Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 127 records · Page 7Linked to original sources

PubMed1998

Pharmacokinetics of CPT-11 in rhesus monkeys.

PURPOSE: To examine the pharmacokinetic relationships between humans and monkeys, we studied the disposition of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), in rhesus monkeys. METHODS: CPT-11 was administered to a total of six monkeys at doses of 3, 7, 15 and 25 mg/kg by intravenous infusion for 10 min and plasma concentrations and pharmacokinetic parameters of CPT-11 determined. RESULTS: Maximum plasma concentrations at 25 mg/kg reached around 10000 ng/ml, and dropped to 500 ng/ml in 8 h. Plasma concentrations of SN-38 remained between 2 and 10 ng/ml. Mean values of systemic clearance, mean residence time and distribution volume at steady state, the major pharmacokinetic parameters for CPT-11, were 13.3 (ml/min per kg), 192 (min) and 2553 (ml/kg), respectively. The initial plasma concentration ratio of lactone to total CPT-11, 76%, declined to about 20% within 75 min, and the final ratio was about 40% at 8 h; the initial ratio of SN-38 was 72%, dropped to 34% within 70 min and finally recovered to 55% at 8 h. CONCLUSION: Comparison with human data revealed that systemic clearances of CPT-11 and the maximum AUC of SN-38 were not as different between humans and monkeys as between humans and mice, but the metabolic conversion of CPT-11 into SN-38 in monkeys was significantly lower than in humans.

Animals↗

PubMed1998

Isolated right ventricular hypoplasia: intraoperative balloon occlusion test.

A 42-year-old woman with isolated right ventricular hypoplasia underwent operation. To determine the optimal procedure, we temporarily occluded the atrial septal defect with a balloon catheter that was introduced through the right atrial appendage. The hemodynamics were stable throughout the occlusion test. Simple closure of the atrial septal defect was safely accomplished. Intraoperative occlusion test with the balloon catheter was a good alternative to preoperative occlusion test.

Adult↗

PubMed1998

Mitochondrial function in Babesia microti and Babesia rodhaini.

The role of mitochondria in the energy metabolism of Babesia microti and Babesia rodhaini was investigated. A variety of mitochondrial inhibitors showed greater sensitivity to B. microti than to B. rodhaini. Additionally, alpha-glycerophosphate- and succinate-cytochrome c reductase activities in the crude mitochondrial fraction from B. microti were substantially higher than those from B. rodhaini. Our results suggest that the mitochondria of these parasites possess a series of "classical" apparati for energy production and their relative functional role may be quantitatively greater in B. microti when compared with B. rodhaini.

ATP Synthetase Complexes↗

PubMed1998

Increased night:day blood pressure ratio in microalbuminuric normotensive NIDDM subjects.

OBJECTIVE: To determine the relationship of day- and night-time blood pressure (BP) with the degree of albuminuria in subjects with non-insulin-dependent diabetes (NIDDM). RESEARCH DESIGN AND METHODS: BP was determined hourly for 24 h in 27 NIDDM normotensive patients, and 10 age- and BMI-matched controls. Diabetic subjects were separated into normo- and microalbuminuric groups according to the urinary albumin excretion rate (AER < 15 and > or = 15 micrograms/min), respectively. RESULTS: Non-dippers defined by a nocturnal fall in BP of less then 10/5 mmHg represented 68.8% of the normo- and 81.8% of the microalbuminuric patients. Microalbuminuric diabetics demonstrated a significantly higher ratio of night:day BP in comparison to controls, but not to normoalbuminuric diabetics. AER was significantly correlated with BP ratio in the normoalbuminuric, but not in microalbuminuric group. CONCLUSIONS: Ambulatory 24-h BP monitoring is useful to find blunted nocturnal fall in BP even in normotensive NIDDM subjects with or without microalbuminuria. However, whether or not an increase in the night-time BP and/or the night:day ratio in NIDDM patients plays a pathogenetic role in the progression of diabetic nephropathy remains to be clarified.

Albuminuria↗

PubMed1998

Effects of administration of monoclonal antibodies (anti-CD4 or anti-CD8) on the development of autoimmune diseases in (NZW x BXSB)F1 mice.

