beraprost and Diabetic-Angiopathies

Diabetes mellitus is an important risk factor for cardiovascular morbidity and mortality. The metabolic abnormalities caused by diabetes mellitus induce vascular endothelial dysfunction that predisposes patients with diabetes mellitus to atherosclerosis. Two mega clinical trials showed that intensive glycemic control does not have favorable effects on reducing macrovascular events although it demonstrated significant reductions in microvascular complications. It is becoming worthwhile to clarify the beneficial effects of tight controls on blood pressure, serum lipids, and postprandial hyperglycemia to prevent atherosclerosis in patients with type 2 diabetes mellitus. Here, we focus on vascular endothelium as a target of the prostaglandin I2 analog beraprost sodium and the peroxisome proliferators-activated receptor alpha activator fenofibrate for the prevention and treatment of atherosclerosis in patients with type 2 diabetes mellitus. Beraprost sodium lowered circulating vascular cell adhesion molecule- 1 (VCAM-1) concentration and prevented the progression of carotid atherosclerosis in type 2 diabetic patients, probably through inhibiting VCAM-1 expression in vascular endothelium. Fenofibrate up-regulated endothelial nitric oxide synthase expression, which may explain its effects to improve endothelium-dependent vasodilatation and to prevent the progression of coronary atherosclerosis. The approaches to target the molecules expressed in vascular endothelium will become important for preventing the atherosclerosis in type 2 diabetes mellitus.

Topics: Antihypertensive Agents; Atherosclerosis; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Endothelium, Vascular; Epoprostenol; Fenofibrate; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Lipid Metabolism; Nitric Oxide Synthase Type III; Vascular Cell Adhesion Molecule-1; Vasodilation; Vasodilator Agents

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Cardiovascular (CV) complications are the most common cause of death among ESRD patients. Beraprost sodium (BPS) is a prostacyclin analog with vasodilatory and antiplatelet effects.. This is a multicenter prospective, randomized, double-blind, placebo-controlled trial to determine whether treatment with BPS improves arterial stiffness in patients with type 2 diabetic nephropathy. A total of 102 participants with type 2 diabetic nephropathy will be screened, enrolled, and randomly assigned to receive either 80 μg BPS or placebo daily for 12 weeks. The primary outcome is the change in brachial-ankle pulse wave velocity between baseline and after 12 weeks of medication use. The secondary outcomes will include changes in the ankle-brachial index, the urine albumin to creatinine ratio, the estimated glomerular filtration rate, lipid profiles, and blood pressure from baseline to after treatment.. This clinical trial is the first to investigate the effects of BPS on changes in CV biomarkers, albuminuria, renal function, and lipid profiles in patients with diabetic nephropathy.. ClinicalTrials.gov number NCT01796418.

Topics: Ankle Brachial Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Double-Blind Method; Epoprostenol; Humans; Prospective Studies; Pulse Wave Analysis; Republic of Korea; Research Design; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilator Agents

Although conventional bypass grafting is commonly used to treat ischemia in lower extremities, graft failure often occurs. This study retrospectively analyzed the factors that affect graft patency to help establish more effective treatment of obstructive arterial disease of the lower limbs. Kaplan-Meier analysis was used to estimate graft patency in 90 legs of 80 patients who underwent femoropopliteal bypass (28 vein grafts and 62 expanded polytetrafluoroethylene grafts) between 1984 and 2003. Patients were randomly selected for graft materials in sequential surgical treatment order. After initial analysis, several risk factors and postoperative medication regimens were analyzed to ascertain any association with graft failure. The overall mean patency period for femoropopliteal bypass was 10.5 +/- 0.7 years. Graft occlusion occurred in 20 limbs. Neither the materials composing the grafts nor the position of distal anastmosis had any influence on patency maintenance. Graft occlusion rates were significantly greater in patients with either diabetes (p = 0.0049) or rest pain before surgery (p = 0.0011). Postoperative administration of beraprost sodium significantly increased the patency period (p = 0.0082). Diabetes and rest pain before surgery are important factors for late graft failure after femoropopliteal bypass. Our data also suggest that administration of beraprost sodium increases the graft patency period.

