scholarly journals Rationale and Design of ST-ON-SET: Assessment of Antiplatelet Effect after Ticagrelor Loading Dose in STEMI pPatients and NSTEMI Patients

2016 ◽  
Vol 8 ◽  
Author(s):  
Hongyi Wu ◽  
Yinman Wang ◽  
Huajie Xu ◽  
Juying Qian ◽  
Junbo Ge
Keyword(s):  
Preliminary Investigation ◽  
Plasma Concentrations ◽  
Unmet Need ◽  
Underlying Mechanism ◽  
Platelet Inhibition ◽  
Light Transmittance ◽  
Chinese Patients ◽  
Loading Dose ◽  
Open Label ◽  
Light Transmittance Aggregometry

<p>Background: Delayed platelet inhibition by ticagrelor has been initially documented in STEMI subjects. To the best of our knowledge, no data exists about the direct description of early onset of platelet inhibition after ticagrelor loading dose (LD) in different clinical forms of ACS, especially in Chinese patients. The ST-ON-SET study is designed to address this unmet need.</p><p><br /> Method/Design: The ST-ON-SET study is a single center, prospective, observational, open-label, investigator-initiated study. Platelet inhibition assessed by Light transmittance aggregometry (LTA) and plasma concentrations of ticagrelor and its metabolites would be investigated serially. The primary outcome is the inhibition of platelet aggregation measured by LTA at 2 hours after ticagrelor LD. Moreover, baseline inflammatory and thrombotic biomarkers would be measured to investigate the potential underlying influences of platelet inhibition.</p>Conclusion: The study is designed to characterize pharmacokinetic and pharmacodynatic profiles of ticagrelor LD in Chinese STEMI and NSTEMI patients. Furthermore, preliminary investigation of the underlying mechanism of initial delayed platelet inhibition by ticagrelor would be conducted.

Thromboxane Formation Assay to Identify High On-Treatment Platelet Reactivity to Aspirin

Pharmacology ◽  
2017 ◽  
Vol 100 (3-4) ◽  
pp. 127-130 ◽  
Author(s):  
Annemarie Mohring ◽  
Kerstin Piayda ◽  
Lisa Dannenberg ◽  
Saif Zako ◽  
Theresa Schneider ◽  
...  
Keyword(s):  
Gold Standard ◽  
Cardiovascular Events ◽  
Platelet Reactivity ◽  
Area Under The Curve ◽  
Platelet Inhibition ◽  
Light Transmittance ◽  
Characteristic Analysis ◽  
Specific Test ◽  
Current Gold Standard ◽  
Light Transmittance Aggregometry

Platelet inhibition by aspirin is indispensable in the secondary prevention of cardiovascular events. Nevertheless, impaired aspirin antiplatelet effects (high on-treatment platelet reactivity [HTPR]) are frequent. This is associated with an enhanced risk of cardiovascular events. The current gold standard to evaluate platelet hyper-reactivity despite aspirin intake is the light-transmittance aggregometry (LTA). However, pharmacologically, the most specific test is the measurement of arachidonic acid (AA)-induced thromboxane (TX) B2 formation. Currently, the optimal cut-off to define HTPR to aspirin by inhibition of TX formation is not known. Therefore, in this pilot study, we aimed to calculate a TX formation cut-off value to detect HTPR defined by the current gold standard LTA. We measured platelet function in 2,507 samples. AA-induced TX formation by ELISA and AA-induced LTA were used to measure aspirin antiplatelet effects. TX formation correlated nonlinearly with the maximum of aggregation in the AA-induced LTA (Spearman's rho R = 0.7396; 95% CI 0.7208-0.7573, p < 0.0001). Receiver operating characteristic analysis and Youden's J statistics revealed 209.8 ng/mL as the optimal cut-off value to detect HTPR to aspirin with the TX ELISA (area under the curve: 0.92, p < 0.0001, sensitivity of 82.7%, specificity of 90.3%). In summary, TX formation ELISA is reliable in detecting HTPR to aspirin. The calculated cut-off level needs to be tested in trials with clinical end points.

Comparison of acetylsalicylic acid and clopidogrel non-responsiveness assessed by light transmittance aggregometry and PFA-100® in patients undergoing neuroendovascular procedures

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Christina C. Rolling ◽  
Julia Tomada ◽  
Andreas M. Frölich ◽  
Brigitte Holst ◽  
Katharina Holstein ◽  
...  
Keyword(s):  
Acetylsalicylic Acid ◽  
Adenosine Diphosphate ◽  
Platelet Inhibition ◽  
Adverse Outcomes ◽  
Light Transmittance ◽  
Prostaglandin E ◽  
Activity Levels ◽  
Platelet Disaggregation ◽  
Light Transmittance Aggregometry ◽  
Function Analyzer

