Sarpogrelate treatment reduces restenosis after coronary stenting

Fujita, Masatoshi; Mizuno, Kyoichi; Ho, Mami; Tsukahara, Reiko; Miyamoto, Akira; Miki, Osamu; Ishii, Katsuhisa; Miwa, Kunihisa

doi:10.1067/mhj.2003.176

Cited by 43 publications

(37 citation statements)

References 11 publications

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“…Sarpogrelate [SAR, a 5-hydroxy-tryptamine 2A (5-HT 2A ) receptor antagonist], and cilostazol [CIL, a phosphodiesterase-III (PDE-III) inhibitor] are novel antiplatelet and vasodilatory agents, which are used in the management of peripheral vascular disease [1,2] as well as in the prevention of restenosis after coronary interventions [3,4]. SAR has been shown to inhibit the serotonin-induced smooth muscle proliferation, vasoconstriction, platelet aggregation and coronary artery spasm [5][6][7].…”

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confidence: 99%

Antiplatelet Agents Sarpogrelate and Cilostazol Affect Experimentally-induced Ventricular Arrhythmias and Mortality

et al. 2008

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Antiplatelet agents, sarpogrelate (SAR), a 5-hydroxy tryptamine 2A receptor antagonist and cilostazol (CIL), a phosphodiesterase-III inhibitor, were observed to be beneficial in attenuating cardiac remodeling and improving cardiac function in congestive heart failure due to myocardial infarction in rats; however, CIL increased ventricular tachycardia and mortality. In order to study the effects of these antiplatelet agents on arrhythmias, Sprague-Dawley rats were pretreated with either SAR or CIL (5 mg/kg/day) for 2 weeks and were then either injected cumulative doses of epinephrine (Epi) or subjected to coronary occlusion. Saline-treated animals served as controls. Electrocardiographic analysis revealed that SAR pretreatment decreased the incidence and severity of ventricular arrhythmias (time of onset of arrhythmias as well as the occurrence of premature ventricular contractions, salvos, tachycardia, and fibrillations), whereas CIL treatment augmented the incidence of cardiac arrhythmias due to both Epi and coronary occlusion. None of the drugs affected the corrected QT interval significantly. Furthermore, the levels of cyclic adenosine monophosphate (cAMP) in left ventricle were markedly higher in CIL-pretreated rats when compared to SAR-pretreated or control rats. It is suggested that an excessive level of cAMP may contribute to increase incidence of ventricular arrhythmias and mortality in animals pretreated with CIL, unlike the SAR-pretreated rats.

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Section: Introductionmentioning

confidence: 99%

Antiplatelet Agents Sarpogrelate and Cilostazol Affect Experimentally-induced Ventricular Arrhythmias and Mortality

et al. 2008

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“…Sarpogrelate has inhibitory effects on serotonininduced platelet aggregation (Hara et al, 1991a;Nakamura et al, 1999), thrombus formation (Hara et al, 1991b;Yamashita et al, 2000), vasoconstriction, and vascular smooth muscle cell proliferation (Sharma et al, 1999), all of which are mediated by 5-HT 2A receptors, and consequently reduces the ischemic symptoms associated with peripheral arterial disease. Additionally, sarpogrelate has beneficial effects in restenosis after coronary stenting (Fujita at al., 2003;Saini et al, 2004), pulmonary hypertension (Saini et al, 2004), angina pectoris (Kinugawa et al, 2002), and diabetes mellitus (Pietraszek et al, 1993;Ogawa et al, 1999), although the precise mechanisms remain unknown. Sarpogrelate is metabolized to (6)-1-{2-[2-(3-methoxyphenil)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol hydrochloride (M-1; Fig.…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes

et al. 2013

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The present study was performed to evaluate the in vitro inhibitory potential of sarpogrelate and its active metabolite, M-1, on the activities of nine human cytochrome (CYP) isoforms. Using a cocktail assay, the effects of sarpogrelate on nine CYP isoforms and M-1 were measured by specific marker reactions in human liver microsomes. Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC 50 (K i ) value of 3.05 mM (1.24 mM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC 50 (K i ) value of 0.201 mM (0.120 mM) was more potent than that of sarpogrelate, and was similarly potent as quinidine (K i , 0.129 mM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and M-1 strongly inhibited both CYP2D6-catalyzed bufuralol 19-hydroxylation and metoprolol a-hydroxylation activities. However, sarpogrelate and M-1 showed no apparent inhibition of the other following eight CYPs: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5. Upon 30-minute preincubation of human liver microsomes with sarpogrelate or M-1 in the presence of NADPH, no obvious shift in IC 50 was observed in terms of inhibition of the nine CYP activities, suggesting that sarpogrelate and M-1 are not time-dependent inactivators. Sarpogrelate strongly inhibited the activity of CYP2D6 at clinically relevant concentrations in human liver microsomes. These observations suggest that sarpogrelate could have an effect on the metabolic clearance of drugs possessing CYP2D6-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug-drug interactions.

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“…For example, sarpogrelate was shown to inhibit restenosis after coronary stenting in humans (Fujita et al, 2003).…”

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confidence: 99%

APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology

Adams

Ramirez²,

Shi³

et al. 2009

J Pharmacol Exp Ther

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We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl-)benzamide] a novel 5-hydroxytryptamine 2A (5-HT 2A ) receptor antagonist. APD791 displayed high-affinity binding to membranes (K i ϭ 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC 50 ϭ 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT 2A receptor. In competition binding assays, APD791 was greater than 2000-fold selective for the 5-HT 2A receptor versus 5-HT 2C and 5-HT 2B receptors, and was inactive when tested against a wide panel of other G-protein-coupled receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC 50 ϭ 8.7 and 23.1 nM, respectively).Similar potency was observed for inhibition of 5-HT-stimulated DNA synthesis in rabbit aortic smooth muscle cells (IC 50 ϭ 13 nM) and 5-HT-mediated vasoconstriction in rabbit aortic rings. Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT 2A receptor antagonist with potent activity on platelets and vascular smooth muscle.Serotonin (5-hydroxytryptamine, 5-HT) is a naturally occurring indoleamine found primarily in brain, enterochromaffin tissue, and platelets. 5-HT exerts a multitude of biological effects mediated through interaction with specific cell surface G-protein-coupled receptors (GPCRs). To date, at least 14 different human 5-HT GPCRs are known (Kaumann and Levy, 2006). Among them, 5-HT 2A receptors on vascular smooth muscle cells and platelets play an important role in the regulation of cardiovascular function.The uptake process and storage capacity for 5-HT by platelets are such that minimal amounts of the amine exist in normal plasma. However, upon platelet activation at sites of vessel injury, 5-HT is released from the dense granules in platelets (Ashton et al., 1986). Although 5-HT by itself is only a weak activator of platelet aggregation, it effectively amplifies aggregation induced by other agonists including collagen, ADP, epinephrine, and thrombin (De Clerck and Herman, 1983;De Clerck and Janssen, 1990). Thus, 5-HT This work was supported by Arena Pharmaceuticals, Inc. Article, publication date, and citation information can be found at

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Sarpogrelate treatment reduces restenosis after coronary stenting

Cited by 43 publications

References 11 publications

Antiplatelet Agents Sarpogrelate and Cilostazol Affect Experimentally-induced Ventricular Arrhythmias and Mortality

Antiplatelet Agents Sarpogrelate and Cilostazol Affect Experimentally-induced Ventricular Arrhythmias and Mortality

Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes

APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology

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