(NZW x BXSB)F1 (W/BF1) mice spontaneously develop autoimmune diseases, characterized by lymphadenopathy, lupus nephritis, and immune thrombocytopenia associated with various autoantibodies such as anti-DNA, anti-platelet and anti-cardiolipin antibodies (Abs). In the present study, we investigate the effects of administration of monoclonal Abs (anti-CD4 or anti-CD8 mAb) on the development of autoimmune diseases in W/BF1 mice. MAb was administered from the age of 7 weeks. Prolongation of survival rate and reduction of severity of autoimmune diseases were observed after treatment with anti-CD4 mAb. However, anti-CD8 mAb treatment accelerated the diseases. Serum levels of IFN-gamma and IL-10 in old W/BF1 mice were significantly high, whereas IL-4 levels were low in comparison with those of young W/BF1 mice; the expression of mRNA of IFN-gamma, IL-4 or IL-10 in CD4+ T cells of old W/BF1 mice was parallel to the serum levels of each cytokine. These observations suggest that CD4+ cells are involved in the development of autoimmune diseases in W/BF1 mice, and that CD8+ cells have a suppressive effect on the development of autoimmune diseases in W/BF1 mice.

Age Factors↗

PubMed1998

Induction of immune-mediated hearing loss in SCID mice by injection of MRL/lpr mouse spleen cells.

Induction of immune-mediated hearing loss in SCID mice by injection of MRL/lpr mouse spleen cells The MRL/lpr mouse, which has a mutation in the Fas gene encoding a cell-surface receptor for apoptosis, shows an accumulation of abnormal immunocompetent cells and SLE-like disease. It has recently been reported that this mouse also manifests sensorineural hearing loss (SHL) with cochlear pathology at 20 weeks of age. We examined the effects of injecting MRL/lpr spleen cells on the development of SHL in severe combined immunodeficient (SCID) mice, which originally develop neither SHL nor cochlear pathology. Immune-mediated SHL and cochlear pathology were, indeed, transferred to the SCID mice by the injection of spleen cells from the MRL/lpr mice. These findings suggest that cell-mediated immunity is involved in the development of SHL and cochlear pathology.

Animals↗

PubMed1998

Role of medial smooth muscle cell function in antithrombogenicity of vein grafts.

OBJECTIVES: To determine the significance of prostaglandin I2 (PGI2) production by medial smooth muscle cells (SMCs), we assessed PGI2 production from denuded vein grafts and their antithrombogenicity. MATERIALS AND METHODS: A total of 30 dogs were divided into two groups: in group I, 14 dogs (27 veins, 188 segments) were used to assay PGI2 production, which was measured as 6-keto-PGF1 alpha. In group II, 16 dogs were used for an implantation study and the thrombus-free surface (TFS) score was calculated 24 h after implantation. Both groups contained the following subgroups: subgroup A, freshly harvested veins; subgroup B, endothelial denuded veins; subgroup C, veins frozen and cryopreserved; subgroup D, veins treated with protease. RESULTS: Values of 6-keto-PGF1 alpha (pg/mg/min) for basal and stimulated states in subgroup I-A through I-D were 58.0 +/- 8.9 and 530.6 +/- 74.7, 26.3 +/- 4.7 and 82.3 +/- 11.4, 17.9 +/- 1.3 and 39.4 +/- 3.3, and 13.3 +/- 1.8 and 32.2 +/- 6.2, respectively. The PGI2 production in subgroup I-A were significantly higher than those in the other three subgroups (p < 0.01 for basal and stimulated), while the production in subgroup I-B was also significantly higher than those in the remaining two (p < 0.05 for basal and stimulated). The TFS scores in subgroup II-A through II-D were 98 +/- 2%, 90 +/- 2%, 38 +/- 5%, and 15 +/- 7%, respectively, showing significantly superior antithrombogenicity in subgroup II-B, as well as in II-A, when compared with the remaining two (p = 0.014). CONCLUSION: The amount of PGI2 generated by the medial SMCs may be sufficient for maintaining the antithrombogenicity of the endothelial denuded AVGs.

Animals↗

PubMed1998

Growth-inhibitory effect of a high glucose concentration on osteoblast-like cells.

Impaired bone formation resulting from a decline of osteoblast activity has been implicated in the pathogenesis of diabetic osteopenia. We examined the effects of high glucose concentration alone, independent of insulin deficiency, on the growth of a human osteoblast-like cell line (MG-63). Sustained exposure to high glucose for 7 days inhibited cell growth in a concentration-dependent manner up to 49.5 mmol/L, as compared with cells cultured with a normal glucose concentration (5.5 mmol/L) or a high mannitol concentration (an iso-osmolar control). Glucose (49.5 mmol/L) attenuated the increment either in DNA content or in [3H]thymidine incorporation induced by insulin-like growth factor I (IGF-I). The IGF-I-induced increase of ornithine decarboxylase (ODC) activity, which plays an important role in cell growth, was also attenuated. The half-life of ODC protein was not shortened by the high glucose culture, but the intracellular content of putrescine (an end product of ODC) was significantly decreased. These changes did not occur in the high mannitol culture, strongly suggesting a specific effect of glucose. In summary, our observations suggest that a high glucose concentration significantly impairs the proliferative response of osteoblastic cells to IGF-I and that the defective cell function caused by sustained exposure to high glucose levels might contribute to impaired bone formation in patients with diabetic osteopenia.

