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Biomedical subjects

K Kubo

Publications and source records attributed to K Kubo.

At least 19 recordsLinked to original sources
PubMed1992

Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 1.

A series of 11-[[2-[(arylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acids and related derivatives were synthesized. The compounds were tested for their antagonizing effects on guinea pig platelet TXA2/PGH2 receptors. Structure-activity relationships are discussed. (+/-)-11-[[2-[(Styrylsulfonyl)amino]ethyl]-thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acid (41) and (+/-)-11-[[2-[(phenylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]thiepin-2-carboxylic acid (4af) were the most promising compounds with K(i) values of 6.5 +/- 0.29 and 3.7 +/- 0.31 nM, respectively, for the TXA2/PGH2 receptor. These compounds also significantly inhibited U-46619-induced guinea pig platelet aggregation ex vivo (10 mg/kg po). Compound 41 was resolved into its optically active form. The (-)-isomer was 60-fold more potent than the (+)-isomer in the TXA2/PGH2 receptor binding assay. Some compounds tested in this study showed both TXA2/PGH2 receptor antagonizing and TXA2 synthase inhibitory effects.

Animals↗
PubMed1992

Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 2.

A series of 11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxep in-2- carboxylic acid derivatives and related compounds were synthesized and found to be potent TXA2/PGH2 receptor antagonists. Each compound synthesized was tested for its ability to displace [3H]U-46619 binding from guinea pig platelet TXA2/PGH2 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced activities: (1) an (E)-2-(1-benzimidazolyl)ethylidene side chain in the 11-position of the dibenzoxepin ring system and (2) a carboxyl group in the 2-position of the dibenzoxepin ring system. The studies also indicated that the TXA2/PGH2 receptor binding affinities of this series of compounds in guinea pig platelet were poorly correlated with those in human platelet. Introduction of substituent(s) to the benzimidazole moiety was effective and sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]- 6,11-dihydrodibenz[b,e]oxepin-2-carboxylate monohydrate (57) recorded the highest affinity for human platelet TXA2/PGH2 receptor with a K(i) value of 1.2 +/- 0.14 nM. It demonstrated potent inhibitory effects on U-46619-induced guinea pig platelet aggregation (in vitro and ex vivo) and human platelet aggregation (in vitro). Compound 57, now designated as KW-3635, is a novel, orally active, and specific TXA2/PGH2 receptor antagonist with neither TXA2/PGH2 receptor agonistic nor TXA2 synthase inhibitory effects. It is now under clinical evaluation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

The particle SSV1 from the extremely thermophilic archaeon Sulfolobus is a virus: demonstration of infectivity and of transfection with viral DNA.

The lemon-shaped "virus-like" particle SSV1 produced by the thermophilic archaeon Sulfolobus shibatae has not previously been observed to infect any host. Using a plaque assay suitable for the extreme growth conditions of this archaeon, we have shown infection of Sulfolobus solfataricus by SSV1. Upon infection, the viral genome was always found integrated into a tRNA gene of the host chromosome, a situation similar to that in S. shibatae, proving that site-specific integration is involved in establishing the lysogenic state. As in S. shibatae, UV-irradiation of lysogenized S. solfataricus led to virus production apparently not accompanied by cell lysis. We have also demonstrated the efficient uptake of exogenous DNA and its expression in Sulfolobus by transfecting S. solfataricus with SSV1 DNA by electroporation. Transfection efficiencies of up to 10(6) transfectants per microgram of DNA were obtained.

Bacteriophages↗
PubMed1992

Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.

