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Biomedical subjects

S Takeyama

Publications and source records attributed to S Takeyama.

At least 73 records · Page 4Linked to original sources
PubMed1988

[Evaluation of adjuvant chemotherapy of osteosarcoma with special reference to adriamycin (final report)].

Adjuvant chemotherapy mainly with ADR performed in 117 patients (pts) with primary osteosarcoma of the extremity for the purpose of preventing pulmonary metastasis after radical ablative surgery. The mean follow-up period for 117 pts was 51.7 months (range: 3 to 137), for 53 survivors, 90.1 months (range: 60 to 137) and for 64 decreased, 20.5 months (range: 3 to 73). ADR was administered intravenously with 0.6-0.8 mg/kg/day for 3 consecutive days at monthly intervals after surgery until reaching 600 or 500 mg/m2 of the total cumulative dose. Five-year overall and disease-free survival rate of all pts was 50.2% and 39.4%, respectively. Thirty-seven pts (multi-drug group) with the combination of ADR and HDMTX had a higher survival rate (63.1% in 5-year overall survival rate and 47.8% in 5-year disease-free survival rate) than that of 80 pts with ADR alone (ADR group) (44.4% in 5-year overall survival rate and 35.6% in 5-year disease-free survival rate). Five-year survival rate for 65 pts administered the greater than 500 mg of ADR was 59.3% compared to 36.9% for 52 pts the less than 500 mg (p less than 0.05). In 65 pts administered the greater than 500 mg of ADR, 5-year survival rate (76.5%) of the multidrug group (17 pts) showed superiority to that 52.1%) of the ADR group (48 pts) (p less than 0.01). Even in the multi-drug group, 5-year survival rate (76.5%) of 17 pts administered the greater than 500 mg of ADR was higher than that (41.3%) of 20 pts given the less than 500 mg (p less than 0.01). Distant metastases were recognized at lung in 52 pts (lung group), lung + extrapulmonary organs in 14 (+ extragroup), and only extrapulmonary organs in 3 (extra group). Five-year survival rate of 66 pts with pulmonary metastasis was 17.1% and 21.2% in the lung group compared with 0% of the extra group (P less than 0.01). Five-year survival rate for 23 pts treated with thoracotomy was 43.5% compared to 2.6% for 43 without it (p less than 0.01).

Adolescent↗
PubMed1988

[Indications for thoracotomy in pulmonary metastatic sarcoma and its prognosis].

Between 1960 and 1987, 46 patients underwent thoracotomy for pulmonary metastatic sarcoma. The histologic classification of the sarcoma was osteosarcoma in 33 patients, other malignant bone tumors in 6 and soft tissue sarcoma in 7. The cumulative five-year survival rate of the 33 patients with osteosarcoma was 23%. Ten patients survived more than 3 years and 8 of them are still alive without pulmonary metastasis. Prognosis was significantly better with intensive multidrug chemotherapy. In this series, prognosis was not significantly related to the interval from initial onset to initial treatment, that from initial treatment to pulmonary metastasis and that from pulmonary metastasis to initial thoracotomy. The five-year survival rate of the 6 patients with other malignant bone tumors was 35%, and that of the 7 patients with soft tissue sarcoma 26%. Good indications for thoracotomy in pulmonary metastatic osteosarcoma are: (1) the primary sarcoma is resected, (2) the interval from initial treatment to pulmonary metastases is more than 6 months, (3) the number of pulmonary metastases is less than 4 or 5 nodules, and (4) the number and diameter of pulmonary metastases is controlled with chemotherapy within 2 or 3 months after occurrence of metastasis.

Adolescent↗
PubMed1987

Beta 1-adrenergic selectivity of the new cardiotonic agent denopamine in its stimulating effects on adenylate cyclase.

