Effect of cilostazol, a selective type-III phosphodiesterase inhibitor, on water-immersion stress-induced gastric mucosal injury in rats

Ohba, Reina; Otaka, Michiro; Odashima, Masaru; Jin, Mario; Komatsu, Kyoji; Konishi, Noriaki; Wada, Isao; Horikawa, Youhei; Matsuhashi, Tamotsu; Oyaké, Jinko; Hatakeyama, Natsumi; Watanabe, Sumio

doi:10.1007/s00535-005-1686-9

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…PTX decreased the levels of TNF-α and IL-1β significantly in EtOH-induced ulcerated gastric mucosa, and the above observation is in confirmation with the reported work of other workers. [2,23,24] TNF-α is reported to stimulate the upregulation of IL-1β levels, so by controlling the TNF-α expression, the IL-1β expression can be controlled. This may be the mechanism by which PTX decreases both the cytokines levels.…”

Section: Discussionmentioning

confidence: 99%

Status of inflammatory markers and growth factor in gastric ulcer protective effects of Punica granatum L. peel extract in rat

Chauhan¹,

Agrawal²,

Goel³

2018

Natl J Physiol Pharm Pharmacol

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Background: Inflammatory markers, namely, myeloperoxidase (MPO), cytokines (tumor necrosis factor-alpha [TNF-α], and interleukin-1 beta ) and vascular endothelial growth factor (VEGF) have been reported to play an important role in ulcerogenesis and healing. Recently, we reported that the gastric ulcer (GU) protective and healing effects of 50% ethanol (EtOH) extract of Punica granatum peel (PGE) in rats were predominantly due to strengthening of mucosal defense and antioxidants status. Aims and Objectives: The present study incorporates the effects of PGE on rat gastric mucosal inflammatory markers (MPO, TNF-α, and IL-1β) and angiogenic factor (VEGF) in GU induced by cold-restraint stress (CRS) and EtOH in rats. Materials and Methods: PGE (100 mg/kg) was administered orally once daily to rats for 7 days before induction of CRS and EtOH GU. Ulcer index (UI), gastric mucosal MPO, TNF-α, and IL-1β, and VEGF were estimated. Results: CRS rats showed increase in UI and MPO (419.5, P < 0.001) compared with unstressed rats while PGE caused decrease in UI (46.1%, P < 0.05) and MPO (51.1%, P < 0.001) compared with CRS rats. EtOH rats showed increase in UI, TNF-α (936.5%, P < 0.001), IL-1β (37.2%, P < 0.05), and VEGF (13.0%, P < 0.05) compared with control normal salinetreated rats. PGE-treated EtOH rats showed decrease in UI (68.9%, P < 0.05), TNF-α (77.9%, P < 0.01), and IL-1β (24.8%, P < 0.05) but tended to decrease VEGF (7.3%, P < 0.2) compared with EtOH rats. Conclusion: Both the inflammatory markers and VEGF were found to increase in GU rats while PGE EtOH extract decreased the status of inflammatory markers with little change in VEGF level with concomitant decrease in ulceration indicating their role in ulcer healing and repair.

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Section: Discussionmentioning

confidence: 99%

Status of inflammatory markers and growth factor in gastric ulcer protective effects of Punica granatum L. peel extract in rat

Chauhan¹,

Agrawal²,

Goel³

2018

Natl J Physiol Pharm Pharmacol

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“…In addition, cilostazol has been reported to inhibit endothelial-neutrophil adhesion by decreasing adhesion molecules expression [12,13]. In the previous study, we reported that cilostazol reduces gastric mucosal lesions induced by water-immersion stress by reducing proinflammatory cytokine production in the gastric mucosa [14].…”

Section: Introductionmentioning

confidence: 98%

Attenuation of Gastric Mucosal Inflammation Induced by Aspirin Through Inhibition of Selective Type III Phospshodiesterase in Rats

et al. 2007

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Cilostazol, a selective type III phosphodiesterase inhibitor, is widely used for treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The activation of inflammatory cells and pro-inflammatory cytokine production play critical roles in the pathogenesis of aspirin-induced gastric irritation. The aim of the present study was to determine whether cilostazol can ameliorate aspirin-induced gastric mucosal lesions in rats, reduce neutrophil accumulation, and reduce the production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 ml/kg). Cilostazol (1-10 mg/kg, IP) was injected 30 min before aspirin administration. Also, we measured the gastric mucosal concentrations of myeloperoxidase and interleukin-1 beta, tumor necrosis factor-alpha, and cytokine-induced neutrophil chemoattractants-1, as an index of neutrophil accumulation, and the pro-inflammatory cytokines. Cilostazol ameliorated the gastric mucosal lesions induced by aspirin administration (P<0.01). The gastric contents of myeloperoxidase and pro-inflammatory cytokines were all increased after aspirin administration and significantly reduced by cilostazol treatment. In this study, we demonstrated that a selective type III phosphodiesterase inhibitor, cilostazol, reduced aspirin-induced gastric inflammation and damage via suppression of the production of proinflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions induced by aspirin.

