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K Inui

Publications and source records attributed to K Inui.

At least 145 records · Page 8Linked to original sources
PubMed1998

Pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure elevation.

OBJECTIVE: To characterize the pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure (IOP) elevation and to provide individual patients with the optimal dosage regimen for this drug. METHODS: We studied 17 patients with transient IOP elevation, who were given 62.5-500 mg acetazolamide orally as single or repetitive doses. Plasma acetazolamide concentration and IOP were measured at approximately 1, 3, 5, and 9 h after the last acetazolamide administration. Pharmacokinetics and pharmacodynamics were analyzed by nonlinear mixed-effect modeling using the program NONMEM. RESULTS: The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption. The apparent oral clearance was related to the creatine clearance (CCR) which was estimated by the Cockcroft and Gault equation, as follows: 0.0468 x CCR1 x h(-1). The estimated apparent oral volume of distribution, first-order absorption rate constant, and absorption lag time were 0.231 l x kg(-1), 0.821 x h(-1), and 0.497 h, respectively. IOP after oral acetazolamide administration was characterized by an Emax model. The maximal effect in lowering the IOP (Emax) was 7.2 mmHg, and the concentration corresponding to 50% of the maximal effect (EC50) was 1.64 microg x ml(-1). As 70% of Emax was achieved at a plasma concentration of 4 microg x ml(-1), this concentration was considered satisfactory for lowering IOP. The recommended dosage was calculated so that the minimum plasma concentration at steady state exceeded this target concentration; 250 mg t.i.d., 125 mg t.i.d., 125 mg b.i.d., and 125 mg once daily for the patients with CCR values of 70, 50, 30, and 10 ml min(-1), respectively. CONCLUSION: Measuring plasma concentrations of acetazolamide and subsequent pharmacokinetic and pharmacodynamic analyses are useful for estimating its concentration-dependent effectiveness in lowering the IOP in individual patients. The dosage regimen presented in this study is expected to improve the benefits of acetazolamide pharmacotherapy in most elderly patients with transient rises in IOP following intraocular surgery.

Acetazolamide↗
PubMed1998

Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein.

We present a digoxin-clarithromycin interaction in two patients in whom digoxin concentrations were unexpectedly increased. The ratio of renal digoxin clearance to creatinine clearance in one patient was lower during the concomitant administration of clarithromycin (0.64 and 0.73) than that after cessation of clarithromycin administration (1.30 +/- 0.20; mean +/- SD). Because P-glycoprotein could play an important role in the renal secretion of digoxin, we hypothesized that clarithromycin decreases renal digoxin excretion by inhibiting P-glycoprotein-mediated transport. Digoxin transport was evaluated with use of a kidney epithelial cell line, which expresses the human P-glycoprotein on the apical membrane by transfection with MDR1 complementary deoxyribonucleic acid. Clarithromycin inhibited the transcellular transport of digoxin from the basolateral to the apical side in a concentration-dependent manner and concomitantly increased the cellular accumulation of digoxin. These results suggest that clarithromycin may inhibit the P-glycoprotein-mediated tubular secretion of digoxin, and this interaction mechanism may contribute to an increase in the serum digoxin concentration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Mutational analyses in four Japanese families with X-linked liver phosphorylase kinase deficiency type 1.

We analysed the gene of the human alpha-subunit of liver phosphorylase kinase (PHKA2) in four Japanese families with X-linked liver phosphorylase kinase deficiency type 1 by RT-PCR followed by PCR-single-strand conformation polymorphism and direct DNA sequencing. In this study, two novel mutations (Y116D and 2675A-->G) and one mutation previously reported (P1205L) were identified, revealing molecular heterogeneity in Japanese patients. Considering the dissimilarity in phenotype among our patients even with an identical mutation in the PHKA2 gene, it seems that each genetic deficiency in this gene may not be the only factor to determine the clinical heterogeneity in this disease.

Base Sequence↗
PubMed1998

Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats.

PURPOSE: Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. METHODS: Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. RESULTS: The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively. indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. CONCLUSIONS: The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Enhanced response of growth hormone to growth hormone-releasing hormone and a decreased content of hypothalamic somatostatin in a stress-induced rat model of depression.

