International Journal of Cardiology 192 (2015) 11–13
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Ticagrelor-related gout: An underestimated side effect Nixiao Zhang, Zhiwei Zhang, Yajuan Yang, Yanmin Xu, Guangping Li, Tong Liu ⁎ Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
a r t i c l e
i n f o
Article history: Received 4 May 2015 Accepted 6 May 2015 Available online 8 May 2015 Keywords: Ticagrelor Gout Hyperuricemia Uric acid Side effect
Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker, has been recognized as the standard therapy in patients with acute coronary syndrome (ACS) and following percutaneous coronary intervention. Ticagrelor, a novel direct, reversibly binding P2Y12 antagonist, has better pharmacodynamic effects and improves clinical outcomes compared with clopidogrel in the setting of ACS [1,2]. However, ticagrelor-related dyspnea [3–5] and bradyarrhythmias have been observed in the PLATO trial [6] and real world ACS patients, and may lead to drug discontinuation. Gaubert et al. [7] demonstrated that ticagrelor-related dyspnea is a major cause of drug discontinuation during one-month follow-up period. In addition, re-hospitalization because of drug-correlated dyspnea accounts for 2% of the study population. Adenosine concentration levels or this reversible P2Y12 antagonist acting on sensory neurons may play a significant role in ticagrelorrelated dyspnea. Besides, ticagrelor may cause bradyarrhythmias in the PLATO trial [8] and may induce complete atrioventricular block [9] and sinus node dysfunction [10] in some case reports. However, no difference in terms of incidence of clinically bradycardia events (syncope, sudden death, cardiac arrest or pacemaker placement) was observed in the PLATO trial [8]. Very recent published data from the PEGASUS-TIMI54 trial [11] indicates that long term use of ticagrelor may increase the incidence of gout in patients with prior myocardial infarction. The PEGASUS-
⁎ Corresponding author at: Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China. E-mail address: [email protected] (T. Liu).
http://dx.doi.org/10.1016/j.ijcard.2015.05.023 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
TIMI54 trial randomly assigned 21,162 patients who had a prior myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed up for a median of 33 months. The results showed that ticagrelor significantly decreased the risk of cardiovascular death, myocardial infarction or stroke during a 33-month follow-up. Besides, the investigators also found that the long term use of ticagrelor was associated with dosedependent 1.48–1.77 fold increased risk of gout compared with placebo. Actually, the previous PLATO trial has also shown that the increases of mean serum uric acid levels from baseline values were 14% and 15% at 1 and 12 months respectively following the ticagrelor treatment compared with clopidogrel, but there was no difference regarding the incidence of gout/gouty arthritis over time between the two groups [6]. To the best of our knowledge, ticagrelor-related gout was not systematically reviewed in the literature. In this letter to the editor, we intend to discuss the potential mechanisms regarding ticagrelor-related gout and propose some suggestions for the prevention of this underestimated side effect during long term use of ticagrelor. Gout is termed as hyperuricemia accompanied with acute arthritis, tophus, chronic arthritis, joint deformity, chronic interstitial nephritis and uric acid stones, which is more prevalent in males more than 40 years old and goes through three stages (asymptomatic period, acute arthritis period, tophus/chronic arthritis) [12,13]. Purine or adenosine is converted to hypoxanthine, then is metabolized to xanthine and ultimately uric acid. The normal value of serum uric acid is 149– 416 μmol/L in males and 89–357 μmol/L in females. Exceeding this level may result in uric acid crystallization and clinical symptoms, just like gout/gouty arthritis. Sudden onset of gouty arthritis mainly results from a rapid rise or fall in serum uric acid, as well as inflammation caused by uric acid crystallization. Ticagrelor, as a reversibly binding P2Y12 receptor antagonist, is rapidly absorbed [14] and metabolized [15]. AR-C124910XX, the major metabolite which it rapidly formed, has a potency approximately equal to that of ticagrelor [16], but with a little difference existing as well. Ticagrelor is not required for hepatic metabolization [17], it is often metabolized in the kidneys. Therefore, the high renal serum drug concentration may influence the renal function so as to interfere with the filtration, absorption, uptake and secretion of uric acid. Several renal urate transporters are involved in this process [18] (Fig. 1). Ticagrelor and its metabolite AR-C124910XX have weak inhibitory effects on urate transporter 1 (URAT1), while AR-C124910XX alone is reported to restrain Xenopus oocytes expressing organic ion transporter (OAT)1 but not ticagrelor [16]. Importantly, OAT3 expressed in Xenopus
12
N. Zhang et al. / International Journal of Cardiology 192 (2015) 11–13
Fig. 1. Uric acid metabolism in proximal tubules. URAT1: urate transporter 1; OAT4: organic ion transporter 4; MRP4: adenosine-5′-triphosphate-dependent urate export transporter; OAT1: organic ion transporter 1; OAT3: organic ion transporter 3.
