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T Wada

Publications and source records attributed to T Wada.

At least 541 records · Page 30Linked to original sources
PubMed1994

Quantitative localization of angiotensin II receptor subtypes in spontaneously hypertensive rats.

Angiotensin II (Ang II) receptors were labelled by in vitro autoradiography using 125I-[Sar1,Ile8]Ang II as a ligand in the kidney, adrenal gland, thoracic aorta, and hindbrain of adult spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Ang II receptors were differentiated into subtypes by susceptibility to subtype 1 (AT1) and subtype 2 (AT2) antagonists. In both rat strains, the adrenal cortex contained predominantly AT1 receptors, while AT2 receptors predominated in the adrenal medulla. The kidney contained exclusively AT1 receptors in glomeruli, proximal tubules, and the outer medulla. AT1 receptors were predominant in the thoracic aorta. The nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus (DM10), area postrema, and spinal trigeminal nucleus (Sp5) contained exclusively AT1 receptors, whereas the nucleus of the inferior olive contained AT2 receptors predominantly. Significant differences in receptor density were observed between SHR and WKY. The adrenal cortex, renal outer medulla, NTS, DM10, and Sp5 displayed higher AT1 receptor density in SHR than in WKY. These results indicate that expression of AT1 receptors is regulated differently in important targets of Ang II in SHR, and suggest that altered regulation of AT1 receptor expression may be relevant to the pathogenesis of hypertension in SHR.

Adrenal Glands↗
PubMed1994

Renal protective effect of TCV-116 in stroke-prone spontaneously hypertensive rats.

We examined the effects of TCV-116, a non-peptide selective AT1 receptor antagonist, on cellular phenotype and on the expression of the transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix genes in the kidneys of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given vehicle or TCV-116 (10 mg/kg/day) by gastric gavage for 10 weeks (from the age of 22 to 32 weeks). Renal mRNA levels were measured by Northern blot analysis. In vehicle-treated 32-week-old SHRSP, urinary albumin excretion per 24 h was about 26-fold greater than that in age-matched Wistar-Kyoto (WKY) rats, and the mRNA levels of renal TGF-beta 1, fibronectin and collagen types I and III in SHRSP were all several-fold higher than those in WKY. Immunohistochemical studies showed the prominent presence of alpha-smooth muscle actin-expressing glomerular cells in SHRSP, in contrast to their absence in WKY. Treatment of SHRSP with TCV-116 decreased urinary albumin excretion and renal mRNA levels for TGF-beta 1 and for the above-mentioned extracellular matrix components. TCV-116 prevented the phenotypic modulation of glomerular cells in SHRSP. These results suggest that AT1 receptor antagonists may have powerful renal protective effects.

Albuminuria↗
PubMed1994

Pharmacological profile of a novel nonpeptide angiotensin II subtype 1 receptor antagonist, TCV-116.

TCV-116, an angiotensin II (AII) receptor antagonist, is a prodrug that is converted in vivo to the active form, CV-11974. CV-11974 selectively and competitively inhibited the specific binding of [125I]AII-(Sar1,lle8) to All subtype 1 (AT1) receptors in rabbit aortic membranes (Ki = 0.64 nM) and insurmountably inhibited the AII-induced maximal contractile response of rabbit aortic strips (pD'2 = 9.97). TCV-116 inhibited the AII-induced pressor response in rats (ID50 = 0.069 mg/kg. p.o.). In spontaneously hypertensive rats (SHR), TCV-116 had a sustained antihypertensive effect (ED25 = 0.68 mg/kg, p.o.). Repeated oral administration of TCV-116 (1 mg/kg) to SHR once daily for 2 weeks reduced blood pressure by 30-50 mmHg over 24 h. The antihypertensive effects of TCV-116 correlated well with the inhibition of AII-induced contractile responses of aortic strips prepared ex vivo after administration of TCV-116. TCV-116 had sustained effects in both 2 kidney, 1 clip hypertensive rats and in 1 kidney, 1 clip hypertensive rats, but had no effect in DOCA/salt hypertensive rats. Unlike enalapril, TCV-116 had no potentiating effect on the incidence of cough induced by citric acid in guinea pigs. These results suggest that TCV-116 is a promising antihypertensive agent with once daily administration.