This study was designed to evaluate changes in the hypothalamic somatostatin-growth hormone axis (SRIF-GH axis) in a stress-induced rat model of depression. We exposed male Wistar rats to intermittent walking stress for two weeks, and then measured their spontaneous running activities for 12 days. We divided the rats into the depression-model group and the partial recovery group according to their spontaneous running activities after the termination of exposure to stress. We examined the secretion of GH from the anterior pituitary by injecting human GH-releasing hormone (hGHRH) with intracardiac cannulae or by applying hGHRH or SRIF to isolated anterior pituitaries using a perifusion system. We also determined SRIF content in the stalk-median eminence (SME) and the plasma concentration of GH. In the depression-model group, intracardiac administration of hGHRH caused the enhanced release of GH into plasma, while application of hGHRH or SRIF to the anterior pituitary in vitro had similar effects on GH release in the control and partial recovery groups. Furthermore, the SRIF content was decreased in the SME and the GH concentration was increased in plasma. The partial recovery group gave similar values to the control group. The enhanced response of GH to hGHRH in the depression-model group might have been caused by the reduced content of SRIF in the SME in view of the unchanged response of GH to the infusion of hGHRH or SRIF in the perifusion system.

Animals↗
PubMed1998

Aprotinin reduces the expression of p-selectin on the surface of platelet and leukocyte-platelet conjugates.

P-Selectin, an adhesion molecule expressed on the surfaces of activated platelets and the vascular endothelium, mediates platelet binding to monocytes and neutrophils. Monocytes and neutrophils produce superoxide anion by activated platelets through p-selectin. Aprotinin, a serine protease inhibitor, inhibits plasmin to activate platelets during cardiopulmonary bypass (CPB). A total of 25 patients were studied to clarify the effects of aprotinin on p-selectin expression during CPB. Nine patients were not given aprotinin (control group), and 16 were given aprotinin of 2 million U in the priming solution (aprotinin group). The platelet count and soluble p-selectin in the plasma, p-selectin on the surface membranes of platelets, and leukocyte-platelet conjugate levels were measured during and after CPB. The platelet count was maintained well in the aprotinin group. The increases of soluble p-selectin in the plasma, platelet surface p-selectin, and leukocyte-platelet conjugates were less in the aprotinin group than in the control group (p < 0.05). In conclusion, aprotinin in patients undergoing CPB may reduce the early inflammatory reactions induced by p-selectin.

Aprotinin↗
PubMed1998

Endoscopic MRI.

We used a new magnetic resonance endoscope with a small radiofrequent (RF) coil attached to the tip. After insertion of the instrument into the second portion of the duodenum, patients were placed in a magnetic resonance imaging (MRI) scanner. Fast spoiled gradient-recalled acquisition (SPGR) pulse sequences were used for this method. After plain scans, six axial scans were performed after intravenous injection of 20 ml of gadolinium-diethylenetriaminepentaacetic acid (DTPA) contrast medium. We performed endo-MRI on 22 patients, 13 with pancreatic carcinoma, four with pancreatic cystoadenoma, and five with other diseases. In the patients with pancreatic carcinoma, tumors were delineated as low-intensity masses after injection of contrast medium. Dilated main pancreatic ducts were clearly defined. In eight patients with carcinoma of the head of the pancreas, tumors were clearly defined in seven (87.5%) cases. In the eighth case, motion artifact prevented acquisition of a clear image of the pancreas. For diagnosis of invasion of the portal vein, the sensitivity of endo-MRI was 80%, the specificity was 100%, and overall accuracy was 87.5%. The new technique of endo-MRI allows the precise diagnosis of pancreatic tumors.

Carcinoma↗
PubMed1998

Ruptured aneurysm of the ductus diverticulum into the pulmonary artery in a man: a successful repair.

Aneurysm of the ductus diverticulum in the adult is rare and its rupture is fatal. A 75-year-old man presented with congestive heart failure that suddenly occurred with a continuous murmur. Angiography showed a left-to-right shunt through a large thrombosed aneurysm of the ductus diverticulum (6 cm), and the pulmonary-to-systemic flow ratio was 2.6. Patch closure of the orifice (3x4 cm) of the aneurysm and repair of the perforated pulmonary artery were done emergently under hypothermic cardiopulmonary bypass with selective cerebral perfusion. He recovered uneventfully. Early recognition and early intervention should be indicated in this otherwise fatal condition.

