Download PDF
Thromb Haemost 2009; 102(03): 538-543
DOI: 10.1160/TH09-03-0158
Platelets and Blood Cells
Schattauer GmbH

Distribution of dipyridamole in blood components among post-stroke patients treated with extended release formulation

Victor Serebruany
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA
,
Elena Sabaeva
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA
,
Christopher Booze
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA
,
Oliver D. Atar
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA
,
Christian Eisert
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA
,
Dan Hanley
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA
,
for the Aggrenox® Compliance Task Force › Author Affiliations
Further Information

Publication History

Received: 10 March 2009

Accepted after major revision: 21 May 2009

Publication Date:
22 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Extended release dipyridamole (ERD) is widely used in patients after ischaemic stroke; however, the ability of this antithrombotic agent to be stored in different blood cells has never been explored in post-stroke patients. We hypothesised that since ERD is known to be highly lipophilic, the drug may be present not only in plasma, but also accumulated in platelets, leukocytes, and erythrocytes. Fifteen patients after documented ischaemic stroke were treated with Aggrenox (ERD and lowdose aspirin combination) BID for 30 days, and 12 of them completed the study. ERD concentrations in blood cells and platelet-poor plasma were measured by spectrofluorimetry at Baseline, Day 14, and Day 30 after the initiation of therapy. The background level of spectrofluorometry readings differs slightly among the blood components (132–211 ng/ml) due to the differences in the preparation of samples and cell isolation techniques. As expected, two weeks of ERD therapy produced steady-state plasma concentration of dipyridamole already at Day 14 (1,680 ±542 ng/ ml), followed by a slight not significant decrease at one month (1,619 ±408 ng/ml). Two weeks of therapy was sufficient to achieve a consistent dipyridamole accumulation in erythrocytes (361 ±43 ng/ml), but not in platelets (244 ±78 ng/ml), or leukocytes (275 ±49 ng/ml).In fact, white blood cells continued dipyridamole intake beyond 14 days period, and this increase (398 ± 66 ng/ml) was significant (p = 0.02) at 30 days. Treatment with ERD in post-stroke patients resulted not only in achievement of therapeutic plasma dipyridamole concentrations, but also deposition of the drug in erythrocytes and leukocytes, but not in platelets. If confirmed, these data will affect our better understanding of dipyridamole pleiotropy, and may explain long-term benefit of ERD formulation.

Keywords

Stroke - dipyridamole - pharmacokinetics - spectrofluorimetry - platelets - erythrocytes - leukocytes - plasma
 

