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US-12616672-B2 - Methods for assessing risk of cardiovascular disease and methods and compounds for use in treating or preventing cardiovascular disease

US12616672B2US 12616672 B2US12616672 B2US 12616672B2US-12616672-B2

Abstract

A method of treating or preventing cardiovascular disease which comprises administering a therapeutically effective amount of at least one n-3 DPA-derived resolvin and/or upregulating or increasing the biosynthesis or activity of at least one n-3 DPA-derived resolvin. n-3 DPA-derived resolvins are normally regulated diurnally in the body and are linked to activation of platelets and leucocytes and formation of platelet-leukocyte aggregates. Dysfunctional regulation of n-3 DPA-derived resolvins may lead to systemic inflammation because of excessive inflammation-inducing eicosanoids, especially in the early hours of the morning. Further, decreased 5-LOX/15-LOX expression and increased systemic adenosine concentrations are found to be associated with reduced resolvin levels and increased risk of cardiovascular disease. n-3 DPA-derived resolvins are administered to achieve maximum absorption in the early hours. Also disclosed are n-3 DPA-derived resolvins for use in the treatment or prevention of cardiovascular disease, and methods for measuring the levels of n-3 DPA-derived resolvins and/or the expression or activity of adenosine or 5-LOX/15-LOX in biological samples obtained from a subject for assessing the subject's risk of cardiovascular disease.

Inventors

  • JESMOND DALLI
  • Romain Alexandre Colas
  • Patricia Regina Souza

Assignees

  • QUEEN MARY UNIVERSITY OF LONDON

Dates

Publication Date
20260505
Application Date
20180919
Priority Date
20170919

Claims (6)

  1. 1 . A method of treating or reducing the risk of developing cardiovascular disease, vascular inflammation, or myocardial infarction, or treating dysfunctional diurnal regulation of one or more n-3 DPA-derived resolvins, or attenuating activation of platelets, or reducing formation of platelet-leukocytes aggregates in a human subject in need thereof, which comprises administering a therapeutically effective amount of at least one n-3 DPA-derived resolvin to a subject in need thereof such that t max occurs between 7 am and 9 am and/or increasing the biosynthesis, activity or expression levels of at least one n-3 DPA-derived resolvin in a subject in need thereof such that t max occurs between 7 am and 9 am, wherein the at least one n-3 DPA-derived resolvin is formulated for immediate or delayed and/or controlled release wherein the at least one n-3 DPA-derived resolvin is RVD 1n-3 DPA , RVD2 n-3 DPA and/or RvD5 n-3 DPA .
  2. 2 . A method as claimed in claim 1 , wherein the at least one n-3 DPA-derived resolvin is administered in a dosage that is calculated to achieve a peak plasma concentration of n-3 DPA-derived resolvin of at least 10 pg/mL.
  3. 3 . A method as claimed in claim 1 , which comprises the simultaneous, sequential or separate administration of a combination of two or more n-3 DPA-derived resolvins to the subject.
  4. 4 . A method as claimed in claim 1 , wherein the at least one n-3 DPA-derived resolvin is administered orally.
  5. 5 . A method as claimed in claim 1 , which comprises reducing the activity or expression levels of adenosine and/or increasing the activity or expression levels of 5-LOX and/or 15-LOX in the subject.
  6. 6 . The method as claimed in claim 2 , wherein the at least one n-3 DPA-derived resolvin is administered in a dosage that is calculated to achieve a peak plasma concentration of n-3 DPA-derived resolvin of 15-25 pg/mL.

Description

FIELD OF THE INVENTION The present invention relates to methods for assessing a risk of cardiovascular disease or myocardial infarction in a human subject, and has particular reference to methods for assessing the risk of cardiovascular disease or myocardial infarction in the early hours of the morning. The invention also provides methods for assessing the efficacy of prophylactic treatments for reducing the risk of cardiovascular disease or myocardial infarction. Further, the present invention provides methods of treating or preventing cardiovascular disease or myocardial infarction, particularly cardiovascular disease or myocardial infarction that occurs in the early hours of the morning, and compounds for use in such methods. BACKGROUND TO THE INVENTION Circadian mechanisms are central to regulating a number of physiological functions, including cardiovascular function and the immune system (Ingle K A et al. Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. Am J Physiol Heart Circ Physiol. 2015; 309(11):H1827-1836; McAlpine C S & Swirski F K. Circadian Influence on Metabolism and Inflammation in Atherosclerosis. Circ Res. 2016; 119(1):131-141). Disturbances to these fundamental mechanisms are thought to be responsible for many diseases that are characterised by a dysregulated inflammatory response, including cardiovascular and metabolic disorders (Ingle K A et al., 2015; McAlpine C S & Swirski F K, 2016; Puttonen S et al. Is shift work a risk factor for rheumatoid arthritis? The Finnish Public Sector study. Ann Rheum Dis. 2010; 69(4):779-780). Circadian responses have been correlated with several inflammatory conditions, including myocardial infarct (Gilbert K et al. Resolvin D1 Reduces Infarct Size Through a Phosphoinositide 3-Kinase/Protein Kinase B Mechanism. J Cardiovasc Pharmacol. 2015; 66(1):72-79; Kain V et al. Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function. J Mol Cell Cardiol. 2015; 84:24-35). In the vasculature, platelet activation is at a maximum during the early hours of the day with the upregulation of several activation markers, including CD62P (Scheer F A et al. The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors. PLoS One. 2011; 6(9):e24549). This increase in platelet activation is coincident with an increase in plasma plasminogen activator inhibitor-1, a serine protease inhibitor that functions as the principal inhibitor of tissue plasminogen activator and urokinase, thereby increasing the risk of thrombosis (Sakata K et al. Circadian fluctuations of tissue plasminogen activator antigen and plasminogen activator inhibitor-1 antigens in vasospastic angina. Am Heart J. 1992; 124(4):854-860). Platelet CD62P mediates platelet-leukocyte interactions, a process which, in addition to facilitating leukocyte recruitment to the vascular endothelium, is also involved in leukocyte activation and the production of inflammatory mediators, including cysteinyl leukotrienes (Shinohara M et al. Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1. Am J Physiol Lung Cell Mol Physiol. 2014; 307(10):L746-757), tumour necrosis factor-α and C—C motif ligand-2 (Furman M I et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol. 2001; 38(4):1002-1006; Pfluecke C et al. Monocyte-platelet aggregates and CD11b expression as markers for thrombogenicity in atrial fibrillation. Clin Res Cardiol. 2016; 105(4):314-322). CD62P enhances platelet adhesion to endothelial cells expressing fractalkine and triggers the release of Weibel-Palade-bodies in endothelial cells, perpetuating the pro-inflammatory and pro-thrombotic status during the early hours of the day. Platelet-leukocyte aggregates are also implicated in vascular disease pathogenesis, including atherosclerosis (Huo Y et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003; 9(1):61-67). Meanwhile, platelet activating factor (PAF) has a reported role in propagating vascular inflammation (Palur Ramakrishnan A V et al. Platelet activating factor: A potential biomarker in acute coronary syndrome? Cardiovasc Ther. 2017; 35(1):64-70). These observations suggest that in healthy individuals endogenous, diurnally regulated, protective mechanisms are engaged that counter-regulate this physiological inflammation to prevent vascular inflammation and thrombus formation. Studies investigating mechanisms engaged by the host to terminate ongoing inflammation have uncovered a new genus of molecules, produced by leukocytes that reprogram both stromal and leukocyte responses (Dalli J et al. Elucidation of novel 13-se