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Biomedical subjects

I Kawamura

Publications and source records attributed to I Kawamura.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of a novel pyridylsulphonyl thiazole derivative, FR115092, on autoimmune and mitomycin C-induced thrombocytopenia in mice.

Dapsone (4,4'-diaminodiphenyl sulphone), an antileprotic and antimalarial drug, has been reported to be of therapeutic benefit in idiopathic thrombocytopenic purpura in the clinic. However, adverse reactions such as haemolytic anaemia have often been observed. In this study, we found that dapsone increased the number of platelets and decreased the number of red blood cells in male (NZWxBXSB)F1 (W/BF1) mice, an animal model of idiopathic thrombocytopenic purpura. In studies to prepare derivatives of dapsone with weaker side effects than the parent compound, FR115092 (2-[5-(2-pyridylsulphonyl)thiazolyl]amine) was discovered. The effect of FR115092 on the number of blood cells was studied and compared with dapsone in mice. FR 115092 increased the number of platelets without reducing the number of red blood cells in W/BF1 mice. This drug significantly suppressed the increase in circulating autoantibodies against platelets and increased the number of megakaryocytes. Furthermore, FR115092 inhibited the reduction of the number of platelets in mitomycin C-induced thrombocytopenic mice, as a consequence of its enhancement of growth and maturation of megakaryocytes. These findings suggest that FR115092 may be effective against various thrombocytopenias, without inducing haemolytic anaemia.

Animals↗
PubMed1999

Effect of insulin resistance on the endothelial vasomotor function of the coronary artery of nondiabetic patients.

Attention has been paid to the relationship between insulin resistance and coronary artery disease. The present study investigated the relationship between insulin resistance and the endothelial vasomotor function of the coronary artery of nondiabetic patients with chest pain and a positive exercise tolerance test. Twenty-five nondiabetic patients with chest pain were included. Patients with a steady state plasma glucose (SSPG) level of greater than or equal to 135 mg/dl were placed in the insulin resistant (IR) group, and those with a SSPG level less than 135 mg/dl were placed in the noninsulin resistant (NIR) group. The effect of acetylcholine, papaverine, and isosorbide dinitrate on the vasomotor response of the coronary endothelium was studied. The percent change in diameter of the coronary artery after injection of acetylcholine (20 microg ml(-1) min(-1)) was 84+/-17% in the IR group, and 109+/-18% in the NIR group. The difference in the degree of the vasodilative response is statistically significant (p<0.01). The percent change in coronary flow velocity after injection of acetylcholine (20 microg ml(-1) min(-1)) in the IR group was 120+/-67%, whereas that in the NIR group was 256+/-58%; the increase in coronary artery flow velocity of the IR group was significantly smaller than that of the NIR group (p<0.01). Nondiabetic patients with insulin resistance have endothelial vasomotor dysfunction, which raises an important question as to whether nondiabetic patients with insulin resistance should be treated to prevent the development of coronary heart disease.

Acetylcholine↗
PubMed1998

FK317: a novel substituted dihydrobenzoxazine with potent antitumor activity which does not induce vascular leak syndrome.

PURPOSE: FK973, a substituted dihydrobenzoxazine, is an antitumor antibiotic which has shown high therapeutic efficacy in a phase I study, but its development has been abandoned because of the side effect of vascular leak syndrome (VLS) in the clinical study. This study was performed to investigate whether or not FK317, a new benzmethoxy derivative of FK973, retains the antitumor activity of FK973 without the side effect of VLS. METHODS: VLS was evaluated by the volume of pleural effusion in rats. Cytotoxic activities were determined by a tetrazolium-based colorimetric assay (MTT assay) against murine (B16, P388) and human (HeLa S3, KB) tumor cell lines. Antitumor activities against murine ascitic leukemia (P388, L1210), murine solid tumors (reticulum cell sarcoma M5076, Colon 38 carcinoma) and human xenografts (mammary carcinoma MX-1, lung carcinoma LX-1) were examined. RESULTS: FK973 (1.8 mg/kg) given i.v. to rats induced pleural effusion, one of the elements of VLS, 36 days after the first dosing, but did not 28 days after dosing. This model reflects clinical VLS delayed-type effusion with high protein concentrations. In contrast, FK317 (1.0-3.2 mg/kg) did not induce pleural effusion at all. FK317 had stronger cytotoxic effects against in vitro cultured B16, P388, HeLa S3 and KB tumor cell lines, and in in vivo experiments, FK317 showed equivalent antitumor activity against P388, M5076 and MX-1, and more potent antitumor activity against L1210, Colon 38 and LX-1 compared with FK973. CONCLUSION: These results suggest that FK317 retains the antitumor activity of FK973 and does not induce VLS, and FK317 is a drug with high clinical potential for treating tumors in humans.

