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Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 73 records · Page 4Linked to original sources
PubMed1990

Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up.

Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosour ea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Log-log plots of body weight (W; kg) vs total plasma clearance (CLtot,p; ml/min) and steady-state distribution volume (Vd,ss; l) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was greater than 97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CLtot,p = 50.6 W0.957; Vd, ss = 1.29 W1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CLutot,p and Vd,uss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CLutot,p = 71.7 W0.891; Vd,uss = 1.82 W0.966) were also high (r greater than or equal to 0.991). The extrapolated values vs those observed in a 70-kg human were the following: CLutot,p, 3,160 vs 2,290 ml/min; Vd,uss, 110 vs 106 l. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation.

Animals↗
PubMed1990

Antitumor activity of MST-16, a novel derivative of bis(2,6-dioxopiperazine), in murine tumor models.

We studied the antitumor activity of newly synthesized bis(1-acyloxymethyl) derivatives of 4,4'-(1,2-ethanediyl)bis(2,6-piperazinedione) using i.p.-i.p. models of P388 leukemia and B16 myeloma. As a result, we found 4,4'-(1,2-ethanediyl)bis(1-isobutoxycarbonyloxymethyl-2,6-piperazi nedione) (MST-16) to possess considerable therapeutic activity. MST-16 showed not only marked life-prolonging effects in both P388 leukemia- and B16 melanoma-bearing mice but also a greater therapeutic ratio than did its parent compounds, ICRF-154 and ICRF-159. Further studies revealed that MST-16 has considerable therapeutic activity against a number of other tumors such as ascitic forms of L1210 leukemia, colon 26 adenocarcinoma, and MH-134 hepatoma and solid forms of B16 melanoma, Lewis lung carcinoma, colon 38 adenocarcinoma, and M5076 fibrosarcoma. These results suggest that MST-16 is very promising as an antitumor agent.

Animals↗
PubMed1990

Increased renal TXA2 synthesis in diabetes mellitus: simultaneous determination of urinary TXB2 and 2,3-dinor-TXB2.

The present study was designed to determine urinary excretion of kallikrein(KAL)-kinin as well as prostaglandin (PG) E2, TXB2 and 2,3-dinor-TXB2, a major urinary metabolite of TXA2 synthesized in platelets, by specific RIAs in patients with diabetes mellitus (DM). KAL or kinin excretion in 26 type II DM did not differ from control values obtained in 18 age-matched healthy subjects (C), although DM with HbA1 greater than 11% excreted less KAL. Urinary PGE2 excretion (7.6 +/- 2.8 ng/mg creatinine, mean +/- SE) was significantly lower in DM compared to C (17.5 +/- 3.9, p less than 0.05), while DM excreted more TXB2 (0.57 +/- 0.09, p less than 0.01) and 2,3-dinor-TXB2 (0.56 +/- 0.12, N.S.) than C (0.19 +/- 0.02 or 0.33 +/- 0.01). DM with or without mild proteinuria demonstrated lower PGE2, but higher TXB2 and 2,3-dinor-TXB2 excretion. A positive correlation of TXB2/2,3-dinor-TXB2 with proteinuria was observed in this group. However, in DM with massive proteinuria over 500 micrograms/mg creatinine, TXB2 and 2,3-dinor-TXB2 excretion decreased to levels almost identical to C. As a whole, a ratio of TXB2 to PGE2 or 2,3-dinor-TXB2 in DM was significantly higher than in C. The results suggest that a relative preponderance of TXB2 to 2,3-dinor-TXB2 may indicate an augmented renal, in addition to platelet, TXA2 synthesis. An excessive vasoconstrictive and proaggregatory TXA2 renal synthesis, concomitant with a decrease in vasodilatory and antiaggregatory PGE2, may have profound effects on renal functions such as protein excretion in DM.

Adult↗
PubMed1990

Effect of human recombinant interleukin-6 on the proliferation of mouse hepatocytes in the primary culture.

Effects of various cytokines on the proliferation of mouse hepatocytes were investigated. Human recombinant IL-6 not only enhanced the proliferation of mouse hepatocytes in the presence of epidermal growth factor, but also without epidermal growth factor. However, other human or mouse cytokines such as recombinant IL-1, IL-2, IL-3, IL-4, IFN-beta and IFN-gamma, which are known to regulate immune responses and/or hematopoiesis, had no effect on the proliferation of hepatocytes. These results suggest that IL-6 plays a crucial role in regulating the regeneration of hepatocytes after hepatitis or partial hepatectomy.

Animals↗
PubMed1990

Auto-MHC class II-reactive T cell line obtained from MRL/+mice suffering from "lpr-GVHD". I. Characterization of surface phenotypes, specificities and functions in vitro.

