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Biomedical subjects

Toshio Ogihara

Publications and source records attributed to Toshio Ogihara.

At least 91 records · Page 5Linked to original sources
PubMed2005

A calcium-channel blocker, benidipine, improves forearm reactive hyperemia in patients with essential hypertension.

The pathophysiological role of endothelial cells is important in the mechanism of progression of atherosclerosis and improvement of endothelial function may be important for cardiovascular morbidity. Calcium antagonists are reported to have protective effects on the endothelium in vitro and in vivo. In this clinical study, we investigated the effect of calcium antagonist, benidipine, on endothelial function in the patients with essential hypertension, which causes endothelial dysfunction. Twenty-five patients with hypertension without other risk factors for atherosclerosis were treated with monotherapy (8 mg benidipine, n=25) for 8 weeks. Blood pressure was reduced significantly. Endothelial function was evaluated using forearm blood flow by strain-gauge plethysmography after 8 weeks of treatment. Changes in vasodilator response to reactive hyperemia were significantly improved (p<0.01), while the response to nitroglycerin was not changed, suggesting the improvement of endothelial function. Moreover, we focused on hepatocyte growth factor (HGF), which is a novel angiogenic growth factor with an anti-apoptotic action on endothelial cells, and evaluated involvement of HGF in improvement of endothelial function. Serum HGF concentration in subjects treated with benidipine was significantly elevated at 8 weeks (p<0.05). Overall, these results demonstrated that benidipine improved endothelial dysfunction in patients with hypertension. Interestingly, an increase in serum HGF concentration by benidipine might contribute to the improvement of endothelial dysfunction.

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PubMed2005

The combination therapy of hypertension to prevent cardiovascular events (COPE) trial: rationale and design.

A number of major clinical trials have demonstrated the clinical benefits of lowering blood pressure and have indicated that a majority of patients with hypertension will require more than one drug to achieve optimal blood pressure control. However, there is little data showing which antihypertensive combination best protects patients from cardiovascular events and which best achieves the target blood pressure with the fewest adverse events. The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial is the first large-scale investigator-initiated multicenter study with a prospective, randomized, open, blinded endpoint evaluation (PROBE) design to directly compare cardiovascular mortality and morbidity, incidence of adverse drug reaction, and degree of blood pressure reduction in Japanese hypertensive patients for a combination of angiotensin receptor blockers, beta-blockers or thiazide diuretics in addition to a calcium antagonist, benidipine hydrochloride, with a response-dependent dose titration scheme. The COPE trial is being conducted with the cooperation of more than 100 centers and clinics in Japan and involves 3,000 patients, who will be followed for 3 years. Eligible patients are being enrolled from May 2003 until May 2006. Results from the COPE trial should provide new evidence for selecting optimal combination therapies for hypertensive patients.

Antihypertensive Agents↗
PubMed2005

Single nucleotide polymorphisms in the interleukin-6 gene associated with blood pressure and atherosclerosis in a Japanese general population.

It is known that increased plasma levels of inflammatory markers, such as interleukin-6 (IL-6), are associated with atherosclerosis and myocardial infarction. The aim of this study was to reveal the contribution of the single nucleotide polymorphisms (SNPs) of the IL-6 gene on the blood pressure regulation and progression of atherosclerosis in a general Japanese population. In order to evaluate the potential implications of genetic variability of the IL-6 gene, we explored eight SNPs by direct sequencing for the entire coding region and the promoter region in the IL-6 gene and genotyped two SNPs, -636G > C in the promoter region and 1691C > G in intron 3, for a total of 2,421 Japanese subjects (1,162 men and 1,259 women). As a consequence, -636 G > C was significantly associated with systolic blood pressure (SBP) and carotid intima-media thickness (IMT) in women, and 1691C > G showed a relationship with SBP and carotid IMT in men after adjustment for all confounding factors. Although neither SNP had a significant correlation to the prevalence of hypertension, the haplotype frequency analysis indicated that the number of hypertensive men with a G allele at both -636 and 1691 was significantly greater than the number of nonhypertensive men with this combination. Thus, these two SNPs in the promoter region and intron 3 of the IL-6 gene might play a role in the blood pressure regulation and progression of atherosclerosis in the Japanese.