Effects of the new selectively beta 1-adrenergic cardiotonic drug denopamine (TA-064), (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, on the adenylate cyclase-adenosine-3',5'-monophosphate (c-AMP) system of various tissues and cells in rats and guinea pigs were investigated in comparison with those of isoproterenol. Denopamine at concentrations above 10(-6) M stimulated lipolysis in vitro, and, above 10(-5) M, elevated the c-AMP level in isolated rat fat cells. The c-AMP level of guinea-pig heart ventricular muscle was also elevated when the heart was perfused with 3 X 10(-6) M denopamine or when slices of ventricular muscle were incubated with 10(-6) M denopamine. These changes were abolished in the presence of beta-adrenergic antagonists. Incubation with denopamine did not cause substantial elevation of c-AMP levels in rat reticulocytes and diaphragm. Denopamine activated adenylate cyclase of the rat cell membranes in a concentration-dependent manner. Although dose dependence was less apparent, denopamine also activated adenylate cyclase of the membrane fraction from guinea pig cardiac muscle, but it hardly activated the same enzyme from rat reticulocytes. Isoproterenol, on the other hand, showed marked concentration-dependent activation of adenylate cyclase in all these preparations. Denopamine did not inhibit c-AMP phosphodiesterase of both particulate and supernatant fractions of guinea-pig cardiac muscle. The stimulation of lipolysis by denopamine was observed even when elevation of the c-AMP level was not detected, while the stimulation of lipolysis by isoproterenol was always accompanied with an elevation of c-AMP. When guinea-pig hearts were perfused with 3 X 10(-6) M denopamine or 10(-7) M isoproterenol, their cardiotonic effects were of the same magnitude whereas the degree of c-AMP elevation in the ventricular tissue by denopamine was significantly less than that by isoproterenol. It was concluded that stimulation of the adenylate cyclase-c-AMP system by denopamine was restricted to the tissues whose receptors were predominantly of the beta 1-type, and that the elevation of c-AMP levels in these tissues by denopamine was less marked than by isoproterenol, suggesting that the stimulation of lipolysis and heart by denopamine may be mediated by a special pool of c-AMP or some other unknown factor(s).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Pharmacokinetic studies on 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea (TA-077). I. Blood and tissue concentrations of a new nitrosourea antitumor agent TA-077 and its metabolite TA-G after intravenous injection of TA-077 in various experimental animals.

1-(2-Chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea (TA-077) is a new masked antitumor agent, which is hydrolyzed by maltase to give rise to a more cell-permeable and, hence, more cytotoxic metabolite, TA-G. TA-077 was intravenously administered to mice, rats, guinea pigs, rabbits and dogs and the time-courses of blood concentrations of TA-077 and TA-G were followed. The time-course patterns of blood TA-077 in these animals were markedly different from one another depending on the level of plasma maltase, while those of blood TA-G were all similar except in the early stage after the injection; i.e., the blood concentration of TA-G reached a peak shortly after the injection and decreased rapidly with a half-life of 6 to 15 min, and the higher the level of plasma maltase, the earlier the time of peak appearance. Tissue concentrations of TA-077 and TA-G in major organs were also measured at various times after intravenous injection of TA-077 to guinea pigs and VX-2 tumor-bearing rabbits. In both species, tissue concentrations of TA-077 did not exceed the blood concentration and rapidly decreased to insignificant levels by 30 to 45 min. The tissue level of TA-G in the kidney, a maltase-rich organ, was always the highest among the organs examined in both species. The concentration of TA-G in the VX-2 tumor was relatively high. Possible significance of tissue maltase to the cellular uptake and antitumor effect of TA-077 is also discussed.

Animals↗
PubMed1987

Pharmacokinetic studies on 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea (TA-077). II. Hydrolysis by tissue homogenates and drug uptake by tumor cells in vitro.

1-(2-Chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea (TA-077) was hydrolyzed to its glucosyl metabolite TA-G by homogenates of guinea pig organs, rabbit VX-2 carcinoma and rat Yoshida sarcoma. The rate of TA-G formation by the kidney was the highest among the tissues examined and that by the diluted blood was undetectably low, reflecting their maltase activities. TA-077 was also hydrolyzed by suspensions of Yoshida sarcoma, AH130 hepatoma, L1210 leukemia, P388 leukemia and DBLA-10/C leukemia cells. The rate of TA-G formation was increased 10 fold by homogenizing the tumor cells. TA-G was taken up by the tumor cells much more efficiently than TA-077, explaining the higher sensitivities of the cultured tumor cells to TA-G than to TA-077. However, neither the maltase activity nor the membrane permeability to the drugs was a factor influential enough to explain the differences in drug sensitivity among the tumor cell lines.

