IIb-IIIa Receptor Antagonists Research Articles

Enantio- and Chemoselective Intramolecular Iridium-Catalyzed O-Allylation of Oximes

A method for the enantio- and chemoselective iridium-catalyzed O-allylation of oximes is described. Kinetic resolution in an intramolecular setting provides enantioenriched oxime ethers and aliphatic allylic alcohols. The synthetic potential of the products generated with this method is showcased by their elaboration into a series of heterocyclic compounds and the formal synthesis of glycoprotein GP IIb-IIIa receptor antagonist (-)-roxifiban. Preliminary mechanistic experiments and computational data shed light on the remarkable chemoselectivity of the reaction.

Platelet reactivity in thromboelastometry. Revision of the FIBTEM test: a basic study

This study aimed to investigate modifications to the FIBTEM test to better assess fibrinogen levels and the quality of fibrin polymerization in citrated blood using Multiplate impedance aggregometry to verify platelet inhibition. Blood samples from 26 healthy volunteers were subjected to thromboelastometry studies (EXTEM/FIBTEM tests) in accordance with the standard study protocol (cytochalasin D) and according to a modified protocol (synthetic IIbIIIa receptor antagonist vs. acetylsalicylic acid [ASA] + synthetic IIbIIIa receptor antagonist instead of cytochalasin D). Independent of thromboelastometry, Multiplate impedance aggregometry was used to assess the degree of restriction by the platelet blocked with the following treatments: (1) cytochalasin D, (2) synthetic IIbIIIa antagonist or (3) ASA + synthetic IIbIIIa antagonist to assess the aggregation response to activation with an agonist (ADP, collagen, thrombin receptor activating peptide-6 [TRAP-6], and arachidonic acid). Via aggregometry, cytochalasin D more weakly inhibited platelet aggregation than simultaneous administration of the -IIbIIIa receptor antagonist with ASA. However, total platelet aggregation inhibition was observed after simultaneous administration of cytochalasin D combined with a synthetic IIbIIIa receptor antagonist. In the thromboelastometry, a significant decrease of the A10, A20 and MCF parameters were observed in the EXTEM/FIBTEM tests after they were modified by the addition of a synthetic IIbIIIa receptor antagonist alone or in combination with ASA. In conclusion, in this Multiplate- and ROTEM-based laboratory approach, a two-way blockade (IIbIIIa-antagonist + cytochalasine D) was sufficient to completely inhibit procoagulant platelet function as observed by aggregometry and thromboelastometry.

