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1
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Zhang L, Hu M, Chen Y, Wang Y. Effects of atorvastatin and ticagrelor combination therapy on renal function and the levels of suppression of tumorigenicity 2 and interleukin-33 in patients with ST-segment elevation myocardial infarction. J Int Med Res 2020; 48:300060520959502. [PMID: 33275460 PMCID: PMC7720335 DOI: 10.1177/0300060520959502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 08/26/2020] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE We evaluated the effects of atorvastatin and ticagrelor combination therapy on renal function and the levels of suppression of tumorigenicity 2 (ST2) and interleukin 33 (IL-33) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS Eighty-four STEMI patients who underwent emergency percutaneous coronary intervention at our hospital from January 2015 to March 2018 were retrospectively analyzed and divided into a control group (n = 44) and an observation group (n = 40). The control group was treated with atorvastatin as routine STEMI treatment, whereas the observation group was concurrently administered ticagrelor. RESULTS After treatment, significantly better outcomes were observed in the control group than in the observation group in terms of clinical indices, including chest pain relief, enzyme levels, duration of reperfusion-associated arrhythmia, and depression of the ST segment. Both groups exhibited improvements in cardiac ultrasound indices, whereas the observation group showed lower left ventricular end-diastolic and end-systolic diameters and higher left ventricular ejection fractions than the control group. CONCLUSIONS Atorvastatin and ticagrelor combination therapy is clinically effective and safe for STEMI patients as it reduces the degree of myocardial infarction, protects the heart and renal functions, improves inflammation, and reduces adverse cardiac event incidences.
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Affiliation(s)
- Li Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Miao Hu
- Department of Pharmacy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuan Chen
- Intensive Care Unit, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yijun Wang
- Department of Pharmacy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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2
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Yeung J, Li W, Holinstat M. Platelet Signaling and Disease: Targeted Therapy for Thrombosis and Other Related Diseases. Pharmacol Rev 2018; 70:526-548. [PMID: 29925522 PMCID: PMC6013590 DOI: 10.1124/pr.117.014530] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Platelets are essential for clotting in the blood and maintenance of normal hemostasis. Under pathologic conditions such as atherosclerosis, vascular injury often results in hyperactive platelet activation, resulting in occlusive thrombus formation, myocardial infarction, and stroke. Recent work in the field has elucidated a number of platelet functions unique from that of maintaining hemostasis, including regulation of tumor growth and metastasis, inflammation, infection, and immune response. Traditional therapeutic targets for inhibiting platelet activation have primarily been limited to cyclooxygenase-1, integrin αIIbβ3, and the P2Y12 receptor. Recently identified signaling pathways regulating platelet function have made it possible to develop novel approaches for pharmacological intervention in the blood to limit platelet reactivity. In this review, we cover the newly discovered roles for platelets as well as their role in hemostasis and thrombosis. These new roles for platelets lend importance to the development of new therapies targeted to the platelet. Additionally, we highlight the promising receptor and enzymatic targets that may further decrease platelet activation and help to address the myriad of pathologic conditions now known to involve platelets without significant effects on hemostasis.