Animals↗
PubMed1987

Pharmacokinetic studies on 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea (TA-077). III. Pharmacokinetics of a new nitrosourea antitumor agent TA-077 in humans (a phase I study).

A new nitrosourea antitumor agent TA-077, 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea, was intravenously administered to 15 cancer patients at doses ranging from 7 to 100 N (1 N = 30 mg/m2) in a phase I clinical trial. Time courses of blood concentrations of TA-077 and its active metabolite TA-G, 3-beta-D-glucopyranosyl analog of TA-077, were followed. The TA-G concentration reached a maximum at 7.0 +/- 2.3 min, and decreased thereafter with a half-life of 12.9 +/- 2.8 min. The time-course patterns and various pharmacokinetic parameters of TA-077 and TA-G were similar to those in the guinea pig, which, like humans, lacks plasma maltase activity. The 2 h-urinary excretion rate of TA-G in the above patients ranged from 0.15 to 7.7% of the dose. The areas under the concentration-time curve and maximal concentration values were both linearly correlated to the dose with correlation coefficients of 0.78 and 0.82, respectively. Repeated administration of TA-077 (29 to 40 N) for 5 or 6 consecutive days did not affect the pharmacokinetic parameters of TA-077 and TA-G in 7 cancer patients except for slight increases in the half-life and area under the curve of blood TA-G.

Adult↗
PubMed1987

Studies on a new antiallergic pyridinecarboxamide TA-5707F and its sodium salt (TA-5707). II. Mechanism of antiallergic action of TA-5707.

Mechanism of the antiallergic action of 6-methyl-N-(1H-tetrazol-5-yl)-2-pyridinecarboxamide (TA-5707F) was studied using the water-soluble sodium salt (TA-5707). 1) TA-5707 administered p.o. at the dose ca. 3 times the ID50 for the PCA reaction did not inhibit capillary dye leakage induced on the rat skin by intracutaneous injection of histamine, serotonin, bradykinin and leukotriene D4 (LTD4). 2) TA-5707, at concentrations above 10(-7) M, inhibited antigen-induced histamine release and dye leakage in the rat peritoneal cavity (passive peritoneal anaphylaxis). 3) TA-5707 inhibited both anaphylactic and compound 48/80-induced histamine release from the rat peritoneal mast cells, the IC50 being ca. 10(-5) M in both cases. It was concluded that TA-5707F exerts its antiallergic action by inhibiting the release of chemical mediators from sensitized cells.

Animals↗
PubMed1987

[Limb salvage in osteosarcoma. Significance of preoperative isolation perfusion chemotherapy].

In our Department since 1960 isolation perfusion chemotherapy has been performed as a preoperative procedure combined with surgery in 134 patients with osteosarcoma of the extremity. In this paper, the significance of isolation perfusion chemotherapy was presented. The cumulative 5-year survival rate of 114 perfused patients was 42.7%, while that of 41 non-perfused patients before 1960 was 17.1%. Of the 114 patients 102 underwent amputation and 12 had limb salvage surgery. The cumulative 5-year survival rate of the 9 patients who have received limb salvage surgery since 1978 is 68%. Eleven patients who received preoperative aggressive chemotherapy including isolation perfusion chemotherapy showed a 91% clinical and radiological response to the drug. The tumor was microscopically analyzed and the ratio of necrotic to viable tumor cells was calculated. The degree of tumor necrosis was classified as excellent (greater than or equal to 95%), good (80-94%), fair (50-79%) and poor (less than 50%). The response in 22 patients who received preoperative aggressive chemotherapy using adriamycin, methotrexate and cis-platinum including the use of isolation perfusion was excellent in 41%, good in 36%, fair in 14% and poor in 9%. We believe that preoperative isolation perfusion chemotherapy is an effective procedure for limb salvage surgery.

Adolescent↗
PubMed1986

Synthesis and hypolipidemic activities of 5-thienyl-4-oxazoleacetic acid derivatives.