Aged↗
PubMed1998

EEG findings in diabetic patients with and without retinopathy.

OBJECTIVES: We showed previously that temporal low-voltage irregular delta waves (TLID) on EEG are indicative of cerebrovascular dysfunction in its early stages. The present study was designed to determine whether the incidence of this finding is elevated in diabetics as compared to normal controls. METHODS: EEGs of 50 diabetics and 50 normal controls were examined. Relationships of blood sugar levels, levels of HbA1C and stages of diabetic retinopathy to TLID were also examined. RESULTS: TLID was found in 56% of EEGs of the diabetics and in 14% of EEGs of the controls (P < 0.0001). The occurrence of TLID was also associated with the presence of diabetic retinopathy. CONCLUSIONS: Our results suggest that the incidence of cerebrovascular dysfunction is elevated in diabetics. Since TLID was associated with diabetic retinopathy, it seems possible that the TLID detected in diabetics might reflect certain functional changes induced by microangiopathy of the brain.

Adult↗
PubMed1998

Mesangial proliferative nephritis in man is associated with increased expression of the cell survival factor, Bcl-2.

Although most studies suggest that the hypercellularity in mesangial proliferative nephritis is due to increased cell proliferation, we hypothesized that it may also be due to increased expression of survival factors that may block their removal (apoptosis). We therefore studied the expression of apoptosis preventing/delaying the bcl-2 gene product in the glomerulus with various human glomerulonephritides. Immunohistochemistry for Bcl-2, proliferating cell associated protein (Ki-67) and alpha-smooth muscle actin (alpha-SMA) was performed on 55 biopsied kidney tissues: 6 cases of orthostatic proteinuria as a control (OP); 6 cases of diffuse proliferative lupus nephritis (WHO type IV, LN-MPGN); 24 cases of IgA nephropathy (IgA); 9 cases of minimal change nephrosis and 10 cases of idiopathic membranous nephropathy. The number of Ki-67-positive cells and the expression of alpha-SMA in the glomerulus were significantly higher in LN-MPGN and IgA. There was a significant positive correlation between glomerular Bcl-2 expression and glomerular cell proliferation evaluated by the number of Ki-67-positive cells (r=0.605, p < 0.01) or glomerular alpha-SMA expression (r=0.674, p < 0.01). Glomerular expression of Bcl-2 in IgA or LN-MPGN was significantly higher than that in OP (p < 0.01 and p < 0.05 vs. OP, respectively). The Bcl-2-positive cells were present in mesangial locations and demonstrated a perinuclear pattern. These results suggest that maintenance of glomerular hypercellularity in human glomerular diseases is partly due to the prevention of mesangial cell death via Bcl-2 expression.

Actins↗
PubMed1998

Hepatic extraction of tacrolimus in rats with experimental liver diseases.

Tacrolimus, an immunosuppressive agent, is metabolized mainly in the liver and has shown large intra- and interindividual pharmacokinetic variability. We investigated the effect of liver dysfunctions on the pharmacokinetics of tacrolimus in rats with experimental liver diseases. Experimental hepatic failure was induced by CCl4-treatment or bile duct ligation. Tacrolimus (1 or 0.3 mg/kg) was administered intravenously or intraportally to the rats (n = 5-6 per group), and blood samples were collected over a 240-min period. The tacrolimus concentrations in the blood were then measured by a high-performance liquid chromatography-enzyme immunoassay. In the normal rats, the hepatic extraction ratio of tacrolimus (EH) was dose-independent, ranging from 0.556-0.598 at 0.3 and 1.0 mg/kg doses. The EH were dose-dependent in the CCl4-treated rats and in the bile duct-ligated rats: the EH at 1.0 mg/kg dose were 0.158-0.170 and those at 0.3 mg/kg dose were 0.329-0.394. The intermediate EH of tacrolimus suggested that the clearance of tacrolimus depends not only on hepatic intrinsic clearance but also on hepatic blood flow. The present pharmacokinetic study also suggested that the decrease of EH and the dose-dependence of EH contribute to the elevation of blood tacrolimus concentrations and to the large variability in the pharmacokinetics of tacrolimus after oral administration in hepatic dysfunctions.

