beraprost and Diabetes-Mellitus--Type-2

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

Patients with type 2 diabetes mellitus (T2DM) are susceptible to developing symptomatic peripheral arterial disease (PAD). As a proven vasodilator and antiplatelet agent, the efficiency of Beraprost sodium (BPS) on the prevention of arteries occlusion and stiffness in T2DM patients with PAD has not yet been fully investigated.. From July 2010 to April 2012, 64 Patients enrolled were randomly assigned to the combined therapy group (n=32), which received combination therapy with BPS (60 μg/day) and aspirin (100 mg/day), or to the control group (n=32), which only received aspirin (100 mg/day). After randomization, the patients were followed up at years 0, 1, 2, 3, 4, and 5 with the evaluation of carotid intima-media thickness (CIMT), pulse wave velocity (PWV), inner artery diameter, stenosis rate, and medial arterial calcification (MAC) of lower limb arteries via high-resolution ultrasound measurement. Adverse events were also recorded in each visit.. There was no significant change of the CIMT during the follow-up in both groups when compared to the baseline. Similar results were also observed in the PWV measurement. Significantly increases in the inner artery diameter of the dorsal pedal artery and posterior tibial artery were observed in patients with BPS and aspirin administration during the follow-up. Patients in the combined therapy group experienced marked improvement of MAC in the dorsal pedal artery and posterior tibial artery at the end of the follow-up. No significant difference in the adverse events was found between the combined therapy group and the aspirin group.. The combined therapy of BPS and aspirin showed a protective effect on arteries occlusion and stiffness in T2DM patients with PAD, along with a significant improvement of inner artery diameter and MAC in lower limbs.. http://www.chictr.org.cn , ChiCTR-TRC-10000919. Prospectively registered on 2010/06/29.

Topics: Arteries; Aspirin; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Epoprostenol; Humans; Prospective Studies; Pulse Wave Analysis; Ultrasonography

In recent years, the number of patients with type 2 diabetes mellitus caused by insulin resistance has continued to increase in Japan. Insulin resistance is considered to be closely related to the risk of cardiovascular diseases and atherosclerotic diseases, represented by arteriosclerosis obliterans (ASO). Therefore, improvement of insulin resistance is one of the important strategies in the treatment of type 2 diabetes mellitus. At present, α-glucosidase inhibitors, incretin-related drugs, and thiazolidinediones are among the most important oral hypoglycemic drugs used to improve insulin resistance. In this study, the effect of beraprost sodium, a prostaglandin I2 derivative, in the treatment of type 2 diabetes mellitus was investigated. In type 2 diabetic patients with ASO who were under treatment with pioglitazone, additional treatment with beraprost sodium exerted a significant synergistic effect in reducing the serum HbA1c levels as compared to treatment with pioglitazone alone. This result indicates that concomitant administration of pioglitazone and beraprost sodium may be useful in the treatment of diabetes -mellitus.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Platelet Aggregation Inhibitors; Thiazolidinediones

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

This study was performed to assess the efficacy of beraprost sodium (BPS) in painful diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. In this randomized clinical trial, 99 T2DM patients (41% male, age 60 ± 6 years) with DPN but without evidence of peripheral artery disease were randomized to receive either BPS (40 µg, tid) or placebo for 8 weeks. The primary end point was the improvement of the total symptom score (TSS), temperature rebound (TR) and nadir to peak (NP) above baseline. After 8 weeks treatment, the change of TSS in the BPS group showed a significant improvement compared to the placebo group (2.80 ± 2.48 vs. 1.60 ± 1.94 points, p = 0.009). Furthermore, the number of patients who showed signs of improvement in TSS and the proportion of patients with 50% relief of symptom was also significantly greater in the BPS group than in the placebo group (83.7 vs. 62%, p = 0.015, 36.2 vs. 14%, p = 0.009, respectively). In conclusion, treatment with BPS significantly improved TSS over an 8-week period.

Topics: Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Epoprostenol; Female; Humans; Male; Middle Aged; Treatment Outcome; Vasodilator Agents

Diabetic nephropathy is one of the primary diseases of refractory renal failure and heads the list of patients undergoing dialysis. Therefore, it is very important to get treatment in incipient nephropathy.. Twenty-seven patients in incipient diabetic nephropathy of type 2 diabetes mellitus who showed signs of microalbuminuria were randomly, but not blindly, assigned to two groups, either the beraprost sodium (PGI(2)) group or the control group, and effects of the preparation on urinary albumin excretion or other parameters were examined for 24 months.. Urinary albumin excretion was significantly decreased after 18 months in beraprost sodium group; however, there was no change in the control group. Difference was observed between the two groups after month 12; however, it was not significant (p = 0.0673 at month 24). Three factors that affect urinary albumin excretion, e.g. blood pressure, blood sugar and protein intake, were almost constant during the study period. The level of creatinine clearance was significantly decreased in beraprost sodium group after 24 months as compared with the control group.. In this study, we found that the long-term 24-month administration of PGI(2) preparation, beraprost sodium, decreased albuminuria in patients of incipient diabetic nephropathy. The possible mechanisms are that the PGI(2) may have alleviated constriction effect of angiotensin II on efferent glomerular arteriole and attenuated glomerular hyperfiltration, and inhibited growth of mesangial cells by platelet-derived growth factor as well.

