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Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 361 records · Page 20Linked to original sources
PubMed1988

Long-term corneal endothelial changes after intraocular lens implantation.

We studied the morphologic characteristics of the corneal endothelium in a series of patients who had undergone phacoemulsification with intraocular lens implantation performed by one surgeon. Specular microscopy and computer-assisted morphometry were performed preoperatively and three years after surgery. Nineteen eyes that received posterior chamber lenses with intracapsular fixation had a mean endothelial cell loss of 18.1%, without any significant change in cell size (polymegethism) or shape variability (pleomorphism). Implantation of anterior chamber lenses with the posterior capsule left intact (18 eyes) caused a similar degree of cell loss (23.5%) but caused marked polymegethism and pleomorphism of the cells. Endothelial cell loss (28.5%) and morphologic changes were greatest in five eyes that received anterior chamber lenses because of a rupture of the posterior capsule.

Cataract Extraction↗
PubMed1988

The function of Ia+ dendritic cells and Ia- dendritic cell precursors in thymocyte mitogenesis to lectin and lectin plus interleukin 1.

The response of thymocytes to lectin is a standard tissue culture model for identifying cytokines such as IL-1 that are required for thymocyte mitogenesis. To study accessory cell requirements for these responses, it was necessary to deplete endogenous accessory cells with two techniques: anti-Ia and complement, and passage over nylon wool. Proliferation to Con A was then restored with 0.1-0.3% exogenous splenic dendritic cells, or 30-fold higher levels of peritoneal macrophages. The "costimulatory" action of IL-1, whereby responses to lectin were enhanced 3-10-fold, required the presence of dendritic cells. This effect of IL-1 could be reproduced by culturing the dendritic cells for 12 h in 1 U/ml human or murine rIL-1 alpha before addition to the thymocyte proliferation assay. The function of IL-1-treated dendritic cells was not blocked by a neutralizing anti-IL-1 antibody. The endogenous population of thymic accessory cells was partially characterized. A trace (0.1-0.3%) fraction of Ia+, Ig-, plastic nonadherent dendritic cells was visualized and enriched to a level of 1-10% by depleting CD4+,CD8+, and Ig+ lymphocytes. When this double-negative population was cultured with IL-1 and washed, the treated thymic dendritic cells were 10-fold more active as accessory cells. When the CD4-,CD8-, Ig- populations were depleted of dendritic cells with anti-Ia and complement, the subsequent addition of IL-1 had a second effect. Ia+ dendritic cells redeveloped over a 2-d interval, and they exhibited the same properties as resident dendritic cells in thymus and spleen. The majority were lysed by 33D1 anti-dendritic cell mAb and complement, lacked Fc receptors, and acted as powerful stimulators of the MLR and Con A mitogenesis. The development of dendritic cells did not occur with IL-2, -3, -4 or granulocyte/macrophage colony-stimulating factor or in nylon-nonadherent populations. The IL-1-dependent, Ia- precursor was not detectable in bone marrow. These results begin to analyze the endogenous accessory function of the thymus in culture. Dendritic cells actively stimulate thymocyte mitogenesis. The mitogenic action of IL-1 involves effects on resident Ia+ dendritic cells as well as a new population of thymic, Ia- precursors.

Animals↗
PubMed1988

Corneal endothelial changes associated with aphakic extended contact lens wear.

Wide-field specular microscopy and computer-assisted morphometry were performed on 20 aphakic eyes in 16 patients who had worn a high-water content hydrogel contact lens on an extended wear basis for at least 12 months (mean, 28 months) following intracapsular cataract extraction. When compared with 22 non-lens-wearing aphakic eyes matched for age and postoperative period, the endothelial cell changes in the above patients included a significantly higher coefficient of variation in cell area (polymegathism) and a marked reduction in the frequency of hexagonal cells (pleomorphism) without any significant difference in cell density. Although the clinical significance of these endothelial changes remains unclear, they may indicate hypoxic stress to the corneal endothelium or be an early sign of ongoing cell loss.

Aged↗
PubMed1988

Comparison of cellular basis of drug sensitivity of human colon, pancreatic, and renal carcinoma cell lines with that of leukemia cell lines.

