WO2017185142A1 - Méthode destinée à prévenir et/ou à traiter la fibrillation auriculaire - Google Patents

Méthode destinée à prévenir et/ou à traiter la fibrillation auriculaire Download PDF

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WO2017185142A1
WO2017185142A1 PCT/AU2017/050393 AU2017050393W WO2017185142A1 WO 2017185142 A1 WO2017185142 A1 WO 2017185142A1 AU 2017050393 W AU2017050393 W AU 2017050393W WO 2017185142 A1 WO2017185142 A1 WO 2017185142A1
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Prior art keywords
atrial
antagonist
subject
atrial fibrillation
endothelin receptor
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Prashanthan SANDERS
Dennis Lau
Rajiv Mahajan
Darragh TWOMEY
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Innovation and Commercial Partners Pty Ltd
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Adelaide Research and Innovation Pty Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present disclosure relates to methods and products for preventing and/or treating atrial fibrillation.
  • Atrial fibrillation is the most prevalent arrhythmia, the incidence of which increases with age and tends to occur more in males than females. Approximately 4% of people over the age of 60 have experienced an episode of atrial fibrillation and this disorder accounts for one-third of hospital admissions for cardiac rhythm disturbances. For example, over 2.2 million people are believed to have AF in the Unites States alone.
  • Atrial fibrillation is often asymptomatic, it may cause palpitations or chest pain. Prolonged atrial fibrillation often results in the development of congestive heart failure and/or stroke.
  • Heart failure develops as the heart attempts to compensate for the reduced cardiac efficiency, while stroke may occur when thrombi form in the atria, pass into the blood stream and lodge in the brain. Pulmonary emboli may also develop in this manner.
  • Clinically atrial fibrillation is diagnosed by irregular rhythm and an absence of P waves on an ECG.
  • the ECG of a patient with atrial fibrillation will usually show a narrow QRS complex, although it may be wide if abnormal conduction or partial or full interruption of electrical conduction in the bundle blocks is present.
  • Anticoagulants such as warfarin, dabigatran, and heparin, are also typically prescribed in order to avoid stroke.
  • Chemotherapeutic treatment of atrial fibrillation includes heart rate control drugs, cardiac glycosides, beta-blockers, and calcium channel blockers which seek to reduce the heart rate to one that is closer to normal to reduce symptoms, and rhythm control drugs which seek to restore and maintain the regular heart rhythm.
  • heart rate control drugs cardiac glycosides, beta-blockers, and calcium channel blockers which seek to reduce the heart rate to one that is closer to normal to reduce symptoms
  • rhythm control drugs which seek to restore and maintain the regular heart rhythm.
  • many of the common agents used to treat atrial fibrillation are relatively toxic and/or have a range of undesirable side effects.
  • clinical studies have indicated that management of atrial fibrillation with rhythm control offers no survival advantage over rate control, and that rate control potentially offers advantages, such as a lower risk of adverse events.
  • the present disclosure relates to the prevention and/or treatment of atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial fibrillation in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide an endothelin receptor antagonist for use in the prevention and/or treatment of atrial fibrillation.
  • Certain embodiments of the present disclosure provide use of an endothelin receptor antagonist in the preparation of a medicament for preventing and/or treating atrial fibrillation. [0013] Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial remodelling due to increased weight gain, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced and/or slowed atrial conduction in subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced atrial conduction velocity in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating increased atrial conduction heterogeneity in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating increased atrial fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating increased atrial inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist. [0019] Certain embodiments of the present disclosure provide a method of treating a subject, the method comprising:
  • identifying a subject suffering from or susceptible to atrial fibrillation and administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for reducing the likelihood of stroke in a subject suffering from or susceptible to atrial fibrillation, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure a method for reducing the dose of an agent for preventing and/or treating atrial fibrillation administered to a subject, the method comprising administering to the subject an endothelin receptor antagonist and thereby reduce the dose of the agent for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method of identifying a subject suffering from or susceptible to atrial fibrillation and suitable for treatment with an endothelin receptor antagonist, the method comprising identifying a subject with one or more of the following characteristics: an increased body mass index; a body mass index of 25 kgm-2 or greater; a body mass index of 25 to 29.9 kgm-2; a body mass index of 30 kgm "2 or greater; overweight; obesity; an increased level of intra-myocardial lipid; an increased level of inter-myocardial lipid; an increased pericardial fat/lipid volume; an increased level of intra-atrial myocardial lipid; an increased level of interatrial myocardial lipid; reduced and/or slowed atrial conduction; reduced atrial conduction velocity; and increased atrial conduction heterogeneity.