oocytes is confirmed to be inhibited by both ticagrelor and ARC124910XX. Therefore, it is reasonable to assume that OAT3 is a probable transporter involved in hyperuricemia and gout related to ticagrelor. Reabsorption of uric acid is regulated by urate transporter 1 (URAT1) [19] and organic ion transporter (OAT)4 [20] in the apical membrane of proximal tubules. The uptake of blood urate into proximal tubules goes through OAT1 [21] and OAT3 [22] in the basolateral membrane. Moreover, the secretion of uric acid lies on an adenosine-5′-triphosphate-dependent urate export transporter (MRP4) [23] in the apical membrane (Fig. 1). The decline in renal urate clearance cannot be neglected as well [24]. On the other hand, when uric acid synthesis increases, the incidence of gout changes correspondingly. Under normal circumstances, adenosine can be transported into erythrocytes or other cells by plasma membrane nucleoside transporters to form hypoxanthine or adenosine triphosphate (ATP) [25,26] (Fig. 2). Ticagrelor and its metabolite have negative effects on such transporters, with the adenosine from extracellular/blood vessels increasing in response to ischemia, hypoxia and inflammation. The inhibitory effects of ticagrelor on the cellular uptake of adenosine, in addition to antagonizing the P2Y12 receptor, is sufficient to increase the circulating levels of adenosine in patients with ACS, which may partly explain its advantageous effects in clinical outcomes compared with other P2Y12 receptor blockers [27]. Consequently, the elevated level of adenosine in extracellular/ blood vessels may further increase uric acid synthesis, which was fortified by tissue with high levels of xanthine oxidase, such as those from the liver, kidney and small intestines [28]. In conclusion, ticagrelor-related gout is an underestimated side effect during long term use of ticagrelor. We recommend that clinicians assess serum uric acid levels regularly and pay more attention to the possible symptoms of gout during long term administration of ticagrelor, especially in patients with hyperuricemia. Also, we need to educate our patients on ticagrelor to avoid a number of foodstuffs which are risk factors for gout, including sugar sweetened beverages, alcohol, red meat, seafood, and fruit juice [12].