A series of 2,5-disubstituted 4-oxazoleacetic acid derivatives was synthesized and evaluated for hypolipidemic activity. Among them, those with a thienyl group at C-5 of the oxazole ring exerted highly potent hypolipidemic effects in rats. 2-(4-Fluorophenyl)-5-(3-thienyl)-4-oxazoleacetic acid (88) was the most potent derivative: it was about 2 times as active in normal SD male rats and about 4 times as active in hereditary hyperlipidemic rats (THLR/1) as clofibrate with an improved antiarteriosclerosis index (HDL-Cho/Total-Cho). In addition, it showed inhibition of platelet aggregation ex vivo.

Animals↗
PubMed1986

Studies on a new antiallergic pyridinecarboxamide TA-5707F and its sodium salt (TA-5707). I. Inhibition of IgE-induced passive cutaneous anaphylaxis (PCA) in rats.

Effects of TA-5707F [6-methyl-N-(1H-tetrazol-5-yl)-2-pyridinecarboxamide] and its sodium salt (TA-5707) on IgE-induced homologous PCA in rats were investigated. 1. Both TA-5707 and TA-5707F were found to be orally effective inhibitors of rat PCA. Maximum activity by oral administration was obtained when they were administered 5 min before the challenge. Their ID50's under these conditions were both approximately 1 mg/kg. Administration 5 min after the challenge was no longer effective. 2. TA-5707 was also effective by intravenous administration, and its ID50, ca. 0.1 mg/kg, was less than that of disodium cromoglycate (DSCG). 3. The PCA-inhibitory activity of TA-5707 was not affected by adrenalectomy and adrenomedullectomy. 4. Daily administration of TA-5707 or TA-5707F for 8 days did not induce drug tolerance. 5. Tachyphylaxis and cross-tachyphylaxis were observed when the PCA-inhibitory activities of TA-5707 and DSCG were tested after intravenous pretreatment with a large dose (ca. 30 times the ID50) of either drug, but not after oral pretreatment with a therapeutic dose of TA-5707 or TA-5707F.

Adrenal Medulla↗
PubMed1984

Effects of (-)-(R)-1-(p-hydroxyphenyl)-2-[3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat.

Effects of the new cardiotonic and selective beta 1-adrenergic agonist TA-064, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, on circulating concentrations of glucose, lactate, free fatty acids (FFA), glycerol, cyclic AMP and the pancreatic hormones insulin (IRI) and glucagon (IRG) were examined in rats. TA-064, administered orally or intraperitoneally at the dose of 10 mg/kg (ca. 50 times the therapeutic dose) or higher, caused a slight transient rise followed by a persistent lowering of blood glucose concentrations, but it did not affect blood lactate levels at all. The same treatment with TA-064 elevated the concentrations of blood FFA, glycerol and plasma IRI and IRG. These changes induced by TA-064 were inhibited by pretreatment with propranolol (a non-selective beta-adrenergic antagonist) and practolol (a selective beta 1-adrenergic antagonist). The non-selective beta-adrenergic agonist isoproterenol and the selective beta 2-adrenergic agonist terbutaline elevated both blood glucose and lactate when administered intraperitoneally. They also brought about sustained rises in blood glycerol and plasma IRI, but only transiently increased the plasma IRG level. The cardiotonic agent prenalterol, claimed to be a selective beta 1-agonist, elevated blood glucose, lactate, and glycerol only slightly, and plasma IRI significantly, but it had no effect on plasma IRG. The cardiotonic agents dobutamine and amrinone also elevated blood glucose. Thus, TA-064 is unique among the beta-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect. Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064.

Adrenergic beta-Agonists↗
PubMed1984

Perfusion preservation of cadaver rat pancreas: I. Morphological observation and biological function of the islets.

When using methods of perfusion to preserve the rat pancreas, we found that perfusion into the celiac axis was the most effective. The viability of the cadaver pancreas from decapitated rats preserved by perfusion into the celiac axis for 6 hours under various conditions of hypothermia, hyperbaria and oxygenation was investigated. The condition of perfusion affected the ratio of degenerative islets/normal islets in the pancreas. The ratio, under conditions of hypothermia and oxygenation was the lowest, while that under conditions of hyperbaria was the highest. Insulin-releasing activity of islets from 6-hour-perfusion-pancreas, under conditions of hypothermia and oxygenation was 86.5 per cent or more of that of the control. Stainings with fluorescent antibody and peroxidase antiperoxidase, revealed a large number of A and B cells in the islets of the pancreas, in cases of up to 6 hours of perfusion.

Animals↗