Antithrombotic Effect of SM-20302, a Nonpeptide GPIIb/IIIa Antagonist, in a Photochemically Induced Thrombosis Model in Guinea Pigs

Horisawa, Seiya; Kaneko, Munekiyo; Ikeda, Y.; Ueki, Yoshitaka; Sakurama, Teruo

doi:10.1016/s0049-3848(98)00215-1

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…In various models, SM-20302 has previously been shown to block the final common pathway in platelet aggregation, thus maintaining vascular integrity and patency. 21,22,24,25 Our study is in agreement with a previous acute focal cerebral ischemia study of Abumiya et al 26 The researchers showed that the antiplatelet compound TP9201 effectively increased microvascular patency after MCA occlusion. However, they also noted that TP9201 caused a dose-dependent increase in hemorrhagic transformations.…”

Section: Discussionsupporting

confidence: 91%

“…This dose of SM-20302 was chosen on the basis of previous in vivo pharmacological studies that showed that doses in the range of 0.1 to 10 mg/kg inhibited platelet aggregation and maintained vessel patency in vivo. 21,22 In the remaining groups of rabbits, we then administered tPA or vehicle 1 hour after embolization according to the aforementioned schedule. The tPA regimen used in this study was as follows: 3.3 mg/kg tPA, 20% as a bolus injection given over 1 minute, followed by the remainder infused over 30 minutes.…”

Section: Drug Administrationmentioning

confidence: 99%

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The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

Lapchak

Araujo²,

Song³

et al. 2002

Stroke

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Background and Purpose-Platelet activation and deposition in brain microvessels appear to be key events in the pathogenesis of ischemia-induced neuronal degeneration and behavioral deficits. It has been hypothesized that activated platelets in combination with polymorphonuclear leukocytes and fibrin may play a role in vessel reocclusion leading to the "no-reflow" phenomenon after administration of the thrombolytic tissue plasminogen activator (tPA). We studied the effects of the novel glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 when administered in combination with tPA on infarct and hemorrhage rate and volume to determine whether activated platelets are involved in either infarct or hemorrhage generation after a thromboembolic stroke. Methods-One hundred thirty-two male New Zealand White rabbits were included in the present study. Rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five or 65 minutes after embolization, SM-20302 (5 mg/kg) was infused intravenously. In drug combination studies, tPA was infused intravenously for 30 minutes starting 60 minutes after embolization, and SM-20302 was administered 5 or 65 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis. Results-In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 33%. There was a significant increase (109%) in the hemorrhage rate in the group of rabbits treated with the thrombolytic tPA. SM-20302 by itself did not significantly alter the embolism-induced hemorrhage rate when administered either 5 or 65 minutes after embolism. The SM-20302 groups had a 42% and 33% incidence of hemorrhage in the 5-and 65-minute groups, respectively. In groups treated with a combination of drugs, the SM-20302/tPA group had a 31% and 71% incidence of hemorrhage when SM-20302 was administered 5 and 65 minutes after embolization, respectively. SM-20302 in combination with tPA also significantly increased infarct rate, but not hemorrhage or infarct volume. Conclusions-This study suggests that treatment of thromboembolic stroke with the combination of a platelet inhibitor and tPA may have a beneficial outcome on the basis of the following: First, acute administration of SM-20302 did not significantly increase hemorrhage rate. Second, SM-20302 in combination with tPA significantly reduced tPA-induced intracerebral hemorrhage. Third, there appears to be a specific window of opportunity when a platelet inhibitor must be administered to produce a beneficial effect. Overall, on the basis of our results, we hypothesize that the increased rate of intracerebral hemorrhage observed after tPA administration may be partly due to increased reocclusion of cerebral vessels following lysis of the emboli and that reocclusion can be controlled by administration of a platelet inhibitor.

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Section: Discussionsupporting

confidence: 91%

Section: Drug Administrationmentioning

confidence: 99%

The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

Lapchak

Araujo²,

Song³

et al. 2002

Stroke

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“…In the RLCEM, SM-20302 decreased hemorrhaging induced by tPA [65] in the same dose range previously shown to inhibit platelet aggregation [62][63][64]. Most of the hemorrhaging was of the HI subtype, whereas the incidence of the more clinically devastating type, PH, was minimal [66].…”

Section: Platelet Inhibitorsmentioning

confidence: 83%

“…Unfortunately, the former also was associated with increased HT [60]. Other platelet inhibitors, including the novel nonpeptide GP IIb/IIIa receptor antagonist SM-20302, block the final common pathway in platelet aggregation, thus maintaining vascular integrity and patency [61], even with relatively low doses ranging from 0.1 to 10 mg/kg [62][63][64].…”