CORRIGENDUM

Journal of Veterinary Emergency and Critical CareVolume 23, Issue 6 p. 670-670 CorrigendumFree Access CORRIGENDUM This article corrects the following: Evaluation of platelet aggregometry in dogs using the Multiplate platelet analyzer: impact of anticoagulant choice and assay duration Clara B. Marschner DVM, Annemarie T. Kristensen DVM, PhD, DACVIM, DECVIM, Eva H. Spodsberg DVM, Bo Wiinberg DVM, PhD, Volume 22Issue 1Journal of Veterinary Emergency and Critical Care pages: 107-115 First Published online: February 17, 2012 First published: 04 December 2013 https://doi.org/10.1111/vec.12126AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Evaluation of platelet aggregometry in dogs using the Multiplate platelet analyzer: impact of anticoagulant choice and assay duration. Clara B. Marschner, DVM; Annemarie T. Kristensen, DVM, PhD, DACVIM, DECVIM; Eva H. Spodsberg, DVM and Bo Wiinberg, DVM, PhD In the February 2012 issue (volume 22(1):107–115), on page 108 of the article entitled “Evaluation of platelet aggregometry in dogs using the Multiplate platelet analyzer: impact of anticoagulant choice and assay duration” by Drs. Marschner, Kristensen, Spodsberg and Wiinberg, there were some omissions that the authors would like to correct. Page 108, first column, first paragraph, fourth sentence should have read: “Furthermore, aggregation in the Multiplate takes place on surfaces, which is a major difference compared to methods such as Born aggregometry and single platelet counting in which platelets aggregate with each other in the liquid phase.§ Such spontaneous aggregation presumable happens only in severely ill patients, as coagulation and platelet aggregation in vivo usually only take place on surfaces such as damaged endothelium.§” Page 108, second column, first paragraph, second sentence should have read: “The term ‘multiplate” refers to the multiple electrodes in the disposable test cell, multiple channels of the instruments, as well as multiple test procedures available.§” The fourth sentence should have read : “The standard test cell uses a sample volume of only 300 μL of whole blood . For research use a mini test cell is available with sample volume of 175 μL, making it suitable for use in small animals.§” Page 108, second column, first paragraph, eighth sentence should have read: “According to the Multiplate manufacturer's website, the ‘Multiplate continuously records platelet aggregation as an increase in impedance, which is transformed into arbitrary aggregation units (AU) and plotted against time (Figure 1). Three parameters are calculated: the most important parameter being the area under the aggregation curve (AUC), which is affected by the total height of the aggregation curve as well as by its slope and is best suited to express the overall platelet activity. Two more parameters are calculated for research use: the ’aggregation’ is the height of the curve and the ’velocity’ is the maximum slope of the curve. The parameters calculated by the software include the mean values of the parameters determined with each curve.’§” Page 108, second column, second paragraph, second sentence should have read: “The manufacturer's website also states that ‘ADPtest: Adenosine diphosphate (ADP)-induced platelet activation sensitive to clopidogrel, prasugrel and other ADP receptor antagonists. ADPtest HS: High sensitivity ADPtest with co-stimulation of platelet aggregation with ADP and prostaglandin E1, especially for the sensitive detection of clopidogrel in heparinized blood. ASPItest: Cyclooxygenase dependent aggregation (using arachidonic acid [AA]), sensitive to aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and other inhibitors of platelet cyclooxygenase. TRAPtest: Platelet stimulation via the thrombin receptor (using TRAP-6), sensitive to IIbIIIa receptor antagonists in people, but demonstrated to work in dogs.9 COLtest: Collagen (COL)- induced aggregation. RISTOtest: vWF and GpIb dependent aggregation (using ristocetin as agonist). Control material: ASA Control (Aspirin (ASA) for in vitro analysis), GpIIbIIIa antagonist (for in vitro analysis), liquid quality control kit.’§” In addition, the figure legends for Figures 1 and 2 should also have stated: “Reproduced with permission from Verum Diagnostica GmbH, Munich, Germany” Reference § Mutiplate Homepage. Available at: http://multiplate.net/en/splashpage2.php. Accessed 18 October , 2013 Google Scholar Volume23, Issue6November/December 2013Pages 670-670 ReferencesRelatedInformation

Antiplatelet Therapy in the Prevention of Coronary Syndromes: Mode of Action, Benefits, Drawbacks

Blood platelets play a key role in normal hemostasis but also in atherothrombosis due to their ability of thrombus formation at site of a ruptured atherosclerotic plaque. Platelets are also involved in vascular inflammation due to interactions with endothelial cells, leukocytes, and smooth muscle cells that may result in an excessive fibroproliferative response after vessel dilatation. This review article describes both, the current status of standard anti-platelet drug therapy using acetylsalicylic acid, adenosine diphosphate or glycoprotein IIb-IIIa receptor antagonists in the prevention of cardiovascular events as well as drawbacks like non-responsiveness or increased bleeding rates leading to enhanced reintervention and transfusion rates, both responsible for adverse clinical outcomes after coronary interventions.

Stent assisted coiling of the ruptured wide necked intracranial aneurysm

BackgroundStent assisted coiling of unruptured wide necked intracranial aneurysms require antiplatelets to prevent stent thrombosis. The effect of the loading dose of antiplatelets prior to the stent coiling procedure in...

Clinical Risk Stratification in the Emergency Department Predicts Long-Term Cardiovascular Outcomes in a Population-Based Cohort Presenting With Acute Chest Pain

The long-term cardiovascular outcomes of a population-based cohort presenting to the emergency department (ED) with chest pain and classified with a clinical risk stratification algorithm are not well documented. The Olmsted County Chest Pain Study is a community-based study that included all consecutive patients presenting with chest pain consistent with unstable angina presenting to all EDs in Olmsted County, Minnesota. Patients were classified according to the Agency for Health Care Policy and Research (AHCPR) criteria. Patients with ST elevation myocardial infarction and chest pain of noncardiac origin were excluded. Main outcome measures were major adverse cardiovascular and cerebrovascular events (MACCE) at 30 days and at a median follow-up of 7.3 years, and mortality through a median of 16.6 years.The 2271 patients were classified as follows: 436 (19.2%) as high risk, 1557 (68.6%) as intermediate risk, and 278 (12.2%) as low risk. Thirty-day MACCE occurred in 11.5% in the high-risk group, 6.2% in the intermediate-risk group, and 2.5% in the low-risk group (p < 0.001). At 7.3 years, significantly more MACCE were recorded in the intermediate-risk (hazard ratio [HR], 1.91; 95% confidence intervals [CI], 1.33-2.75) and high-risk groups (HR, 2.45; 95% CI, 1.67-3.58). Intermediate- and high-risk patients demonstrated a 1.38-fold (95% CI, 0.95-2.01; p = 0.09) and a 1.68-fold (95% CI, 1.13-2.50; p = 0.011) higher mortality, respectively, compared to low-risk patients at 16.6 years. At 7.3 and at 16.6 years of follow-up, biomarkers were not incrementally predictive of cardiovascular risk.In conclusion, a widely applicable rapid clinical algorithm using AHCPR criteria can reliably predict long-term mortality and cardiovascular outcomes. This algorithm, when applied in the ED, affords an excellent opportunity to identify patients who might benefit from a more aggressive cardiovascular risk factor management strategy.

P-selectin antagonism reduces thrombus formation in humans.

Interaction of P-selectin with its glycoprotein ligand (P-selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P-selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis. To investigate the effects of the novel small molecule P-selectin antagonist PSI-697 on thrombus formation in humans. In a double-blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low-dose (2 m) and high-dose (20 m) PSI-697 and the glycoprotein IIb-IIIa receptor antagonist tirofiban (50 ng mL(-1)) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb-IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low-shear and high-shear chambers, respectively. PSI-697 caused a dose-dependent, but more modest, reduction in thrombus formation. Low-dose PSI-796 (2 m) reduced total thrombus area by 14% (P = 0.04) and 30% (P = 0.0002) in the low-shear and high-shear chambers, respectively. At the high dose (20 m), PSI-697 reduced total thrombus area by 18% (P = 0.0094) and 41% (P = 0.0008) in the low-shear and high-shear chambers, respectively. P-selectin antagonism with PSI-697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P-selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.

ChemInform Abstract: Guanidino Substituted Isoindolones as Novel Glycoprotein IIb—IIIa Receptor Antagonists.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

New Ion‐Exchange cum Separation Technique: A Study for the Synthesis of ω‐Guanidine containing Peptides using ω‐Amino Acid as Surrogate

This article describes a systematic study for the introduction of ω‐guanidine function at a late stage of synthesis using a protected amino group as a surrogate to improve overall yield. This concept was used to design and synthesize pseudo‐peptides as GP IIb–IIIa receptor antagonist wherein glycine in endogenous ligand Arg‐Gly‐Asp (RGD) is replaced by 2‐amino‐thiazole‐4‐ylacetic acid (Tha) as a spacer. Further, we describe here a unique salt exchange cum purification technology based on reverse phase (RP‐18) medium‐pressure liquid chromatography.

Understanding thrombocytopenia and antigenicity with glycoprotein IIb-IIIa inhibitors

Platelet glycoprotein (GP) IIb-IIIa receptor antagonists are being used with increasing frequency in the settings of percutaneous coronary interventions and acute ischemic syndromes. The development of thrombocytopenia after GP IIb-IIIa blockade has been observed to some extent with all parenteral GP IIb-IIIa inhibitors studied to date and could potentially limit their effectiveness. The incidence and severity of thrombocytopenia has varied in large clinical trials with GP IIb-IIIa inhibitors, presumably as a consequence of the different structural and pharmacokinetic characteristics of the agents, the dose administered and duration of use, repetition of exposure, and the various drugs coadministered with these agents. Certain baseline characteristics may be predictive. In most cases, severe thrombocytopenia associated with the use of GP IIb-IIIa receptor antagonists was readily reversible with platelet transfusion and was not usually associated with major clinical sequelae. Although the exact mechanisms responsible for thrombocytopenia after GP IIb-IIIa blockade are poorly understood, an immune mechanism is suggested in which the binding of the antagonist to GP IIb-IIIa receptors leads to the exposure of ligand-induced binding sites recognized by preexisting or induced antibodies. Alternatively, the receptor–drug metabolite complex itself may induce an immune response. All patients receiving parenteral GP IIb-IIIa inhibitors should be monitored within 24 hours of initiation of therapy for the development of thrombocytopenia. An algorithm for the detection and management of thrombocytopenia after GP IIb-IIIa inhibitor therapy is proposed. (Am Heart J 1999;138:S317-S326.)

Intravenous Administration of the Glycoprotein IIb-IIIa Receptor Antagonist 7E3 Induces Reperfusion of an Acute Thrombotic Occlusion of the Canine Coronary Artery

The ability of the F(ab’) 2 fragment of the murine monoclonal antibody 7E3 directed against the platelet glycoprotein IIb-IIIa receptor complex, to cause reperfusion of a totally occluding coronary artery thrombus was examined alone and in combination with aspirin and heparin in a canine model of coronary artery thrombosis. A localized thrombus was produced in the left circumflex coronary artery in open-chest dogs by electrolytic injury of the endothelium. Intravenous administration of a single injection of 5.0 mg/kg aspirin and heparin (80 U/kg bolus plus 30 U/kg/hr×2hr) maintained vessel patency for approximately 101±15 minutes. After vessels had been completely occluded for 5 minutes (in the presence of aspirin+heparin), a single intravenous injection of saline (10 ml) or 0.8 mg/kg 7E3 was administered. Reperfusion was observed in all dogs (6 of 6) receiving 7E3; 4 of 6 dogs maintained vessel patency throughout the course of the 2 hour observation period. Activated partial thromboplastin and thrombin times were elevated 1.4 and 9 fold, respectively, in groups that received heparin. Template bleeding times were significantly elevated in the groups receiving 7E3. In the control group, 2 of 5 dogs reperfused briefly, however neither were patent at the end of the observation period. A third group of 4 dogs which did not receive the aspirin+heparin regimen was allowed to occlude and 5 minutes later received a single intravenous injection of 0.8 mg/kg 7E3. None of the 4 dogs in this group reperfused at any time during the study. There were no significant differences between groups in regards to hematological or hemodynamic measurements during the experiment. We concluded from these findings that the monoclonal antibody, 7E3 can promote the dissolution of friable coronary artery thrombi that evolve during standard anticoagulant and antiplatelet therapy.

Effect of SR121566A, a Potent GP IIb-IIIa Antagonist, on the HIT Serum/heparin-Induced Platelet Mediated Activation of Human Endothelial Cells

Heparin-induced thrombocytopenia (HIT) is a common adverse effect of heparin therapy that carries a risk of serious thrombotic events. This condition is caused by platelet aggregation, which is mediated by anti-heparin/platelet factor 4 antibodies. Sera from patients with HIT in the presence of platelets, induced the expression of E-selectin, VCAM, ICAM-1 and tissue factor and the release of IL1beta, IL6, TNFalpha and PAI-1 by human umbilical vein endothelial cells (HUVECs) in vitro and initiated platelet adhesion to activated HUVECs. These effects which occurred in a time-dependent manner were significant in the first 1-2 h of incubation and reached a maximum after 6 to 9 h. The GP IIb-1IIa receptor antagonist SR121566A which has been shown to block platelet aggregation induced by a wide variety of agonists including HIT serum/heparin, reduced in a dose-dependent manner the HIT serum/heparin-induced, platelet mediated expression and release of the above mentioned proteins. The IC50 for inhibition of HIT serum/ heparin-induced platelet dependent HUVEC activation by SR121566A was approximately 10-20 nM. ADP, but not serotonin release, also appeared to be involved as apyrase and ATPgammaS blocked platelet-dependent, HIT serum/heparin-induced cell surface protein expression and cytokine release by HUVECs. Increased platelet adherence to HIT serum/heparin-activated HUVECs was inhibited by SR121566A and, to a lesser extent, by apyrase and ATPgammaS, showing that platelet activation and release was at the origin of the HIT serum/heparin-induced expression of these proteins by HUVECs. Thus, sera from patients with HIT induced the expression of adhesive and coagulation proteins and the release of cytokines by HUVECs through the activation of platelets which occurred in a GP IIb-IIIa-dependent manner, a process that could be selectively blocked by SR121566A.

Antithrombotic assessment of the effects of combination therapy with the anticoagulants efegatran and heparin and the glycoprotein IIb-IIIa platelet receptor antagonist 7E3 in a canine model of coronary artery thrombosis.

There is a paucity of data regarding the antithrombotic pharmacology of the drug-drug interactions between the newer anticoagulant and antiplatelet agents. In this investigation, we have studied the antithrombotic effects of combinations of minimum effective doses of the glycoprotein IIb-IIIa receptor antagonist 7E3 [murine F(ab')2] with both heparin and the novel tripeptide arginal antithrombin efegatran (LY294468) in a canine model of coronary artery thrombosis. Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. The groups studied were efegatran (0.25 mg . kg-1. h-1), heparin (80 U/kg, single injection, plus 30 U . kg-1. h-1), 7E3 (0.4 mg/kg, single injection), 7E3+efegatran, and 7E3+heparin. The combination of 7E3+efegatran was found to maintain better vessel patency (P < .05) at the end of the experiment (4 of 5 vessels) than all other groups (0 of 5, 0 of 4, 1 of 6, 2 of 7, and 1 of 6 for the vehicle-, heparin-, 7E3-, efegatran-, and 7E3+heparin-treated groups, respectively). Bleeding times were increased (P < .05) in both the 7E3+heparin group (fourfold) and the 7E3+efegatran group (threefold). 7E3 alone and both combination treatments produced significant reductions in ADP, arachidonic acid, and thrombin-induced platelet aggregation, whereas efegatran and heparin abolished only thrombin-induced aggregation. The present investigation demonstrates that combination therapy with minimum effective doses of 7E3+efegatran provided enhanced antithrombotic efficacy compared with 7E3+heparin in this model of thrombosis.

Calcium, calmodulin and protein kinase C dependence of platelet shape change

Platelet shape change (PSC) represents the initial phase of platelet activation and is normally investigated in ethylene diamine tetraacetic acid (EDTA) containing platelet rich plasma (PRP); EDTA is a potent chelator of calcium and therefore reduces ionized calcium to negligible levels. It is therefore assumed that it is a process independent of calcium. To test the hypothesis that PSC may be dependent upon intracellular calcium, we examined the effect of 8-(N,N-Diethylamino) octyl 3,4,5-Trimethoxybenzoate hydrochloride (TMB-8), an inhibitor of intercellular calcium mobilization on PSC. It produced a dose dependent inhibition of PSC. We then examined whether PSC was dependent upon calmodulin and protein kinase C, a calcium dependent enzyme which is cardinal to platelet aggregation. Both calmidazolium, a specific inhibitor of calmodulin, and H-9, a specific inhibitor of protein kinase C, produced dose dependent inhibition of PSC. Finally, we investigated whether GP IIb IIIa receptor which binds fibrinogen was involved in PSC; DMP 728 [(cyclic [D-2-amino-butyryl-N2-methyl-L-arginyl-glycyl-L-aspartyl-3- (a min o-methyl-benzoic acid], methanesulfonic acid salt] a potent GP IIb IIIa receptor antagonist was without any effect on PSC. We conclude that PSC is a calcium, calmodulin and protein kinase C dependent process like platelet aggregation but that it does not require extracellular calcium or the participation of platelet GP IIb IIIa complex.