In an attempt to find how much the low therapeutic effectiveness of antitumor drugs against so-called chemotherapy-refractory tumors such as colon carcinoma depends on drug sensitivity at the cellular level, sensitivity of five carcinoma cell lines (three colorectal, one pancreatic, and one renal) to nine typical anticancer agents was compared in vitro with that of four generally chemotherapy-susceptible leukemia cell lines. Sensitivity was assessed in terms of the percentage cell growth in control cultures, which was determined by exposing exponentially growing cells for 48 h to the following antitumor drugs: 1-(4-amino-2-methylpyridine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU), adriamycin (ADM), bleomycin (BLM), cisplatin (DDP), etoposide (VP-16), 5-fluorouracil (5FU), mitomycin C (MMC), methotrexate (MTX), and vinblastine (VLB). As expected, 10-fold or greater differences in sensitivity were scarcely ever observed between the two kinds of cell lines. Thus, we recorded a result of more (or less) sensitivity when there was a difference of 3-fold or more; and compared the drug sensitivity in every pair of carcinoma and leukemia cell lines (20 pairs for each drug). We found that carcinoma cell lines were less sensitive to VP-16, ADM, DDP, and MTX than leukemia cell lines in 18, 15, 12, and 10 of 20 pairs, respectively; only one opposite case was observed, with DDP. On the other hand, no such tendency between the two groups was observed with BLM, 5FU, or MMC. Overall, significantly different sensitivities were observed between them in 91 out of 180 pairs (i.e., 9 antitumor drugs x 5 carcinomas x 4 leukemias), and carcinoma cell lines were less sensitive than leukemia cell lines in 79 of these 91 pairs. These results suggest that the refractoriness of colon carcinoma, etc. to chemotherapy is, at least in part, due to low drug sensitivity of the tumor cell itself.

Adenocarcinoma↗
PubMed1988

Cell killing action of cell cycle phase-non-specific antitumor agents is dependent on concentration--time product.

Based on a pharmacokinetic model proposed by Jusko, which assumes that the cell killing action of cell cycle phase-non-specific agents occurs as a bimolecular reaction depending on drug concentration and cell density, we derived a cell kill kinetic equation for these drugs, including the decomposition constant in culture medium. This equation revealed that the cell killing activity of these drugs depends on the value of concentration x exposure time or the area under the drug concentration--time curve (AUC). It was also clarified that the curves for concentration--exposure time necessary for 90% cell kill on a log scale simulated on the basis of the equation differ according as whether drugs are stable or unstable in the culture medium, being expected to be linear with a slope of -1 in the former case, and to take the form of an asymptotic curve in the latter. For three cell cycle phase-non-specific agents, mitomycin C (MMC), 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosoure a hydro-chloride (ACNU), and nitrogen mustard (HN2), we assessed the concentrations necessary for 90% cell kill (IC90) with various exposure times and the degradation rate constants under the culture conditions used. MMC was quite stable during the incubation, while ACNU and HN2 were unstable. When IC90's and exposure times were plotted on the above-mentioned graph, a linear relationship with a slope of -1 was seen for MMC, while for ACNU and HN2 the anticipated asymptotic curves resulted. We also ascertained that the decomposition constants for ACNU and HN2 expected on the basis of these curves showed a good agreement with the corresponding experimentally observed values. These results indicate that the cell killing action of cell cycle phase-non-specific drugs can be well described by a pharmacodynamic model and equation employing their decomposition constants and are dependent on the concentration-time product.

Animals↗
PubMed1988

Biological activity of 26,26,26,27,27,27-hexafluorinated analogs of vitamin D3 in inhibiting interleukin-2 production by peripheral blood mononuclear cells stimulated by phytohemagglutinin.

Vitamin D compounds suppress the production of interleukin-2 (IL-2) by peripheral blood mononuclear cells (PBMCs) stimulated with phytohemagglutinin in a dose-dependent manner. We used this suppression to test 26,26,26,27,27,27-hexafluorinated analogs of vitamin D3 for their immunosuppressive activity in PBMCs. 26,26,26,27,27,27-Hexafluoro-1,25-dihydroxyvitamin D3 and 26,26,26,27,27,27-hexafluoro-1,24-dihydroxyvitamin D3 were approximately 10 times more potent than 1,25-dihydroxyvitamin D3 in suppressing IL-2 production. 26,26,26,27,27,27-Hexafluoro-1-hydroxyvitamin D3 was 20 to 30 times less potent than 1,25-dihydroxyvitamin D3 in causing this effect. The relative biopotency of each vitamin D3 analog toward PBMC proliferation was roughly similar to that toward IL-2 production by PBMCs. Suppression of PBMC proliferation by vitamin D3 analogs seemed to be a secondary effect of their inhibition of IL-2 production.

Calcitriol↗
PubMed1988

Wheat germ agglutinin-positive cells in a stem cell-enriched fraction of mouse bone marrow have potent natural suppressor activity.

In the present study we have characterized natural suppressor (NS) cells, which nonspecifically suppress mitogen responses and mixed-lymphocyte reaction. The strongest NS activity was found in a fraction of relatively low-density cells (1.063 less than p less than 1.075) obtained by equilibrium density centrifugation. Further purification and characterization of these NS cells by using a fluorescence-activated cell sorter indicated that wheat germ agglutinin (WGA)-positive cells have potent NS activity, whereas WGA-negative cells have no NS activity. Spleen colony-forming unit (CFU-S) assays demonstrated a significant correlation between the number of CFU-S cells and the NS activity in the bone marrow. However, WGA-positive cells obtained from the bone marrow of animals treated with 5-fluorouracil, which cells in turn were exposed to 5-fluorouracil, showed a marked reduction in NS activity. These results suggest that the pluripotent stem cells have NS activity when the cells are in the cycling phase but not when the cells are in the G0 phase. It seems possible that apparently primitive cells play an important role in down-regulation of immune responses.

Animals↗
PubMed1988

Pharmacokinetic approach to rational therapeutic doses for human tumor-bearing nude mice.

To improve clinical predictability from therapeutic results of various antitumor agents in human tumor/nude mouse models it seems to be important to use a dose pharmacokinetically equivalent to the clinical dose. Thus, we attempted to find the dose of a given drug that can reproduce in the nude mouse a plasma level similar to that seen in human patients treated with an effective dose of the drug based on comparative pharmacokinetic studies between man and nude mouse. As a result, those of 3 alkylating agents, mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) and cyclophosphamide, and those of 2 antimitotic agents, vincristine and vinblastine, were estimated to be one-fourth or one-fifth of their maximum tolerated doses (MTD's). On the other hand, in the case of adriamycin, its MTD was approximately equivalent to its clinical dose pharmacokinetically. In contrast, clinically equivalent doses of 2 antimetabolites tested, 5-fluorouracil and methotrexate, were significantly greater than their MTD's; i.e., their plasma levels did not reach the effective clinical ones even when their MTD's were administered to the nude mice. These results suggest that the antitumor effects of most antitumor agents are over- or underestimated in this model when MTD's are used as a therapeutic dose, and indicate that the use of clinically equivalent doses determined pharmacokinetically is desirable.

Animals↗
PubMed1988

Responsiveness of human gastric tumors implanted in nude mice to clinically equivalent doses of various antitumor agents.

To reproduce clinical effects of various antitumor agents in the human tumor/nude mouse model, we investigated the responsiveness of 11 lines of human gastric tumor xenografts to doses of the agents pharmacokinetically equivalent to the respective clinical doses, which we designated the "rational dose" (RD). We found that the response rates to mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl]methyl-1-[2-chloroethyl]-1- nitrosourea (ACNU), adriamycin, 5-fluorouracil were 18%, and that to vinblastine was 30%; on the other hand, those to vincristine, methotrexate, and cyclophosphamide were poor. In contrast, in our previous study using the maximum tolerated doses, response rates to mitomycin C, ACNU, and vinblastine were as high as 64-82%, and those to adriamycin and 5-fluorouracil were 18%. When these results were compared with the clinical response rates of gastric tumors, as a whole, the results with RD's exhibited much better coincidence with the clinical data in terms of relative therapeutic potency, indicating the validity of the use of clinically equivalent doses instead of maximum tolerated doses in the human tumor model.

Animals↗
PubMed1988

Calcium/calmodulin-mediated action of calcitonin on lipid metabolism in rats.

The effects of calcitonin on lipid metabolism were investigated in three kinds of rats, one strain of rabbits, and a primary culture of rat hepatocytes. In a short-term experiment, calcitonin decreased serum cholesterol and triglycerides after injection in rats on either an ordinary or high-fat diet. In a long-term experiment, calcitonin decreased the serum cholesterol and triglycerides in uremic rats, hypothalamic obese rats, and Watanabe-heritable hyperlipidemic rabbits. In cultured hepatocytes, calcitonin reduced the incorporation of [14C]acetate into cholesterol and triglycerides in a dose-dependent way. Treatment with W7, a calmodulin inhibitor, overcame the decrease caused by calcitonin in serum lipids in rats and in the synthesis of triglycerides from acetate or palmitate in the hepatocytes, but did not alter the intracellular cAMP level or incorporation of [32P]Pi into PI in the cells. The results suggest that calcitonin lowers serum lipid levels and lipogenesis in hepatocytes in a calcium/calmodulin-dependent way.