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PubMed2005

Hepatocyte growth factor as potential cardiovascular therapy.

Hepatocyte growth factor is a mesenchyme-derived pleiotropic factor that regulates the growth, motility and morphogenesis of various types of cells, and is also a member of the angiogenic growth factors. Hepatocyte growth factor is secreted by vascular endothelial cells and smooth muscle cells, and the hepatocyte growth factor receptor, c-met, was also observed in these vascular cells. Treatment of human aortic endothelial cells with recombinant hepatocyte growth factor resulted in a significant increase in cell proliferation, accompanied by mitogen-activated protein kinase and Akt/protein kinase B phosphorylation. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to augment collateral artery development has been proposed. As preclinical study of gene therapy using hepatocyte growth factor to treat peripheral arterial disease, naked hepatocyte growth factor plasmid was intramuscularly injected into the ischemic hind limb of rabbits in order to evaluate its angiogenic activity. Intramuscular injection of hepatocyte growth factor plasmid once on day 10 following surgery, produced significant augmentation of collateral vessel development in the ischemic limb on day 30. In the clinical setting, the authors further investigated the safety and efficacy of hepatocyte growth factor plasmid DNA in patients with critical limb ischemia, in a prospective open-labeled trial. Intramuscular injection of naked plasmid DNA was performed in the ischemic limbs of six patients with critical limb ischemia with arteriosclerosis obliterans (n = 3) or Buerger disease (n = 3) graded as Fontaine III or IV. In the efficacy evaluation, a reduction of pain scale of more than 1 cm on a visual analog pain scale was observed in five out of six patients. An increase in ankle pressure index of more than 0.1 was observed in five out of five patients. The long diameter of eight out of 11 ischemic ulcers in four patients was reduced by more than 25%. Intramuscular injection of naked hepatocyte growth factor plasmid is safe, feasible and can achieve successful improvement of ischemic limbs. Although the present data were obtained to demonstrate safety in a Phase I/early Phase II trial, the initial clinical outcome with hepatocyte growth factor gene transfer seems to indicate its usefulness as sole therapy for critical limb ischemia. Randomized placebo-controlled clinical trials of alternative dosing regimens of gene therapy will be required to define the efficiency of this therapy.

Animals↗
PubMed2005

Hypertension in the elderly: a Japanese perspective.

Elderly individuals with hypertension show specific characteristics as a result of advancing arteriosclerosis, a high frequency of isolated systolic hypertension, increased pulse pressure and orthostatic hypotension. The necessity to treat hypertension in the elderly, including isolated systolic hypertension, has been demonstrated in many large-scale intervention trials. Young-old (65-74 years of age) hypertensive patients should be treated the same as nonelderly hypertensive patients. In old-old (75-84 years of age) patients with mild hypertension (140-159/90-99 mm Hg), the recommended target blood pressure (BP) is <140/90 mm Hg. In old-old (75-84 years of age) and oldest-old (> or =85 years of age) patients with systolic BP > or =160 mm Hg, cautious treatment is required. An intermediate target BP of <150 mm Hg is appropriate, followed by a final target BP of <140 mm Hg, if tolerated. Nonmedical therapy, such as salt restriction, exercise and weight reduction, is useful in the elderly. However, individualised management of nonmedical therapy is necessary to avoid deterioration of quality of life resulting from strict management of the patient's lifestyle. Diuretics, calcium channel antagonists, ACE inhibitors and angiotensin II type 1 receptor antagonists have been established as first-line antihypertensive drugs in the elderly. Use of combination therapy helps to achieve target BPs. The starting dose of each drug should be half the usual dose for nonelderly patients, and may be increased at intervals of >4 weeks, with achievement of the target BP in 3-6 months or longer. In hypertensive patients with co-morbid diseases, the target BP should be determined individually and antihypertensive drugs selected bearing in mind the patient's clinical circumstances. Avoiding hypoperfusion of target organs is very important in elderly hypertensive patients. When treating hypertension in elderly patients, the approach should be to identify individual pathophysiological characteristics and lower the BP cautiously and slowly.

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PubMed2005

Genetic heterogeneity in association of the SUMO4 M55V variant with susceptibility to type 1 diabetes.