Animals↗
PubMed1998

Depressive disorders as psychiatric complications after obesity surgery.

Three case reports of morbidly obese patients (two women and a man) who underwent vertical banded gastroplasty and who subsequently fell into depression, are presented here. The psychiatric diagnosis according to DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised), the eating pattern before obesity surgery, the past history of mental disorder, social adaptation before surgery, psychological gain from their obese state, and the presence of unrealistic expectations of obesity surgery were investigated. Case 1 was diagnosed postoperatively as having a major depressive episode without a personality disorder. Case 2 was diagnosed post-operatively as having a major depressive episode. Case 3 had a depressive disorder not otherwise specified. Cases 2 and 3 had a social phobia with comorbidity of personality disorders. Binge eating disorder was confirmed in all patients before obesity surgery. There were differences between case 1 and cases 2 and 3 based on the presence of personality disorder and the time of onset of depression. When some psychiatric characteristics are confirmed in obese patients, obesity surgery should be undertaken more prudently because the patients may manifest depression postoperatively. The pre-operative psychiatric assessment is essential for a decision on indication of obesity surgery.

Adult↗
PubMed1998

Different effects of FK317 on multidrug-resistant tumor in vivo and in vitro.

FK317, a novel substituted dihydrobenzoxazine, was examined for antitumor effects on multidrug-resistant (MDR) tumor cells in vitro and in vivo. In nude mice, FK317 markedly inhibited the growth of s.c. implanted KB-V1 vinblastine (VLB)-resistant human epidermal carcinoma KB cells, as well as the parent cells (KB-3-1). However, KB-V1 showed much greater resistance to FK317 than to VLB and adriamycin (ADM) in the in vitro study. This resistance was reversed by the addition of verapamil, whereby intracellular accumulation of FK317 in the KB-V1 cells was also decreased. After incubation of FK317 in human and mouse blood, it was shown to be rapidly metabolized to a monodeacetylated form, and slowly metabolized further to a dideacetylated form. With the removal of the acetyl groups from FK317, resistance indexes in KB-V1 and SBC-3/ADM, ADM-resistant human lung carcinoma, decreased. In addition, photolabeling of P-glycoprotein with [3H]azidopine in KB-V1 plasma membrane was completely inhibited by FK317, but not by the deacetylated metabolites. These results indicate that FK317 is metabolized to deacetylated forms, which do not bind to P-glycoprotein and are incorporated into MDR cells, causing cytotoxic effects.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

FK317, a novel substituted dihydrobenzoxazine, exhibits potent antitumor activity against human tumor xenografts in nude mice.

The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growth-inhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials.

Adenocarcinoma↗
PubMed1998

Anti-cachectic effect of FK317, a novel anti-cancer agent, in colon26 and LX-1 models in mice.

The effects of FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6- methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0(2, 7). 0(10, 2] tetradeca-2,4,6-trien-9-yl acetate), a novel anti-cancer agent, on murine adenocarcinoma colon26- and human lung carcinoma LX-1-induced cachexia were investigated in mice. Mice bearing colon26 or LX-1 s.c. lost weight and became cachectic, associated with tumor growth. FK317 and mitomycin C (MMC) inhibited the growth of both tumors. FK317 ameliorated the weight loss induced by the presence of colon26 or LX-1, while MMC enhanced it. An attenuation of the reduction in the weights of epididymal fat, gastrocnemius muscle and carcass was observed in FK317-treated tumor-bearing mice in both cachexia models, but not in MMC-treated mice. The decreases in the circulating levels of triglyceride, glucose and non-esterified fatty acid, which were induced by the presence of colon26, was partially inhibited by treatment with FK317. Overall, this study revealed that FK317 is a potent anti-cancer drug with anti-cachectic activity, suggesting that FK317 has potential utility for the treatment of cancer.