Acetyltransferases↗

PubMed1998

Lymphoblastoid interferon-alpha downregulates parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor expression in human osteoblastic cells (Saos-2).

Interferon-alpha (IFN-alpha) is a pleiotropic cytokine that modulates the cellular functions of both osteoblastic and osteoclastic lineages. It remains unclear whether IFN-alpha regulates the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor, which is a major target molecule regulating skeletal metabolism. In this study, we examined the effect of IFN-alpha on the expression of PTH/PTHrP receptor in human osteoblastic cells (Saos-2). IFN-alpha inhibited the expression of PTH/PTHrP receptor gene in both a time- and dose-dependent manner. The mRNA level was decreased to 61.1% of that of the untreated control by 48 h treatment with 6000 U/mL of IFN-alpha. IFN-alpha also decreased cAMP response to PTH(1-34) in a dose-dependent manner and significantly depressed expression of the receptor protein. However, IFN-alpha did not exert any effect on other osteoblastic markers, such as alkaline phosphatase (ALP) activity, cAMP response to prostaglandin E2 (PGE2), and secretion of bone gla-protein (BGP) and bone sialoprotein (BSP). Finally, IFN-alpha decreased PTH/PTHrP receptor mRNA to 60.7% that of control in the presence of actinomycin D. These data suggest that IFN-alpha downregulates the expression of PTH/PTHrP receptor and its signaling without affecting other osteoblastic markers, and that IFN-alpha regulates its gene expression mainly by decreasing the stability of its mRNA.

Alkaline Phosphatase↗

PubMed1998

Apoptosis of colorectal adenocarcinoma (COLO 201) by tumour necrosis factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma), resulting from down-modulation of Bcl-2 expression.

Fas antigen is constitutively expressed in the normal colon epithelium, but considerably diminished in most colorectal carcinomas. In the present study, we examine the relationship between Fas antigen expression and apoptosis using the colorectal carcinoma cell line COLO 201, on which a low grade of Fas antigen is expressed. Anti-Fas antibody had no effect on the induction of apoptosis of COLO 201. However, TNF-alpha and/or IFN-gamma, independently and additively, up-regulated Fas antigen expression on COLO 201 and induced apoptosis in a dose-dependent manner. Both cytokines also increased the COLO 201 sensitivity to anti-Fas antibody, resulting from the down-modulation of Bcl-2 and the up-regulation of Bax. These findings indicate that cytokine(s) plus anti-Fas antibody (which mimics natural Fas ligand) are more effective in inducing apoptosis of COLO 201 than cytokine(s) alone. These findings suggest that immunotherapy in combination with cytokine(s) and lymphokine-activated killer (LAK) cells will become a more effective therapy for cancer than cytokine(s) or LAK cells alone, since the Fas ligand is expressed on activated T cells, natural killer cells and macrophages.

Adenocarcinoma↗

PubMed1998

Increased sensitivity to long-term 5-fluorouracil exposure of human colon cancer HT-29 cells resistant to short-term exposure.

A 5-fluorouracil (5-FU)-resistant subline of human colon cancer HT-29 cells was developed by repeated 1-h exposure in vitro to 5-FU. This subline (HT-29/5-FU/S) had 8-fold resistance to 5-FU in a 1-h exposure assay. However, it had rather increased sensitivity to 5-FU when assayed after a continuous 96-h exposure to it. Significantly less 5-fluorouridine-5'-triphosphate was produced in the resistant cells, leading to a lower level of 5-FU incorporation into the cellular RNA. The reduced activity of orotate phosphoribosyltransferase might explain these results. In contrast, the HT-29/5-FU/S cells were more sensitive to the inhibition of in situ thymidylate synthase (TS) by 5-FU than were the parent cells. The lower in situ TS activity may have made HT-29/5-FU/S cells more sensitive to TS inhibition by 5-FU as compared with the parent cells. The fact that HT-29/5-FU/S was more resistant to short-term 5-FU exposure but more sensitive to long-term exposure than the parent line confirmed the existence of different modes of action of 5-FU, depending on the exposure time.

Colonic Neoplasms↗

PubMed1998

An autopsy case of fetal Gaucher disease.