Angiotensin Receptor Antagonists↗
PubMed1994

[DNA ploidy and proliferating cell nuclear antigen positivity rate as predictive indication of effectiveness of preoperative radiation].

We compared histological effects following radiotherapy in relation to the DNA ploidy pattern and the proliferating cell nuclear antigen (PCNA) positivity rate in 37 patients with rectal cancer who underwent preoperative radiation therapy. Twelve of 23 cases in which the PCNA positivity rate before irradiation was more than 25% showed the effectiveness of radiotherapy (52.2%), against 2 of 6 cases with a rate of less than 25%. Cases in which the rate was more than 25% tended to show more effectiveness. Seventeen of 23 cases in which the PCNA positivity rate was more than 25% showed a decrease in PCNA positivity rate (73.9%). The rate in 6 cases showed no change, and no cases had an increase. In particular, in 12 cases in which the PCNA positivity rate was more than 55%, half showed effectiveness, and the PCNA rate decreased 20% on average. The PCNA positivity rate tended to decrease as a result of irradiation, and especially in diploid cases there were significant differences in the rate before and after irradiation. We suggest that cases in which the PCNA positivity rate is more than 55% with diploid DNA pattern would show most effect. The effects of irradiation could be predicted with biopsy materials and by measuring the DNA ploidy pattern and the PCNA positivity rate.

Adenocarcinoma↗
PubMed1994

Essential involvement of interleukin-8 (IL-8) in acute inflammation.

Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to the infiltration at inflammatory sites. Interleukin-8 (IL-8), a novel leukocyte chemotactic activating cytokine (chemokine), is produced by various types of cells upon stimulation with inflammatory stimuli and exerts a variety of functions on leukocytes, particularly, neutrophils in vitro. However, no definitive evidence has been presented on its role in recruiting and activating neutrophils in the lesions of various types of inflammatory reactions. We administered a highly specific neutralizing antibody against IL-8 in several types of acute inflammatory reactions, including lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex-type glomerulonephritis. Anti-IL-8 treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in these conditions. These results suggest that IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.

Animals↗
PubMed1994

[The comparison of clinical features between early rheumatoid arthritis and established rheumatoid arthritis].

Clinical features between 69 early RA patients (within a year duration) and 79 established RA patients (more than 3 years duration) were compared retrospectively. There were no significant differences about frequencies of morning stiffness (68.2% vs 54.4%) and rheumatoid nodules (20.2% vs 15.2%) between early RA and established RA. There were also no significant differences between two groups about elevation of ESR (92.8% vs 97.4%), positivity of CRP (97.1% vs 94.9%) and rheumatoid factor (RF) (82.6% vs 93.7%), and Lansbury activity index (AI) (mean 68.8% vs 78.8%). After hospitalization and treatment, all clinical indices (ESR, CRP, RF, AI) improved significantly in both groups. There, however, were clinically more "marked improvement" (39.1% vs 16.4%) and "remission" (8.7% vs none) in early RA group. We conclude that by hospitalization and treatment, clinical improvement can be expected in both early and established RA, but to secure satisfactory improvement, early detection and intervention of RA would be recommended.

Adult↗
PubMed1994

[Phase II study of CGS16949A, a new aromatase inhibitor--a dose finding study].

A dose finding phase II study of a novel aromatase inhibitor CGS16949A was performed in postmenopausal patients with advanced breast cancer. The daily dose of 1 mg (0.5 mg b.i.d.), 2 mg (1 mg b.i.d.) or 4 mg (2 mg b.i.d.) CGS16949A was administered orally for 8 weeks or more on dose escalation schedule. The response rates (CR+PR) in the evaluable cases were 13.6%, 22.0% and 13.3% in 1 mg/day group (1 mg group), 2 mg/day group (2 mg group) and 4 mg/day group (4 mg group), respectively. There was no statistically significant difference in the response rates among the three treatment groups. Median time to the onset of PR was 99, 113 and 114 days in 1 mg, 2 mg and 4 mg group, respectively, and the median duration of response was 276 days, 391 days and 277 days in 1 mg, 2 mg and 4 mg group, respectively. Five patients in each treatment group showed prolonged stabilization of disease ("long NC", lasting > or = 6 months). Median durations of stabilization were 223 and 241 days in 2 and 4 mg group respectively. The incidence of adverse effects were 11.9%, 7.5% and 13.0% in 1 mg, 2 mg and 4 mg group respectively, and 30 out of 33 symptoms (90.9%) were of mild. Laboratory abnormalities were observed in 12.2%, 22.9% and 23.8% in the respective groups of 1, 2 and 4 mg, and no patient experienced clinical symptoms related to these changes. Plasma estradiol concentration at one month after initiation of the treatment decreased significantly in comparison with pretreatment levels, and was slightly exceeding the limit of detection. Plasma cortisol was not changed. As shown in this results, CGS16949A showed sufficient efficacy and good tolerability in postmenopausal patients with advanced breast cancer. It was considered that the optimal dose in clinical use judged as 2 mg/day.

Administration, Oral↗
PubMed1994

[Late phase II study of CGS16949A, a new aromatase inhibitor--a multicentral cooperative study (Western Japan Group)].

A late phase II study of a new non-steroidal aromatase inhibitor CGS16949A was performed in postmenopausal patients with advanced or recurrent breast cancer. The drug was given orally, 1 mg twice daily for 12 weeks or more. Of 72 evaluable cases, there were 1-CR, 10-PR, 17-"long NC", 12 NC and 32-PD, with "long NC" defined as disease stabilization for more than 6 months. Median time to the onset of PR and median duration of objective tumor responses were 85 and 278 days, respectively. Maximum and median duration of long NC were 471 and 243 days, respectively. Adverse effects were observed in 5 (7.8%) of 64 cases. In laboratory evaluations, slight abnormalities were observed in 11 (17.2%) of 64 cases. No adverse effect and laboratory abnormality was found worse than Grade 1 toxicity. As for Global Utility Rating, treatment with CGS16949A was considered to be useful or better in 24 (32.9%) of 73 cases. Plasma estradiol and estrone concentrations at one month after initiation of the treatment decreased significantly in comparison with pre-treatment levels. Plasma cortisol, testosterone and androstenedione was not changed. Thus, CGS16949A showed good efficacy, tolerability and usefulness in postmenopausal patients with advanced or recurrent breast cancer.

Administration, Oral↗
PubMed1994

Antihypertensive effects of a highly potent and long-acting angiotensin II subtype-1 receptor antagonist, (+-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116), in various hypertensive rats.

The antihypertensive effects of (+-)-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2'-(1H- tetrazol-5- yl)biphenyl-4-yl]methyl]-1-H-benzimidazole-7-carboxylate (TCV-116), an angiotensin II (AII) subtype-1 receptor antagonist, were studied in various hypertensive and normotensive rats, using 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl-4- yl)methyl]-imidazole, potassium salt (losartan) as a reference compound. TCV-116 is a prodrug, which is converted in vivo to the active component, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974). In spontaneously hypertensive rats (SHR) p.o. TCV-116 (0.1 mg/kg) demonstrated a sustained antihypertensive effect that lasted for more than 10 hr and the dose that reduced the blood pressure by an average of 25 mm Hg for 24 hr (ED25), was 0.68 mg/kg. Intravenous CV-11974 reduced the blood pressure with an ED25 of 0.0027 mg/kg. Repeated p.o. administration of TCV-116 (1 mg/kg) to SHR once daily for 2 weeks reduced the blood pressure by 30 to 50 mm Hg over 24 hr without any heart rate changes. The antihypertensive effects of TCV-116 correlated well with the inhibition of angiotensin II-induced contractile responses of aortic strips prepared ex vivo after p.o. administration of TCV-116. Oral TCV-116 had a sustained antihypertensive effect with ED25 of 0.03 and 0.23 mg/kg in two-kidney, one-clip and one-kidney, one-clip hypertensive rats, respectively, and was much more potent in SHR and renal-hypertensive rats than losartan.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1994

Efficacy of additive DMARD therapy in patients with rheumatoid arthritis. Double blind controlled trial using bucillamine and placebo with maintenance doses of gold sodium thiomalate.

OBJECTIVE: To examine the efficacy of the addition of small doses of additional disease modifying antirheumatic drugs (DMARD) to ongoing DMARD treatment [additive DMARD therapy (ADT)]. METHODS: A 3-month prospective, double blind, randomized, placebo controlled study was performed using either 100 mg/day of bucillamine (Buc) or an inactive placebo (P1). Two groups of 12 patients each who had experienced an insufficient benefit from gold sodium thiomalate (GSTM) alone were enrolled in the study. RESULTS: The addition of Buc proved more beneficial than P1 regarding improvement in disease activity (p = 0.0032) and drug usefulness (p = 0.0025). A significant within group improvement was observed in joint swelling count, the Lansbury activity index, erythrocyte sedimentation rate and C-reactive protein. However, the difference in the clinical variables between the 2 groups was minimal. CONCLUSION: The usefulness of ADT was suggested by this trial; however, further confirmation by additional studies is still needed.

Aged↗
PubMed1994

[Clinical study of fluconazole-injectable and -granules in pediatric patients].

In this study, we have investigated the clinical effectiveness of fluconazole (FLCZ) given intravenously or orally to pediatric patients with systemic fungal infections. FLCZ was administered intravenously to two patients with acute leukemia (multiple hepatosplenic candidiasis and aspergillosis) and orally to two mycosis complicated with neuroblastoma and aplastic anemia, respectively. Clinical efficacies were excellent and no side effects were observed in any patients. Pharmacokinetic analysis in 6 neonates revealed that the plasma half-life is 37-41 hours after administration of single dose of intravenous infusion of 3 mg/kg of FLCZ.

Administration, Oral↗
PubMed1994

[Two cases of aortoesophageal fistula due to ruptured thoracic aortic aneurysm].

Aortoesophageal fistula due to ruptured thoracic aortic aneurysm is uncommon, and exhibits extremely high mortality. We experienced two cases of such lesion. The first case showed aneurysm in the aortic arch closed with Dacron patch but leaving the esophageal defect. The patient died of an infection of the patch graft after oral feeding. The second case was demonstrated infected aneurysm of the descending aorta. The patient was rescued by primary operation, replacement of the aorta by an artificial graft and resection of the esophagus, and the secondary operation, reconstruction of the esophagus. We recommend resection of aneurysm and the esophagus as well in the aspect of lower post-operative infection in the graft and of the better prognosis of the lesion.

Aged↗
PubMed1993

Inhibition of rabbit aortic angiotensin II (AII) receptor by CV-11974, a new nonpeptide AII antagonist.

The angiotensin II (AII) antagonistic action of CV-11974 (2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylic acid) was investigated in an AII-receptor binding assay using rabbit aortic membranes and an AII-induced contraction assay using rabbit aortic strips. A single class of [125I]AII-(Sar1,Ile8) binding sites was found in the membranes with a dissociation constant (Kd) of 0.15 nM and a receptor concentration (Bmax) of 86.9 fmol/mg protein. CV-11974 markedly reduced Kd without affecting Bmax. The specific binding of [125I]AII-(Sar1,Ile8) in this preparation was inhibited completely by CV-11974 [the inhibition constant (Ki) = 0.64 nM], DuP 753 [an angiotensin II type I (AT1) receptor-selective antagonist] (Ki = 51 nM) and EXP3174 (an active metabolite of DuP 753) (Ki = 6.8 nM), but was not affected by PD123177 (an AT2 receptor-selective antagonist). These results suggest that the single binding site in rabbit aortic membranes is an AT1 receptor subtype. The affinity of CV-11974 to these AT1 receptors was approximately 80 and 10 times higher than that of DuP 753 and EXP3174, respectively. CV-11974 showed no appreciable affinity for the AT2 receptors found in bovine cerebellum. In the in vitro functional study, CV-11974 markedly reduced the AII-induced maximal contractile response of rabbit aortic strips (pD'2 = 9.97). In contrast, Compound 7-H, which lacks the carboxyl group at the benzimidazole ring of CV-11974, inhibited the contraction in a competitive manner. The inhibition by CV-11974 was long lasting. These results suggest that CV-11974 is a potent and long-acting AT1 receptor-selective, competitive antagonist. The carboxyl group at the benzimidazole ring plays an important role in the interaction between CV-11974 and the AT1 receptor.

Angiotensin II↗