Diuretic activities of xanthine or nonxanthine adenosine antagonists and their ameliorative effects against glycerol-induced acute renal failure in rats were investigated in order to clarify the physiological and pathological function of adenosine receptors in the kidney. Diuretic and natriuretic activities of a variety of adenosine antagonists clarified systematically for the first time that the blockade of A1 receptors is more important than that of A2 receptors in sodium and water excretion and support the hypothesis that endogenous intrarenal levels of adenosine directly enhance tubular sodium readsorption. Studies of structure-activity relationships of 8-substituted xanthines in the acute renal failure demonstrated that the activation of adenosine A1 receptor was an important factor in developing such a renal failure. A series of 8-(3-noradamantyl)xanthines exhibited the extremely potent diuretic and natriuretic activities (24; 2.5 micrograms/kg, po, the ratio of urinary excretion value in treated rats to urinary excretion value in control rats = 1.69, the ratio of Na+/K+ in treated rats to Na+/K+ in control rats = 1.76) and potent ameliorative effects against glycerol-induced acute renal failure (24; 10 micrograms/kg, ip, 55% inhibition). From our detailed studies of structure-activity relationships, we can speculate that some tissue differences of the adenosine A1 receptor might exist between kidney and brain and sites of action for adenosine antagonists could be different between two renal pharmacological assays. 1,3-Dipropyl-8-(3-noradamantyl)xanthine, KW-3902 (24), was chosen for further studies and is under development as a drug for treating the acute renal failure.

Acute Kidney Injury↗
PubMed1992

Hyaluronate synthesized by cultured skin fibroblasts derived from patients with Werner's syndrome.

Hyaluronate in cultured skin fibroblasts derived from patients with Werner's syndrome, who excrete large amounts of urinary hyaluronate, was investigated. The amount of hyaluronate secreted into the medium by Werner's fibroblasts was 2-3-times that of normal fibroblasts, whereas no difference in enzyme activities related to the degradation of hyaluronate was found. Werner's fibroblasts were then cultured in the presence of [3H]glucosamine, and the amount of [3H]hyaluronate and its chain lengths in the medium and matrix (trypsinate) fractions were compared with those of normal cells. No significant difference in the chain length of hyaluronate was observed between normal and Werner's fibroblasts. On the other hand, a significant increase of hyaluronate was found in the matrix fraction of Werner's fibroblasts when the cells reached confluency. In addition, a hyaluronate of small chain length was found in the matrix fraction of Werner's fibroblasts, although this was absent from that of normal cells. It was concluded that the constituents of the extracellular matrix of Werner's fibroblasts differed from those of normal cells, characterized by the presence of a large amount of hyaluronate and a relatively small hyaluronate chain.

Adult↗
PubMed1992

[MR imaging of hilar cholangiocarcinoma--comparative study with CT].

Magnetic resonance (MR) images of 18 cases of hilar cholangiocarcinoma were evaluated to compare the effectiveness of Gd-DTPA with that of high dose contrast enhancement computed tomography (HCE-CT) in detecting the primary tumor. The primary tumor was demonstrated as having slightly low intensity compared with liver parenchyma and high intensity compared with the dilated bile duct on T1 weighted images. In contrast, MRI using Gd-DTPA, which was carried out in five cases, revealed intense enhancement of the tumor. As the differentiation between cholangiocarcinoma and dilated bile duct was difficult, it was concluded that the use of Gd-DTPA improves the efficacy of MRI in diagnosing cholangiocarcinoma. Gd-DTPA was also effective in differentiating the growth pattern of the tumor: the infiltrating type was demonstrated as thickening of the wall of the bile duct, the polypoid type as a soft tissue mass in the bile duct. Contrast MRI study is effective for the detection of cholangiocarcinoma. It is also expected to be effective in the staging diagnosis of cholangiocarcinoma.

Adenoma, Bile Duct↗
PubMed1992

A novel, sensitive, and specific assay for abasic sites, the most commonly produced DNA lesion.

Free radicals produce a wide spectrum of damages; among these are DNA base damages and abasic (AP) sites. Although several methods have been used to detect and quantify AP sites, they either are relatively laborious or require the use of radioactivity. A novel reagent for detecting abasic sites in DNA was prepared by reacting O-(carboxymethyl)hydroxylamine with biotin hydrazide in the presence of carbodiimide. This reagent, called Aldehyde Reactive Probe (ARP), specifically tagged AP sites in DNA with biotin residues. The number of biotin-tagged AP sites was then determined colorimetrically by an ELISA-like assay using avidin/biotin complex conjugated to horseradish peroxidase as the indicator enzyme. With heat/acid-depurinated calf thymus or bacteriophage f1 DNA, ARP detected femtomoles of AP sites in DNA. Using this assay, DNA damages generated in calf thymus, phi X174 RF, and f1 single-stranded DNA, X-irradiated in phosphate buffer, were easily detectable at 10 rad (0.1 Gy). Furthermore, ARP sites were detectable in DNA isolated from heat-inactivated X-irradiated (10 Gy) and methyl methanesulfonate (MMS)-treated (5 microM) Escherichia coli cells. The rate of production of ARP sites was proportional to the X-ray dose as well as to the concentration of MMS. Thus, the sensitivity and simplicity of the ARP assay should provide a potentially powerful method for the quantitation of AP sites or other DNA lesions containing an aldehyde group.

