Crohn's disease. However, the fistulas were closed or improved in 70% of 10 patients by 6MP treatment. The adverse effects of small doses of 6MP were minimal. These results confirm that immunosuppressive agents are effective for patients with inflammatory bowel disease. In a rat colitis model induced by immunization with trinitrobenzene (TNB), we used anti-CD4 monoclonal antibodies to prevent colonic inflammation; these antibodies were effective for this colitis model, suggesting that a novel therapy targeting CD4 intestinal lymphocytes may be feasible in the treatment of Crohn's disease.

Animals↗
PubMed1994

Enzyme linked immunosorbent assay (ELISA) and immunoprecipitation studies on anti-goblet cell antibody using a mucin producing cell line in patients with inflammatory bowel disease.

Circulating anti-goblet cell antibody and its corresponding antigen in patients with inflammatory bowel disease were investigated. Anti-goblet cell antibody in the serum was examined by immunocytochemistry and enzyme linked immunosorbent assay (ELISA), using a colonic cancer cell line, HT29-18-N2, which differentiates into intestinal goblet cells. The frequencies of anti-goblet cell antibody detected by immunocytochemistry were 14 in 48 patients with ulcerative colitis (29%) and five in 15 patients with Crohn's disease (33%). By ELISA, the frequencies of anti-goblet cell antibody were 38% in ulcerative colitis and 33% in Crohn's disease. This antibody did not relate directly to anti-neutrophil cytoplasmic antibodies (ANCA), although the serum samples positive for anti-goblet cell antibody were commonly positive for ANCA in ulcerative colitis. Immunoprecipitation and SDS polyacrylamide gel electrophoresis (PAGE) study showed that the antibody in the ELISA positive serum samples recognised a > 200 kD goblet cell antigen, which remained unchanged after reduction, indicating that it consists of single chain polypeptides. These results suggest that there is a subgroup of inflammatory bowel disease that has circulating anti-goblet cell antibody reactive with a > 200 kD antigen. The antibody detected by newly established ELISA will be a disease marker for this group and the identification of the corresponding antigens may be important for the understanding of the underlying immune abnormalities.

Adolescent↗
PubMed1993

Carcinoembryonic antigen mediates in vitro cell aggregation induced by interferon-gamma in a human colon cancer cell line: requirement for active metabolism and intact cytoskeleton.

The homotypic cell aggregation of a carcinoembryonic antigen (CEA) positive colon cancer cell line (Colo 205) was induced in vitro by interferon-gamma (IFN-gamma) treatment. Divalent cations were required for this aggregation, as it was inhibited by EDTA. The partial inhibition by cytochalasin B and the complete inhibition by a mixture of sodium azide and 2-deoxyglucose suggests that the aggregation requires the integrity of cytoskeleton and active metabolism. The expression of CEA was increased in the cytoplasm and on the membrane of Colo 205 by IFN-gamma treatment. Furthermore, this aggregation was inhibited completely by anti-CEA monoclonal antibody (mAb) and partially by mAb against intercellular adhesion molecule-1. This in vitro study suggests that CEA molecule participates in the IFN-gamma induced homotypic adhesion of some CEA positive cancer cells and that IFN-gamma has an important role in the regulation of cell-cell interaction mediated by CEA molecule.

Antibodies, Monoclonal↗
PubMed1993

Use of adenosine (5')polyphospho(5')pyridoxals to study the substrate-binding region of glutathione synthetase from Escherichia coli B.

Adenosine(5')polyphospho(5')pyridoxals (APn-PLs, n = 2, 3, 4) were examined for affinity labeling of glutathione synthetase (EC 6.3.2.3) from Escherichia coli B. When the enzyme was incubated with an APn-PL or pyridoxal phosphate in the presence of Mg2+ and then reduced with sodium borohydride, it was most rapidly inactivated by AP4-PL. AP4-PL had a high affinity to the enzyme. The dissociation constant of AP4-PL in the inactivation process was 23 microM. The enzyme was almost completely protected from inactivation by addition of either ATP or gamma-glutamylcysteine. Complete inactivation corresponded to the incorporation of 1 mol of AP4-PL/mol of subunit of the tetrameric enzyme. Proteolytic digestion and sequence analysis of the AP4-PL-labeled enzyme revealed that only Lys-18 was modified. In contrast, the less efficient AP3-PL was found attached to Lys-17, Lys-18, Lys-144, and Lys-148. In the three-dimensional structure of the enzyme, Lys-18 is located close to the putative gamma-glutamylcysteine-binding site, but Lys-17, Lys-144, and Lys-148 are in the mouth of the inner-solvent region, at the bottom of which is the active-site cleft. Furthermore, difference Fourier analysis with the AP4-PL-soaked crystal of the enzyme showed that the adenosine moiety of the bound AP4-PL was in the crevice, which is the ATP-binding site of the enzyme. These results demonstrate the bivalent binding of AP4-PL lying across the gamma-glutamylcysteine- and ATP-binding sites.

Adenine Nucleotides↗