BACKGROUND: A case of fetal form of Gaucher disease in a Japanese fetus is presented. RESULTS: A macerated baby showing hydrops fetalis was dissected at 29 weeks of gestation. The fetus was heavier in the body, liver and spleen than a normal fetus at the same gestation period. It also suffered from pericardial effusion and ascites. The diagnosis of Gaucher disease was made by histological and biochemical findings. In microscopical examinations 'Gaucher cells', which were periodic acid-Shiff (PAS)-positive, alcian blue-positive and CD68-positive, existed in the lungs, liver, spleen, thymus, adrenal glands, bone marrow and brain. In thin layer chromatography, a large quantity of glucocerebroside was seen to have accumulated in the patient's organs.

Adult↗

PubMed1998

Mechanisms for 5-fluorouracil resistance in human colon cancer DLD-1 cells.

A 5-fluorouracil (5-FU)-resistant subline, DLD-1/5-FU, was established by repeated 5-d exposures of human colon cancer DLD-1 cells to 5-FU. DLD-1/5-FU cells were 41- and more than 75-fold resistant to 96-h and 1-h exposures to 5-FU, respectively. When exposed to 5-FU, DLD-1/5-FU cells exhibited marked resistance to in situ thymidylate synthase (TS) inhibition by 5-FU as compared to DLD-1 cells, and incorporation of 5-FU into cellular RNA in DLD-1/5-FU cells decreased to 25% of that in DLD-1 cells. As causes of resistance to DNA and RNA-directed actions of 5-FU, remarkable reduction of intracellular levels of both 5-fluorouridine 5'-triphosphate (FUTP) and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) in DLD-1/5-FU cells was confirmed. It was found that activities of uridine kinase, orotate phosphoribosyltransferase and thymidine kinase of DLD-1/5-FU cells were significantly lower than those of the parent cells. Intracellular levels of TS were similar between the two cell lines. These results indicated that the mechanism of resistance to 5-FU in DLD-1/5-FU cells involves reduced enzymatic activation of 5-FU.

Antimetabolites, Antineoplastic↗

PubMed1998

Proline, leucine, and alanine transport in placental microvillous membrane vesicles prepared from late gestational rats.

To characterize the active transport of amino acids across the placenta, uptakes of proline, leucine, and alanine were kinetically examined in placental microvillous membrane vesicles (PMV) prepared from rats in the late gestational period. Uptake rates of these amino acids in PMV showed saturable hyperbolic curves that obeyed Michaelis-Menten kinetics. Proline, leucine, and alanine transport were demonstrated to be carrier mediated systems with sodium-dependent, -independent, and both manner, respectively. In addition, sodium-dependent L-alanine transport showed two different systems, and new sodium-independent alanine transport system (K(m) of 1.12 mM) was observed in rat placenta. From these results, rat placenta has carrier mediated amino acid transport systems, and possesses at least three different transport systems for alanine.

Alanine↗

PubMed1998

Temporal and spatial distribution of alkaline phosphatase activity in male hypogonadic rat (hgn/hgn) testis during postnatal development.

In male hypogonadic mutant rat (hgn/hgn), gonocytes degenerate and peritubular cells form multiple layers around seminiferous tubules during early postnatal testicular development. Alkaline phosphatase (AP) activity has been used as not only a tracer for the primordial germ cells (PGCs) but also a histochemical marker for the peritubular myoid cells. In the present study, we examined the localization of AP activity during the postnatal testicular development in the hgn/hgn and phenotypically normal (+/+ or +/hgn) rat. In the normal testis, high AP activity was located in the surface of the PGCs on 3 days of age. As the PGCs differentiated into spermatogonia, the AP activity drastically decreased in intensity on 7 days and was completely lost by 12 days. In the hgn/hgn, the PGCs showing high AP activity occupied the inside of dilated seminiferous tubules on 3 and 7 days of age. The luminal AP activity declined gradually by 18 days and disappeared on 21 days, when the germ cells completely degenerated in the hgn/hgn testis. In the normal, high AP activity emerged in a layer of the peritubular cells surrounding the tubules on 7 days and afterwards, indicating that the peritubular cells were differentiating into myoid cells. In the hgn/hgn, the peritubular cells formed multiple layers around the tubules and showed weak AP activity on 3 to 18 days of age. On 21 days of age, high AP activity emerged in a single layer of the peritubular cells directly attached to the basement membrane in the hgn/hgn. These results indicate that the PGCs showing AP activity kept remained at later stage in the hgn/ hgn and that the single layer of mature myoid cells showing high AP activity appeared much later in the hgn/hgn testis than in normal.

Aging↗

PubMed1998

Stiffness indexes beta of the common carotid and femoral arteries are associated with insulin resistance in NIDDM.