Conflicts of interest None. Financial disclosures None. Acknowledgment The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] S. De Servi, C. Cavallini, S. Leonardi, M. Ferlini, Prasugrel and ticagrelor compared to clopidogrel in non-st-segment elevation acute coronary syndromes undergoing percutaneous coronary interventions: certainties and uncertainties, Int. J. Cardiol. 181 (2015) 443–445. [2] L. Bonello, C. Frere, S. Cointe, M. Laine, J. Mancini, F. Thuny, et al., Ticagrelor increases endothelial progenitor cell level compared to clopidogrel in acute coronary syndromes: a prospective randomized study, Int. J. Cardiol. 187 (2015) 502–507. [3] M.J. Sanchez-Galian, P.J. Flores-Blanco, A. Lopez-Cuenca, M. Gomez-Molina, E. Guerrero-Perez, F. Cambronero-Sanchez, et al., Ticagrelor related dyspnea in patients with acute coronary syndromes: incidence and implication on ticagrelor withdrawn, Int. J. Cardiol. 187 (2015) 517–518. [4] N. Lombardi, M.C. Lenti, R. Matucci, A. Mugelli, A. Vannacci, Ticagrelor-related dyspnea: an underestimated and poorly managed event? Int. J. Cardiol. 179 (2015) 238–239. [5] H. Wu, Q. Wang, J. Zhou, J. Qian, J. Ge, First report of stent thrombosis after a switch therapy resulting from ticagrelor-related dyspnea, Int. J. Cardiol. 176 (2014) e127–e128. [6] L. Wallentin, R.C. Becker, A. Budaj, C.P. Cannon, H. Emanuelsson, C. Held, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N. Engl. J. Med. 361 (2009) 1045–1057. [7] M. Gaubert, M. Laine, T. Richard, N. Fournier, C. Gramond, J. Bessereau, et al., Effect of ticagrelor-related dyspnea on compliance with therapy in acute coronary syndrome patients, Int. J. Cardiol. 173 (2014) 120–121.
Fig. 2. Adenosine transformation. ① Plasma membrane nucleoside transporter; AMP: adenosine monophosphate; ATP: adenosine triphosphate.
N. Zhang et al. / International Journal of Cardiology 192 (2015) 11–13 [8] B.M. Scirica, C.P. Cannon, H. Emanuelsson, E.L. Michelson, R.A. Harrington, S. Husted, et al., The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (platelet inhibition and patient outcomes) trial: results of the continuous electrocardiographic assessment substudy, J. Am. Coll. Cardiol. 57 (2011) 1908–1916. [9] A. Goldberg, I. Rosenfeld, I. Nordkin, M. Halabi, Life-threatening complete atrioventricular block associated with ticagrelor therapy, Int. J. Cardiol. 182 (2015) 379–380. [10] M. Nicol, J. Deblaise, R. Choussat, O. Dubourg, N. Mansencal, Side effects of ticagrelor: sinus node dysfunction with ventricular pause, Int. J. Cardiol. (2015) (Epub ahead of print). [11] M.P. Bonaca, D.L. Bhatt, M. Cohen, P.G. Steg, R.F. Storey, E.C. Jensen, et al., Long-term use of ticagrelor in patients with prior myocardial infarction, N. Engl. J. Med. 372 (2015) 1791–1800. [12] P.C. Robinson, Horsburgh S. Gout, Joints and beyond, epidemiology, clinical features, treatment and co-morbidities, Maturitas 78 (2014) 245–251. [13] J. He, Y. Yang, D.Q. Peng, Monosodium urate (MSU) crystals increase gout associated coronary heart disease (CHD) risk through the activation of nlrp3 inflammasome, Int. J. Cardiol. 160 (2012) 72–73. [14] R.F. Storey, S. Husted, R.A. Harrington, S. Heptinstall, R.G. Wilcox, G. Peters, et al., Inhibition of platelet aggregation by azd6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes, J. Am. Coll. Cardiol. 50 (2007) 1852–1856. [15] R. Teng, S. Oliver, M.A. Hayes, K. Butler, Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects, Drug Metab. Dispos. 38 (2010) 1514–1521. [16] K. Butler, R. Teng, Evaluation and characterization of the effects of ticagrelor on serum and urinary uric acid in healthy volunteers, Clin. Pharmacol. Ther. 91 (2012) 264–271. [17] S. Husted, H. Emanuelsson, S. Heptinstall, P.M. Sandset, M. Wickens, G. Peters, Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist azd6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin, Eur. Heart J. 27 (2006) 1038–1047.
