beraprost and Pain

In the current study, we hypothesized that beraprost would: 1) improve treadmill exercise performance and quality of life; and 2) decrease rates of ischemic events in patients with intermittent claudication.. Previous trials with beraprost sodium, an orally active prostaglandin I(2) analogue, in the treatment of claudication in patients with peripheral arterial disease (PAD) have been inconsistent.. Patients with intermittent claudication (n = 897) were randomized to receive either 40 microg three times a day of beraprost with meals (n = 385) or placebo (n = 377) in a double-blinded manner for one year. The primary efficacy parameter was treadmill-measured maximum walking distance, as assessed at three and six months after randomization. Secondary efficacy parameters included treadmill-measured pain-free walking distance and change in quality of life.. There was no significant improvement in maximum walking distance in the beraprost group (16.7%) as compared with the placebo group (14.6%, p = NS). Administration of beraprost did not improve the pain-free walking distance (p = NS between treatment groups), and there was no improvement in the quality-of-life measures between the treatment groups. The incidence of critical cardiovascular events was 7.3% in the beraprost group and 11.4% in the placebo group (p = NS). There was a significant reduction in the combination of cardiovascular death and myocardial infarction in the beraprost group (p = 0.01).. Despite previous investigations suggesting efficacy, these results indicate that beraprost is not an effective treatment to improve symptoms of intermittent claudication in patients with PAD. The potential benefit of beraprost on critical cardiovascular events would require confirmation in a larger prospective investigation.

Topics: Administration, Oral; Aged; Double-Blind Method; Epoprostenol; Exercise Test; Exercise Tolerance; Female; Humans; Intermittent Claudication; Male; Middle Aged; Pain; Platelet Aggregation Inhibitors; Quality of Life; Vasodilator Agents; Walking

The inhibition of prostaglandin (PG) synthesis is at the center of current anti-inflammatory therapies. Because cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of multiple PGs, there is currently a strong focus on characterizing the role of the different PGs in the inflammation process and development of arthritis. Evidence to date suggests that both PGE(2) and PGI(2) act as mediators of pain and inflammation. Most of the data indicating a role for PGI(2) in this context have been generated in animal models of acute pain. Herein, we describe the role of PGI(2) in models of osteoarthritis (OA) and rheumatoid arthritis using a highly selective PGI(2) receptor (IP, Ptgir) antagonist and IP receptor-deficient mice. In the rat OA model using monoiodoacetate injection into the knee joint, the IP antagonist reduced pain with an efficacy approaching that of the NSAID diclofenac. In a chronic model of inflammatory arthritis, collagen-antibody induced arthritis model in mice, IP receptor-deficient mice displayed a 91% reduction in arthritis score. Interestingly, pretreatment with the IP [N-[4-(imidazolidin-2-ylideneamino)-benzyl]-4-methoxy-benzamide] antagonist in this model also caused a significant reduction of the symptoms, whereas administration of the compound after the initiation of arthritis had no detectable effect. Our data indicate that, in addition to its role in acute inflammation, PGI(2) is involved in the development of chronic inflammation. The results also suggest that the inhibition of PGI(2) synthesis by NSAIDs and COX-2 inhibitors, in addition to that of PGE(2), contributes to their efficacy in treating the signs of arthritis.

Topics: Animals; Arthritis, Experimental; Carrageenan; Chromatography, High Pressure Liquid; Chronic Disease; Collagen; Cyclooxygenase 2 Inhibitors; Edema; Epoprostenol; Hot Temperature; Hyperalgesia; Inflammation; Iodoacetates; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoarthritis; Ovalbumin; Pain; Prostaglandins I; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol

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