Animals↗
PubMed1988

The effects of intracerebroventricular administration of adrenergic agonists and antagonists on adrenaline secretion from the adrenal medulla in stressed conscious rats.

The effects of intracerebroventricular (i.c.v.) administration of adrenergic agonists and antagonists on the increase in serum adrenaline (Ad) induced by immobilization stress were examined in unanesthetized, unrestrained rats. The serum Ad of rats showed a significant linear increase as time elapsed after the induction of immobilization stress. This immobilization stress-induced increase was inhibited by the i.c.v. administration of a small amount of noradrenaline (NA) and phenylephrine. Isoproterenol and clonidine failed to inhibit the immobilization stress-induced increase. The inhibition of the immobilization stress-induced increase by i.c.v. administration of NA was antagonized by pretreatment with phentolamine and prazosin, but not by pretreatment with yohimbine and propranolol. These results suggested that NA administered via an i.c.v. route may inhibit the stress-induced increase in adrenomedullary Ad secretion by an action on the central alpha 1-adrenoceptor.

Adrenal Medulla↗
PubMed1988

Effect of intracerebroventricular administration of opioid peptides on basal serum adrenaline levels in conscious rats.

It is considered that adrenomedullary secretion of adrenaline is centrally regulated by various endogenous substances. Recently, opioid peptides have been reported as one of this group of endogenous substances. However, the receptor through which these endogenous opioid peptides regulate adrenomedullary adrenaline secretion has not been elucidated. In the present study, various opioid peptides were administered intracerebroventricularly in conscious, unrestrained rats, and blood catecholamine levels were measured at various periods to determine which cerebral opioid peptide receptor is involved in the mechanism of basal adrenomedullary adrenaline secretion. The results indicate that delta-receptor stimulation has a positive effect on basal adrenomedullary adrenaline secretion, while mu- and kappa-receptors are not involved in this mechanism.

Adrenal Medulla↗
PubMed1988

Effect of tolbutamide and glyburide on cAMP-dependent protein kinase activity in rat liver cytosol.

The effect of sulfonylureas tolbutamide and glyburide on adenylate cyclase- and cAMP-dependent protein kinase (A-kinase) was examined in rat liver cytosol. Both tolbutamide and glyburide inhibited the A-kinase activity in a dose-dependent manner. Half-maximal inhibition was obtained at 10 mM with tolbutamide and at 0.2 mM with glyburide, indicating that glyburide was 50-fold as potent as tolbutamide. Neither tolbutamide nor glyburide affected [3H]cAMP binding to the protein kinase, but both inhibited the activity of catalytic units of the A-kinase. Lineweaver-Burk double-reciprocal plots revealed that the inhibitory effects of these drugs were noncompetitive with respect to the protein substrate histone, as well as to the phosphate-donor substrate ATP. Thus, tolbutamide and glyburide inhibited the A-kinase activity in rat liver cytosol, and it was suggested that, through the inhibition of A-kinase, the sulfonylureas would affect the carbohydrate metabolism in the liver. In fact, the relative potencies of these two drugs on A-kinase activity corresponded well with those of their reported antidiabetic effects.

Adenosine Triphosphate↗
PubMed1988

[Potentiation of the antitumor activity of 5-fluorouracil by biochemical modulators].

About 30 kinds of biochemical modulators of 5-fluorouracil (5-FU) are described. They modify the metabolism and cytotoxic action of 5-FU through an alteration in (1) intracellular concentration of 5-FU or its metabolites, (2) intracellular pool of co-substrates essential for 5-FU metabolism, and (3) intracellular pool of normal substrates which compete with 5-FU metabolism. As a result, they affect either its inhibitory effect on thymidylate synthase or incorporation into RNA, or both. Thus, some of these modulators can improve antitumor activity of 5-FU by potentiating its tumor-selective toxicity or reducing its host toxicity selectively. From such various points of view, a variety of biochemical modulators of 5-FU are reviewed.

Animals↗