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Affiliation(s)
- Jennifer Yeung
- Departments of Pharmacology (J.Y., W.L., M.H.) and Internal Medicine, Division of Cardiovascular Medicine (M.H.), University of Michigan, Ann Arbor, Michigan
| | - Wenjie Li
- Departments of Pharmacology (J.Y., W.L., M.H.) and Internal Medicine, Division of Cardiovascular Medicine (M.H.), University of Michigan, Ann Arbor, Michigan
| | - Michael Holinstat
- Departments of Pharmacology (J.Y., W.L., M.H.) and Internal Medicine, Division of Cardiovascular Medicine (M.H.), University of Michigan, Ann Arbor, Michigan
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3
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Yurtdas M, Ozdemir M. Ticagrelor-Associated Conduction Disorder: A Case Report and Review of the Literature. Cardiol Res 2017; 8:123-127. [PMID: 28725329 PMCID: PMC5505296 DOI: 10.14740/cr556w] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 05/24/2017] [Indexed: 01/19/2023] Open
Abstract
A 47-year-old female presented to emergency clinic due to non-ST-elevation myocardial infarction (NSTEMI). After receiving acetylsalicylic acid, a loading dose of ticagrelor 180 mg and intravenous unfractionated heparin, she underwent successful placement of drug eluting stent on the distal part of non-dominant left circumflex artery. The patient had no pre-existing atrioventricular (AV) block and did not use AV blocking agent. Approximately 10 h after taking a loading dose of ticagrelor, baseline normal rhythm degenerated to the first and then complete AV block, with mild dizziness. Following cessation of ticagrelor, cardiac rhythm returned to normal level within 2 days. The close monitoring of patients after starting ticagrelor is imperative, so ticagrelor may result in advanced conduction disorders. Here, we report a patient who developed various types of AV block associated with the ticagrelor taken during successful percutaneous coronary intervention for NSTEMI. We also reviewed the literature on the association between ticagrelor use and conduction abnormalities.
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Affiliation(s)
| | - Mahmut Ozdemir
- Department of Cardiology, Cihanpol Hospital, Mardin, Turkey
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4
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De Maria E, Borghi A, Modonesi L, Cappelli S. Ticagrelor therapy and atrioventricular block: Do we need to worry? World J Clin Cases 2017; 5:178-182. [PMID: 28560235 PMCID: PMC5434317 DOI: 10.12998/wjcc.v5.i5.178] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 02/20/2017] [Accepted: 03/12/2017] [Indexed: 02/05/2023] Open
Abstract
Ticagrelor is a potent, direct P2Y12 antagonist with rapid onset of action and intense platelet inhibition, indicated in patients with acute coronary syndromes (ACS). This drug is usually well tolerated, but some patients experience serious adverse effects: Major bleeding; gastrointestinal disturbances; dyspnoea; ventricular pauses > 3 s. Given the unexpected high incidence of bradyarrhythmias, a PLATO substudy monitored this side effect, showing that ticagrelor was associated with an increase in the rate of sinus bradycardia and sinus arrest compared to clopidogrel. This side effect was usually transient, asymptomatic and not associated with higher incidence of severe atrioventricular (AV) block or pacemaker needs. A panel of experts from Food and Drug Administration did not consider bradyarrhythmias a serious problem in clinical practice and, accordingly, current labeling of the drug does not give any precaution or contraindication regarding this issue. However, recently some articles have described ACS patients with high-degree, life-threatening, AV block requiring drug discontinuation and, in some cases, pacemaker implantation. In this paper, we describe and discuss five published case reports of severe AV block following ticagrelor therapy and two other cases managed in our Hospital. The analysis of literature suggests that, although rarely, ticagrelor can be associated with life-threatening AV block. Caution and careful monitoring are required especially in patients with already compromised conduction system and/or treated with AV blocking agents. Future studies, with long-term rhythm monitoring, would help to define the outcome of patients at higher risk of developing this complication.
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Marsousi N, Samer CF, Fontana P, Reny JL, Rudaz S, Desmeules JA, Daali Y. Coadministration of ticagrelor and ritonavir: Toward prospective dose adjustment to maintain an optimal platelet inhibition using the PBPK approach. Clin Pharmacol Ther 2016; 100:295-304. [PMID: 27264793 DOI: 10.1002/cpt.407] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 05/27/2016] [Accepted: 06/01/2016] [Indexed: 11/09/2022]
Abstract
Ticagrelor is a potent antiplatelet drug metabolized by cytochrome (CYP)3A. It is contraindicated in patients with human immunodeficiency virus (HIV) because of the expected CYP3A inhibition by most protease inhibitors, such as ritonavir and an increased bleeding risk. In this study, a physiologically based pharmacokinetic (PBPK) model was created for ticagrelor and its active metabolite (AM). Based on the simulated interaction between ticagrelor 180 mg and ritonavir 100 mg, a lower dose of ticagrelor was calculated to obtain, when coadministered with ritonavir, the same pharmacokinetic (PK) and platelet inhibition as ticagrelor administered alone. A clinical study was thereafter conducted in healthy volunteers. Observed PK profiles of ticagrelor and its AM were successfully predicted with the model. Platelet inhibition was nearly complete in both sessions despite administration of a fourfold lower dose of ticagrelor in the second session. This PBPK model could be prospectively used to broaden the usage of ticagrelor in patients with ritonavir-treated HIV regardless of the CYP3A inhibition.
