Protective effect of ticlopidine on experimentally induced peripheral arterial occlusive disease in rats

Ashida, Shinji; Ishihara, Mamoru; Ogawa, Hidemasa; Abiko, Yasushi

doi:10.1016/0049-3848(80)90170-x

Cited by 59 publications

(43 citation statements)

References 20 publications

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“…To date, PAD/CLI models such as multivessel ligation, vessel excision, and lauric acid injection have been widely used in nonclinical studies of PAD 17, 18, 19. Previous studies with these CLI models have reported improvements in blood flow, walking function, and/or gangrene of the ischemic limb, in response to a variety of antiplatelet agents such as thromboxane A 2 receptor antagonist,29 5‐HT 2A receptor antagonists,30, 31 phosphodiesterase 3 inhibitors,20, 21 and P2Y 12 antagonists 19, 32.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies with these CLI models have reported improvements in blood flow, walking function, and/or gangrene of the ischemic limb, in response to a variety of antiplatelet agents such as thromboxane A 2 receptor antagonist,29 5‐HT 2A receptor antagonists,30, 31 phosphodiesterase 3 inhibitors,20, 21 and P2Y 12 antagonists 19, 32. However, in PAD patients, the complications of CLI are typically defined as severe rest pain and ischemic skin lesions,33, 34 and many of the CLI animal models report severe necrosis at the periphery of the ischemic limb, presumably due to severe occlusion of the proximal arteries 19, 35, 36. Approximately 1% to 3% of PAD patients are clinically classified as having CLI, whereas 30% to 50% experience intermittent claudication and 50% to 70% are asymptomatic, with the latter group being classified as having “mild” PAD 5.…”

Section: Discussionmentioning

confidence: 99%

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Prasugrel, a Platelet P2Y ₁₂ Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

Ohno

Tomizawa

Mizuno

et al. 2016

JAHA

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BackgroundThe efficacy of P2Y12 inhibition for the prevention of cardiovascular events in patients with peripheral arterial disease (PAD) has been established. However, the therapeutic effects on ischemic limb complications are less clear. Accordingly, we aimed to develop a novel murine model of thrombotic hindlimb ischemia to reflect that found in patients with PAD exhibiting ischemic limb symptoms. We further investigated the effects of P2Y12 deficiency and P2Y12 inhibition by prasugrel in this model.Methods and ResultsThrombus formation induced by application of ferric chloride to the femoral artery resulted in a significant reduction in blood flow in the injured limb. In gait analysis using the CatWalk system, moderate difficulties in grounding and weight bearing of the ischemic limb, including reduction of maximum contact area and stance phase duration and increasing in swing phase duration in the ischemic limb, were observed in this model. Blood flow reduction and gait abnormalities gradually recovered over 21 days to levels present before arterial injury. Compared to wild‐type (WT) mice, significant increases in blood flow and improvement in gait were observed in P2Y12‐deficient mice. In addition, daily oral administration of prasugrel (3 mg/kg per day) to WT mice resulted in significant inhibition of blood flow reduction and gait abnormalities to levels found in P2Y12 deficient mice.ConclusionsAcute femoral artery thrombosis resulted in hindlimb ischemia and moderate gait abnormalities in mice. In addition, the present study suggests a possible role of P2Y12 in the complications with thrombotic limb ischemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prasugrel, a Platelet P2Y ₁₂ Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

Ohno

Tomizawa

Mizuno

et al. 2016

JAHA

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“…Based on these factors, various experimental models in animals have been reported (7,8,11). In this study, we examined the effect of OP-41483•a-CD and PGE1-CD on experimental models of peripheral vascu lar lesion that were induced by the injection of laurate into the femoral artery (arterial thrombotic model) or by the subcutaneous injection of epinephrine to the tail and subcutaneous injection of ergotamine to the back (vasoconstriction model).…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the laurate-induced model, it has been re ported that platelet aggregation is a major contributing factor, in the initiation and the progression of vascular lesions, based on the fact that vascular lesions are sup pressed by the treatment with antiplatelet agents or antiplatelet serum (7). Laurate-induced damage of the vascular wall triggers platelet adhesion and aggregation to form occlusive thrombi with some participation of the coagulation system.…”

Section: Discussionmentioning

confidence: 99%

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Inhibitory Effect of OP-41483·α-CD, a Prostacyclin Analog, on Peripheral Vascular Lesion Models in Rats

