beraprost and Diabetic-Neuropathies

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

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

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

The effect of a prostacyclin analog, beraprost sodium, on the electroretinogram, motor nerve conduction velocity, and nerve blood flow was determined in rats with streptozotocin-induced diabetes and was compared with the effect of insulin. Beraprost sodium (0.01 mg x kg-1 x day-1 for 8 weeks) significantly shortened the peak latency of the electroretinogram b-wave, increased tail nerve conduction velocity, and increased sciatic nerve blood flow in diabetic rats (P < 0.0003, 0.0001, and 0.0001 vs. untreated diabetic rats, respectively). This was accompanied by a significant increase in the 6-keto-prostaglandin F1alpha content of the thoracic aorta and a marked increase in the cAMP content of the sciatic nerve. Beraprost sodium had no effect on the sorbitol and fructose contents of the sciatic nerve and retina, but insulin (8-10 U/day) significantly reduced both parameters. These findings suggest that beraprost sodium may be useful for prevention of vascular and neural dysfunction in the retina and peripheral nerve.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diabetic Retinopathy; Electroretinography; Epoprostenol; Insulin; Male; Neural Conduction; Rats; Rats, Wistar; Retina; Sciatic Nerve

The effects of beraprost sodium (BPS), a stable prostacyclin analogue, on the tail flick (TF) latency were investigated in streptozotocin-induced (STZ;55mg/kg, i.p.) diabetic male Sprague-Dawley (SD) rats and in spontaneously diabetic WBN/Kob rats. The SD rats were divided into 5 groups, i.e., (I) normal, (II) diabetic control, diabetic treated with (III) BPS (10 micrograms/kg/day), (IV) BPS (30 micrograms/kg/ day), and (V) aldose reductase inhibitor (ARI; epalrestat, 50 micrograms/kg/day). The drugs were administered orally. At 12 weeks, TF latency was significantly longer in untreated diabetic rats than in normal rats. After 4 weeks treatment, BPS significantly improved the abnormality in TF latency dose-dependently. But ARI did not normalize the response. The 45 weeks male WBN/Kob rats were divided into 2 groups: diabetic control and diabetic treated with BPS at 30 micrograms/kg/day, p.o., respectively. Untreated, age-matched wistar rats were served as the normal group. At 61 weeks, TF latency was significantly longer in control WBN/Kob rats than in normal wistar rats in time-dependent manner. After 16 weeks treatment, BPS significantly normalized the prolongation in TF latency. In in vivo experiments, BPS significantly increased the cyclic AMP (cAMP) content in sciatic nerves from normal rats dose-dependently. In STZ-induced diabetic rats, cAMP content in sciatic nerves were significantly reduced, and 4 weeks treatment of BPS significantly restored this reduced cAMP content. It was suggested that BPS may be effective on diabetic neuropathy by, at least in part, maintenance of cAMP contents in the nerves.

Topics: Animals; Blood Glucose; Body Weight; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Epoprostenol; Male; Pain; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Sciatic Nerve; Time Factors; Vasodilator Agents

The effects of beraprost sodium (BPS), a stable prostacyclin analogue, on motor nerve conduction velocity and nerve blood flow of the sciatic nerve were investigated in streptozotocin-induced diabetic rats, and they were compared with the effects of epalrestat (aldose reductase inhibitor). Treatment with BPS for 4 weeks significantly inhibited the decrease in motor nerve conduction velocity and nerve blood flow dose-dependently, but epalrestat had no effect on nerve blood flow. Morphological changes of the myelinated fibers of the sciatic nerve were observed macroscopically. The mean axonal area and the mean circularity index of diabetic control rats were significantly less than that of normal rats, while after 6 weeks of BPS treatment, these decreases of the axonal area and the circularity index were inhibited. The enlargement of the mean lumen area of microvessels in the diabetic rats was significantly inhibited after 6 weeks of BPS treatment. Additionally, augmentation of the washed platelet aggregation in diabetic rats was significantly normalized by BPS. It was suggested that BPS is effective on diabetic neuropathy via amelioration of the decrease of blood supply to the structure. The effects of BPS on platelets might also contribute to the improvement of neuronal circulatory deficiency.

Topics: Animals; Blood Flow Velocity; Diabetic Neuropathies; Disease Models, Animal; Epoprostenol; Male; Neural Conduction; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Streptozocin

The effects of the prostacyclin analog beraprost sodium on motor nerve function and nerve blood-flow were examined in streptozotocin-induced diabetic rats. Oral administration of beraprost sodium 0.1 mg/kg/day for 8 wks significantly (P < 0.001) improved caudal motor nerve conduction velocity and sciatic nerve blood-flow, both of which are impaired in diabetic rats. Beraprost sodium did not affect glucose, sorbitol, or fructose levels in the sciatic nerve. However, a decreased content of cyclic AMP in the sciatic nerve and higher level of thromboxane B2 in the thoracic aorta of diabetic rats, as compared with those in normal rats, were reversed by the treatment with beraprost sodium (P < 0.01). Results suggest that beraprost sodium may have value in treating diabetic neuropathy, mainly by improving endoneurial blood-flow.

Topics: Animals; Aorta, Thoracic; Blood Glucose; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Epoprostenol; Fructose; Glucose; Male; Motor Neurons; Muscle, Smooth, Vascular; Neural Conduction; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Reference Values; Regional Blood Flow; Sciatic Nerve; Sorbitol; Thromboxane B2