Association studies are a potentially powerful approach to identifying susceptibility variants for common multifactorial diseases such as type 1 diabetes, but the results are not always consistently reproducible. The IDDM5 locus has recently been narrowed to an approximately 200-kb interval on chromosome 6q25 by two independent groups. These studies demonstrated that alleles at markers in the mitogen-activating protein kinase 7 interacting protein 2 (MAP3K7IP2)/SUMO4 region were associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association of the SUMO4 gene with type 1 diabetes. To clarify the contribution of the M55V polymorphism of the SUMO4 gene to type 1 diabetes susceptibility, 541 type 1 diabetic patients and 768 control subjects were studied in Asian populations. The M55V polymorphism was significantly associated with type 1 diabetes in Asian populations (summary odds ratio [OR] 1.46, P = 0.00083, Mantel-Haenszel test). Meta-analysis of published studies and the present data confirmed a highly significant association in Asian populations (summary OR 1.29, P = 7.0 x 10(-6)) but indicated heterogeneity in the genetic effect of the SUMO4/MAP3K7IP2 locus on type 1 diabetes among diverse ethnic groups. These data indicate that the MAP3K7IP2/SUMO4 locus in the IDDM5 interval is associated with type 1 diabetes in Asian populations.

Asian People↗
PubMed2005

[Gene therapy for peripheral arterial diseases].

Therapeutic angiogenesis using angiogenic growth factor is expected to be a new treatment for with patients with critical limb ischemia. The first human clinical trial treating peripheral vascular disease was started in 1994 using vascular endothelial growth factor (VEGF). To date, other potent angiogenic growth factors, such as fibroblast growth factor(FGF) or hepatocyte growth factor(HGF), have been also estimated in clinical trials for peripheral arterial disease. Several results from phase 1 or 2 trials using VEGF, FGF and HGF gene were encouraging. Phase 3 trials are now ongoing and their results are expected.

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PubMed2005

[Concept and clinical character of hypertension in the elderly].

Although blood pressure in the elderly was modulated by "physiological" changes due to aging, "pathological" changes in the elderly patients with essential hypertension cause to increase cardiovascular events and mortality. Hypertension in the elderly shows increase of pulse pressure, abnormal blood pressure daily profile and orthostatic hypotension. The importance of control of blood pressure in the elderly hypertensive patients is quite clear, however, the optimal blood pressure is still unclear. Very recently, clinical guideline of JSH 2004 by Japanese Society of Hypertension was published. We should try to control blood pressure in the elderly patients according to this guideline.

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PubMed2005

[Intervention trials for elderly hypertension in Western countries].

Many large-scale intervention trials performed in Western countries have proven the necessity of treatment of hypertension in the elderly, including isolated systolic hypertension. However, it is still unclear the benefit of antihypertensive treatment in mild hypertensive patients and that in very elderly patients with hypertension. An ongoing clinical trial, the Hypertension in the Very Elderly Trial (HYVET), may clarify whether or not antihypertensive treatment is beneficial in the very elderly. Regarding target blood pressure, there is no clinical study in which average of systolic blood pressure at the end of study decreased lower than 140 mmHg. Regarding the first-line drugs for elderly hypertension, usefulness of diuretics and calcium channel blockers has been demonstrated in studies with placebo control group. Usefulness of inhibitors of the rennin-angiotensin system has been also reported in LIFE substudy and ANBP2. It is still required to perform large scale trials in the elderly hypertension to answer these undissolved problems.

Aged↗
PubMed2005

[Motilin].

Explore the source record for details and available documents.

Biomarkers↗
PubMed2005

[Calcium antagonists and endothelial function].

Endothelial dysfunction is an early sign of atherosclerosis. Patients with risk factors for atherosclerosis (e.g., hypertension, hyperlipidemia and diabetes mellitus) often show endothelial dysfunction at early stages of atherosclerosis before cardiovascular complications develop. Clinical studies and basic researches are revealing that calcium antagonists not only protect the endothelium through their hypotensive action but also improve the endothelial function through the stimulation of NO production. Regarding the mechanism for this kind of action by nifedipine (a calcium antagonist), it seems likely that the drug stimulates SOD expression in endothelial cells through enhanced VEGF expression by vascular smooth muscle cells, and thus reduces oxidative stress, leading to increased NO production.

Antihypertensive Agents↗