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“…A recent randomized, crossover study of healthy CYP2C19 ＊ 1/ ＊ 1 subjects (n = 160) also demonstrated that the effect of omeprazole on the plasma concentration and antiplatelet actions of clopidogrel appears to be greater than that of lansoprazole 6) . The results of the present study including stented patients highlight the significant interaction between lansoprazole and clopidogrel, although the observed stress-induced gastric mucosal inflammation and injury by suppressing the production of pro-inflammatory cytokines in rats 35,36) . In contrast to aspirin and thienopyridine, cilostazol does not significantly prolong the bleeding time; this property remains even when cilostazol is added to other antiplatelet regimens 37) .…”

Section: Discussionmentioning

confidence: 50%

“…On the other hand, clopidogrel does not have a direct effect on the gastric mucosa, but rather inhibits the healing process of gastric mucosal injury induced by aspirin. In contrast to that observed with aspirin and clopidogrel, several experimental studies have shown the beneficial effects of cilostazol on gastric mucosal damage and/or bleeding [34][35][36][37] . Compared with aspirin, cilostazol significantly ameliorated microcirculatory and villous damage to the intestinal mucosa following ischemia-reperfusion injury in a mice study 34) .…”

Section: Discussionmentioning

confidence: 78%

Pharmacodynamic Effects of Cilostazol Versus Clopidogrel in Stented Patients under Proton Pump Inhibitor Co-administration: The ACCEL-PARAZOL Study

Park¹,

Jung²,

Tantry³

et al. 2014

JAT

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Aim: Proton pump inhibitor (PPI) therapy has been shown to attenuate the antiplatelet effects of clopidogrel. The aim of this study was to compare the antiplatelet effects of cilostazol versus clopidogrel in patients co-administered a PPI. Methods: We enrolled PPI-naïve stented patients treated with standard clopidogrel and aspirin therapy for at least six months (n = 100). The patients were randomly assigned to receive either cilostazol at a dose of 100 mg twice daily (CILO group) or clopidogrel at a dose of 75 mg daily (CLPD group) in addition to lansoprazole (30 mg daily). The platelet aggregation (PA) determined using light transmittance aggregometry and the platelet reactivity index (PRI) obtained using a vasodilator-stimulated phosphoprotein phosphorylation assay were measured before randomization and at the 14-day follow-up visit. The primary endpoint was the PRI value at follow-up. Results: At follow-up, the CLPD group showed similar values of PRI as the CILO group (66.9±14.0% vs. 63.1±14.1%; mean difference: 3.9%; 95% confidence interval of difference: −1.7% to 9.4%; p=0.174). However, the 6 μg/mL collagen-and 0.5 mg/mL arachidonic acid-induced PA values in the CLPD group were higher than those observed in the CILO group (mean differences: 9.8% to 11.1%; all p values ＜0.001). CYP2C19 loss-of-function allele carriage was the major contributing factor associated with the PRI level in the absence of lansoprazole treatment (with a gene-dose effect); this association was not observed in the subjects receiving lansoprazole co-administration in the CLPD group. Conclusions: During lansoprazole co-administration, cilostazol treatment achieves a more favorable platelet function profile than clopidogrel therapy. The use of combination treatment with cilostazol and aspirin deserves further attention with respect to the management of stable stented patients requiring PPI co-administration. IntroductionDual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been shown to reduce major cardiovascular events following percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS). However, the risk of gastrointestinal (GI) Park Y and Jung JM contributed equally to this work. cilostazol compared with that of ADP P2Y12 receptor blockers and the findings of a previous report of healthy subjects showing relatively lower inhibitory effects of ADP-mediated platelet aggregation by cilostazol than with clopidogrel 18) may limit its clinical application in stented patients. Since cilostazol is also metabolized by the CYP2C19 enzyme 19) , the CYP2C19 genetic polymorphism and/or concomitant use of a PPI may influence its pharmacodynamic effect.In the current study, we therefore evaluated the influence of lansoprazole administration on the effects of clopidogrel and compared the pharmacodynamic actions of cilostazol vs. clopidogrel treatment during PPI co-administration in patients with a history of coronary stenting. Methods Patient Selection and Study DesignThis ACCEL-PARAZOL (phArmacodynamic effect of Cilos...

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Effect of cilostazol, a selective type-III phosphodiesterase inhibitor, on water-immersion stress-induced gastric mucosal injury in rats

Abstract: In this study, we demonstrated that a selective type-III phosphodiesterase inhibitor, cilostazol, inhibited stress-induced gastric inflammation and damage via suppressing the production of pro-inflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions.

Cited by 19 publications

References 29 publications

Status of inflammatory markers and growth factor in gastric ulcer protective effects of Punica granatum L. peel extract in rat

Status of inflammatory markers and growth factor in gastric ulcer protective effects of Punica granatum L. peel extract in rat

Attenuation of Gastric Mucosal Inflammation Induced by Aspirin Through Inhibition of Selective Type III Phospshodiesterase in Rats

Pharmacodynamic Effects of Cilostazol Versus Clopidogrel in Stented Patients under Proton Pump Inhibitor Co-administration: The ACCEL-PARAZOL Study

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