Wakitani

Takakuwa

Sugioka

et al. 1992

Japanese Journal of Pharmacology

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ABSTRACT-The effect of a chemically stable prostacyclin analog, OP-41483 a-cyclodextrin clathrate (OP-41483•a-CD), on vascular lesions, platelet aggregation and blood pressure were examined and compared with those of prostaglandin E1 a-cyclodextrin clathrate (PGE1.CD) in in vivo rat models. Prostacyclin is a chemically unstable compound that possesses both potent antiplatelet (1) and hypotensive (2) actions. Because of its clinical potential, various prostacyclin derivatives have been developed with the aims of increasing its chemical stability and dissociating these two actions. OP-41483•a-CD, 5(E)-6,9a methylene-15-cyclopentyl-16,17,18,19,20-pentanor-PG12 a-cyclodextrin clathrate, is a novel and chemically stable prostacyclin analog that inhibits platelet functions (adhesion and aggregation) and prevents thrombus formation in an electrically induced thrombus model in guinea pigs (3). The inhibitory effects of OP-41483•a CD on platelet functions are produced through dual mechanisms: one mediated by activation of adenylate cyclase and the other by inhibition of Ca 2+ influx (4). This compound also has a more potent antiplatelet effect than hypotensive activity in baboons (5) and hu mans (6). Therefore, OP-41483•a-CD may have anti thrombotic properties for the treatment of thrombotic and ischemic vascular diseases.In this study, we compared the inhibitory effect of OP-41483•a-CD with that of prostaglandin El a-cyclo dextrin clathrate (PGE1•CD) on two peripheral vascu lar lesion models in rats: the arterial thrombotic model induced by intraarterial injection of laurate and the vasoconstriction model induced by subcutaneous injec tion of epinephrine and ergotamine. Furthermore, the effects of both compounds on platelet aggregation (in vivo) and blood pressure were examined in conscious rats. MATERIALS AND METHODS AnimalsMale Wistar rats were purchased from Kitayama Labes and Shizuoka Laboratory Animal Center. All animals were kept in an animal room maintained at 24 ± 1°C with 60 ± 10% humidity and illuminated for 12 hr (8:00 AM-8:00 PM). They were fed a standard laboratory diet (Funabashi, MM-5) and tap water ad libitum.

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Preventive effects of batroxobin on experimental canine coronary thrombosis

Tomaru

Uchida

Sonoki

et al. 1988

Clinical Cardiology

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Summary: The thrombolytic effects of urokinase (UK) and preventive effects of batroxobin, heparin, and aspirin on the recurrence of thrombosis in the coronary artery were studied in 118 anesthetized dogs with severe endothelial denudation and luminal stenosis of the coronary artery. Occlusive thrombi developed in 68 (58%) preparations (dogs), accompanied by a decrease of coronary blood flow and pressure, an electrocardiographic ST elevation, and epicardial cyanosis. An intravenous infusion of 20,000 IU/kg of UK reopened the occluded coronary artery in all 32 preparations with l-h-old thrombi, in 6 (86%) of 7 preparations with 2-h-old thrombi, and in 5 (83%) of 6 preparations with 3-h-old thrombi. However, recanalization was not observed in preparations with thrombi more than 4-h-old. Occlusion recurred within 6 h after recanalization in 2 (18%) of 18 preparations pretreated with batroxobin (1-2 BU/kg) (p < .005 vs. control UK group), in 1 (14%) of 7 prepamtions administered a contiriuous infusion of 30 U/kg per h of heparin (p < .05 vs. control UK group), in 4 (57%) of 7 preparations pretreated with 2 mg/kg of aspirin, and in 7 (64%) of 11 preparations not pretreated (control UK group). Complete prevention was observed only in the group administered 2 BU/kg of batroxobin. Histologically, these thrombi closely simulated clinical arterial thrombi. Myocardial hemorrhage and contraction band necrosis were observed in the reperfused hearts. In conclusion, experimental canine coronary thrombi more than 4-h-old were resistant to thrombolytic therapy, and batroxobin and heparin were effective in the prevention of coronary reocclusion.

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Protective effect of ticlopidine on experimentally induced peripheral arterial occlusive disease in rats

Cited by 59 publications

References 20 publications

Prasugrel, a Platelet P2Y ₁₂ Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

Prasugrel, a Platelet P2Y ₁₂ Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

Inhibitory Effect of OP-41483·α-CD, a Prostacyclin Analog, on Peripheral Vascular Lesion Models in Rats

Preventive effects of batroxobin on experimental canine coronary thrombosis

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Protective effect of ticlopidine on experimentally induced peripheral arterial occlusive disease in rats

Cited by 59 publications

References 20 publications

Prasugrel, a Platelet P2Y 12 Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

Prasugrel, a Platelet P2Y 12 Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

Inhibitory Effect of OP-41483·α-CD, a Prostacyclin Analog, on Peripheral Vascular Lesion Models in Rats

Preventive effects of batroxobin on experimental canine coronary thrombosis

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Product

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Prasugrel, a Platelet P2Y ₁₂ Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

Prasugrel, a Platelet P2Y ₁₂ Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia