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Biomedical subjects

T Shindo

Publications and source records attributed to T Shindo.

At least 19 recordsLinked to original sources
PubMed2005

Safety, tolerability, and pharmacokinetics of TAS-108 in normal healthy post-menopausal female subjects: a phase I study on single oral dose.

OBJECTIVES: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of TAS-108 after ascending single oral doses and to analyse preliminarily the effect of food on the pharmacokinetics of TAS-108 in normal healthy post-menopausal female subjects. METHODS: Twelve healthy subjects participated in an open-label, ascending single-dose, alternating group, safety, tolerance, and pharmacokinetic study of TAS-108 administered orally to two groups of the subjects, one given alternating doses of 10, 40, 120 mg (group A) and the other of 20, 80, 160 mg (group B), in the fasting state. In addition, six subjects (group A) were administered an additional dose at 120 mg TAS-108 after food consumption. Plasma and urine samples for measurement of TAS-108 were analysed by validated analytical procedures using a liquid chromatographic method with tandem mass spectrometric detection (LC/MS/MS). RESULTS: There was no dose-dependent increase in any adverse events (AEs), and there were no serious AEs or deaths. TAS-108 was readily absorbed following oral administration of the 80-, 120- and 160-mg doses. Plasma TAS-108 levels steadily declined, generally in a mono-exponential manner, with overall mean t(1/2) values ranging from 3.04 to 4.43 h in the fasting groups. Administration of TAS-108 after a high-fat meal markedly increased the bioavailability of the drug. The mean C(max) and AUC(0--t) values increased after a high-fat breakfast by 182 and 191% compared with the fasting value respectively. CONCLUSIONS: In this escalating dose study of TAS-108, the drug was well tolerated by the participants. The maximum and systemic exposure to TAS-108 tended to increase with increasing dose and its bioavailability markedly increased after high-fat food intake.

Adult↗
PubMed2005

Significance of the transcription factor KLF5 in cardiovascular remodeling.

Structural remodeling of the heart and blood vessels is an important pathologic process in the development of many cardiovascular diseases. However, transcriptional regulation of altered gene expression during cardiovascular remodeling is not well understood. We previously isolated KLF5/basic transcription element-binding (BTEB)2, a Krüppel-like factor, as a transcription factor that binds the promoter of the embryonic smooth muscle myosin heavy chain gene (SMemb). KLF5 activates many genes inducible during cardiovascular remodeling, such as platelet-derived growth factor (PDGF)-A/B, Egr-1, plasminogen activator inhibitor-1 (PAI-1), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) receptors. KLF5 is abundantly expressed in embryonic smooth muscles and is down-regulated with vascular development, but reinduced in proliferative neointimal smooth muscles in response to vascular injury. In KLF5 gene-targeted mice, homozygotes die at an early embryonic stage whereas heterozygotes are apparently normal. However, in response to external stress, arteries of heterozygotes exhibit diminished levels of smooth muscle and adventitial cell activation. Furthermore, angiotensin II-induced cardiac hypertrophy and fibrosis are attenuated in heterozygotes. KLF5 activities are regulated by many transcriptional regulators and nuclear receptors, such as retinoic acid receptor-alpha (RAR alpha), NF-kappaB, PPAR gamma, p300, and SET. Interestingly, RAR alpha agonist suppresses KLF5 and cardiovascular remodeling, whereas RAR alpha antagonist activates KLF5 and induces angiogenesis. These results indicate that KLF5 is an essential transcription factor in cardiovascular remodeling and a potential therapeutic target for cardiovascular disease.

Angiotensin II↗
PubMed2005

Implantation of a pleurovenous shunt for massive chylothorax in a patient with yellow nail syndrome.

Yellow nail syndrome is a type of lymphatic dysplasia syndrome characterised by the triad of yellow nails, lymphoedema, and pleural effusions. The case history is presented of a 70 year old patient with yellow nail syndrome who complained of dyspnoea caused by massive chylothorax. The patient underwent insertion of a pleuroperitoneal shunt which resulted in abdominal distension and deterioration of leg oedema. The pleuroperitoneal shunt was replaced by a pleurovenous shunt on the right side which led to an improvement in the bilateral pleural effusions, abdominal distension, and leg oedema. A pleurovenous shunt may be an alternative rescue therapy for yellow nail syndrome.

Aged↗
PubMed2001

Elevated sympathetic nervous activity in mice deficient in alphaCGRP.

alpha-Calcitonin gene-related peptide (alphaCGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of alphaCGRP, we developed an alphaCGRP-null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained alphaCGRP-null mice than in corresponding wild-type mice. The elevated MAP in alphaCGRP-null mice was shown to be the result of elevated peripheral vascular resistance by alpha-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between alphaCGRP-null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in alphaCGRP-null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that alphaCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.