Animals↗
PubMed1998

Simvastatin suppresses glomerular cell proliferation and macrophage infiltration in rats with mesangial proliferative nephritis.

Inhibition of 3-hydro-3-methylglutaryl coenzyme A reductase inhibits the production of mevalonate and has been shown to suppress proliferation in many cell types. Therefore, 3-hydro-3-methylglutaryl coenzyme A reductase inhibitors may have a beneficial effect in glomerular disease, because glomerular cell proliferation is a central feature in the active glomerular injury. This study examines the effect of simvastatin on glomerular pathology in a rat mesangial proliferative glomerulonephritis (GN) induced by anti-thymocyte antibody (anti-Thy 1.1 GN). There was no difference in the degree of the antibody and complement-mediated initial injuries between simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell proliferation. The proliferative activity was maximal at day 4 after disease induction (26.5+/-7.0 of proliferating cell nuclear antigen-positive cells/glomerulus); however, approximately 70% of proliferation was suppressed by simvastatin treatment. At day 4 after disease induction, simvastatin administration also decreased alpha-smooth muscle actin expression in the glomerulus, which is a marker for mesangial cell activation. Inhibition of monocyte/macrophage recruitment into glomeruli by simvastatin was also a prominent feature. There was a 30% decrease in the number of glomerular ED-1+ cells by simvastatin treatment at day 2 after disease induction. Furthermore, simvastatin remarkably suppressed subsequent mesangial matrix expansion and type IV collagen accumulation in glomeruli. We also found that the platelet-derived growth factor expression was reduced in simvastatin-treated nephritic rats, which might simply reflect the reduction in mesangial cell proliferation and mesangial cellularity. There was no significant difference in plasma cholesterol or triglyceride levels between simvastatin- and vehicle-treated nephritic rats at day 2 and day 4, which corresponded to the times when simvastatin treatment resulted in a reduction in mesangial cell proliferation. In conclusion, this is the first report to find that mesangial cell proliferation and matrix expansion have been blocked by simvastatin in vivo. The protective effect of simvastatin in the matrix expansion in anti-Thy1.1 GN was partly by inhibition of mesangial cell proliferation and monocyte/ macrophage recruitment into glomeruli, which were independent of a change in circulating lipids.

Actins↗
PubMed1998

Aortic valve replacement through the transected aorta in a patient with aortic stenosis and a calcified ascending aorta.

This report describes a surgical approach of aortic valve replacement in a patient with a calcified ascending aorta, calcified aortic valve stenosis and coronary artery disease. The aortic valve was replaced with a 19 mm St. Jude Medical prosthetic valve through the transected aorta while the distal ascending aorta was cross-clamped at a narrow but not calcified band approximately 4.5 cm distal to the aortic anulus. These procedures were successfully done and no neurological deficit was found after surgery. The aortic valve replacement through the transected aorta may be one of the alternatives in selected patients with porcelain aortas and calcified aortic valves.

Aged↗
PubMed1998

Efflux of intracellular alpha-ketoglutarate via p-aminohippurate/dicarboxylate exchange in OK kidney epithelial cells.

The involvement of intracellular alpha-ketoglutarate (alpha-KG) in p-aminohippurate (PAH) transport was investigated in OK kidney epithelial cells. Efflux of intracellular alpha-KG from the OK cells to the basolateral side was increased by applying PAH to the basolateral side of the cells. In contrast, the intracellular alpha-KG concentration was not influenced by the addition of PAH. The alpha-KG efflux across the basolateral membrane induced by PAH was higher than that across the apical membrane. Probenecid inhibited the PAH-dependent alpha-KG efflux. The alpha-KG efflux to the basolateral side was saturable with increasing concentration of PAH in the basolateral medium. Antimycin A, a metabolic inhibitor, inhibited [14C]PAH uptake across the basolateral membrane of OK cells in a dose-dependent manner. In addition, both the alpha-KG efflux induced by PAH and the intracellular alpha-KG concentration were decreased by antimycin A dose-dependently. These results directly show that alpha-KG generated by intracellular metabolism is effluxed via PAH/dicarboxylate exchange in the basolateral membrane of OK cells.

Antimycin A↗