OBJECTIVE: To investigate the association between arterial wall stiffness indexes beta of the common carotid artery (CCA) and the femoral artery (FA) and insulin resistance in NIDDM subjects in a cross-sectional study. RESEARCH DESIGN AND METHODS: We evaluated the arterial stiffness indexes beta of CCA and FA using an ultrasonic phase-locked echo-tracking system in 60 NIDDM subjects attending the diabetes center in Osaka City University Hospital, compared with 120 age- and sex-matched control subjects. Insulin sensitivity indexes were evaluated using a euglycemic-hyperinsulinemic clamp. RESULTS: Stiffness indexes beta of both CCA and FA were significantly higher in NIDDM subjects than in control subjects (CCA 18.1 +/- 0.9 vs. 11.7 +/- 0.3, respectively, P < 0.001; FA 35.7 +/- 2.3 vs. 23.7 +/- 0.8, respectively, P < 0.001). The mean insulin sensitivity index in NIDDM subjects was 4.69 +/- 0.29 mg.kg-1.min-1.mU-1.l. The stiffness indexes beta of both CCA and FA were inversely correlated with insulin sensitivity indexes (CCA r = -0.393, P = 0.002; FA r = -0.329, P = 0.010), as well as with age, duration of diabetes, and mean blood pressure. In stepwise multiple regression analyses, insulin sensitivity index and duration of diabetes were identified as significant independent variables for stiffness indexes beta in both CCA and FA (CCA R2 = 0.249, P = 0.0003; FA R2 = 0.336, P < 0.001). CONCLUSIONS: Arterial stiffness indexes beta of CCA and FA were associated with insulin resistance in NIDDM subjects.

Adult↗

PubMed1998

Sympathetic function test of vasoconstrictor changes in foot arteries in diabetic patients.

OBJECTIVE: We studied the relationship between vasoconstrictor changes in foot arteries (pedal, metatarsal, and digital arteries) and autonomic neuropathy in diabetic patients to estimate the degrees of sympathetic dysfunction. RESEARCH DESIGN AND METHODS: Sixty-two patients and nineteen age-matched control subjects were studied. The resistance index (RI) and pulsatility index (PI) were measured as vascular hemodynamic parameters using Doppler sonography, and the increases in these hemodynamic parameters (%RI and %PI) from rest to a deep breath were measured as indexes of the degrees of sympathetic vasoconstrictor function. Cardiovascular autonomic function tests (AFTs) were performed and the score was compared to %RI and %PI values obtained. RESULTS: Of the 62 diabetic patients, 51 had various degrees of autonomic neuropathy. Both %RI and %PI in the diabetic patients were significantly less than those in the control subjects for all foot arteries tested (all P < 0.001). There were strongly inverse correlations between the %RI and %PI of foot arteries and the AFT score (r = -0.556 to -0.846, P < 0.0001). The %RI of the digital artery was the most strongly correlated with AFT score (r = -0.846, P < 0.0001) among foot arteries tested. The abnormality of sympathetic vasoconstriction was detectable in the majority of the diabetic patients with the early phase of autonomic neuropathy (%RI: 89.5%; %PI: 94.5%). CONCLUSIONS: We conclude that the %RI of the digital artery is a useful and reliable sympathetic function test of early phase in diabetic patients.

Adult↗

PubMed1998

Effect of the vasodilatory beta-blocker, nipradilol, and Ca-antagonist, barnidipine, on insulin sensitivity in patients with essential hypertension.

OBJECTIVES: To assess the effects of a vasodilatory beta-adrenoceptor blocker, nipradilol, and a long-acting Ca channel blocker, barnidipine, on insulin sensitivity. DESIGN: Insulin sensitivity was determined using a euglycemic hyperinsulinemic clamp technique before and after a 12-week treatment period in eighteen patients with essential hypertension. RESULTS: Both drugs decreased blood pressure without affecting any serum parameters of glucose and lipid metabolism. Nipradilol significantly augmented glucose infusion rate (GIR) from 3.11+/-0.28 to 4.69+/-0.57mg/kg/min (p=0.027). Barnidipine also increased GIR from 3.91+/-0.43 to 5.29+/-0.43 mg/kg/min (p=0.028). Plasma norepinephrine concentrations significantly increased with barnidipine treatment, while nipradilol had no effect on plasma norepinephrine levels. No adverse events were reported during the study. CONCLUSIONS: These results suggest that vasodilatory beta-blockers such as nipradilol and long-acting Ca channel blockers such as barnidipine may be useful in the treatment of insulin resistant hypertensive patients.

Adrenergic beta-Antagonists↗