  • References

  • 1 Diener HC, Cunha L, Forbes C. et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
    CrossrefPubMedGoogle Scholar
  • 2 ESPRIT Study Group. Halkes PH, van Gijn J, Kappelle LJ. et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665-1673.
    CrossrefPubMedGoogle Scholar
  • 3 Albers GW, Amarenco P, Easton JD. et al. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 483S-512S.
    CrossrefPubMedGoogle Scholar
  • 4 Sacco RL, Diener HC, Yusuf S. et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359: 1238-1251.
    CrossrefPubMedGoogle Scholar
  • 5 Gresele P, Zoja C, Deckmyn H. et al. Dipyridamole inhibits platelet aggregation in whole blood. Thromb Haemost 1983; 50: 852-856.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Akinboboye OO, Idris O, Chou RL. et al. Absolute quantitation of coronary steal induced by intravenous dipyridamole. J Am Coll Cardiol 2001; 37: 109-116.
    CrossrefPubMedGoogle Scholar
  • 7 Eisert WG. Near-field amplification of antithrombotic effects of dipyridamole through vessel wall cells. Neurology 2001; 57: S20-S23.
    CrossrefPubMedGoogle Scholar
  • 8 Iuliano L, Pedersen JZ, Rotilio G. et al A potent chain-breaking antioxidant activity of the cardiovascular drug dipyridamole. Free Radical Biol Med 1995; 18: 239-247.
    CrossrefPubMedGoogle Scholar
  • 9 Neri Serneri GG, Masotti G, Poggesi L. et al. Enhanced prostacyclin production by dipyridamole in man. Eur J Clin Pharmacol 1981; 21: 9-15.
    PubMedGoogle Scholar
  • 10 Bult H, Fret HR, Jordaens FH. et al. Dipyridamole potentiates the anti-aggregating and vasodilator activity of nitric oxide. Eur J Pharmacol 1991; 199: 1-8.
    CrossrefPubMedGoogle Scholar
  • 11 Singh JP, Rothfuss KJ, Wiernicki TR. et al. Dipyridamole directly inhibits vascular smooth muscle cell profileration in vitro and in vivo: implications in the treatment of restenosis after angioplasty. J Am Coll Cardiol 1994; 23: 665-671.
    CrossrefPubMedGoogle Scholar
  • 12 Ruggiero AC, Nepomuceno MF, Jacob RF. et al. Antioxidant effect of dipyridamole and its derivative RA 25 upon lipid peroxidation and hemolysis in red blood cells. 1: Physiol Chem Phys Med NMR 2000; 32: 35-48.
    PubMedGoogle Scholar
  • 13 Pulgarin JAM, Alanon Molina A, Fernandez Lopez P. Direct determination of dipyridamole in serum. Anal Biochem 1997; 245: 8-16.
    CrossrefPubMedGoogle Scholar
  • 14 Serebruany V, Pokov I, Hanley D. Spectrofluorimetric assessment of plasma dipyridamole stability: Sample storage for multicenter clinical trials?. Thromb Res 2008; 123: 184-186.
    CrossrefPubMedGoogle Scholar
  • 15 Gencheva E, Sloan M, Leurgans S. et al. Attrition and non-compliance in secondary stroke prevention trials. Neuroepidemiology 2004; 23: 61-66.
    CrossrefPubMedGoogle Scholar
  • 16 Serebruany VL, Hanley DF, Atar D. et al. Non - compliance in antiplatelet trials: The AGATE trial perspective. Stroke 2004; 35: 143.
    CrossrefPubMedGoogle Scholar
  • 17 Nagaeva O, Bondestam K, Olofsson J. et al. An optimized technique for separation of human decidual leukocytes for cellular and molecular analyses. Am J Reprod Immunol 2002; 47: 203-212.
    CrossrefPubMedGoogle Scholar
  • 18 Ford TC, Graham J, Rickwood D. A new, rapid, onestep method for the isolation of platelets from human blood Clin Chim Acta. 1990; 192: 115-120.
    PubMedGoogle Scholar
  • 19 Oshrine BR, Malinin AI, Pokov AN. et al. Changes of pH are critical for accurate fluorometric measurements of dipyridamole levels in biological fluids. Meth Find Exp Clin Pharm 2005; 27: 95-100.
    PubMedGoogle Scholar
  • 20 Mahony C, Cox JL, Bjornsson TD. Plasma dipyridamole concentrations after two different dosage regimens in patients. J Clin Pharmacol 1983; 23: 123-126.
    CrossrefPubMedGoogle Scholar
  • 21 Bjornsson TD, Mahony C. Clinical pharmacokinetics of dipyridamole. Thromb Res (Suppl) 1983; 04: 93-104.
    PubMedGoogle Scholar
  • 22 Tyce GM, Fuster V, Owen Jr CA. Dipyridamole levels in plasma of man and other species. Res Commun Chem Pathol Pharmacol 1979; 26: 495-508.
    PubMedGoogle Scholar
  • 23 Müller TH, Su CA, Weisenberger H. et al. Dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo. Br J Clin Pharmacol 1990; 30: 179-186.
    CrossrefPubMedGoogle Scholar
  • 24 Casper ES, Baselga J, Smart TB. et al. A phase II trial of PALA + dipyridamole in patients with advanced soft-tissue sarcoma. Cancer Chemother Pharmacol 1991; 28: 51-54.
    CrossrefPubMedGoogle Scholar
  • 25 Serebruany VL, Malinin AI, Hanley DF. Magnitude and time course of platelet inhibition with extended release dipyridamole with or without aspirin in healthy Japanese volunteers. The AGgrenox versus Aspirin Therapy Evaluation (AGATE-Japan). Thromb Haemost 2008; 99: 116-120.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Stafford NP, Pink AE, White AE. et al. Mechanisms involved in adenosine triphosphate--induced platelet aggregation in whole blood. Arterioscler Thromb Vasc Biol 2003; 23: 1928-1933.
    CrossrefPubMedGoogle Scholar
  • 27 Besselink GA, van Engelenburg FA, Ebbing IG. et al. Additive effects of dipyridamole and Trolox in protecting human red cells during photodynamic treatment. Vox Sang 2003; 85: 25-30.
    CrossrefPubMedGoogle Scholar
  • 28 Vargas F, Cheng AT, Velutini G. et al. In vitro antioxidant and photo-oxidant properties of dipyridamole. Int J Toxicol 2001; 20: 363-368.
    CrossrefPubMedGoogle Scholar
  • 29 Ruggiero AC, Nepomuceno MF, Jacob RF. et al. Antioxidant effect of dipyridamole (DIP) and its derivative RA 25 upon lipid peroxidation and hemolysis in red blood cells. Physiol Chem Phys Med NMR 2000; 32: 35-48.
    PubMedGoogle Scholar
  • 30 Bozzo J, Hernández MR, Ordinas A. Reduced red cell deformability associated with blood flow and platelet activation: improved by dipyridamole alone or combined with aspirin. Cardiovasc Res 1995; 30: 725-730.
    CrossrefPubMedGoogle Scholar
  • 31 Coccia R, Spadaccio C, Foppoli C. et al. The effect of simvastatin on erythrocyte membrane fluidity during oxidative stress induced by cardiopulmonary bypass: a randomized controlled study. Clin Ther 2007; 29: 1706-1717.
    CrossrefPubMedGoogle Scholar
  • 32 Hallevi H, Hazan-Halevy I, Paran E. Modification of neutrophil adhesion to human endothelial cell line in acute ischemic stroke by dipyridamole and candesartan. Eur J Neurol 2007; 14: 1002-1007.
    CrossrefPubMedGoogle Scholar
  • 33 Al-Bahrani A, Taha S, Shaath H. et al. TNF-alpha and IL-8 in acute stroke and the modulation of these cytokines by antiplatelet agents. Curr Neurovasc Res 2007; 04: 31-37.
    CrossrefPubMedGoogle Scholar
  • 34 Weyrich AS, Kraiss LW, Prescott SM, Zimmerman GA. New roles for an old drug: inhibition of gene expression by dipyridamole in platelet-leukocyte aggregates. Trends Cardiovasc Med 2006; 16: 75-80.
    CrossrefPubMedGoogle Scholar
  • 35 Kim HH, Liao JK. Translational therapeutics of dipyridamole. Arterioscler Thromb Vasc Biol 2008; 28: s39-42.
    CrossrefPubMedGoogle Scholar
  • 36 Aktas B, Utz A, Hoenig-Liedl P. et al. Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets: in vitro and in vivo/ex vivo studies. Stroke 2003; 34: 764-769.
    CrossrefPubMedGoogle Scholar