Biomedical subjects

T Takeshita

Publications and source records attributed to T Takeshita.

At least 19 recordsLinked to original sources

PubMed1992

Relationship between tissue content of TC-81 and relaxation of rat aorta.

This study dealt with the relationship between the relaxant action of TC-81, a new Ca2+ antagonist, and its distribution in rat aorta depolarized by high K+ (65.4 mM). The inhibitory effect by TC-81 on K(+)-induced contraction and 45Ca2+ uptake was strongly time-dependent. TC-81 and nicardipine, each 10(-9) M, produced gradual relaxation of high-K(+)-induced contraction. The tissue contents of TC-81 and nicardipine increased with time courses that reflected decreasing tension. Both the maximum tissue content of TC-81 and the maximum relaxation were significantly greater than those for nicardipine. Also, the relaxations produced by TC-81 and nicardipine were correlated with the logarithm of the content of each drug in muscle tissues. However, the dissociation of TC-81 from the tissues was slower than that of nicardipine. The data suggest that the action of TC-81 is closely related to a gradual distribution of drug into muscle tissue, resulting in a slow onset of action. Also, the saturation time of TC-81 was longer than that of nicardipine, thereby accounting for the greater relaxation with TC-81.

Animals↗

PubMed1992

[MR imaging during arterio-portography (MR-AP) in the detection of hepatic cancer].

Magnetic resonance imaging during arterio-portography (MR-AP) was performed in 2 patients of hepatic cancer. Low dose of meglumine gadopentetate (4 ml of a 0.5 mmol/L solution) was injected into a superior mesenteric artery during acquisition of a Turbo-FLASH sequence. An increase in liver to lesion contrast was obtained with MR-AP and it is also useful in the late phase to distinguish a flow defect lesion due to portal obstruction from the tumor.

Gadolinium DTPA↗

PubMed1992

Cell type-specific tyrosine phosphorylation of IL-2 receptor beta chain in response to IL-2.

Functional activities of the IL-2 receptor (IL-2R) beta chain exogenously expressed on lymphoid and non-lymphoid cells were examined in terms of phosphorylation of IL-2R beta and cell growth. Lymphoid MOLT-4 and its transfectants expressing IL-2R beta either alone or with IL-2R alpha chain were found to be rapidly phosphorylated predominantly at tyrosine residues of IL-2R beta and to be affected in their growth in an IL-2-dependent manner. In contrast, IL-2 induced neither phosphorylation of IL-2R beta nor cell growth in non-lymphoid transfectants derived from COS7, HeLa and L929, even though they acquired the IL-2 binding ability when coexpressed as IL-2R beta and IL-2R alpha. These results suggest that IL-2 induces activation of a tyrosine kinase possibly associated with IL-2R beta in a cell type-specific manner.

Cell Division↗

PubMed1992

Cloning of the gamma chain of the human IL-2 receptor.

A third subunit, the gamma chain, of the human interleukin-2 receptor (IL-2R) was identified, and a complementary DNA clone encoding this member of the cytokine receptor family was isolated. The gamma chain is necessary for the formation of the high- and intermediate-affinity receptors, which consists of alpha beta gamma heterotrimers and beta gamma heterodimers, respectively. The IL-2R on murine fibroblastoid cells can be internalized after binding IL-2 only if the gamma chain is present; alpha and beta are insufficient for internalization. Thus, the gamma chain is an indispensable component of the functional IL-2R.

Amino Acid Sequence↗

PubMed1992

[Combined treatment of invasive bladder cancer by intra-arterial infusion chemotherapy of cisplatin with or without other anticancer agents and concurrent radiotherapy--initial response and side effects].