Animals↗
PubMed1992

[Treatment results of radiotherapy for squamous cell carcinoma of the cheek mucosa].

The results of radiotherapeutic treatment in 71 patients with squamous cell carcinoma of the cheek mucosa were reviewed. The actuarial 5-year local control rate was 100% for T1 (8 patients), 62% for T2 (43), 65% for T3 (17) and 0% for T4 (3). The patients were divided into four groups according to treatment modality; group 1 was treated by radiotherapy alone (R), group 2 by radiotherapy combined with chemotherapy of BLM or PEP (R + C), group 3 by external radiotherapy followed by surgery (R + S) and group 4 by a combination of radiotherapy, chemotherapy and surgery (R + C + S). The 5-year local control rate was 44% for R (11 patients), 61% for R + C (39), 63% for R + S (6) and 80% for R + C + S (15). Nine of 14 cases or 64% of the surgical specimens in the R + C + S group showed no tumor cells microscopically, a rate comparable with the 5-year local control rate of the R + C group. Including the results of secondary treatment by surgery for recurrent cases, the ultimate local control rate was 83% in both the R and R + C groups. The local control rate was 88% for carcinoma located in the anterior half of the cheek and 53% for that in the posterior cheek. The results suggested that tumors extending to the bucco-alveolar sulci would be more difficult to control by radiotherapy alone, with or without chemotherapy.

Adult↗
PubMed1992

Hypoxia-induced ANP secretion in subjects susceptible to high-altitude pulmonary edema.

We investigated the effects of acute hypoxia (10% O2) on plasma level of atrial natriuretic peptide (ANP) and pulmonary hemodynamics in five subjects with a history of high-altitude pulmonary edema (HAPE). Plasma renin activity and plasma levels of aldosterone, epinephrine and norepinephrine were also measured. The plasma ANP levels in HAPE-susceptible subjects rose significantly in response to 10% O2 (from 34.8 +/- 5.4 to 51.4 +/- 7.3 pg.ml-1; P less than 0.05), not associated with any increase in either atrial pressure. Compared with six control subjects, the rise of ANP level was greater in HAPE-susceptible subjects (16.6 +/- 4.4 vs 3.9 +/- 1.2 pg.ml-1; P less than 0.05). There was a significant positive correlation between the rise of ANP level and the increase of pulmonary arterial pressure. No significant difference was observed in any of other hormonal responses to acute hypoxia between the two groups. We interpret these results as indicating that the ANP secretory response to acute hypoxia in HAPE-susceptible subjects, which is not mediated by an increase in atrial pressure, may be greater than that in nonsusceptible subjects in association with a greater pressor response of pulmonary circulation.

Adult↗
PubMed1992

Islet amyloid polypeptide (IAPP) secretion from islet cells and its plasma concentration in patients with non-insulin-dependent diabetes mellitus.

Islet amyloid polypeptide (IAPP/Amylin) is a novel peptide which was extracted from islet amyloid deposits in patients with non-insulin-dependent diabetes mellitus (NIDDM). However, its pattern of secretions and plasma concentrations under various conditions has not yet been made clear enough. In this study, we examined IAPP secretion from islet beta-cells in vitro using cultured islet cells of neonatal rat pancreas and plasma IAPP responses under various conditions in vivo in normal control subjects and patients with glucose intolerance. Our data revealed that (1) IAPP is co-secreted with insulin from islet cells of the rat pancreas by glucose and non-glucose stimuli; (2) fasting plasma IAPP levels in normal control subjects are 24.9 +/- 2.0 pg/ml and the molar ratio of IAPP/insulin is approximately 1/7; (3) fasting IAPP levels are high in obese patients and low in insulin-dependent diabetic patients, and the molar ratio of IAPP/C-peptide in NIDDM patients is lower than that in normal control subjects, suggesting the basal hyposecretion of IAPP relative to insulin in NIDDM; and (4) the obese patients who had a hyperresponsiveness of insulin relative to C-peptide had the hyperresponsiveness of IAPP relative to C-peptide during an oral glucose load, suggesting that IAPP may have some physiological effect in glucose metabolism.