When MRL/Mp-(+)/+ (MRL/+) mice are lethally irradiated and then reconstituted with bone marrow or spleen cells from MRL/Mp-lpr/lpr (MRL/lpr) mice, they develop a graft-versus-host disease (GVHD)-like syndrome, colloquially known as "lpr-GVHD". To analyze the roles of the MRL/lpr T cells in the development of "lpr-GVHD" and autoimmune diseases, several T cell lines were established from the spleen cells of MRL/+ mice suffering from "lpr-GVHD". The surface phenotypes, specificities, and functions of a representative clone (l/+T1) of the cloned T cell lines were characterized. The l/+T1 cells showed Thy-1.2+, L3T4+ and T3+, but Lyt-2- and B220- phenotypes. Proliferative response was observed by co-culturing the cells with spleen cells from MRL/+, MRL/lpr, AKR/J, and C3H/HeN mice, but not from BALB/c or C57BL/6 mice. Furthermore, the l/+ T1 cells responded to spleen cells of B10.BR and B10.A but not B10.D2 mice. The proliferative response of l/+ T1 cells to MRL/+ spleen cells was inhibited by anti-I-Ek (but not anti-I-Ak or anti-Kk) antibodies, suggesting that the specificity of l/+T1 cell culture enhanced the proliferative response only in the presence of appropriate stimulators. Treatment of stimulator cells with J11d.2 + C (but not anti-Thy-1.2 + C or 33D1 + C) abolished the stimulatory effect, indicating that B cells are effective stimulator cells for auto-MHC class II-reactive l/+T1 cells. When MRL/+ splenic B cells were co-cultured with l/+T1 cells, both B cell proliferation and IgM production were observed. In addition, IgM-class rheumatoid factor and anti-ssDNA antibody activities were found in the supernatants of MRL/+ splenic B cells co-cultured with l/+T1 cells. These results are discussed in relation to "lpr-GVHD" and autoimmunity in MRL/lpr mice.

Animals↗
PubMed1990

Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells.

Transplantation of bone marrow cells from nonobese diabetic (NOD) mice, a model for type 1 diabetes mellitus, to C3H/HeN mice, which express I-E alpha molecules and have aspartic acid at residue 57 of the I-A beta chain, induced insulitis followed by overt diabetes in the recipient C3H/HeN mice more than 40 weeks after bone marrow transplantation. When cyclosporin A, which perturbs T-cell functions, was injected intraperitoneally into [NOD----C3H/HeN] chimeric mice daily for 1 month, the chimeric mice developed insulitis and overt diabetes within 20 weeks following bone marrow transplantation. Transplantation of bone marrow cells from (NZW x BXSB)F1 mice, which develop lupus nephritis, myocardial infarction, and idiopathic thrombocytopenic purpura, into C3H/HeN or C57BL/6J mice induced in the recipient strains both lupus nephritis and idiopathic thrombocytopenic purpura more than 3 months after transplantation. Transplantation of a stem-cell-enriched population from (NZW x BXSB)F1 mice into normal mice also induced autoimmune disease in the recipients. These results indicate that both systemic autoimmune disease and organ-specific autoimmune disease originate from defects that reside within the stem cells; the thymus and environmental factors such as sex hormones appear to act only as accelerating factors.

Animals↗
PubMed1990

Interferon-alpha and interferon-beta induce Ia expression in limited protein synthesis condition.

We investigated the regulatory effect of interferons (IFNs) on macrophage (m phi) Ia antigen expression. Unlike type II IFN (IFN-gamma), type I IFNs (IFN-alpha and IFN-beta) were incapable of inducing the accumulation of Ia mRNA. However, when cultured with type I IFN plus cycloheximide (CHX), M phi accumulated significant amounts of Ia-specific mRNA, which was translated into Ia molecules expressed on the cell surface after the removal of CHX. Significant enhancement of Ia mRNA accumulation and the Ia expression were observed also in M phi stimulated with IFN-gamma plus CHX. Type I IFNs suppressed IFN-gamma-dependent Ia expression through the inhibition of Ia mRNA accumulation, but such suppression was not directed to the post-transcriptional step in M phi that had accumulated Ia mRNA in response to stimulation by type I or type II IFN plus CHX. These results seem to indicate that type I IFNs can induce Ia mRNA accumulation but that they also induce some inhibitory protein, the synthesis of which precedes it and is dominant, so that the Ia expression is masked.

Animals↗
PubMed1990

Kinetic analysis of 5-fluorouracil action against various cancer cells.

