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Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 379 records · Page 21Linked to original sources
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↗
PubMed1988

[P388].

Explore the source record for details and available documents.

Animals↗
PubMed1988

Corneal endothelial changes associated with herpetic stromal keratitis.

Wide-field specular microscopy was performed on both eyes of 33 patients with unilateral herpetic stromal keratitis. Endothelial changes were quantitated by computerized morphometric analysis of individual cells. In the 16 patients with disciform keratitis, the corneal endothelium of the affected eyes showed no difference in cell density but demonstrated significant increases of variation in cell size (polymegathism) and shape (pleomorphism) when compared to the cells in the fellow unaffected eyes. The eyes with keratouveitis (17 patients), however, had marked polymegathism and pleomorphism of the endothelium and a distinctly lower endothelial cell density (mean, 19%) than the healthy fellow eyes.

Adolescent↗
PubMed1987

Biological activity of fluorinated vitamin D analogs at C-26 and C-27 on human promyelocytic leukemia cells, HL-60.

Vitamin D compounds added to the culture medium induce HL-60 cells to differentiate into macrophage/monocytes via a receptor mechanism. This system provides a biologically relevant assay for the study of biopotency of vitamin D analogs. Using this system, the biological activity of various fluorinated derivatives of vitamin D3 was compared with that of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). As assessed by cell morphology, nitroblue tetrazolium reduction and nonspecific esterase activity, 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 (26,27-F6-1,25-(OH)2D3) and 26,26,26,27,27,27-hexafluoro-1,24-dihydroxyvitamin D3 (26,27-F6-1,24-(OH)2D3) were about 10 times as potent as 1,25-(OH)2D3 in suppressing HL-60 cell proliferation and inducing cell differentiation. The biological activity of 26,26,26,27,27,27-hexafluoro-1-hydroxyvitamin D3 (26,27-F6-1-OH-D3) was equal to that of 1,25-(OH)2D3 in this system. 1,25-(OH)2D3 and its fluorinated analogs exerted their effects on HL-60 cells in a dose-dependent manner. HL-60 cells have a specific receptor for 1,25-(OH)2D3 with an apparent Kd of 0.25 nM, identical with that of chick intestinal receptor. While the binding affinities of 26,27-F6-1,25-(OH)2D3 and 26,27-F6-1,24-(OH)2D3 for chick intestinal receptor were lower than that of 1,25-(OH)2D3 by factors of 3 and 1.5, respectively, they were as competent as 1,25-(OH)2D3 in binding to HL-60 cell receptor. The ability of 26,27-F6-1-OH-D3 to compete for receptor protein from HL-60 cells and chick intestine was about 1/70 that of 1,25-(OH)2D3. These results indicate that trifluorination of carbons 26 and 27 of vitamin D3 can markedly enhance the effect on HL-60 cells.

Animals↗
PubMed1987

Treatment of type 1 diabetes mellitus in non-obese diabetic mice by transplantation of allogeneic bone marrow and pancreatic tissue.

Non-obese diabetic (NOD) mice provide a model for type 1 diabetes mellitus. We previously showed that allogeneic bone marrow transplantation (ABMT) can prevent and treat insulitis and overt diabetes in NOD mice. However, ABMT alone could not be used to treat overt diabetes in NOD mice whose islets had been completely destroyed. To provide insulin-producing cells, pancreatic tissue from newborn mice was grafted under the renal capsules in combination with ABMT. The aims of concomitant ABMT are as follows. (i) It induces immunological tolerance to the donor-type major histocompatibility complex determinants and permits the host to accept subsequent pancreatic allografts from the bone marrow donor. (ii) ABMT replaces abnormal stem cells with normal stem cells. After transplantation of bone marrow plus newborn pancreas, NOD mice showed reduction of the glycosuria and a normal response in the glucose-tolerance test. Immunohistological study revealed the presence of clustered insulin-containing beta cells in the grafted pancreatic transplants. ABMT may become a viable treatment of established type 1 diabetes mellitus in humans.

Animals↗
PubMed1987

A case of hyponatremia in panhypopituitarism caused by the primary empty sella syndrome.

A 64-year-old woman was admitted for evaluation of hyponatremia. She was maintained on hypertonic saline administration. Without this therapy, the serum Na concentration decreased progressively to 127 mEq/L and the plasma osmolality to 254 mOsm/Kg H2O, on Day 3. At that time, the concentration of antidiuretic hormone (ADH) was as high as 3.5 pg/ml. A skull radiogram revealed an enlarged sella turcica. Computed tomography (CT) revealed a low density in the sella, and magnetic resonance imaging revealed equal intensity of the sella turcica and the cerebrospinal fluid. A diagnosis of empty sella syndrome was made by metrizamide cisternography in conjunction with CT scanning. A diagnosis of panhypopituitarism was made by endocrine function tests. 123I-thyroidal uptake was 6% when her serum TSH was 10.9 microU/ml, suggesting that she might also have primary hypothyroidism. When this patient was given glucocorticoid before levothyroxine replacement, her serum Na concentration rose up to about 140 mEq/L and a normal relationship between her plasma ADH level (2.4 pg/ml) and plasma osmolality (281 mOsm/kg H2O) was restored. Therefore, it was suggested that ADH hypersecretion induced by the glucocorticoid deficiency might in part contribute to the development of hyponatremia. This is the case of primary empty syndrome associated with panhypopituitarism, in whom initial symptom was caused by hyponatremia.

17-Hydroxycorticosteroids↗
PubMed1987

The effects of aldose reductase inhibitor on the corneal endothelial morphology in diabetic rats.

Diabetic rats were produced by intravenous injection of streptozotocin. Of these, eleven rats were treated with topical instillation of 0.5% aldose reductase inhibitor (ARI), while ten received vehicle alone. The corneal endothelium of these diabetic rats was examined by specular microscopy and compared to age-matched nondiabetic rats (ten rats). Computerized morphometric analysis of individual cells demonstrated that the endothelium of the untreated diabetic rats had marked polymegathism (increased coefficient of variation in cell area) and pleomorphism (decreased percentage of hexagonal cells), as previously observed in diabetic patients. Similar endothelial changes were also noted in the ARI-treated diabetic rats, but to a significantly lesser extent. These results suggest that topically applied ARI can be effective in reducing morphologic changes of the diabetic endothelium, and that activation of the sorbitol pathway may be implicated in the etiology of such endothelial changes.

Aldehyde Reductase↗
PubMed1987

Selective IgM deficiency in adults: phenotypically and functionally altered profiles of peripheral blood lymphocytes.

Peripheral blood lymphocytes from four patients with selective IgM deficiency were examined phenotypically and functionally. Although B cell subpopulations determined by surface immunoglobulins were within normal or nearly normal range, T8+ cells were significantly increased and T4/T8 ratios were inverted in three patients. IgM specific hyporesponsiveness in the PWM-driven immunoglobulin production system was observed in all four patients. Ia-like antigen positive T cells were increased in two patients; both had increased Leu2a+ Leu15+ suppressor-effector cells. In addition, Leu3a+ Leu8+ suppressor-inducer cells were increased in one of these two patients. Excessive (either IgM-specific or isotype non-specific) suppressor activity of T cells and IgM specific hyporesponsiveness of non-T cells were observed in these two patients in the recombination plaque assay. Although these results showed the complexity of the pathogenesis of this syndrome, they suggested that suppressor-associated T cells may play a role in some patients with selective IgM deficiency.

Adult↗
PubMed1987

Thymic rudiments are responsible for induction of functional T cells in nu/nu mice.

Congenitally athymic nude (nu/nu) mice have been thought to exhibit no T cell functions despite the presence of some Thy-1 positive (Thy-1+) cells. However, we detected a significant number of Con A-responsive cells in spleens of nu/nu mice after the age of 2 months when the spleen cells were cultured in a medium containing 5% human plasma or human serum, but not when they were cultured in fetal calf serum. Cytotoxic test using anti-Thy-1.2 antibody plus complement has revealed that these Con A-responsive cells are indeed Thy-1+. The Con A-responsive T cells increase with age. PHA-responsive and alloreactive T cells are also detected in the spleens of 11-month-old nu/nu mice. To probe the origins of the T-lymphocytes of the nu/nu mice we examined extensively and systematically the thymic remnants in the mediastinum and neck region of the nu/nu mice in search for T cell development in thymic rudiments. In these investigations we regularly found small accumulations of cells comprising almost entirely Thy-1+ lymphocytes surrounding accumulations surrounded by epithelial cells. These findings suggest that apparent sites of T cell development in thymic rudiments are indeed present in nude mice and appear to be functioning to induce expression T cell markers on precursor cells in the lymphoid lineage. Together with our prior findings the evidence presented in this report shows that a pathway exists in nude mice. In the converse these findings suggest that the thymus is the sole site for induction of the differentiation of stem cells or precursor T cells into mature T-lymphocytes. The findings suggest that indications of alternative differentiation pathways for T-lymphocytes must seek the location of these pathways within the thymus itself.

Aging↗
PubMed1987

Energy metabolism in canine erythrocytes associated with inherited high Na+- and K+-stimulated adenosine triphosphatase activity.

Energy metabolism in canine erythrocytes associated with inherited high Na+- and K+-stimulated adenosine triphosphatase [(Na,K)-ATPase] activity (HK cells) was compared with that in normal canine erythrocytes (LK cells). Activities of some of the glycolytic enzymes in the HK cells were significantly higher than those in LK cells. The concentrations of adenosine triphosphate (ATP) and glycolytic intermediates in HK cells were almost equal to those in LK cells. Glucose utilization and lactate production by HK cells in vitro and incorporation of [32P]orthophosphate or [14C]glucose into 2,3-diphosphoglycerate in HK cells were higher than in LK cells. Radioactivity of [32P]ATP in HK cells was lower than in LK cells, but increased to approximately that of LK cells when (Na,K)-ATPase of HK cells was completely blocked by ouabain. When HK cells and LK cells were incubated in the absence of glucose, the concentration of ATP in HK cells was decreased more than that of LK cells. Although ouabain reduced the rate of decrease in ATP in HK cells, the decrease in ATP in HK cells was still 2-fold that in LK cells. The half-life of HK cells was about one-half that of LK cells. The results indicated that glycolysis is greater in HK cells than in LK cells, and that the increased glycolysis in HK cells was stimulated by an increased rate of ATP breakdown for active cation transport by the (Na,K)-ATPase and by increased degradation of ATP for some other pathway, eg, glutathione synthesis. Thus, the increased demand for ATP in HK cells might result in shortening the lifespan of HK erythrocytes.

Animals↗
PubMed1987

Kinetic analysis of active efflux of vincristine from multidrug-resistant P388 leukemia cells.

Kinetic analysis of vincristine transport in parental and multidrug-resistant P388 leukemia cells was attempted by indirect assessment of its efflux. Practically, the initial velocity and steady-state level of vincristine uptake by ATP-depleted cells, and its steady-state level in untreated cells, were measured. As a result, a saturable process of not only influx but also efflux of vincristine was observed for the first time with both cell lines, suggesting the existence of a carrier-mediated system for influx and efflux. With increasing extracellular drug concentrations, the contribution of the mediated transport to the total flux was decreased and that of the unsaturable process, that is, simple diffusion, was increased. It should be particularly noted that the Km and Vmax values of efflux in the resistant cells were significantly less and greater, respectively, than those of the sensitive cells, providing a biochemical basis for enhanced efflux as a mechanism of multidrug-resistance. No significant difference in kinetic parameters of vincristine influx and intracellular binding contributing to resistance was found between the two cell lines.

Animals↗
PubMed1987

Successful pancreatic allografts in combination with bone marrow transplantation in mice.

We have established a new method for pancreatic allografts in mice by combining pancreatic transplantation with allogeneic bone marrow transplantation. In this approach, we first transplanted bone marrow to induce tolerance to both donor-type and host-type major histocompatibility complex (MHC) determinants. Pancreatic tissue from the same mouse strain as bone marrow donor was then grafted under the renal capsule. Acceptance of the grafts was confirmed by histopathological and immunohistochemical techniques. BALB/c mice reconstituted with C57BL/6J bone marrow cells accepted pancreatic tissue from both bone marrow donor (C57BL/6J)-type and host (BALB/c)-type mice. An immunohistochemical study revealed the presence of functional islets under the renal capsules. Assays for both mixed lymphocyte reaction (MLR) and induction of cytotoxic T lymphocytes indicated that the newly developed T cells are tolerant of both donor (stem cell)-type and host-type MHC determinants. By contrast, the T cells of these chimeras showed a significant responsiveness to third party MHC determinants. These findings suggest that pancreatic allografts combined with bone marrow transplantation may become a viable strategy for the treatment of patients with diabetes or patients who have undergone pancreatectomy.

Animals↗
PubMed1987

[Quantitative analysis of cell-kill effects of anticancer drugs: consideration of both in vitro and in vivo experimental systems].

After examining the in vitro cell-kill kinetics of various anticancer drugs by using cultured human cell lines, Shimoyama et al. classified the drugs into two groups according to the types of action: 1) type-I drugs (cytocidal and concentration-dependent action) such as alkylating agents and anticancer antibiotics; 2) type-II drugs (cytostatic and time-dependent action) such as antimetabolites, Vinca alkaloids and L-asparaginase. In the present paper, we will present a rational basis for such a classification by using cell-kill pharmacodynamic models, and consider the optimal dosage regimen depending on the type of drugs by combining the cell-kill kinetic and pharmacokinetic models. In these models, classification of the drugs depends on whether the cell population is kinetically homogenous or not. It is assumed that cell population is homogenous for type-I drugs and there exist both drug sensitive and insensitive cell populations for type-II drugs. The concentration (or dose)-time-cell survival curves in both in vitro and in vivo, which are simulated based on the kinetic models, are consistent with the experimental data found in the literature. Further analysis on the optimal dose regimen according to these kinetic models clarified that the type-I drugs showed a similar cell-kill effect irrespective of the mode of administration as long as the area under the plasma unbound concentration curves (AUCp, free) is kept constant, while the type-II drugs are more effective by multiple dosing or infusion regimen than single administration of a large dose of drugs. In other words, the extents of AUCp, free and the residence time in the plasma (above certain concentrations of drugs) are determinants of the in vivo cell-kill effects of type-I drugs and type-II drugs, respectively. If the pharmacokinetics of newly developed anticancer drugs in human are predicted from the animal data according to the so-called "animal scale-up" technique and combined with the in vitro cell-kill kinetic data by the use of proposed kinetic models, one may obtain not only the optimal dosage regimen but also good screening systems for truly active drugs for the treatment of human cancer.

Antineoplastic Agents↗
PubMed1987

[Studies on the mechanism of multidrug resistance].

We have introduced two different approaches which we have introduced recently in an attempt to understand the mechanism of multidrug resistance, which was shown to be successfully reversed using non-antitumor analogs of anthracycline and vinca alkaloid. This approach was adopted on the basis of our hypothesis that these substances can inhibit the accelerated drug efflux of the resistant cells. On the other hand, we found that such efflux consists of a saturable as well as an unsaturable process using our newly-designed kinetic approach. In addition, greater Vmax and lower Km were found in the saturable process of efflux in resistant cells as compared with those in sensitive cells. In conclusion, these results suggest that broad cross-resistance among structurally unrelated drugs, i.e., multidrug resistance, is associated with an efflux-oriented transport carrier with broad affinity for these lipophilic drugs with a polycyclic structure.

Animals↗
PubMed1987

Increased thromboxane B2 excretion in diabetes mellitus.

Thromboxane (TX) A2 is a potent vasoconstrictor as well as a proaggregator of platelets. Augmented TXB2 platelet synthesis and attenuated vascular prostacyclin formation have been demonstrated in diabetes mellitus. We undertook to establish a simple method of extracting urinary TXB2 (UTXB2) and to elucidate the pathophysiologic role of renal TXA2 in diabetes mellitus. One-step extraction of UTXB2 with an octadecylsilyl-silica column was sufficient as pretreatment for TXB2 radioimmunoassay because recovery of UTXB2 was good, the eluate was parallel with the dose-response curve, and the value coincided with that obtained by the conventional method. When platelet TXA2 synthesis was completely suppressed by administration of 100 mg aspirin, urinary TXB2 excretion (UTXB2V) declined to 41% of the initial levels, suggesting that renal TXA2 formation contributes significantly to UTXB2V. UTXB2V was 94.5 +/- 14.0 ng/day or 108.8 +/- 17.3 ng/gm creatinine in controls. Approximately half of the patients with diabetes demonstrated a UTXB2 level higher than the mean + 2 SD level of controls. Although UTXB2V did not show a significant correlation with protein excretion, UTXB2V in patients with diabetes with proteinuria greater than 100 mg/day was augmented (224.4 +/- 30.5 ng/day) compared with that in patients with diabetes without proteinuria greater than 100 mg/day. Furthermore, UTXB2V correlated negatively with the p-aminohippuric acid clearance rate, but not with the creatinine clearance rate. The results suggest that renal TXA2 synthesis may be augmented in diabetic nephropathy and may play a pathophysiologic role in renal hemodynamics as well as in protein excretion.

Adult↗
PubMed1987

Methionine toxicosis in cats.

Cats given DL-methionine (1 g/kg of body weight/day) developed severe hemolytic anemia with marked increase of methemoglobin (MetHb) concentration and Heinz-body formation at treatment-day 6 to 10. Cats fed 0.5 g of methionine/kg for 52 days had a moderate Heinz-body hemolytic anemia with methemoglobinemia at treatment days 17 to 31, but thereafter recovered from the anemia despite continuation of methionine feeding, indicating an adaptation of the cats. In vitro, significant (P less than 0.01) increases of MetHb concentration and Heinz-body formation were observed when RBC were incubated with plasma from cats fed (1 g of methionine/kg) or with 10 mM 3-methylthiopropionate, a product of methionine catabolism. However, these increases were not observed when RBC were incubated with 10 mM methionine. Seemingly, excessive methionine intake leads to production of an intermediate of the methionine catabolism that may affect RBC directly as an intensive oxidizing agent, resulting in an excessive oxidation of hemoglobin to MetHb and Heinz-body formation.

Amino Acids↗