Topics: Aged; Arteriosclerosis Obliterans; Blood Vessel Prosthesis Implantation; Diabetic Angiopathies; Epoprostenol; Female; Femoral Artery; Graft Occlusion, Vascular; Humans; Leg; Male; Middle Aged; Platelet Aggregation Inhibitors; Popliteal Artery; Postoperative Period; Retrospective Studies; Vascular Patency

Beraprost sodium is an orally active prostaglandin (PG)I(2) analogue, which has antiplatelet and vasodilating properties. In this study, we investigated the effects of beraprost on the expression of vascular cell adhesion molecule-1 (VCAM-1), one of the key molecules involved in atherosclerosis, in cultured vascular endothelial cells. In addition, we examined the effects of beraprost on circulating VCAM-1 level and atherosclerosis progression in patients with type 2 diabetes mellitus. Beraprost significantly decreased tumor necrosis factor-alpha (TNF-alpha)-induced VCAM-1 expression in human vascular endothelial cells. Beraprost also repressed human monocytoid U937 cell adhesion to the vascular endothelial cells. Twenty-five patients with type 2 diabetes mellitus who had atherosclerotic change of carotid arteries were enrolled for an open prospective study: 11 patients received beraprost for 3 years, while the other 14 did not. The 3-year changes of circulating VCAM-1 level, as well as those of carotid arterial intima-media thickness (IMT) were significantly lower in the patients receiving the beraprost treatment than that in the patients without the treatment. Thus, beraprost had an ability to repress the expression of VCAM-1 in human vascular endothelial cells. In addition, beraprost lowered circulating VCAM-1 level and prevented the increase of carotid IMT in patients with type 2 diabetes mellitus. Considering that circulating VCAM-1 and IMT are predictive of future vascular events, beraprost may have a beneficial effect on progression of atherosclerosis in diabetic patients.

Topics: Carotid Arteries; Carotid Artery Diseases; Cell Adhesion; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Administration Schedule; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Middle Aged; Tumor Necrosis Factor-alpha; Tunica Intima; Tunica Media; Ultrasonography; Vascular Cell Adhesion Molecule-1

To determine whether a decrease in prostacyclin production is involved in the increase in endothelial permeability induced by a high concentration of glucose, we evaluated the effect of beraprost sodium, a stable prostacyclin analog, on the transendothelial permeation of albumin in cultured aortic cells. Permeation of albumin across an endothelial cell monolayer was significantly greater when the cells were cultured with a high concentration of glucose (400 or 800 mg/dl) than when they were cultured with 100 mg/dl glucose. No significant change in the permeation of albumin was observed when cells were cultured with 100 mg/dl glucose as compared with 100 mg/dl glucose plus 700 mg/dl mannitol. The addition of beraprost sodium to the culture medium completely restored the increase in the permeation of albumin brought about by 400 mg/dl glucose. These results suggest that increased transendothelial permeation of albumin by high glucose may be due in part to a decrease in prostacyclin production by the endothelial cells. Beraprost sodium may restore the endothelial barrier function affected by a high concentration of glucose.

Topics: Albumins; Animals; Aorta; Cattle; Cell Membrane Permeability; Cells, Cultured; Diabetic Angiopathies; Dose-Response Relationship, Drug; Endothelium, Vascular; Epoprostenol; Glucose; Vasodilator Agents

To determine the relationship of skin microangiopathy and other diabetic microvascular complications, we measured changes in skin blood flow after the administration of the prostacyclin (PGI2) analogue, beraprost sodium (BPS), in 82 patients with non-insulin-dependent diabetes mellitus and 20 healthy subjects. The diabetic patients had various degrees of retinopathy and nephropathy. Using laser Doppler flowmetry we measured skin blood flow at the dorsum of the right big toe at various times after the administration of 40 micrograms BPS and calculated the blood flow change (delta flux = peak flux--basal flux). We also determined the ankle pressure index (API), an ankle/brachial systolic pressure ratio. The basal blood flow was higher in healthy subjects than in diabetic patients (P < 0.001). BPS significantly increased blood flow in both diabetic patients and healthy subjects (P < 0.001). In all 102 subjects delta flux was positively correlated with the API (R = 0.40, P < 0.001). Despite no differences in API among the diabetic retinopathy and nephropathy subgroups, the delta flux in diabetic patients with progressive retinopathy and macroalbuminuria was significantly lower than in healthy subjects or in diabetic patients with less severe retinopathy and nephropathy (P < 0.05). The results suggested that BPS increases skin blood flow and the flow increase induced by BPS is related partly to the levels of API. The effect of BPS on skin blood flow decreased with an increases in the severity of retinopathy and nephropathy. Diabetic skin microangiopathy appears to coexist with other microvascular diabetic complications and may be proportional to their severity.

Topics: Adult; Albuminuria; Ankle; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Epoprostenol; Female; Humans; Laser-Doppler Flowmetry; Male; Middle Aged; Pressure; Reference Values; Regional Blood Flow; Skin; Skin Temperature; Ultrasonography; Vasodilation; Vasodilator Agents