13
[18] M.A. Hediger, R.J. Johnson, H. Miyazaki, H. Endou, Molecular physiology of urate transport, Physiology (Bethesda) 20 (2005) 125–133. [19] A. Enomoto, H. Kimura, A. Chairoungdua, Y. Shigeta, P. Jutabha, S.H. Cha, et al., Molecular identification of a renal urate anion exchanger that regulates blood urate levels, Nature 417 (2002) 447–452. [20] Y. Hagos, D. Stein, B. Ugele, G. Burckhardt, A. Bahn, Human renal organic anion transporter 4 operates as an asymmetric urate transporter, J. Am. Soc. Nephrol. 18 (2007) 430–439. [21] K. Ichida, M. Hosoyamada, H. Kimura, M. Takeda, Y. Utsunomiya, T. Hosoya, et al., Urate transport via human PAH transporter HOAT1 and its gene structure, Kidney Int. 63 (2003) 143–155. [22] A. Bakhiya, A. Bahn, G. Burckhardt, N. Wolff, Human organic anion transporter 3 (HOAT3) can operate as an exchanger and mediate secretory urate flux, Cell. Physiol. Biochem. 13 (2003) 249–256. [23] R.A. Van Aubel, P.H. Smeets, J.J. van den Heuvel, F.G. Russel, Human organic anion transporter mrp4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites, Am. J. Physiol. Ren. Physiol. 288 (2005) F327–F333. [24] S. Khamdang, M. Takeda, R. Noshiro, S. Narikawa, A. Enomoto, N. Anzai, et al., Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs, J. Pharmacol. Exp. Ther. 303 (2002) 534–539. [25] R.W. Li, C. Yang, A.S. Sit, S.Y. Lin, E.Y. Ho, G.P. Leung, Physiological and pharmacological roles of vascular nucleoside transporters, J. Cardiovasc. Pharmacol. 59 (2012) 10–15. [26] M. Loffler, J.C. Morote-Garcia, S.A. Eltzschig, I.R. Coe, H.K. Eltzschig, Physiological roles of vascular nucleoside transporters, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 1004–1013. [27] M. Cattaneo, R. Schulz, S. Nylander, Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance, J. Am. Coll. Cardiol. 63 (2014) 2503–2509. [28] R. Harrison, Structure and function of xanthine oxidoreductase: where are we now? Free Radic. Biol. Med. 33 (2002) 774–797.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Ticagrelor-related gout: An underestimated side effect Nixiao Zhang, Zhiwei Zhang, Yajuan Yang, Yanmin Xu, Guangping Li, Tong Liu ⁎ Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
a r t i c l e
i n f o
Article history: Received 4 May 2015 Accepted 6 May 2015 Available online 8 May 2015 Keywords: Ticagrelor Gout Hyperuricemia Uric acid Side effect
Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker, has been recognized as the standard therapy in patients with acute coronary syndrome (ACS) and following percutaneous coronary intervention. Ticagrelor, a novel direct, reversibly binding P2Y12 antagonist, has better pharmacodynamic effects and improves clinical outcomes compared with clopidogrel in the setting of ACS [1,2]. However, ticagrelor-related dyspnea [3–5] and bradyarrhythmias have been observed in the PLATO trial [6] and real world ACS patients, and may lead to drug discontinuation. Gaubert et al. [7] demonstrated that ticagrelor-related dyspnea is a major cause of drug discontinuation during one-month follow-up period. In addition, re-hospitalization because of drug-correlated dyspnea accounts for 2% of the study population. Adenosine concentration levels or this reversible P2Y12 antagonist acting on sensory neurons may play a significant role in ticagrelorrelated dyspnea. Besides, ticagrelor may cause bradyarrhythmias in the PLATO trial [8] and may induce complete atrioventricular block [9] and sinus node dysfunction [10] in some case reports. However, no difference in terms of incidence of clinically bradycardia events (syncope, sudden death, cardiac arrest or pacemaker placement) was observed in the PLATO trial [8]. Very recent published data from the PEGASUS-TIMI54 trial [11] indicates that long term use of ticagrelor may increase the incidence of gout in patients with prior myocardial infarction. The PEGASUS-
⁎ Corresponding author at: Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China. E-mail address: [email protected] (T. Liu).
