mdl-100907 and Peripheral-Vascular-Diseases

Peripheral arterial disease (PAD) is 1 of the major manifestations of atherosclerosis. PAD is associated with endothelial dysfunction. Sarpogrelate hydrochloride, a selective 5-HT2A antagonist, has been widely used as an anti-platelet agent for the treatment of PAD. There is no information on whether endothelial function is improved after initiation of sarpogrelate treatment in patients with PAD. The purpose of this study was to evaluate the effects of sarpogrelate on endothelial function in patients with PAD. We divided PAD patients into 2 groups: those treated with sarpogrelate at a dose of 100 mg 3 times per day orally for 12 weeks (sarpogrelate group, n = 10), and those who remained on conventional therapy (control group, n = 11). Forearm blood flow (FBF) and leg blood flow (LBF) responses to reactive hyperemia (RH) and sublingual administration of nitroglycerin (NTG) were measured using strain-gauge plethysmography. After 12 weeks of sarpogrelate administration, FBF and LBF responses during RH showed significant increases from 13.2 +/- 1.7 to 18.1 +/- 2.2 mL/min per 100 mL tissue (P < 0.01) and from 8.2 +/- 0.9 to 14.2 +/- 2.1 mL/min per 100 mL tissue (P < 0.05), respectively. Sarpogrelate-induced augmentation of FBF and LBF responses to RH was maintained at 24 weeks. No change was observed in the control group at each follow-up time point. The changes in FBF and LBF after sublingual NTG were similar during follow-up periods in the 2 groups. These findings suggest that long-term oral administration of sarpogrelate improves vascular function in patients with PAD.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Arterial Occlusive Diseases; Biomarkers; Endothelium, Vascular; Female; Follow-Up Studies; Forearm; Humans; Hyperemia; Leg; Male; Nitroglycerin; Peripheral Vascular Diseases; Regional Blood Flow; Research Design; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates; Time Factors; Treatment Outcome; Vasodilator Agents

There is considerable interest in the pleiotropic pharmacological action of sarpogrelate hydrochloride, a novel selective serotonin 2A receptor antagonist. In the present study the persistent insulin-sensitizing effects of sarpogrelate were investigated in non-diabetic and non-medicated diabetic patients with peripheral artery disease (PAD).. Indices of insulin resistance (IR) (fasting immunoreactive insulin (IRI) and calculated homeostasis model assessment (HOMA-R)) and adiponectin were measured before and after 2 weeks of sarpogrelate administration (300 mg/day) in 24 patients (19 men, 76+/-9 years) with PAD. Sixteen of the 24 patients were examined after 3 months of treatment for assessment of the chronic effect of sarpogrelate on IR. After 2 weeks of treatment, significant decreases in fasting IRI (p=0.03) and HOMA-R (p=0.024), but not in adiponectin, were observed. After 3 months of treatment, significant decreases in fasting IRI (16.0+/-10.3 vs 9.2+/-2.0 microU/ml, p=0.03) and HOMA-R (4.30+/-2.83 vs 2.40+/-0.74, p=0.025) were maintained. Furthermore, adiponectin was significantly increased (8.11+/-4.13 vs 9.64+/-4.37 microg/ml, p=0.027). All of the examined HOMA-R had a significant correlation with all of the examined adiponectin (p<0.001, r=-0.441).. Sarpogrelate has a persistent insulin-sensitizing effect through adiponectin modification and might be beneficial for anti-atherosclerotic therapy, at least, in non-diabetic and non-medicated diabetic patients with PAD.

Topics: Adiponectin; Aged; Aged, 80 and over; Atherosclerosis; Blood Pressure; Female; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Peripheral Vascular Diseases; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates

R-102444 is a prodrug that is metabolized into R-96544, a potent and selective 5-hydroxytryptamine2A (5-HT2A) receptor antagonist. The effects of R-102444 on peripheral vascular disease were examined using two different rat models: one induced by lauric acid and the other by ergotamine plus epinephrine. R-96544 (0.3-30 nM) relaxed the 5-HT (3 microM)-precontracted rat caudal artery in a concentration-dependent manner. The intravenous administration of R-96544 (0.3-3 microg/kg) to anesthetized rats inhibited the pressor response to 5-HT (50 microg/kg i.v.) dose dependently. The oral administration of R-102444 (1 mg/kg) to rats resulted in a marked inhibition of platelet aggregation induced by 5-HT plus ADP, and statistically significant inhibition was still evident 8 h after the dosing. In contrast, sarpogrelate, at a dose of 100 mg/kg p.o., produced only a moderate antiplatelet effect. Oral administration of R-102444 (1 mg/kg/day, o.d.) significantly prevented the progression of peripheral vascular lesion induced by the injection of lauric acid into a rat femoral artery, whereas sarpogrelate (100 mg/kg/day) showed only a minimal effect. Both 5-day treatments with R-102444 (1-30 mg/kg/day p.o., o.d.), one commenced 1 h before the injection of epinephrine plus ergotamine and one just after injection, resulted in the prevention of rat tail gangrene in a dose-dependent manner, whereas sarpogrelate (100 mg/kg) produced a minimal protection in this model. Based on these results, we conclude that 5-HT2A receptor activation is involved in peripheral vascular disease in the rat and that R-102444 is a useful oral agent for the investigation of diseases involving 5-HT2A receptor activation.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Peripheral Vascular Diseases; Pyrrolidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Vasodilation