Section: Platelet Inhibitorsmentioning

confidence: 99%

Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment

Lapchak

2002

Curr Neurol Neurosci Rep

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Hemorrhagic transformation (HT) is a frequent consequence of ischemic stroke that becomes more prevalent after thrombolytic therapy. Despite concerns about safety parameters, thrombolytic drugs remain the first course of action available to clinicians for stroke management. However, recent efforts in preclinical studies have attempted to discover other drugs that can lessen the risk of hemorrhage associated with thrombolytic administration. This review focuses on three classes of pharmacologic agents that have shown some promise in animal models of stroke, and can thus be considered as possible candidates for coadministration with thrombolytics in the treatment of stroke. These include the following: 1) spin trap agents, such as alpha-phenyl-N-t-butylnitrone (PBN) that scavenge free radicals; 2) matrix metalloproteinase (MMP) inhibitors, such as BB-94, that prevent membrane and vessel remodeling following ischemia; and 3) the novel glycoprotein (GP) IIb/IIIa platelet receptor antagonist SM-20302. Although these drugs affect different mechanisms, the common denominator seemed to be their effectiveness in reducing the incidence of hemorrhage in response to thrombolytic infusion following an embolic stroke.

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“…It has been estimated in the literature that the mean ionized calcium ion concentration in citrated plasma is reduced to 40-50 μM [20,21]. In contrast, the calcium ion concentration in blood is approximately 1 mM (and is unchanged in heparinized plasma).…”

Section: Resultsmentioning

confidence: 99%

Engineered human soluble calcium-activated nucleotidase inhibits coagulation in vitro and thrombosis in vivo

Yang

Kirley

2008

Thrombosis Research

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Human soluble calcium-activated nucleotidase (human SCAN) is a homologue of the salivary anticoagulant apyrases injected by insects into their hosts to allow blood feeding. However, the human enzyme, unlike its insect counterparts, does not efficiently hydrolyze the platelet agonist, ADP. By site-directed mutagenesis, two mutant human SCANs were constructed and expressed in bacteria. Following refolding from inclusion bodies and purification, these enzymes were assessed for anticoagulant and anti-thrombotic efficacy. These engineered proteins include both active site mutations and a dimer interface mutation to increase the stability and ADPase activity of the modified human nucleotidase. The ADPase activity of these mutants increased more than ten fold. The E130Y/ K201M/E216M SCAN mutant efficiently inhibited platelet aggregation in vitro. In addition, the E130Y/K201M/T206K/T207E/E216M mutant inhibited jugular vein thrombosis in the murine ferric chloride-induced model of thrombosis, as assessed by laser Doppler blood flow measurements. The bed bug insect homologue of human SCAN was also expressed and purified, and used in these in vivo experiments as a benchmark to assess the therapeutic potential of the engineered human enzymes. The most active modified human enzyme was able to completely inhibit the thrombosis induced by ferric chloride at roughly double the protein dose used for the bed bug enzyme. Thus, for the first time, we show that an engineered form of this human protein is efficacious in an in vivo model of thrombosis, demonstrating that suitably modified human SCAN enzymes have therapeutic potential as anti-coagulant and anti-thrombotic therapeutic agents. This suggests their utility in future treatment strategies for thrombotic cardiovascular diseases, including myocardial infarctions and ischemic strokes. Keywordscalcium-activated nucleotidase; ferric chloride-induced thrombosis; aggregometry; platelets; anticoagulant proteins; laser Doppler blood flow Cardiovascular and cerebrovascular diseases continue to be the leading causes of death in the developed world, with more than 450,000 patients in the United States afflicted by stroke annually [1]. The platelet is a major contributor to occlusive thrombus formation in acute Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of Interest StatementThere are no conflicts of interest to declare. The sole funding for this study was obtained via NIH grant HL72882 to T.L.K. Mammals express a protein homologous to the nucleotidases found in the saliva of bloodsucking insects. In insects, these soluble pro...

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Antithrombotic Effect of SM-20302, a Nonpeptide GPIIb/IIIa Antagonist, in a Photochemically Induced Thrombosis Model in Guinea Pigs

Cited by 12 publications

References 30 publications

The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment

Engineered human soluble calcium-activated nucleotidase inhibits coagulation in vitro and thrombosis in vivo

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