Adrenergic alpha-Antagonists↗
PubMed2001

Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1.

The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.

Aging↗
PubMed2001

Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene.

BACKGROUND: Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. METHODS AND RESULTS: Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. CONCLUSIONS: AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.

Adrenomedullin↗
PubMed2001

Vascular smooth muscle cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxide-induced vasodilation in mice.

To elucidate pathophysiological roles of heme oxygenase (HO)-1 in regulation of vascular tone in vivo, we have developed and characterized transgenic (Tg) mice that overexpress HO-1 site specifically in vascular smooth muscle cells (VSMCs). The Tg mice were generated by use of human HO-1 cDNA under the control of SM22-alpha promoter. The HO-1 gene overexpression was demonstrated by Northern blot analysis and coincided with increases in the protein expression in VSMCs and total HO activities. Tg mice exhibited a significant increase in arterial pressure at various ages and displayed impaired nitrovasodilatory responses in isolated aortic segments versus nontransgenic littermates while enhancing their nitric oxide (NO) production. The pressure of Tg mice was unchanged by systemic administration of either N(omega)-nitro-L-arginine or SNP. Furthermore, the isolated aorta in these mice exhibited lesser extents of NO-elicited cGMP elevation via soluble guanylate cyclase (sGC), while exhibiting no notable downregulation of sGC expression. Such impairment of the NO-elicited cGMP increase was restored significantly by tin protoporphyrin IX, an HO inhibitor. On the other hand, 3-(5'-hydroxymethyl-2' furyl)-1-benzyl-indazol (YC-1), an NO-independent activator of sGC, increased cGMP and relaxed aortas from Tg mice to levels comparable with those from nontransgenic mice, which indicates that contents of functionally intact sGC are unlikely to differ between the two systems. These findings suggest that site-specific overexpression of HO-1 in VSMCs suppresses vasodilatory response to NO and thereby leads to an elevation of arterial pressure.

Animals↗
PubMed2001

Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury.

BACKGROUND: Increasing evidence indicates that elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and endothelial dysfunction, although little specific information on the mechanisms responsible for the atherogenic effects of homocysteine or on the in vivo contribution made by hyperhomocysteinemia to atherosclerosis is currently available. Because homocysteine is known to exert a direct inhibitory effect on endothelial cell growth in vitro, we hypothesized that this effect contributes to the progression of atherosclerotic lesions initiated by endothelial damage caused by mechanical injury. METHODS AND RESULTS: We prepared diet-induced hyperhomocysteinemic rats in which neointima formation after balloon injury to the common carotid artery was assessed. Moderate hyperhomocysteinemia (plasma homocysteine levels 3- to 4-fold higher than control) significantly exacerbated neointima formation. Oral administration of folate, which had a homocysteine-lowering effect, diminished neointima formation induced by moderate hyperhomocysteinemia. Furthermore, the attenuation of reendothelialization was shown in diet-induced hyperhomocysteinemic rats with Evans blue staining. CONCLUSIONS: Diet-induced hyperhomocysteinemia, even mild to moderate, exacerbates neointima formation after denuding injury, making hyperhomocysteinemia a likely risk factor for postangioplasty restenosis. It may be mediated through an inhibitory effect of homocysteine on reendothelialization. Homocysteine lowering with folate supplementation can effectively ameliorate the detrimental effects of moderate hyperhomocysteinemia. Clinical trials would seem to be warranted.

Administration, Oral↗
PubMed2001

Thymoma. Analysis of prognostic factors.

OBJECTIVE: We evaluated the prognostic factors for thymoma that remain controversial. METHODS: We studied 72 consecutive patients treated for thymoma during the period between 1966 and 1997. Recurrence-free interval rates and overall survival rates calculated by the Kaplan-Meier method were compared using log-rank test by the Masaoka stage, extent of surgical resection, histology, or associated disease(s). Multivariate analysis was performed using Cox's proportional hazards model. RESULTS: Thirty-two thymomas were at Masaoka stage I, 9 at stage II, 15 at stage III, and 16 were at stage IV. There were 56 complete resections, 7 incomplete resections (2 at stage III and 5 at stage IV), and 9 biopsies (1 at stage III and 8 at stage IV). Forty-one thymomas were cortical, 16 medullary, and 15 were mixed form. Association of myasthenia gravis was found in 20 patients, and pure red cell aplasia in 7. After an average follow-up period of 103 months, the recurrence-free 5-, 10-, 15-year interval rate was 89%, 80%, 80%, respectively, and overall 5-, 10-, 15-year survival rate was 86%, 71%, 59%, respectively. Factors influencing the recurrence-free interval and overall survival included the Masaoka stage, extent of surgical resection, and association with pure red cell aplasia. Multivariate analysis revealed stage IV tumor and association with pure red cell aplasia as risk factors for recurrence. Pure red cell aplasia indicated poor prognosis for overall survival. CONCLUSIONS: Masaoka stage, extent of surgical resection, and association with pure red cell aplasia were prognostic factors for thymoma. Multidisciplinary treatment for stage IV tumors and better control of pure red cell aplasia, if associated, should be investigated.