Fourteen patients with invasive bladder cancer were treated by bilateral internal iliac artery infusion of cisplatin, with or without other anticancer agents, and concurrent radiotherapy. Angiotensin II was simultaneously infused in 10 cases. Of the 14 patients, complete response and partial response were achieved in 9 (64%) and 3, respectively. Hematuria was controlled in all 8 patients, and pain was relieved in 3 of 4 patients. Side effects were observed in 8 patients: appetite loss in 8, nausea and/or vomiting in 7, and leukocytopenia in 6 patients, in 3 of whom radiotherapy had to be intermittent because of severe leukocytopenia (less than 2000/mm3). However, restoration of leukocytopenia occurred one week later. Thus, intra-arterial anticancer agents including cisplatin together with concurrent radiation may be one of the most effective therapies for invasive bladder cancer.

Aged↗

PubMed1992

IL-2-dependent in vivo and in vitro tyrosine phosphorylation of IL-2 receptor gamma chain.

We previously reported a molecule, p64, which was tentatively named the gamma chain, coprecipitable with the beta chain of human interleukin-2 receptor (IL-2R). The present study demonstrated that the gamma chain, as well as the beta chain expressed on IL-2-responsive cells, is phosphorylated on tyrosine residues in an IL-2-dependent manner in vivo and in vitro. The in vivo tyrosine phosphorylation of both chains was similarly induced within 1 min after IL-2 stimulation, and their in vitro tyrosine phosphorylation with the anti-IL-2R beta antibody-directed immunocomplex was also increased by treatment of cells with IL-2. These results suggest that a tyrosine kinase is associated with the beta gamma subunit complex, of which activation by IL-2 may result in transduction of intracellular signals.

Amino Acid Sequence↗

PubMed1992

Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules.

T cell stimulation by the human immunodeficiency virus 1 gp160-derived peptide p18 presented by H-2Dd class I major histocompatibility complex molecules in a cell-free system was found to require proteolytic cleavage. This extracellular processing was mediated by peptidases present in fetal calf serum. In vitro processing of p18 resulted in a distinct reverse phase high performance liquid chromatography profile, from which a biologically active product was isolated and sequenced. This peptide processing can be specifically blocked by the angiotensin-1 converting enzyme (ACE) inhibitor captopril, and can occur by exposing p18 to purified ACE. The ability of naturally occurring extracellular proteases to convert inactive peptides to T cell antigens has important implications for understanding cytotoxic T lymphocyte responses in vivo, and for rational peptide vaccine design.

Amino Acid Sequence↗

PubMed1992

An associated molecule, p64, with IL-2 receptor beta chain. Its possible involvement in the formation of the functional intermediate-affinity IL-2 receptor complex.

We identified previously a membrane molecule, p64, which co-precipitates with the IL-2R beta-chain in human T cells. We have now investigated the biologic significance of p64 in the formation of the functional IL-2R complex with cell lines transfected with cDNA of IL-2R alpha- and/or beta-chains. Two functional parameters associated with IL-2R, IL-2 binding ability and association of p64 with the beta-chain, were examined. Two subclones, MOLT beta-11 and MOLT beta-12, of an IL-2R beta cDNA-transfected MOLT4 clone expressed similar numbers of IL-2R beta molecules on cell surfaces and bound to IL-2 with intermediate affinity. However, the numbers of IL-2 binding sites were significantly lower than those of IL-2R beta molecules and considerably different between the two subclones. The amount of p64 co-precipitated with IL-2R beta was proportional to numbers of the IL-2 binding sites in the two subclones. In addition, neither p64 co-precipitation nor IL-2 binding was detected in HeLa and COS7 cells transfected with IL-2R beta, and no p64 precipitation was seen even in those transfectants with both IL-2R alpha and beta cDNAs, which bind to IL-2 with high affinity but are not able to transduce intracellular signals. These results suggest the possibility that p64 associates with IL-2R beta and has an important role in formation of the functional IL-2R complex.

Binding Sites↗

PubMed1992

The effect of aging on cell-cycle kinetics and X-ray-induced chromosome aberrations in cultured lymphocytes from patients with Down syndrome.