http://dx.doi.org/10.1016/j.ijcard.2015.05.023 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
TIMI54 trial randomly assigned 21,162 patients who had a prior myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed up for a median of 33 months. The results showed that ticagrelor significantly decreased the risk of cardiovascular death, myocardial infarction or stroke during a 33-month follow-up. Besides, the investigators also found that the long term use of ticagrelor was associated with dosedependent 1.48–1.77 fold increased risk of gout compared with placebo. Actually, the previous PLATO trial has also shown that the increases of mean serum uric acid levels from baseline values were 14% and 15% at 1 and 12 months respectively following the ticagrelor treatment compared with clopidogrel, but there was no difference regarding the incidence of gout/gouty arthritis over time between the two groups [6]. To the best of our knowledge, ticagrelor-related gout was not systematically reviewed in the literature. In this letter to the editor, we intend to discuss the potential mechanisms regarding ticagrelor-related gout and propose some suggestions for the prevention of this underestimated side effect during long term use of ticagrelor. Gout is termed as hyperuricemia accompanied with acute arthritis, tophus, chronic arthritis, joint deformity, chronic interstitial nephritis and uric acid stones, which is more prevalent in males more than 40 years old and goes through three stages (asymptomatic period, acute arthritis period, tophus/chronic arthritis) [12,13]. Purine or adenosine is converted to hypoxanthine, then is metabolized to xanthine and ultimately uric acid. The normal value of serum uric acid is 149– 416 μmol/L in males and 89–357 μmol/L in females. Exceeding this level may result in uric acid crystallization and clinical symptoms, just like gout/gouty arthritis. Sudden onset of gouty arthritis mainly results from a rapid rise or fall in serum uric acid, as well as inflammation caused by uric acid crystallization. Ticagrelor, as a reversibly binding P2Y12 receptor antagonist, is rapidly absorbed [14] and metabolized [15]. AR-C124910XX, the major metabolite which it rapidly formed, has a potency approximately equal to that of ticagrelor [16], but with a little difference existing as well. Ticagrelor is not required for hepatic metabolization [17], it is often metabolized in the kidneys. Therefore, the high renal serum drug concentration may influence the renal function so as to interfere with the filtration, absorption, uptake and secretion of uric acid. Several renal urate transporters are involved in this process [18] (Fig. 1). Ticagrelor and its metabolite AR-C124910XX have weak inhibitory effects on urate transporter 1 (URAT1), while AR-C124910XX alone is reported to restrain Xenopus oocytes expressing organic ion transporter (OAT)1 but not ticagrelor [16]. Importantly, OAT3 expressed in Xenopus
12
N. Zhang et al. / International Journal of Cardiology 192 (2015) 11–13
Fig. 1. Uric acid metabolism in proximal tubules. URAT1: urate transporter 1; OAT4: organic ion transporter 4; MRP4: adenosine-5′-triphosphate-dependent urate export transporter; OAT1: organic ion transporter 1; OAT3: organic ion transporter 3.
oocytes is confirmed to be inhibited by both ticagrelor and ARC124910XX. Therefore, it is reasonable to assume that OAT3 is a probable transporter involved in hyperuricemia and gout related to ticagrelor. Reabsorption of uric acid is regulated by urate transporter 1 (URAT1) [19] and organic ion transporter (OAT)4 [20] in the apical membrane of proximal tubules. The uptake of blood urate into proximal tubules goes through OAT1 [21] and OAT3 [22] in the basolateral membrane. Moreover, the secretion of uric acid lies on an adenosine-5′-triphosphate-dependent urate export transporter (MRP4) [23] in the apical membrane (Fig. 1). The decline in renal urate clearance cannot be neglected as well [24]. On the other hand, when uric acid synthesis increases, the incidence of gout changes correspondingly. Under normal circumstances, adenosine can be transported into erythrocytes or other cells by plasma membrane nucleoside transporters to form hypoxanthine or adenosine triphosphate (ATP) [25,26] (Fig. 2). Ticagrelor and its metabolite have negative effects on such transporters, with the adenosine from extracellular/blood vessels increasing in response to ischemia, hypoxia and inflammation. The inhibitory effects of ticagrelor on the cellular uptake of adenosine, in addition to antagonizing the P2Y12 receptor, is sufficient to increase the circulating levels of adenosine in patients with ACS, which may partly explain its advantageous effects in clinical outcomes compared with other P2Y12 receptor blockers [27]. Consequently, the elevated level of adenosine in extracellular/ blood vessels may further increase uric acid synthesis, which was fortified by tissue with high levels of xanthine oxidase, such as those from the liver, kidney and small intestines [28]. In conclusion, ticagrelor-related gout is an underestimated side effect during long term use of ticagrelor. We recommend that clinicians assess serum uric acid levels regularly and pay more attention to the possible symptoms of gout during long term administration of ticagrelor, especially in patients with hyperuricemia. Also, we need to educate our patients on ticagrelor to avoid a number of foodstuffs which are risk factors for gout, including sugar sweetened beverages, alcohol, red meat, seafood, and fruit juice [12].