Based on our recent kinetic analysis, which made it possible to distinguish between the cell-killing actions of cell cycle phase-specific and non-specific agents, we attempted to elucidate the actions of 5-fluorouracil (FUra) on three different cancer cell lines. By colony-forming assay, the concentrations of fluorouridine (FUrd), fluorodeoxyuridine (FdUrd) or FUra giving 90% cell kill (IC90) at various exposure times (texps) were obtained. With P388 cells, the curve of texps-IC90 for FUrd on a log-log scale was linear with a slope of -1, which is typical for cell cycle phase-nonspecific agents. In contrast, the curve for FdUrd showed a much steeper slope than -1, which is characteristic for cell cycle phase-specific agents. We found that the curve for FUra was exactly the same as that for FUrd, indicating that the mode of FUra action on P388 leukemia is analogous to that of FUrd. Similar results were observed with human colon and renal cancer cell lines, HT-29 and KU-2, although when the cells were exposed to relatively low concentrations of FUra for a long time, a cell cycle phase-specific action became evident.

Animals↗
PubMed1990

Hyperreninemia due to increased renal renin synthesis in BioBreeding Worcester rats.

It is well known that diabetes mellitus is often associated with hypertension. We previously reported the unresponsiveness of renin release to volume depletion with impaired renal prostaglandin E2 synthesis in rats with streptozotocin-induced diabetes. However, we have found that BioBreeding Worcester rats, spontaneously susceptible to diabetes mellitus either before or after the onset of diabetes, showed a pronounced fourfold to ninefold increase in plasma renin activity in comparison with control Wistar rats. Furthermore, these rats developed mild hypertension as high as 134 mm Hg after the age of 90 days. The hyperreninemia responded to 1-week sodium loading or restriction; the blood pressure increased during sodium loading. Oral administration of captopril (30 mg/kg) for 1 week resulted in a large blood pressure decrease (-47.1 +/- 5.9 mm Hg, n = 10) in comparison with controls (-17.0 +/- 4.7 mm Hg, n = 12). Vascular response to angiotensin II was also attenuated. Plasma angiotensin II levels were 5.7-fold higher and associated with a 1.5-fold increase of plasma aldosterone concentration compared with control rats, whereas angiotensinogen-plasma concentrations were lower than in control rats. The renal renin content determined enzymatically or histochemically was more enhanced in BioBreeding Worcester rats than in control rats, but the renal renin messenger RNA levels did not differ. These results suggest that the strain-specific hyperreninemia in BioBreeding Worcester rats might be due to posttranscriptional abnormalities of renal renin synthesis. Further work is needed to elucidate the specific mechanism or mechanisms responsible.

Angiotensin II↗
PubMed1990

Thymic dendritic cells and B cells: isolation and function.

The thymus is the primary organ in which T cells undergo rearrangement of T cell receptor alpha and beta genes, positive selection for affinity to self MHC products, and elimination (negative selection) of reactivity to self antigens. These events require an interaction of the developing T cell with other cell types in the thymus. The latter include epithelial cells, macrophages, dendritic cells, and the recently described thymic B cells the majority of which are CD5+. Here we review the identification and isolation of thymic dendritic cells and CD5+ B cells. We consider phenotype, ontogeny, and function, including possible contributions to the induction of self tolerance. Thymic dendritic cells are similar to spleen dendritic cells, but are larger and exhibit a few differences in phenotype. Dendritic cells from both organs are equally potent accessory cells for the MLR and lectin-induced, T cell proliferation. Thymic dendritic cells have higher levels of Fc receptors and support anti-CD3 dependent mitogenesis. Thymic CD5+ B cells share phenotypic features with peritoneal CD5+ B cells. However thymic B cells neither proliferate nor form antibody producing cells in response to the stimulation with LPS or anti-IgM plus IL-4, but do respond to stimulation with MHC class II-restricted helper T cells. Thymic dendritic cells and CD5+ B cells both appear at a similar time in ontogeny, about 14 d of gestation, which is the time T cell differentiation begins to take place. Dendritic cells from spleen, which are potent activators for peripheral T cells, are also potent inactivators for thymic-derived cytotoxic T cells. A correlation between reactivity to MIs products and the expression of TCR-V beta genes is well documented, and B cells are the primary APC for this antigen. Therefore, thymic CD5+ B cells may be a good tool for the investigation of tolerance to M1s products.

Animals↗
PubMed1990

[Antitumor activity of polyanion and its application for drug delivery system of antitumor drugs].

Polyanionid copolymer of divinyl ether and maleic anhydride (DIVEMA) with narrow molecular weight distribution was synthesized and tested of its antitumor activity. DIVEMA showed a significant antitumor activity against colon 26 adenocarcinoma and FSaI fibrosarcoma transplanted in syngenic mice. Furthermore, DIVEMA was used as a polymeric drug carrier of antitumor drugs to reduce side effects and enhance the antitumor activity of the drugs. Adriamycin and neocarzinostatin were attached covalently to DIVEMA and the polymeric conjugates showed higher antitumor activity than the corresponding mother drugs against P 388 leukemic mice.