To evaluate the effects of aging on cytogenetic characteristics of lymphocytes from Down syndrome (DS), cell-cycle kinetics after PHA stimulation and chromosome-type aberration frequencies after X-ray exposure were investigated in vitro in the lymphocytes derived from 4 (or 3 for X-ray treatment) age groups of DS patients and age-matched controls. The results clearly showed higher mitotic and proliferation index levels in younger groups compared to older groups at the various culture intervals, whether the lymphocytes were from the DS patients or controls. The age-related changes of the proliferation index were mainly attributed to a delayed response to PHA as age increased. The changes of PHA responses seemed to be particularly marked during adolescence. Nonetheless, no significant differences were observed between the DS patients and age-matched controls for each age group. In all age groups, frequencies of both chromosome-type exchanges and deletions were elevated in the DS patients by about 1.3 times in comparison with the controls. The magnitude of radiosensitivity, however, seemed to decrease slightly in the 40-49-year group. To our knowledge, the present study is the first report in the literature to deal with the effect of aging on the greater radiosensitivity of DS lymphocytes.

Adolescent↗

PubMed1992

Differences in responses to TC-81 among various arteries in dogs.

The vasodilation induced by TC-81 was investigated in vitro and in vivo. In helical strips of dog arteries precontracted with 65.4 mM KCl, TC-81, nicardipine, nifedipine, diltiazem, and papaverine produced concentration-dependent relaxation. The potencies of TC-81 were in the following order: basilar > coronary > femoral > renal > mesenteric arteries. The other drugs also showed a similar property of greater response in basilar and coronary arteries than in renal and mesenteric arteries. However, the difference in reactivity to TC-81 was greater. On the other hand, TC-81, nicardipine, and papaverine dose-dependently increased the blood flow in vertebral, coronary, and femoral arteries in anesthetized dogs. However, the blood flow in renal and mesenteric arteries was not changed or decreased. The decreases in vessel resistance induced by TC-81 were in the following order: vertebral > coronary > femoral > renal = mesenteric arteries, agreeing with the experimental results in vitro. These results suggest that Ca2+ antagonists have the pharmacological property of vasodilating cerebral and heart blood vessels more selectively than other arteries, and this property of TC-81 might be an advantage compared with other drugs.

Animals↗

PubMed1992

Genetic and environmental factors of bone mineral density indicated in Japanese twins.

To evaluate the effects of genetic and environmental factors on the bone mass, we determined the bone mineral density (BMD) in the total body, the lumbar spine and in the femoral neck in 23 Japanese twin pairs including 21 monozygotic (MZ) pairs, applying dual-energy X-ray absorptiometry. In MZ pairs aged 20-49 years, highly significant intraclass correlation coefficients, ranging from 0.775 to 0.926, were observed at several sites, including the lumbar spine and the femoral neck, which suggests considerable contributions of genetic factors to the BMD. Neither intraclass correlation coefficients nor intrapair differences were found to change with increasing age in the present analysis. In female MZ pairs, exercises both at the present time and in the past were correlated with the BMD at several sites as well as body mass index in multiple regression analyses.

Absorptiometry, Photon↗

PubMed1992

Synthesis and antihypertensive activity of 1,4-dihydropyridine derivatives with a 4-(disubstituted phenyl) ring and an aminoalkyl ester group: highly potent and long-lasting calcium antagonists.

New 1,4-dihydropyridine derivatives bearing a 4-(disubstituted phenyl) ring and an aminoethyl ester or an amino-2,2-dimethyl-propyl ester were synthesized and their antihypertensive activities were examined in normotensive rats and spontaneously hypertensive rats. The effects of phenyl substituents and ester groups on the antihypertensive activity are discussed. Several compounds showed a more potent antihypertensive activity than nicardipine and most compounds had a longer duration of action. Among them, 7B.HCl (TC-81) showed highly potent and long-lasting activity and was selected as a candidate for further pharmacological investigations.

Animals↗

PubMed1992

Triterpene glycosides from the seeds of Astragalus sinicus L.