Topics: Aged; Albuminuria; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dietary Proteins; Epoprostenol; Female; Hemoglobin A; Humans; Lipids; Male; Middle Aged; Time Factors

Prostaglandin I2 (PGI2) produces greater vasodilating and anti-platelet effects than PGE1, but is chemically unstable. Beraprost sodium, a stable analog of PGI2, was given orally, 120 micrograms daily for 12 weeks, to 15 patients with non-insulin-dependent diabetes mellitus to evaluate its effect on autonomic function. The effect of the drug on heart rate (HR) was evaluated in response to standing, rest, and deep breathing. The drug had a significant effect on HR in response to standing, but not during rest or deep breathing. Nine patients without preproliferative or proliferative retinopathy, and in whom factor analysis suggested the drug was effective with respect to autonomic nerve dysfunction, showed a significant improvement in their response to the three tests after beraprost administration for 12 weeks. Blood glucose was unaffected. Results thus indicate that beraprost sodium alleviates autonomic nerve dysfunction in diabetic patients in the absence of severe retinopathy.

Topics: Adult; Autonomic Nervous System; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Epoprostenol; Female; Heart Rate; Humans; Male; Middle Aged; Posture; Respiration; Rest; Sleep; Vasodilator Agents

The acute effects of beraprost sodium (sodium (+/-)-(1R*, 2R, 3aS*, 8bS*)-2, 3, 3a 8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-I- octen-6-ynyl] -1H-cyclopenta [b] bensofuran-5-butyrate), a stable analogue of prostaglandin I2 which works as a vasodilator and anti-platelet agent, were investigated in patients with non-insulin dependent diabetes mellitus. Its effects on the dorsal pedis artery were examined using a new real-time two-dimensional Doppler ultrasonographic technique and by laser blood flowmetry. Before and 60 min after oral administration of beraprost sodium (Dolner 40 micrograms) and elastase (Elaszym 1800 U), the cross-sectional area (CSA) of the dorsal pedis artery and its blood flow index (BFI), calculated from the maximum flow velocity and area, were determined. Dermal microcirculatory blood volume (MBV) was also measured by laser blood flowmetry. In the beraprost sodium group, the CSA, BFI and MBV were significantly increased, while in the elastase group, no significant changes were observed. These result suggest that beraprost sodium has a beneficial effect on diabetic macro- and microangiopathy.

Topics: Arteries; Blood Pressure; Blood Volume; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Epoprostenol; Female; Growth Inhibitors; Humans; Laser-Doppler Flowmetry; Lower Extremity; Male; Middle Aged; Platelet Aggregation Inhibitors; Pulse; Regional Blood Flow; Ultrasonography, Doppler, Color; Vasodilator Agents

To confirm whether a prostacyclin (prostaglandin I (2)) affects the increased TNF-alpha concentration in sera of diabetic patients, we measured serum TNF-alpha concentration and treated these patients with oral administration of the stable prostacyclin analogue (Beraprost). Twelve of 20 type II diabetic patients were investigated for follow up-study and 6 of those patients were for therapy with Beraprost for diabetic neuropathy.. Serum TNF-alpha concentration was quantified by EASIA using monoclonal antibodies directed against distinct epitopes of TNF-alpha.. In diabetic patients, serum TNF-alpha concentration was significantly increased compared with that of healthy subjects. The augmented TNF-alpha concentration in these patients was not decreased by diabetic control using antihyperglycemic agents for 8 weeks but was reduced with oral administration of a stable prostacyclin (prostaglandin I (2)) analogue for 5 weeks without any changes of blood glucose levels.. Stable prostacyclin analogue administration for a short term period reduced increased TNF-alpha levels in diabetic patients, not through the improved hyperglycemic condition but another pathway, probably a cAMP system. These results imply that treatment with the prostacyclin analogue may contribute to the prevention of progression in diabetic complications.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Epoprostenol; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Tumor Necrosis Factor-alpha

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

In a previous study, we reported that beraprost sodium (BPS), a stable prostaglandin I(2) (PGI(2)) analog, increases skin blood flow in the feet of both control subjects and patients with type 2 diabetes, and that the flow increase induced by BPS is lower in diabetic patients than in controls. The present study was undertaken to clarify factors associated with smaller increases in skin blood flow in the feet of patients with type 2 diabetes after the administration of BPS, and to investigate the relationship between microalbuminuria and the changes in skin blood flow induced by the PGI(2) analog. We studied 61 patients with type 2 diabetes: 10 received placebo (control) and 51 (31 with normoalbuminuria and 20 with microalbuminuria) received BPS. Using laser Doppler flowmetry, we measured the skin blood flow at the pulp of the right big toe before and 90 minutes after administration of 40 microg BPS, and calculated the change in blood flow, i.e., delta flux (peak flux at 90 minutes - basal flux at 0 minutes). Plasma concentrations of soluble thrombomodulin (TM) were determined using an enzyme immunoassay (EIA) sandwich method. BPS significantly increased skin blood flow in the treatment group compared with the placebo group (P <.01). The delta flux was positively correlated with the value of the ankle brachial index (ABI) (r =.41, P <.0038) and was negatively correlated with plasma TM levels (r = -.53, P <.0001). By multiple regression analysis both the ABI value and the plasma TM level retained a significant influence on delta flux. Furthermore, both the delta flux and the ABI value in patients with microalbuminuria were lower than in patients with normoalbuminuria (P <.05). The results suggest that BPS increases the skin blood flow of the toe of patients with type 2 diabetes and that the increased flow is independently influenced by the value of the ABI and the plasma TM levels; in addition, microalbuminuria is associated with the impairment of vasodilation in the feet in response to BPS.

Topics: Adult; Albuminuria; Ankle; Blood Flow Velocity; Brachial Artery; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Epoprostenol; Female; Foot; Glycated Hemoglobin; Humans; Kinetics; Lipids; Male; Middle Aged; Regression Analysis; Skin; Skin Temperature; Thrombomodulin

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