Adult↗
PubMed1992

Properties of a monoclonal antibody for the detection of abasic sites, a common DNA lesion.

The abasic site is one of the most frequent changes occurring in DNA and has been shown to be lethal and mutagenic. An abasic site in DNA can be tagged by reaction with O-4-nitrobenzylhydroxylamine (NBHA), resulting in the formation of an oxime linkage between the abasic site and the NBHA moiety. In order to measure NBHA-tagged abasic sites, a monoclonal antibody was elicited against a 5'-phosphodeoxyribosyl O-4-nitrobenzyl hydroxylamine-BSA conjugate. The antibody was specific for the NBHA residue as demonstrated by hapten inhibition, with IC50 values for 5'-phosphodeoxyribosyl-NBHA, deoxyribosyl-NBHA, ribosyl-NBHA and NBHA of 0.3 microM, 5 microM, 5 microM and 7 microM, respectively. Other haptens examined, including benzylhydroxylamine, 5'-phosphodeoxyribosyl-, deoxyribosyl-, and ribosyl-benzylhydroxylamine, showed no inhibition even at 1 mM. The antibody showed high specificity for NBHA-modified AP sites in DNA and exhibited no cross reactivity with normal DNA bases, otherwise-modified DNA bases or unmodified AP sites. Using a direct ELISA assay, the antibody detected 1 AP site (after NBHA-modification) per 10,000 base-pairs or approximately 10 femtomoles of AP sites in DNA. DNA lesions were detectable in 60Co gamma-irradiated DNA at a dose as low as 10 rad (0.1 Gy) and the production of antibody detectable sites was proportional to the gamma-ray dose. Since NBHA reacts with lesions containing an aldehyde group, the simplicity and sensitivity of the antibody assay should provide a useful method for the quantitation of AP sites or other DNA lesions containing an aldehyde group.

Animals↗
PubMed1992

Seizure-like movements during induction of anaesthesia with sevoflurane.

Clonic and tonic seizure-like movements of the extremities were observed during induction of anaesthesia with sevoflurane in a 9-yr-old girl. The tonic movements were associated with respiratory alkalosis and were not abolished by an i.v. injection of thiamylal 75 mg. Arterial pressure, heart rate and body temperature remained normal during the episode. Ventilation was assisted easily and then controlled via a face mask. No neurological abnormalities were obvious after the anaesthesia. The movements may have been the result of seizure activity in the central nervous system, or myoclonus of the extremities.

Alkalosis, Respiratory↗
PubMed1992

Site-dependent development of complete and incomplete intestinal metaplasia types in the human stomach.

The topographical distribution of complete and incomplete types of intestinal metaplasia in human stomach samples was investigated in order to elucidate their mutual histogenetic relationship and significance in carcinogenesis. Subgross stereomicroscopic examination of alcian blue and hematoxylin-stained gastric mucosae allowed clear distinction of complete and incomplete intestinal metaplasia types as white (with or without purple hue) and purple foci, respectively, against the background magenta areas of non-intestinalized mucosa. Intestinal metaplasias which developed in the fundic area were predominantly of the complete type whereas those of the antrum were a mixture of both with a distinct predilection for expression of the incomplete type. Although there was some variation among foci regarding the hue of white or purple, the color feature was principally homogeneous within each individual intestinal metaplasia focus. Thus phenotypic analysis indicated intestinal metaplasia expression to be clearly influenced by intragastric topography. The study did not provide any evidence that a shift from incomplete to complete type intestinal metaplasia may occur with time or that the incomplete type may be more intimately associated with development of well-differentiated carcinomas.

Adult↗
PubMed1992

Unusual huge intramuscular granuloma with calcium phosphate crystal deposition in the buttock.

An unusual case of a huge granuloma featuring marked calcium phosphate crystal deposition in muscle is presented. A 58-year-old male demonstrated a well-circumscribed, large, elastic firm mass which had slowly grown over 8 years in the left buttock. Clinical examinations including X-ray, ultrasonography and computed tomography all suggested a neoplastic growth. Surgical excision revealed three inter-connected irregular-shaped masses, measuring up to 11 x 10 x 6 cm in size. The histological appearance was of granulomas composed of numerous small crystals surrounded by reactive mononuclear cells embedded in fibrous tissue containing many foreign body type giant cells. Chemical analysis demonstrated the crystals to be made up of calcium phosphate.

Buttocks↗
PubMed1992

Preliminary experience with gadolinium-enhanced dynamic MR imaging for uterine neoplasms.

Usefulness of gadopentetate dimeglumine in magnetic resonance (MR) imaging of uterine neoplasms was evaluated in 53 patients with endometrial carcinoma and 15 patients with cervical carcinoma. T1- and T2-weighted MR images were obtained before the contrast material was administered. After a bolus injection of gadopentetate dimeglumine, dynamic MR images were acquired, followed by static T1-weighted images. Gadolinium-enhanced MR images revealed relatively small endometrial carcinomas in the uterine cavity as high signal intensity in four cases and invasion of the myometrium as low signal intensity in 20 cases. In eight cases, endometrial tumors showed irregular, early enhancement compared with that of the myometrium on dynamic images; these cases were associated with poor prognosis. Tumor extension into the lower part of the uterus, parametrium, and paracervical fat was well seen on enhanced images in cases of cervical carcinoma. The authors believe that gadolinium-enhanced MR imaging will prove helpful in the staging of uterine neoplasms.

Adenocarcinoma↗
PubMed1992

Effects of thromboxane synthase inhibition on tumor necrosis factor-induced lung injury in sheep.

To examine the role of thromboxane (Tx) A2 in the pathogenesis of acute lung injury caused by tumor necrosis factor alpha (TNF), we tested the effects of OKY-046, a selective thromboxane synthase inhibitor, on pulmonary hemodynamics, lung lymph balance, circulating leukocytes, arterial blood gas analysis, and TxA2 (as TxB2) and prostacyclin (as 6-keto-prostaglandin F1 alpha) levels in plasma and lung lymph after TNF infusion in awake sheep. Infusion of human recombinant TNF (3.5 micrograms/kg) into a chronically instrumented awake sheep caused a transient increase in pulmonary arterial pressure (Ppa). The Ppa peaked within 15 min of the start of TNF infusion from 23.3 +/- 1.1 (SE) cmH2O of baseline to 42.3 +/- 2.3 cmH2O and then decreased toward baseline. The pulmonary hypertension was accompanied by transient hypoxemia, peripheral leukopenia, and the increases in TxB2 in plasma and lung lymph. These changes were followed by an increase in flow of protein-rich lung lymph, consistent with an increase in pulmonary microvascular permeability. OKY-046 significantly prevented the rises of Ppa and TxB2 concentrations in plasma and lung lymph during early phase after TNF infusion. OKY-046, however, did not attenuate the increase of lung lymph flow, transient hypoxemia, and leukopenia. From these data, and by comparison with our previous studies of OKY-046-pretreated sheep during endotoxemia, we conclude that TxA2 has an important role of the increase in the early pulmonary hypertension, but it is not related to the early hypoxemia, leukopenia, and lung lymph balances in TNF-induced lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Effective treatment of adult T cell leukemia/lymphoma with a novel oral antitumor agent, MST-16.

Adult T cell leukemia/lymphoma (ATLL) induced by human T cell leukemia virus I is resistant to conventional therapy. Six patients with ATLL were treated with a new antitumor agent, MST-16, which is a derivative of bis(2,6-dioxopiperazine). Two patients achieved complete remission, lasting 12 months and more than 8 months, and 2 others partial remission, lasting 2 months and 6 weeks, respectively. The major toxicity was myelosuppression. Other toxicities were not severe and were well tolerable. Orally administered MST-16 is a promising agent for the treatment of ATLL.

Administration, Oral↗