From the seeds of Astragalus sinicus L. (Leguminosae), seven triterpene glycosides were isolated and identified as soyasaponin I-III methyl esters (1-3) which were treated with CH2N2 during the separation procedure, soyasaponin IV (4), soyasapogenol B 3-O-beta-D-glucuronopyranoside (5), 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-xylopyranosyl(1-->2)-beta-D- glucuronopyranosyl 3 beta, 22 beta, 24-trihydroxy-11-oxoolean-12-ene (6), whose sapogenol (8) was obtained by enzymatic hydrolysis using glycyrrhizinic acid hydrolase, unambiguously characterized and designated as complogenin, and 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-galactopyranosyl(1-->2)-beta-D - glucuronopyranosyl complogenin (7).

Glycosides↗

PubMed1992

The IL-2/IL-2 receptor system: involvement of a novel receptor subunit, gamma chain, in growth signal transduction.

We previously demonstrated the existence of a third component, p64, of IL-2 receptor (IL-2R), tentatively named the gamma chain of IL-2R. Our recent studies provided evidence suggesting that the gamma chain endows the beta chain of IL-2R with IL-2 binding ability. The gamma chain was detected in lymphoid transfectants of IL-2R beta cDNA, which showed the intermediate-affinity IL-2R, but not in nonlymphoid transfectants of IL-2R beta cDNA, which showed no IL-2 binding activity. The comparative study between two subclones of lymphoid MOLT4 transfectant of IL-2R beta cDNA demonstrated that the amount of the gamma chain coprecipitated with IL-2R beta was proportional to numbers of the IL-2 binding sites. These results suggest the possibility that the gamma chain associates with IL-2R beta and has an important role in formation of the intermediate-affinity IL-2R complex. On the other hand, we have also demonstrated the association of IL-2R beta with a certain tyrosine kinase, of which activation by IL-2 could be indispensable process at the initial pathway of signal transduction.

Animals↗

PubMed1992

[Anticancer effect and side effect of arterial chemoembolization using cis-diamine-dichloroplatinum (II)/4-0-tetrahydropyranyl-adriamycin-lipiodol (CTL) suspension on hepatocellular carcinoma].

Seventeen patients with hepatocellular carcinoma were treated by intraarterial injection of CTL suspension. The doses of CTL suspension, CDDP and THP(mean +/- SD)/injection were 4.1 +/- 1.6 ml, 81.9 +/- 31.6 mg and 13.5 +/- 5.2 mg, respectively. The therapy was given once in 10 patients, twice in 6 and 4 times in one. Over 50 per cent reduction in tumor size was obtained in 5 patients (30%). Fifty or more % decrease in serum alpha-feto-protein (AFP) levels was observed in 3 of 7 patients (43%) with the initial serum AFP level of more than 200 ng/ml, Fever, abdominal pain, nausea and vomiting were noted in most cases. However, they disappeared within 2 weeks after therapy was completed. No severe complications were encountered except one case of a liver abscess which healed by administration of antibiotics. No severe changes in laboratory data were observed. This study suggests that a new method of intraarterial injection must be developed to enhance the therapeutic effect even more, in addition to an increased injection dose of CDDP/THP-LPD and higher concentration of CDDP and THP in LPD.

Adult↗

PubMed1992

Antihypertensive effect of the new calcium antagonist (+-)-3-(benzylmethylamino)-2,2-dimethylpropyl-methyl-4-(2-fluoro-5- nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate hydrochloride in rats.