Adenocarcinoma↗
PubMed1998

Cytotoxic mechanisms of FK317, a new class of bioreductive agent with potent antitumor activity.

FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metabolite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death.

Animals↗
PubMed1997

Involvement of inflammatory cytokines and nitric oxide in the expression of non-specific resistance to Listeria monocytogenes in mice induced by viable but not killed Mycobacterium bovis BCG.

The non-specific defense against Listeria monocytogenes could be induced by viable BCG but not by killed BCG in mice. In order to understand the mechanism of antilisterial activity, viable and killed BCG were compared for their ability of inducing cytokine gene expression in spleen cells. Both viable and killed BCG induced the same level of mRNA expression of interleukin 10 (IL-10), transforming growth factor beta (TGF-beta), IL-12 and tumor necrosis factor alpha (TNF-alpha). Gene expression and production of IL-1 alpha and gamma interferon (IFN-gamma) could be induced by stimulation only with viable BCG. Viable BCG but not killed BCG induced the mRNA expression of inducible nitric oxide synthase (iNOS). Treatment of mice with NG-monomethyl-L-arginine acetate (NMMA) significantly impaired the non-specific antilisterial action induced by viable BCG. These results demonstrated that NO is an important mediator for the non-specific antilisterial activity induced by viable BCG, and IFN-gamma, IL-1 alpha and TNF-alpha may play a critical role in the non-specific antilisterial activity.

Animals↗
PubMed1997

Requirement of the initial production of gamma interferon in the generation of protective immunity of mice against Listeria monocytogenes.

Protective immunity of mice against Listeria monocytogenes, which is mediated mainly by gamma interferon (IFN-gamma)-producing T cells, was induced by immunization with viable bacteria but not with killed bacteria. By comparing mice immunized with either viable or killed L. monocytogenes, it was found that IFN-gamma was produced at the initial stage only after immunization with viable bacteria. This finding prompted us to investigate the effect of neutralizing the IFN-gamma on the final generation of protective T cells against L. monocytogenes. When endogenous IFN-gamma was neutralized by administration of anti-IFN-gamma monoclonal antibody for the initial 2 days in mice immunized with viable bacteria, the generation of protective T cells on day 6 was completely blocked, as revealed by T-cell adoptive transfer. The generation of listeria-specific IFN-gamma-producing T cells was also abolished. These results clearly demonstrated that endogenous IFN-gamma, which is produced at the initial stage of immunization, actually plays a critical role in the generation of protective T cells against L. monocytogenes in vivo. Moreover, this study suggested that the lack of IFN-gamma-inducing ability is responsible for the inability of killed L. monocytogenes to induce protective T cells in mice.

Adoptive Transfer↗
PubMed1997

Effects of a new non-steroidal 5 alpha-reductase inhibitor, FK143, on the prostate gland in beagle dogs.

FK143 (4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl] - butyric acid) is a new non-steroidal inhibitor of steroid 5 alpha-reductase (5 alpha-reductase). The effects of FK143 on prostate size and histopathology of mature male beagle dogs were investigated and compared with those of finasteride (a steroidal 5 alpha-reductase inhibitor), and allylestrenol and chlormadinone acetate (CMA) (androgen receptor antagonists). FK143 was orally administered to the dogs daily for 12 weeks. At doses of 10 and 32 mg/kg, FK143 significantly reduced prostate volume to about 60% of the initial value, and dogs treated with FK143 showed a dose-dependent glandular epithelial atrophy in the prostate. FK143 showed no abnormal changes in organ weights and histopathology of the adrenal, testis, pituitary and liver. The degree of prostate reduction in the dogs treated with FK143 (10 and 32 mg/kg) was almost the same as that by finasteride (1.0 mg/kg) and smaller than that by allylestrenol (10 mg/kg) or CMA (10 mg/kg). However, allylestrenol increased liver weights, and CMA increased liver and reduced adrenal weights. These results demonstrate that FK143 can decrease the volume of the dog prostate without any influence on other organs, and they suggest that FK143 is a good candidate for the treatment for benign prostatic hyperplasia.

5-alpha Reductase Inhibitors↗
PubMed1997

Does gender make a difference in the risk of falls? A Japanese study.

The number of elderly people in the world is increasing at a remarkable rate and the rate of aging in Japan is the world's highest. According to a statistical survey done in 1994, people over 65 years of age constitute 14.1% of the Japanese population. In addition, the Japanese average life expectancy in 1991 was the highest in the world, reaching 76.1 years for men and 82.1 years for women. A prominent health problem among elderly people is immobility which can result in elderly patients becoming bedridden (Eto, 1992). Recently, the problem of falls among the frail elderly has received increased interest. Although fall mortality in the Japanese elderly was not as high as those of France or the United States (Rockett & Smith, 1989), falls lead to deterioration in the health and physical status of the elderly. If falls could be reduced among the elderly, many of the health problems attributed to immobility among the Japanese elderly would be reduced. Some falls have a single and obvious cause, but most appear to result from several factors. With better knowledge of the causes and risk factors for falls among the elderly, effective preventive measures can be instituted (Tinetti, Speechley, & Ginter, 1988; Ryynanen, 1994; Teno, Kiel, & Mor 1990). There are few studies concerning falls among the institutionalized elderly (Haga, Shibata, Shichida, Matsuzaki, & Hatano, 1986) and community-dwelling elderly in Japan (Yasumura et al., 1994; Niino et al., 1995; Suzuki et al., 1991, 1992; Suzuki, Yamada, Takahashi, & Tsuchiya, 1991; Suzuki, Yamada, & Tsuchiya, 1993). The purpose of this study was to investigate falls among the elderly, selected at random, who live in Koga, a city in eastern Japan.

Accidental Falls↗
PubMed1996

Suppression of IFN-gamma production from Listeria monocytogenes-specific T cells by endogenously produced nitric oxide.

The induction of nitric oxide (NO) by IFN-gamma has been well documented in a variety of experimental settings, but so far there has been no report on whether the endogenously produced NO can suppress IFN-gamma production. In the present study, CD4+ T cells from Listeria monocytogenes-immune mice produced IFN-gamma upon stimulation with specific antigen and NO was generated in culture. When NG-monomethyl-L-arginine (NMMA) was added to the culture at a dose sufficient for the complete blockade of NO production, there was a significant level of enhancement of IFN-gamma production, which was also dose dependently correlated with addition of NMMA. RT-PCR revealed that IFN-gamma mRNA per given amount of total RNA remained the same irrespective of NO blockade by NMMA; however, total RNA recovery was significantly higher in the culture with NMMA. The endogenously produced NO suppressed T-cell proliferation which can be restored by the addition of NMMA. Sodium nitroprusside, a spontaneous NO generator, inhibited T-cell proliferation dose dependently and suppressed IFN-gamma production. Taken together, it may be concluded that NO down-regulates IFN-gamma production mainly by inhibiting T-cell proliferation.

Animals↗
PubMed1996

Induction of cytokine gene expression by listeriolysin O and roles of macrophages and NK cells.

To determine the role of listeriolysin O (LLO) of Listeria monocytogenes in the host response at the initial stage of infection, cytokine gene expression in mouse peritoneal exudate macrophages and spleen cells was examined by reverse transcription-PCR. Expression of various cytokine mRNAs, especially those of interleukin-1 (IL-1), tumor necrosis factor alpha, gamma interferon (IFN-gamma), and IL-12, was observed to occur in spleen cells after direct stimulation with an LLO preparation purified to a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Induction of mRNA expression by LLO was not blocked by cholesterol, which abrogated the hemolytic activity of LLO. After the depletion of NK cells in spleen cells by treatment with anti-asialo GM1 antibody plus complement, LLO-induced expression of IFN-gamma was decreased, indicating that NK cells were the main source of IFN-gamma. After depletion of macrophages by passing spleen cells over a Sephadex G-10 column, expression of macrophage-derived cytokines, including IL-1alpha, tumor necrosis factor alpha, and IL-12, was diminished. In addition, IFN-gamma mRNA expression was impaired, indicating that IFN-gamma mRNA expression from NK cells required signaling from macrophages. It is suggested that LLO is capable of inducing endogenous cytokines of mice, and both NK cells and macrophages are involved in the host cytokine response to LLO.

Animals↗
PubMed1996

Urinary albumin excretion in short children treated with recombinant human growth hormone.

The urinary levels of albumin, beta 2-microglobulin (BMG) and beta-D-N-acetyl glucosaminidase (NAG) were studied in 30 children with short stature due to partial or complete growth hormone (GH) deficiency under treatment. All 30 children had a normal urinalysis and no clinical evidence of renal disease. They were treated with recombinant GH in a dose of 0.5 IU/kg/week given subcutaneously. The mean albumin excretion rate (9.13 +/- 8.33 micrograms/min/1.73 m2) of these children was significantly higher than that (4.2 +/- 2.27 micrograms/min/1.73 m2) of 30 age-, sex- and pubertal status-matched normal children (p < 0.01). BMG and NAG excretion was normal in both groups. There was no correlation between the urinary albumin excretion rate and the duration of GH treatment. Among the GH-treated children, the urinary albumin excretion rate was correlated significantly with circulatory insulin-like growth factor I (IGF-I) (r = 0.65, p < 0.01). In 7 other children analyzed before and three months after start of GH treatment, the mean urinary albumin excretion rate increased significantly from 4.71 +/- 3.95 micrograms/min/1.73 m2 to 8.29 +/- 2.70 micrograms/min/1.73 m2 (p < 0.03). These results suggest the possibility of functional glomerular alterations during GH therapy.

Acetylglucosaminidase↗
PubMed1995

Involvement of natural killer cells in nitric oxide production by spleen cells after stimulation with Mycobacterium bovis BCG. Study of the mechanism of the different abilities of viable and killed BCG.

Viable and killed BCG were compared for the ability to induce nitric oxide (NO) production in normal spleen cells and peritoneal exudate macrophages. Stimulation of spleen cells with viable BCG resulted in a strong expression of inducible NO synthase followed by an enhanced production of nitrite. However, those responses were not induced after stimulation with killed BCG or when macrophages were stimulated with killed and viable BCG. The same level of TNF-alpha mRNA expression was observed in reverse transcription-PCR after stimulation of spleen cells with viable and killed BCG. However, IFN-gamma production was induced only when spleen cells were stimulated with viable BCG. Concurrent stimulation of rIFN-gamma with either viable or killed BCG resulted in a strong nitrite production by macrophages. Neutralization of IFN-gamma and TNF-alpha caused a complete inhibition of nitrite production. Furthermore, anti-asialo GM1 Ab plus complement treatment abolished IFN-gamma production after stimulation with viable BCG, indicating that the NK cell was the major source of IFN-gamma, and its production was triggered only by stimulation with viable BCG. The present study showed that the ability of viable BCG to induce NO production is superior to that of killed BCG, and both IFN-gamma and TNF-alpha are essential for BCG-induced NO production by spleen cells. NK cells appeared to be important as a source of IFN-gamma, and the insufficient NO induction by killed BCG was due to the inability to induce IFN-gamma from NK cells.

Animals↗
PubMed1995

Decreased capacity of aged mice to produce interferon-gamma in Legionella pneumophila infection.

We investigated the difference in natural resistance to Legionella pneumophila infection between aged (18-20-month-old) and young (3-month-old) mice of ddY strain. Aged mice were more susceptible to the bacterial infection than young mice; 50% lethal doses of L. pneumophila for aged and young mice were 2.2 x 10(7) and 8.5 x 10(7) colony forming units (CFU), respectively, after intraperitoneal injection of the bacteria. The bacterial burden in the livers was larger in aged than young mice after a challenge with a sublethal dose of L. pneumophila. However, peritoneal macrophages of aged mice paradoxically had a greater capacity to kill intracellular L. pneumophila than those of young mice. Interferon-gamma (IFN-gamma) production from naive spleen cells was compared after an in vitro stimulation with formalin-killed L. pneumophila. Spleen cells of aged mice produced significantly less IFN-gamma than those of young mice. When anti-murine IFN-gamma monoclonal antibody was administered before the bacterial infection, the subsequent bacterial burden in the livers significantly increased in young but not in aged mice. These data suggest that, in aged mice, IFN-gamma production is depressed at an early phase of L. pneumophila infection and it renders aged mice more susceptible to the infection.

Aging↗