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Affiliation(s)
- N Marsousi
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,School of Pharmaceutical Sciences, Geneva University, Switzerland
| | - C F Samer
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
| | - P Fontana
- Division of Angiology and Haemostasis, Geneva University Hospitals, Switzerland.,Geneva Platelet Group, Faculty of Medicine, University of Geneva, Switzerland
| | - J L Reny
- Geneva Platelet Group, Faculty of Medicine, University of Geneva, Switzerland.,Department of General Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals, Switzerland
| | - S Rudaz
- School of Pharmaceutical Sciences, Geneva University, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
| | - J A Desmeules
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,School of Pharmaceutical Sciences, Geneva University, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
| | - Y Daali
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,School of Pharmaceutical Sciences, Geneva University, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
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6
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Ozturk C, Unlu M, Yildirim AO, Erdogan S, Demir M, Balta S, Demirkol S, Celik T, Iyisoy A. The progressed atrioventricular block associated with ticagrelor therapy may not require permanent pacemaker after acute coronary syndrome; it may be reversible. Int J Cardiol 2015; 203:822-4. [PMID: 26595794 DOI: 10.1016/j.ijcard.2015.11.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 11/04/2015] [Indexed: 12/16/2022]
Affiliation(s)
- Cengiz Ozturk
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey.
| | - Murat Unlu
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
| | - Ali Osman Yildirim
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
| | - Sıddık Erdogan
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
| | - Mustafa Demir
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
| | - Sevket Balta
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
| | - Sait Demirkol
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
| | - Turgay Celik
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
| | - Atila Iyisoy
- Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey
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An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers. Int J Clin Pharmacol Ther 2015; 53:182-9. [PMID: 25500486 PMCID: PMC4302705 DOI: 10.5414/cp202202] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2015] [Indexed: 12/26/2022] Open
Abstract
Objective: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally. Methods: In this single-center, open-label, randomized, three-treatment crossover study, 36 healthy volunteers were randomized to receive a single 90-mg dose of ticagrelor administered orally as a whole tablet or as crushed tablets suspended in water and given orally or via a nasogastric tube into the stomach, with a minimum 7-day wash-out between treatments. Plasma concentrations of ticagrelor and AR-C124910XX were assessed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post-ticagrelor dose for pharmacokinetic analyses. Safety and tolerability was assessed throughout the study. Results: At 0.5 hours postdose, plasma concentrations of ticagrelor and AR-C124910XX were higher with crushed tablets administered orally (148.6 ng/mL and 13.0 ng/mL, respectively) or via nasogastric tube (264.6 ng/mL and 28.6 ng/mL, respectively) compared with whole-tablet administration (33.3 ng/mL and 5.2 ng/mL, respectively). A similar trend was observed at 1 hour postdose. Ticagrelor tmax was shorter following crushed vs. whole-tablet administration (1 vs. 2 hours, respectively). Geometric mean ratios between treatments for AUC and Cmax were contained within the bioequivalence limits of 80 – 125% for ticagrelor and AR-C124910XX. All treatments were generally well tolerated. Conclusions: Ticagrelor administered as a crushed tablet is bioequivalent to whole-tablet administration, independent of mode of administration (oral or via nasogastric tube), and resulted in increased plasma concentrations of ticagrelor and AR-C124910XX at early timepoints.