The antihypertensive effect of TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl-methyl-4-(2-f luoro-5- nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate hydrochloride), a new calcium antagonist, was investigated in normotensive and hypertensive rats. By oral administration, the antihypertensive activity of TC-81 (ED20% in spontaneous hypertensive rats (SHR), DOCA-salt hypertensive rats and renal hypertensive rats were 0.37, 0.32, and 0.38 mg/kg p.o., respectively) was 7-14 times more potent in conscious hypertensive rats in comparison with nicardipine. Duration of the antihypertensive effect of TC-81 was about 2 times longer than that of nicardipine, and the response was elicited more slowly than that of nicardipine at an equipotent dose. Similar results were observed by intravenous injection, but the potency of TC-81 was only 3 times higher than that of nicardipine in anesthetized rats. Tolerance of the antihypertensive effect of TC-81 in long-term daily dosing and the rebound phenomenon after discontinuance of the treatment were not observed in hypertensive rats. TC-81, at a concentration of 10(-10)-3 x 10(-9) mol/l, inhibited the KCl-induced contraction of isolated rat vascular preparations. Moreover, TC-81 inhibited the norepinephrine-induced contraction of isolated SHR aorta preparation, but in isolated normotensive rat aorta, TC-81 inhibited the norepinephrine-induced contraction very little. From these observations, TC-81 can be characterized as having a strong, long-lasting, and slow-onset antihypertensive activity, especially by oral administration. Therefore, this new calcium antagonist may be useful for long-term antihypertensive therapy.

Animals↗

PubMed1992

Antihypertensive effect of the new dihydropyridine calcium antagonist (+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedica rbo xylate hydrochloride in dogs.

The antihypertensive effect of TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate hydrochloride, CAS 96515-74-1), a new calcium antagonist, was investigated in normotensive dogs (NTD) and renal hypertensive dogs (RHD). By oral administration, the antihypertensive activity of TC-81 (ED20% was 0.09 mg/kg p.o.) was about 18 times more potent in conscious RHD in comparison with nicardipine (ED20% was 1.65 mg/kg p.o.). Duration of the antihypertensive effect of TC-81 was about 2 times longer than that of nicardipine, and the response was elicited more slowly than that of nicardipine at equipotent dose. Similar results were observed more clearly by intravenous injection, but the potency of TC-81 was only 3 times higher than that of nicardipine in anesthetized dogs. Tolerance of the antihypertensive effect of TC-81 in daily dosing for 2 weeks and the rebound phenomena after discontinuance of the treatment were not observed in RHD. TC-81 at a concentration of 10(10)-3 x 10(-9) mol/l inhibited the KCl- or norepinephrine-induced contraction of isolated dog femoral artery. From these observations, TC-81 can be characterized as having a strong, long-lasting, and slow-onset antihypertensive activity, especially by oral administration. Therefore, this new calcium antagonist may be useful for long-term antihypertensive therapy.

Anesthesia↗

PubMed1992

Distribution to and elimination from tissues following a single or repeated administration of 14C-(+-)-3-(benzyl-methylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedica rbo xylate hydrochloride in rats.

A newly synthesized calcium antagonist, TC-81((+-)-3-benzylmethylamino)-2,2-dimethylpropyl methyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate hydrochloride, CAS 96515-74-1) was administered to adult male rats, pregnant and lactating rats with a single oral dose or with repeated doses of 0.3 mg/kg for 2 weeks. The distribution to tissues, placental transfer and secretion of the radioactive drug into milk was studied using whole body autoradiography methods and quantitative determination of total radioactivity after autopsy. 14C-TC-81 was distributed rapidly but disproportionately to the tissues after single administration. The highest concentration of radioactivity was observed in the liver. The radioactivity in the various tissues declined slowly comparing to the plasma but at 96 h after dosing the radioactivity was detected only in the liver. The radioactivity penetrated the blood-placental barrier to a low extent after oral administration of 14C-TC-81 to pregnant rats. When 14C-TC-81 was administered to lactating rats, the radioactivity was secreted into the milk with the maximum concentration of radioactivity, 86% of the corresponding plasma concentration. Following 14-day oral treatments of male rats the equivalent concentration in the plasma was increased 1.5 fold as compared to the single treatment. In all tissues, the AUC0-24 h after 1, 7, and 14 days treatment were gradually increased, but these increases were almost the same as or even less than the rise observed in the plasma. After the last dosing, the radioactivity declined slowly with time in most of the tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