Conflicts of interest None. Financial disclosures None. Acknowledgment The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] S. De Servi, C. Cavallini, S. Leonardi, M. Ferlini, Prasugrel and ticagrelor compared to clopidogrel in non-st-segment elevation acute coronary syndromes undergoing percutaneous coronary interventions: certainties and uncertainties, Int. J. Cardiol. 181 (2015) 443–445. [2] L. Bonello, C. Frere, S. Cointe, M. Laine, J. Mancini, F. Thuny, et al., Ticagrelor increases endothelial progenitor cell level compared to clopidogrel in acute coronary syndromes: a prospective randomized study, Int. J. Cardiol. 187 (2015) 502–507. [3] M.J. Sanchez-Galian, P.J. Flores-Blanco, A. Lopez-Cuenca, M. Gomez-Molina, E. Guerrero-Perez, F. Cambronero-Sanchez, et al., Ticagrelor related dyspnea in patients with acute coronary syndromes: incidence and implication on ticagrelor withdrawn, Int. J. Cardiol. 187 (2015) 517–518. [4] N. Lombardi, M.C. Lenti, R. Matucci, A. Mugelli, A. Vannacci, Ticagrelor-related dyspnea: an underestimated and poorly managed event? Int. J. Cardiol. 179 (2015) 238–239. [5] H. Wu, Q. Wang, J. Zhou, J. Qian, J. Ge, First report of stent thrombosis after a switch therapy resulting from ticagrelor-related dyspnea, Int. J. Cardiol. 176 (2014) e127–e128. [6] L. Wallentin, R.C. Becker, A. Budaj, C.P. Cannon, H. Emanuelsson, C. Held, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N. Engl. J. Med. 361 (2009) 1045–1057. [7] M. Gaubert, M. Laine, T. Richard, N. Fournier, C. Gramond, J. Bessereau, et al., Effect of ticagrelor-related dyspnea on compliance with therapy in acute coronary syndrome patients, Int. J. Cardiol. 173 (2014) 120–121.
Fig. 2. Adenosine transformation. ① Plasma membrane nucleoside transporter; AMP: adenosine monophosphate; ATP: adenosine triphosphate.