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8
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Ünlü M, Demirkol S, Yildirim AO, Balta Ş, Öztürk C, Iyisoy A. Atrioventricular block associated with ticagrelor therapy may require permanent pacemaker. Int J Cardiol 2015; 202:946-7. [PMID: 26478523 DOI: 10.1016/j.ijcard.2015.08.067] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 08/04/2015] [Indexed: 12/17/2022]
Affiliation(s)
- Murat Ünlü
- Gulhane Medical Academy, Department of Cardiology, Ankara, Turkey.
| | - Sait Demirkol
- Gulhane Medical Academy, Department of Cardiology, Ankara, Turkey
| | | | - Şevket Balta
- Gulhane Medical Academy, Department of Cardiology, Ankara, Turkey
| | - Cengiz Öztürk
- Gulhane Medical Academy, Department of Cardiology, Ankara, Turkey
| | - Atila Iyisoy
- Gulhane Medical Academy, Department of Cardiology, Ankara, Turkey
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9
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Goldberg A, Rosenfeld I, Nordkin I, Halabi M. Life-threatening complete atrioventricular block associated with ticagrelor therapy. Int J Cardiol 2015; 182:379-80. [PMID: 25594929 DOI: 10.1016/j.ijcard.2014.12.162] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 12/31/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Alexander Goldberg
- Interventional Cardiology Unit, Ziv Medical Center, Zfat, Israel; Faculty of Medicine in Galilee, Bar-Ilan University, Zfat, Israel.
| | - Inna Rosenfeld
- Department of Cardiology, Ziv Medical Center, Zfat, Israel
| | - Irena Nordkin
- Department of Cardiology, Ziv Medical Center, Zfat, Israel
| | - Majdi Halabi
- Faculty of Medicine in Galilee, Bar-Ilan University, Zfat, Israel; Department of Cardiology, Ziv Medical Center, Zfat, Israel
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10
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Pharmacodynamics, pharmacokinetics and safety of ticagrelor in Asian patients with stable coronary artery disease. Cardiovasc Interv Ther 2014; 29:324-33. [DOI: 10.1007/s12928-014-0277-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 05/30/2014] [Indexed: 12/11/2022]
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11
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Pharmacokinetic Interaction Study of Ticagrelor and Cyclosporine in Healthy Volunteers. Clin Drug Investig 2014; 34:529-36. [DOI: 10.1007/s40261-014-0205-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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12
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Teng R, Butler K. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers. J Drug Assess 2013; 2:30-9. [PMID: 27536435 PMCID: PMC4937655 DOI: 10.3109/21556660.2013.785413] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2013] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Two open-label, two-period, crossover studies in healthy volunteers were designed to determine the pharmacokinetic interactions between ticagrelor, a P2Y12 receptor antagonist, and a moderate (diltiazem) and a strong (ketoconazole) cytochrome P450 (CYP) 3A inhibitor. METHODS Seventeen volunteers received diltiazem (240 mg once daily) for 14 days. In the second study, ketoconazole (n = 14) 200 mg twice daily was given for 10 days. A single oral 90-mg ticagrelor dose was administered on day 8 (diltiazem) or day 4 (ketoconazole). In each study, volunteers received a single 90-mg oral dose of ticagrelor before or after washout (≥14 days). Pharmacokinetic parameters for ticagrelor, AR-C124910XX (primary metabolite), diltiazem, and ketoconazole were assessed. RESULTS Compared with ticagrelor alone, diltiazem co-administration significantly increased the mean maximum concentration (C max) and mean area under the plasma concentration-time curve (AUC) for ticagrelor by 69% and 174%, respectively. Diltiazem co-administration reduced C max by 38% but had no significant effect on AUC for AR-C124910XX. C max and AUC for ticagrelor were increased by 135% and 632%, respectively, by ketoconazole co-administration, whereas these parameters were reduced by 89% and 56%, respectively, for AR-C124910XX. Diltiazem and ketoconazole pharmacokinetic parameters were not significantly affected by the presence of ticagrelor. CONCLUSIONS These results suggest that ticagrelor can be co-administered with moderate CYP3A inhibitors. However, co-administration of strong CYP3A inhibitors with ticagrelor is not recommended.
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