Adult↗
PubMed2001

Effects of 5-fluorouracil on the drug-metabolizing enzymes of the small intestine and the consequent drug interaction with nifedipine in rats.

5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU therapy often causes gastrointestinal toxicity, which is suppressed by concomitant administration of potassium oxonate (Oxo). Here, we investigated the effect of 5-FU on the small-intestinal drug-metabolizing enzymes, which play important roles in the first-pass metabolism of drugs, in rats, by enzyme measurements and immunoblot analyses. During repeated administration of a combination of 1-(2-tetrahydrofuryl)-5-fluorouracil, an oral 5-FU-derivative drug, and 5-chloro-2,4-dihydroxypyridine (FCD), an inhibitor of 5-FU degradation, the activities of 7-ethoxyresorufin-O-deethylase, testosterone 6beta-hydroxylase, 4-methylumbelliferone UDP-glucuronyltransferase, and 1-chloro-2,4-dinitrobenzene glutathione S-transferase decreased significantly on day 4, and the activity of NADPH-cytochrome P450 (CYP) reductase decreased significantly on day 7. These effects were found to be attributable to a reduction in the enzyme protein contents in the small-intestinal mucosa. The enzymatic alterations significantly increased the plasma concentrations of orally administered nifedipine, which was prevented by concomitant administration of Oxo with FCD. However, consecutive administration of FCD for 4 days did not cause any alterations in the activity of the hepatic CYP isozyme-supported testosterone hydroxylase. These results suggest that continuous exposure to 5-FU leads to a decrease in the activities of drug-metabolizing enzymes in the intestinal mucosa by decreasing their enzyme protein contents, and increases the plasma concentrations of orally administered nifedipine, and that the sensitivity of these enzymes to the drug is greater than that of the enzymes of the liver. These effects were prevented by concomitant administration of Oxo.

Administration, Oral↗
PubMed2000

Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature.

BACKGROUND: Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. To determine the extent to which chronic AM overproduction affects circulatory physiology under normal and pathological conditions, we used a preproendothelin-1 promoter to establish transgenic mouse lines overexpressing AM in their vasculature. METHODS AND RESULTS: Transgenic mice overexpressing AM mainly in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure (BP) and higher plasma cGMP levels than their wild-type littermates. Blockade of NO synthase with N(G)-monomethyl-L-arginine elevated BP to a greater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopolysaccharide elicited smaller declines in BP and less severe organ damage in AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survival rate after induction of lipopolysaccharide shock was significantly higher in the transgenic mice. CONCLUSIONS: A chronic increase in vascular AM production reduces BP at least in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulatory collapse, organ damage, and mortality characteristic of endotoxic shock.

Adrenomedullin↗
PubMed2000

Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases.

Paraoxonase 1 (PON1) is proposed to have an anti-atherogenic action. Two polymorphisms at the PON1 (M/L55 and Q/R192) have been shown to be associated with coronary artery disease (CAD). This conclusion is not drawn universally, however, and specific ethnic characteristics may be important determinants in this association. Recently two homologues of PON1 - PON2 and PON3 - were identified and Sanghera et al. demonstrated C/S311 polymorphism at PON2 was associated with the risk of CAD. Within that context, we investigated the association between the aforementioned three polymorphisms and CAD and ischemic stroke in a Japanese population. The study population included 431 control subjects, 210 CAD patients, and 235 ischemic stroke patients. Genotype distributions and allele frequencies of M/L55 and C/S311 were similar among the control and patient groups, whereas the R192 allele frequency was significantly higher (P<0.001) in CAD (75%) and ischemic stroke (76%) patients than in control subjects (65%). When confounding influences of other risk factors were controlled for by multivariate analysis, R192 remained an independent risk determinant (additive model: OR (95% CI), P value CAD: 2.01 (1.45-2.79), 0.0001; ischemic stroke: 1.84 (1.34-2.52), 0.0002 (three genotypes into calculation)). Taken together, our data indicate that the Q/R192 is principally associated with both CAD and ischemic stroke in Japanese.

Aged↗
PubMed2000

Analysis of risk factors in bronchopleural fistula after pulmonary resection for primary lung cancer.

OBJECTIVES: Despite the advances in surgical technology, bronchopleural fistulas (BPFs) still occur and are often fatal. We studied the risk factors for BPF formation after lung cancer operation to clarify the indication of preventive bronchial stump coverage. In addition, the reliability of our methods of bronchial closure was evaluated. METHODS: We reviewed 557 consecutive bronchial stumps, corresponding to 547 patients without any coverage in pulmonary resection for lung cancer between 1989 and 1998. According to nine variables, stumps that made dehiscence were compared with uneventful ones using contingency table analysis. The incidence of BPFs according to each method of bronchial closure was calculated. RESULTS: BPFs developed in ten patients (1.8%). Compared with the lobar bronchus (LB), the main bronchus (MB; P<0.01; odds ratio, 23.0) and the intermediate bronchus (IB; P=0.03; odds ratio, 10.7) carried a high risk. Previous ipsilateral thoracotomy (P<0.01; odds ratio, 37.9) and preoperative chemotherapy and/or radiotherapy (P=0.02; odds ratio, 13.2) increased the risk. The incidence of BPFs with manual suture, stapling devices only, reinforcement suture at the distal side of staplers, or reinforcement suture at the proximal side of staplers was 1.8, 5.0, 1.9 and 1.0%, respectively. CONCLUSIONS: The main and intermediate bronchial stumps, and the stumps in cases with previous ipsilateral thoracotomy or receiving induction therapy are prone to BPFs. Preventive coverage should be considered for these stumps. Our methods for reinforcement of stapled stumps are thought to be reliable.

Adenocarcinoma↗
PubMed2000

ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function.

A disintegrin and metalloproteinase (ADAM) represents a protein family possessing both metalloproteinase and disintegrin domains. ADAMTS-1, an ADAM family member cloned from cachexigenic colon adenocarcinoma, is unusual in that it contains thrombospondin type I motifs and anchors to the extracellular matrix. To elucidate the biological role of ADAMTS-1, we developed ADAMTS-1-null mice by gene targeting. Targeted disruption of the mouse ADAMTS-1 gene resulted in growth retardation with adipose tissue malformation. Impaired female fertilization accompanied by histological changes in the uterus and ovaries also resulted. Furthermore, ADAMTS-1(-/-) mice demonstrated enlarged renal calices with fibrotic changes from the ureteropelvic junction through the ureter, and abnormal adrenal medullary architecture without capillary formation. ADAMTS-1 thus appears necessary for normal growth, fertility, and organ morphology and function. Moreover, the resemblance of the renal phenotype to human ureteropelvic junction obstruction may provide a clue to the pathogenesis of this common congenital disease.

ADAM Proteins↗
PubMed2000

MCC-134, a novel vascular relaxing agent, is an inverse agonist for the pancreatic-type ATP-sensitive K(+) channel.

The effects of a novel vasorelaxant agent, MCC-134 (1-[4-(1H-imidazol-1-yl)benzoyl]-N-methyl-cyclobutanecarbothioamide++ +), were examined on reconstituted ATP-sensitive K(+) (K(ATP)) channels, which are composed of an inwardly rectifying K(+) channel, Kir6.2, and three types of sulfonylurea receptors (SUR): SUR1, SUR2A, and SUR2B. Each type of K(ATP) channel was heterologously expressed in human embryonic kidney 293T cells. The expressed K(ATP) channel currents were measured with the whole-cell configuration of the patch-clamp method. MCC-134 activated the SUR2B/Kir6.2 channel, was a weak activator of the SUR2A/Kir6.2 channel, but did not activate the SUR1/Kir6.2 channel. MCC-134 suppressed SUR1/Kir6.2 channel currents that had been fully activated by either diazoxide or NaCN, whereas it did not affect the fully activated SUR2A/Kir6.2 or SUR2B/Kir6.2 channel currents. Thus, MCC-134, which is a relatively effective opener of the vascular smooth muscle type (SUR2B) of K(ATP) channel, is an antagonist of the pancreatic type (SUR1) of K(ATP) channel. Therefore, depending on the subtype of SUR, a pharmacological agent can cause either activation or inhibition of K(ATP) channel activity.

ATP-Binding Cassette Transporters↗