N. Zhang et al. / International Journal of Cardiology 192 (2015) 11–13 [8] B.M. Scirica, C.P. Cannon, H. Emanuelsson, E.L. Michelson, R.A. Harrington, S. Husted, et al., The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (platelet inhibition and patient outcomes) trial: results of the continuous electrocardiographic assessment substudy, J. Am. Coll. Cardiol. 57 (2011) 1908–1916. [9] A. Goldberg, I. Rosenfeld, I. Nordkin, M. Halabi, Life-threatening complete atrioventricular block associated with ticagrelor therapy, Int. J. Cardiol. 182 (2015) 379–380. [10] M. Nicol, J. Deblaise, R. Choussat, O. Dubourg, N. Mansencal, Side effects of ticagrelor: sinus node dysfunction with ventricular pause, Int. J. Cardiol. (2015) (Epub ahead of print). [11] M.P. Bonaca, D.L. Bhatt, M. Cohen, P.G. Steg, R.F. Storey, E.C. Jensen, et al., Long-term use of ticagrelor in patients with prior myocardial infarction, N. Engl. J. Med. 372 (2015) 1791–1800. [12] P.C. Robinson, Horsburgh S. Gout, Joints and beyond, epidemiology, clinical features, treatment and co-morbidities, Maturitas 78 (2014) 245–251. [13] J. He, Y. Yang, D.Q. Peng, Monosodium urate (MSU) crystals increase gout associated coronary heart disease (CHD) risk through the activation of nlrp3 inflammasome, Int. J. Cardiol. 160 (2012) 72–73. [14] R.F. Storey, S. Husted, R.A. Harrington, S. Heptinstall, R.G. Wilcox, G. Peters, et al., Inhibition of platelet aggregation by azd6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes, J. Am. Coll. Cardiol. 50 (2007) 1852–1856. [15] R. Teng, S. Oliver, M.A. Hayes, K. Butler, Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects, Drug Metab. Dispos. 38 (2010) 1514–1521. [16] K. Butler, R. Teng, Evaluation and characterization of the effects of ticagrelor on serum and urinary uric acid in healthy volunteers, Clin. Pharmacol. Ther. 91 (2012) 264–271. [17] S. Husted, H. Emanuelsson, S. Heptinstall, P.M. Sandset, M. Wickens, G. Peters, Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist azd6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin, Eur. Heart J. 27 (2006) 1038–1047.
13
[18] M.A. Hediger, R.J. Johnson, H. Miyazaki, H. Endou, Molecular physiology of urate transport, Physiology (Bethesda) 20 (2005) 125–133. [19] A. Enomoto, H. Kimura, A. Chairoungdua, Y. Shigeta, P. Jutabha, S.H. Cha, et al., Molecular identification of a renal urate anion exchanger that regulates blood urate levels, Nature 417 (2002) 447–452. [20] Y. Hagos, D. Stein, B. Ugele, G. Burckhardt, A. Bahn, Human renal organic anion transporter 4 operates as an asymmetric urate transporter, J. Am. Soc. Nephrol. 18 (2007) 430–439. [21] K. Ichida, M. Hosoyamada, H. Kimura, M. Takeda, Y. Utsunomiya, T. Hosoya, et al., Urate transport via human PAH transporter HOAT1 and its gene structure, Kidney Int. 63 (2003) 143–155. [22] A. Bakhiya, A. Bahn, G. Burckhardt, N. Wolff, Human organic anion transporter 3 (HOAT3) can operate as an exchanger and mediate secretory urate flux, Cell. Physiol. Biochem. 13 (2003) 249–256. [23] R.A. Van Aubel, P.H. Smeets, J.J. van den Heuvel, F.G. Russel, Human organic anion transporter mrp4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites, Am. J. Physiol. Ren. Physiol. 288 (2005) F327–F333. [24] S. Khamdang, M. Takeda, R. Noshiro, S. Narikawa, A. Enomoto, N. Anzai, et al., Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs, J. Pharmacol. Exp. Ther. 303 (2002) 534–539. [25] R.W. Li, C. Yang, A.S. Sit, S.Y. Lin, E.Y. Ho, G.P. Leung, Physiological and pharmacological roles of vascular nucleoside transporters, J. Cardiovasc. Pharmacol. 59 (2012) 10–15. [26] M. Loffler, J.C. Morote-Garcia, S.A. Eltzschig, I.R. Coe, H.K. Eltzschig, Physiological roles of vascular nucleoside transporters, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 1004–1013. [27] M. Cattaneo, R. Schulz, S. Nylander, Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance, J. Am. Coll. Cardiol. 63 (2014) 2503–2509. [28] R. Harrison, Structure and function of xanthine oxidoreductase: where are we now? Free Radic. Biol. Med. 33 (2002) 774–797.