AbstractObjectivesDual platelet inhibition is commonly used for prevention of cardiovascular events in patients undergoing neuroendovascular procedures. Non-responsiveness to platelet inhibitors may be associated with adverse outcomes. The aim of this study was to evaluate the reliability of the platelet function analyzer PFA-100® in comparison to light transmittance aggregometry (LTA) for monitoring clopidogrel and acetylsalicylic acid (ASA) non-responsiveness in a cohort of patients treated for intracranial aneurysm or cranial artery stenosis.MethodsNon-responsiveness to clopidogrel and ASA was assessed by LTA using adenosine diphosphate (ADP) and arachidonic acid and by PFA-100® with the ADP/prostaglandin E1 (PGE1) and collagen/epinephrine cartridges, respectively.ResultsA total of 203 patients (145 females; median age, 57 years) were analyzed. Agreement between the two tests was poor for clopidogrel non-responsiveness (ƙ=0.19) and not better than chance for ASA non-responsiveness (ƙ=0.01). Clopidogrel non-responsiveness by LTA and PFA-100® was associated with higher von Willebrand factor antigen and activity levels. ADP-induced platelet disaggregation was lower in patients with clopidogrel non-responsiveness as assessed by PFA-100®. Clopidogrel non-responsiveness by LTA was associated with a higher prevalence of diabetes and a higher body mass index (BMI). Adverse outcomes (death, thromboembolism, or in-stent thrombosis) occurred in 13% (n=26) of all patients independently of ASA and clopidogrel non-responsiveness as assessed by both devices.ConclusionsOur results show that LTA and PFA-100® are not interchangeable in the assessment of ASA and clopidogrel non-responsiveness in patients undergoing neuroendovascular interventions.

scholarly journals Influence of CYP2D6 and CYP3A5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Bisoprolol in Hypertensive Chinese Patients

2021 ◽  
Vol 8 ◽  
Author(s):  
Sze Wa Chan ◽  
Tanya T. W. Chu ◽  
Chung Shun Ho ◽  
Alice P. S. Kong ◽  
Brian Tomlinson ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Chinese Patients ◽  
Open Label ◽  
Post Dose ◽  
Treatment Clinic ◽  
Liquid Chromatography Tandem Mass ◽  
The Common ◽  
Trough Levels ◽  
Trough Plasma

Purpose: This study was performed to investigate the effects of common polymorphisms in CYP2D6 and CYP3A5 on the plasma concentrations and antihypertensive effects of bisoprolol in hypertensive Chinese patients.Methods: One hundred patients with essential hypertension were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Clinic blood pressure (BP) and ambulatory BP (ABP) were measured after the placebo run-in and after 6 weeks treatment. Peak plasma concentrations of bisoprolol were measured at 3 h after the first dose and 3 h after the dose after 6 weeks treatment. Trough levels were measured before the dose after 6 weeks treatment. Bisoprolol plasma concentrations were measured with a validated liquid chromatography tandem mass spectrometry method. Six common polymorphisms in CYP2D6 and the CYP3A5*3 polymorphism were genotyped by TaqMan® assay.Results: After 6 weeks of treatment, clinic BP and heart rate were significantly reduced by 14.3 ± 10.9/8.4 ± 6.2 mmHg (P &lt; 0.01) and 6.3 ± 7.6 BPM (P &lt; 0.01), respectively. Similar reductions were seen in ABP values. Bisoprolol plasma concentration at 3 h after the first dose and 3 h post-dose after 6 weeks of treatment were significantly associated with baseline body weight (P &lt; 0.001) but there was no significant effect of the CYP2D6 and CYP3A5 polymorphisms on these or the trough plasma concentrations. There was no significant association of the CYP2D6 and CYP3A5 polymorphisms or plasma bisoprolol concentrations with the clinic BP or ABP responses to bisoprolol.Conclusion: Bisoprolol 2.5 mg daily effectively reduced BP and HR. The common polymorphisms in CYP2D6 that were examined and the CYP3A5*3 polymorphism appear to have no benefit in predicting the hemodynamic response to bisoprolol in these patients.

How Long Does It Take for Clopidogrel and Ticagrelor to Inhibit Platelets in Patients Undergoing Primary Percutaneous Coronary Intervention? A Detailed Pharmacodynamic Analysis: Time Course of Platelet Reactivity in STEMI (TOPS)

2017 ◽  
Vol 43 (04) ◽  
pp. 439-446 ◽  
Author(s):  
Thomas Bergmeijer ◽  
Thea Godschalk ◽  
Paul Janssen ◽  
Kim Berge ◽  
Nicoline Breet ◽  
...  
Keyword(s):  
Percutaneous Coronary Intervention ◽  
Antiplatelet Therapy ◽  
Stent Thrombosis ◽  
Primary Percutaneous Coronary Intervention ◽  
Platelet Reactivity ◽  
Coronary Intervention ◽  
Platelet Inhibition ◽  
Light Transmittance ◽  
Loading Dose ◽  
Percutaneous Coronary

AbstractAntiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 µmol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of < 236 P2Y12 reaction units or LTA maximum platelet aggregation of < 64.5% was reached. A total of 28 patients were participated in this study. Platelet reactivity dropped below the high platelet reactivity cutoff level after 11.4 (VerifyNow) and 5.7 (LTA) hours in patients who were loaded with clopidogrel, and after 2.4 (VerifyNow) and 3.9 (LTA) hours in patients who were loaded with ticagrelor. Despite the administration of a clopidogrel or ticagrelor loading dose, it still takes multiple hours (2–11) to reach adequate platelet inhibition in STEMI patients. This might indicate the need for additional antiplatelet therapy in the first hours after loading in patients undergoing pPCI with stenting.