  • compositions when used to prevent and/or treat atrial fibrillation comprising a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition when used to prevent and/or treat atrial fibrillation, the pharmaceutical composition comprising a therapeutically effective amount of bosentan and/or macitentan, and/or a pharmaceutically acceptable salt or hydrate thereof.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition comprising a therapeutically effective amount of an endothelin receptor antagonist, and an inhibitor of the renin-angiotensin-aldosterone axis and/or a TGF- ⁇ antagonist.
  • Certain embodiments of the present disclosure provide a combination product comprising:
  • Certain embodiments of the present disclosure provide a method for identifying an agent for preventing and/or treating atrial fibrillation, the method comprising identifying an endothelin receptor antagonist as an agent for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method for identifying an agent for preventing and/or treating atrial fibrillation, the method comprising:
  • test agent as an agent for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide method of preventing and/or treating atrial fibrillation in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist and/or tranilast.
  • Figure 1 shows a diagrammatic representation of the study outline.
  • EPS electrophysiology study.
  • CMR cardiac magnetic resonance imaging.
  • Figure 2 shows representative CMR cines of atrial volumes (top panel) and pericardial fat volume (bottom panel) from baseline, overweight and obese cohorts (across). Maximum atrial volumes shown at ventricular end-systole.
  • Figure 3 shows activation isochronal maps of LAA pacing at 400 msec. Demonstrated are representative examples of SI (top row) and S2 (bottom row) for an animal at baseline (left column), overweight (middle column) and obese (right column) cohorts.
  • Figure 4 shows the effect of progressive obesity on regional slowing in conduction velocity at the 4 pre-defined pacing sites. This relationship persisted following adjustment for hemodynamic variables.
  • RAA right atrial appendage
  • RAFW right atrial free wall
  • LAA left atrial appendage
  • LAFW left atrial free wall.
  • CLs of 500ms and 200ms are presented.
  • Figure 5 shows pacing train (SI) and premature extra stimulus (S2) impact on CV decrement with increasing weight.
  • Figure 6 shows changes in biatrial conduction heterogeneity index with increasing adiposity. CLs of 500ms and 200ms are presented.
  • Figure 7 shows histology from left atrial tissue. From top panel; Inflammatory infiltrates on H&E, myocardial lipidosis on oil-red-0 and myocardial fibrosis on Picrosirius red staining.
  • Figure 8 shows Endothelin Receptor A (ETA) receptor (63kDa) OD, Endothelin Receptor B (ETB) receptor (30kDa) OD and a- Tubulin (55kDa). Two bands are shown per group.
  • ETA Endothelin Receptor A
  • EMB Endothelin Receptor B
  • Figure 9 shows the study design for an interventional study of rhe role of endothelin-receptor blockade in the prevention of the substrate for atrial fibrillation.
  • Figure 10 shows the conduction velocity (CV) at the study baseline, midpoint and endpoint (left) and by region at endpoint study (right)
  • Figure 11 shows the epicardial conduction velocity (CV) at each corner of the LA plaque (top) and conduction heterogeneity (bottom), both with representative examples.
  • Figure 12 shows the effective refractory periods (ERP).
  • the upper panel shows endocardial results at study baseline, midpoint and end point, the lower panel shows epicardial results at study endpoint.
  • Left panels are with a drivetrain of 400ms, right at 200ms.
  • Figure 13 shows proportion of fractionated signal at baseline, midpoint and endpoint (top). Representative examples of LA voltage and fractionation maps in both groups at baseline and endpoint (bottom). Markers represent points with fractionated signal.
  • Figure 14 shows AF inducibility at end point study. Total AF duration (log transformed for statistical analysis) is shown on the left, number of episodes >2s is shown on the right.
  • Figure 15 shows Masson's tri chrome staining of LAA tissue at 40x magnification (upper panels). Immunohistochemistry of gap junction protein connexin43 at 40x magnification (lower panels).
  • FIG. 16 shows LAA immunohistochemistry with representative examples on the left and comparison of treatment and control groups on the left.
  • TGF- ⁇ Transforming growth factor
  • Angll Angiotensin II
  • CTGF Connective tissue growth factor
  • PDGF Platelet derived growth factor.
  • Figure 17 shows AF inducibility at end point study. The proportion of episodes >2s is shown on the left, the total AF duration (log transformed for statistical analysis) on the left.
  • Figure 18 shows study design for treatment studies with tranilast to prevent atrial remodelling and AF in an obese ovine model.
  • Figure 19 shows conduction velocity (CV) at the study baseline, 32 weeks and 64 weeks (left) and by region at endpoint study (right).
  • Figure 20 shows epicardial conduction velocity (CV) at each site (left) and conduction heterogeneity (right).
