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Biomedical subjects

M Inami

Publications and source records attributed to M Inami.

At least 19 recordsLinked 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↗
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

Efficacy and safety of fluorescein angiography with orally administered sodium fluorescein.

PURPOSE: To report the efficacy and safety of fluorescein angiography after oral administration of fluorescein solution in a large number of patients during a period of 8 years. METHODS: A total of 1,787 patients (2,625 eyes) underwent fluorescein angiography after oral administration of sodium fluorescein at Hara Eye Hospital, Utsunomiya, Japan, between January 1989 and March 1997. The ingestible solution was 10 ml of 10% sodium fluorescein, the same material generally used for injection in conventional fluorescein angiography. Retinal photography began 15 minutes after ingestion and continued for 1 hour. The camera and the photography and film processing techniques were the same as those used for conventional fluorescein angiography using injected sodium fluorescein. RESULTS: In 2,554 (97.3%) of 2,625 eyes, photographs adequate for clinical use were obtained. In 1,787 patients, no anaphylactic or other severe adverse effects were observed, and only 31 patients (1.7%) experienced minimal itching, discomfort, or nausea after oral sodium fluorescein intake. For conditions such as central serous chorioretinopathy, retinal vein occlusion, diabetic retinopathy, and cystoid macular edema, sufficient information for clinical use was obtained. CONCLUSIONS: Fluorescein angiography using orally administered sodium fluorescein is generally effective and safe in standard clinical practice.

Administration, Oral↗
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

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↗
PubMed1995

FK143, a novel nonsteroidal inhibitor of steroid 5 alpha-reductase: (1) In vitro effects on human and animal prostatic enzymes.

Steroid 5 alpha-reductase is an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) in men. We studied in vitro effects of FK143, a nonsteroidal new compound, on 5 alpha-reductase in human and animal prostates. Prostates were obtained from Wistar rats, Beagle dogs, and Cynomolgus monkeys as well as prostatic tissue from BPH patients obtained by the prostatectomy. Nuclear membrane fraction of prostates showed pH dependent 5 alpha-reductase activities, and inhibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5 alpha-reductase in a dose-dependent manner with an IC50 of 1.9 nM and also inhibited animal 5 alpha-reductases with similar IC50 values. FK143 inhibited human and rat 5 alpha-reductases in a noncompetitive fashion while finasteride, a steroidal 5 alpha-reductase inhibitor, showed competitive inhibition. The affinities of FK143 for the human 5 alpha-reductase is constant at pH 5 and 6.5. No inhibitory effects were shown to other oxidoreductases. These results indicate that FK143 is a new type of potent and selective 5 alpha-reductase inhibitor.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1995

FK143, a novel nonsteroidal inhibitor of steroid 5 alpha-reductase: (2) In vivo effects on rat and dog prostates.

FK143 is a nonsteroidal new inhibitor of steroid 5 alpha-reductase, an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT). We studied in vivo effects of FK143 on rat and dog prostates. FK143 was orally administered to mature male rats for 14 days. At doses above 1 mg/kg, FK143 significantly reduced the wet weights of the ventral prostate and seminal vesicle, but showed no effects on those of the epididymis, testis, and adrenal. Growth of ventral prostate and seminal vesicle was induced by the subcutaneous injection of testosterone propionate (TP) in the castrated young rats and was reduced by FK143 administration at doses above 3.2 mg/kg, while growth induced by 5 alpha-dihydrotestosterone propionate (DHTP) was not affected. FK143 had no binding affinity for the rat androgen receptor. FK143 showed neither estrogenic and antiestrogenic effects on the rat uterus nor androgenic effect on the rat prostate. Concentration of testosterone and DHT in the rat and dog prostates were measured by GC-MS, and administration of 10 mg/kg of FK143 significantly reduced the intraprostatic concentration of DHT. These results indicate that FK143 reduced the prostate growth by inhibiting 5 alpha-reductase activities in the prostates.

5-alpha Reductase Inhibitors↗
PubMed1993

Evidence that the enzyme catalyzing the conversion of guanosine diphosphate D-mannose to a 4-keto sugar nucleotide intermediate requires nicotinamide adenine dinucleotide phosphate.

The first enzyme in the formation of GDP-L-fucose from GDP-D-mannose, which forms a GDP-4-keto sugar intermediate, was purified to homogeneity from cell extracts of Klebsiella pneumoniae. During purification, the enzyme was found to be highly activated by NADP. It was proven that the pyridine nucleotide coenzyme of the enzyme was NADP, not NAD, which differs from previously accepted information. NAD had no effect on enzyme activity. The product of the enzyme reaction with NADP as coenzyme was separated from other nucleotides by high-performance liquid chromatography, and using ion spray liquid chromatography/mass spectrometry the mass was determined for the first time, as 587, which is same as the calculated mass of GDP-4-keto-6-deoxy-D-mannose.

Carbohydrate Dehydrogenases↗
PubMed1990

Suppressor T-lymphocyte dysfunction in MCNS: role of the H2 histamine receptor-bearing suppressor T lymphocytes.

To evaluate the number and function of suppressor T cells in children with minimal change nephrotic syndrome (MCNS), we performed an inhibition test of rosette formation and measured leukocyte procoagulant activity. The number of histamine H2 receptor-bearing T lymphocytes (histamine H2 R+ lymphocytes) was markedly decreased at the onset of MCNS but gradually increased and was normalized following steroid therapy. The production of leukocyte procoagulant activity by normal T lymphocytes was abolished by incubation with patient's lymphocytes. However, pretreatment of the normal T lymphocytes with cimetidine markedly decreased the suppression. The results suggest an abnormality in the histamine H2 receptors on the patient's suppressor T lymphocytes.

Blood Coagulation Factors↗
PubMed1981

Psychomotor status induced by temporal lobe encephalitis.

A case report of psychomotor status was presented. A 51-year-old male caught a cold and had a high fever at the end of September, 1979. On October 7th, he had a visual hallucination followed by a generalized seizure. After hospitalization he went through several fits of automatism. On October 15th, he was seized with automatism status in which the seizures were repeated every 25 minutes and there was no recovery of consciousness between the seizures. Although an intravenous injection of diazepam interrupted this status, on October 17th he showed subclinical seizure status on the EEG during which automatism traces were rarely found. By the medication of carbamazepine and clonazepam, he improved gradually. CT-scan revealed the disappearance of the right sylvian fissure and CSF showed findings of viral encephalitis. Consequently, he was considered to have been suffering from temporal lobe encephalitis and shown an episode of psychomotor status with automatisms and automatism traces during which typical automatism status was observed as well.

Automatism↗