scholarly journals Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension

2021 ◽  
Author(s):  
Arthur Lo ◽  
Lucy Norcliffe-Kaufmann ◽  
Ross Vickery ◽  
David Bourdet ◽  
Jitendra Kanodia
Keyword(s):  
Orthostatic Hypotension ◽  
Sympathetic Neurons ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Treatment Phase ◽  
Target Population ◽  
Neurogenic Orthostatic Hypotension ◽  
Open Label ◽  
Once Daily ◽  
Norepinephrine Reuptake

Abstract Purpose Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. Methods Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine. Results Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6–9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). Conclusions Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.

High-Dose Clopidogrel Loading in Percutaneous Coronary Intervention

2005 ◽  
Vol 39 (5) ◽  
pp. 918-922 ◽  
Author(s):  
Kristen L Longstreth ◽  
James R Wertz
Keyword(s):  
Percutaneous Coronary Intervention ◽  
Coronary Intervention ◽  
Drug Manufacturer ◽  
Platelet Inhibition ◽  
High Dose ◽  
Loading Dose ◽  
Percutaneous Coronary ◽  
Safety Studies ◽  
Risk Patients ◽  
Time Required

OBJECTIVE: To review the use of a 600-mg clopidogrel loading dose in patients undergoing percutaneous coronary intervention (PCI). DATA SOURCES: Human clinical trials and platelet studies available through PubMed (1966–March 2005), bibliographies of pertinent articles, and citations supplied by the drug manufacturer were accessed. DATA SYNTHESIS: The administration of a 600-mg loading dose of clopidogrel can decrease the time required for maximum platelet inhibition to 2 hours compared with ⩾6 hours achieved with 300 mg. This higher loading dose has been investigated in multiple platelet studies and one observational report. Several randomized controlled trials have used a 600-mg loading dose; however, these studies were not designed to evaluate the efficacy and safety of this loading regimen. To date, only one randomized trial has compared the 600-mg loading dose with a 300-mg loading dose. CONCLUSIONS: When compared with a conventional loading regimen of 300 mg in lower-risk patients, pretreatment with clopidogrel 600 mg was shown to be more effective in reducing periprocedural events and demonstrated similar safety. Studies are needed to clarify the use of a 600-mg loading dose in higher-risk patients, with concomitant glycoprotein IIb/IIIa receptor antagonism, or when administration is delayed until immediately before or after PCI.

scholarly journals ANalgesic Efficacy and safety of MOrphiNe versus methoxyflurane in patients with acute myocardial infarction: the rationale and design of the ANEMON-SIRIO 3 study: a multicentre, open-label, phase II, randomised clinical trial

BMJ Open ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. e043330
Author(s):  
Aldona Kubica ◽  
Agata Kosobucka ◽  
Piotr Niezgoda ◽  
Piotr Adamski ◽  
Katarzyna Buszko ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Analgesic Efficacy ◽  
Randomised Clinical Trial ◽  
Ethical Standards ◽  
Loading Dose ◽  
Efficacy And Safety ◽  
Open Label ◽  
Analgesic Treatment ◽  
Open Label Phase ◽  
St Elevation

IntroductionThe unfavourable influence of morphine on the pharmacokinetics of ticagrelor resulting in weaker and retarded antiplatelet effect in patients with acute coronary syndrome (ACS) has been previously shown. Replacing morphine with methoxyflurane, a potent, non-opioid analgesic agent, that does not weaken or delay the effect of antiplatelet agents may improve the clinical efficacy of treatment of patients with ACS.MethodsThe ANEMON-SIRIO 3 study was designed as a multicentre, open-label, phase II, randomised clinical trial aimed to test the analgesic efficacy and safety of methoxyflurane in patients with ACS. The study population will comprise patients with ST-elevation myocardial infarction or non-ST-elevation ACS admitted to the study centres with typical chest pain requiring analgesic treatment. Before percutaneous coronary intervention (PCI) for the patients with index ACS will be randomly assigned in 1:1 ratio to receive methoxyflurane administered by inhalation, or to obtain morphine administered intravenously. Analgesic treatment will be followed by 300 mg loading dose of aspirin and 180 mg loading dose of ticagrelor. Patients will be assessed with regard to pain intensity according to the Numeric Pain Rating Scale at baseline, 3 min after study drug administration and immediately after PCI. Moreover, patients will be actively monitored with regard to the occurrence of side effects of evaluated therapies, as well as adverse events that may be related to insufficient platelet inhibition (no-reflow phenomenon assessed immediately after PCI, administration of GPIIb/IIIa inhibitors during PCI, acute stent thrombosis).Ethics and disseminationThe study will be conducted in six Polish clinical centres from the beginning of in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Trial registration detailsClinicalTrials.gov, NCT04476173.

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