Adenocarcinoma↗
PubMed1990

Histogenesis of hemopoietic bone marrow in adult mice.

Based on the concept that the hierarchy of regulatory genes may specify mammalian development, we attempted to evaluate how morphological and functional phenotypes of hemopoietic bone marrow develop in murine models. From studies of local irradiation, s.c. implantation of bone with or without marrow, and renal subcapsular implantation of marrow plugs or bone without marrow, we identified four sequential (necrotic, clearing, stromal proliferating, and hemopoiesis-recovering) responses in the early phase of the reconstruction of hemopoietic marrow that spatially and temporally proceeded in this restricted order. In addition, characteristic hexagonal sinuses were found to participate in the development of hemopoietic marrow in the early phase. The development of hexagonally arranged sinuses seems to coincide with the formation of abundant osseous trabeculae and to precede the appearance of colony-forming units in culture (CFU-C) and spleen colony-forming units (CFU-S). These findings are discussed from the point of the hierarchy of regulation.

Animals↗
PubMed1989

O-N-acetyl-D-glucosamine moiety on discrete peptide of multiple protein 4.1 isoforms regulated by alternative pathways.

Erythrocyte protein 4.1 is a cytoplasmic protein that possesses a protein-saccharide modification structure, an O-N-acetyl-D-glucosamine (GlcNAc) moiety. We determined the amino acid sequence of the proteolytic fragment containing the O-GlcNAc moiety after labeling the saccharide with [3H]galactose in the presence of bovine milk galactosyltransferase. Glycosylation appears to occur on one or more serine or threonine residues in the following sequence: Thr-Ala-Gln-Thr-Ile-Thr-Ser-Glu-Thr-Pro-Ser-Ser-Thr-Thr-Thr-Thr-Gln-Ile-Thr-Lys . This sequence corresponds to the carboxyl-terminal half of the 34-amino acid peptide in the 22/24-kDa carboxyl-terminal domain of protein 4.1, which is one of the discrete peptides regulated by alternative RNA splicing. Multiple protein 4.1 isoforms in erythroid and nonerythroid cells including major components of erythrocyte membrane proteins, 4.1a and 4.1b, appear to contain this sequence since most immunochemically reactive proteins were labeled with [3H]galactose, with the exception of several variant polypeptides. These results appear to suggest the functional or biological significance of the O-GlcNAc linkage in protein 4.1.

Acetylglucosamine↗
PubMed1989

Evaluation of antitumor activity in a human breast tumor/nude mouse model with a special emphasis on treatment dose.

Eight lines of human breast tumors implanted in nude mice were treated with various antitumor agents at two different doses, maximum tolerated doses (MTD) and rational doses (RD) that were pharmacokinetically equivalent to the clinical doses; the response rates to both doses were compared. With MTD, the response rates to mitomycin C and vinblastine were 100%, and those to other agents including cyclophosphamide, nimustine (a water-soluble nitrosourea), vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 5-fluorouracil (5-FU), and methotrexate were 30%-50%, indicating high responsiveness to the former two agents. In contrast, when the RD were used, the response rates to the majority of these agents were 25%-40%, and those to vincristine and nimustine were 13% and 0%, respectively. These results agree with the reported clinical results compared with those with MTD, suggesting the importance of the use of clinically equivalent doses in the evaluation of antitumor efficacy in a human tumor/nude mouse system.

Animals↗
PubMed1989

A new hypoglycemic agent, midaglizole, blunts diabetic platelet aggregation: a possible role of alpha 2 blockade.

A newly developed alpha 2 blocker, midaglizole (DG-5128, 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesquihydrate) has been shown to have a hypoglycemic action in healthy controls as well as in diabetics. Since human platelets are rich in alpha 2 receptors, the effects of midaglizole on platelet aggregation were investigated. In normal controls, ADP- or epinephrine-induced platelet aggregation was significantly inhibited 2 h after oral administration of 300 mg midaglizole. Midaglizole also suppressed diabetic platelet aggregation stimulated by 10 or 100 microM epinephrine and delayed the initiation of collagen-induced aggregation at 30 micrograms/ml. In vitro addition of midaglizole at 9 or 90 microM significantly inhibited epinephrine-induced platelet aggregation. Furthermore, long-term administration of midaglizole suppressed diabetic platelet aggregation induced by 0.5-1 microM ADP or 1 microM epinephrine. These results suggest that alpha 2 blockade not only blunts diabetic epinephrine-induced platelet aggregation but also affects ADP- or collagen-stimulated platelet aggregation, indicating that this alpha 2 blocker may offer a new approach to the treatment of diabetic microangiopathy.

Adrenergic alpha-Antagonists↗