  • Figure 21 shows effective refractory periods (ERP). Endocardial results at each timepoint (upper) and epicardial results at study endpoint (lower). Left panels are at a 400ms cycle length, right at 200ms.
  • Figure 22 shows proportion of fractionated signal at baseline, midpoint and endpoint.
  • Figure 23 shows AF inducibility at end point study.
  • the present disclosure relates to methods and products for the prevention and/or treatment of atrial fibrillation.
  • Certain embodiments of the present disclosure are directed to methods for preventing and/or treating atrial fibrillation, pharmaceutical compositions for preventing and/or treating atrial fibrillation, kits and products for preventing and/or treating atrial fibrillation, and methods for identifying agents for preventing and/or treating atrial fibrillation.
  • Certain disclosed embodiments provide methods, compositions, products and kits for preventing and/or treating atrial fibrillation that have one or more combinations of advantages.
  • some of the advantages of some of the embodiments disclosed herein include one or more of the following: providing another or alternative form of treatment for subjects suffering from, or susceptible to, atrial fibrillation; providing improved efficacy of treatment; providing a treatment which has improved efficacy for specific types of subjects; providing a treatment that allows reduced dosages of existing drugs to treat atrial fibrillation; providing a treatment that reduces the likelihood of stroke occurring; providing a treatment for atrial fibrillation in overweight or obese subjects; to address one or more problems in the art; to provide one or more advantages in the art; and/or to provide a useful commercial choice.
  • Other advantages of certain embodiments of the present disclosure are also disclosed herein.
  • the present disclosure is based, at least in part, on the determination that in an animal model, intervention with an endothelin receptor antagonist prevents atrial electrical remodelling due to obesity.
  • Certain embodiments provide a method for preventing and/or treating atrial fibrillation in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Atrial fibrillation occurs when the heart's two upper chambers (the right and left atria) quiver instead of beating and contracting rhythmically. Electrocardiographically, atrial fibrillation is characterized by a highly disorganized atrial electrical activity that often results in fast and irregular beating of the heart's two lower chambers (the right and left ventricles). Methods for assessing atrial fibrillation are known in the art.
  • the atrial fibrillation is atrial fibrillation associated with obesity. In certain embodiments, the atrial fibrillation is atrial fibrillation associated with weight gain. [0062] In certain embodiments, the atrial fibrillation is acute atrial fibrillation, spontaneous fibrillation or chronic atrial fibrillation.
  • the atrial fibrillation comprises spontaneous atrial fibrillation, paroxysmal atrial fibrillation, recurrent atrial fibrillation, persistent atrial fibrillation, or permanent atrial fibrillation.
  • preventing refers to obtaining a desired pharmacologic and/or physiologic effect in terms of arresting or suppressing the appearance of one or more symptoms in the subject.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect in terms of improving the condition of the subject, ameliorating, arresting, suppressing, relieving and/or slowing the progression of one or more symptoms in the subject, a partial or complete stabilization of the subject, a regression of the one or more symptoms, or a cure of a disease, condition or state in the subject.
  • the subject is human subject.
  • the subject is a mammalian subject, a livestock animal (such as a horse, a cow, a sheep, a goat, a pig), a domestic animal (such as a dog or a cat) and other types of animals such as monkeys, rabbits, mice and laboratory animals. Other types of animals are contemplated.
  • livestock animal such as a horse, a cow, a sheep, a goat, a pig
  • domestic animal such as a dog or a cat
  • other types of animals such as monkeys, rabbits, mice and laboratory animals.
  • Other types of animals are contemplated.
  • Veterinary applications of the present disclosure are contemplated.
  • the subject is suffering from atrial fibrillation.
  • the subject is suffering from acute atrial fibrillation, chronic atrial fibrillation, spontaneous atrial fibrillation, paroxysmal atrial fibrillation, recurrent atrial fibrillation, persistent atrial fibrillation, or permanent atrial fibrillation.
  • the subject is susceptible to atrial fibrillation.
  • the subject is susceptible to acute atrial fibrillation, chronic atrial fibrillation, spontaneous atrial fibrillation, paroxysmal atrial fibrillation, recurrent atrial fibrillation, persistent atrial fibrillation, or permanent atrial fibrillation.
  • the subject has an increased risk or likelihood of suffering from atrial fibrillation. In certain embodiments, the subject has an increased risk or likelihood of suffering from acute atrial fibrillation, chronic atrial fibrillation, spontaneous atrial fibrillation, paroxysmal atrial fibrillation, recurrent atrial fibrillation, persistent atrial fibrillation, or permanent atrial fibrillation.
  • the subject is suffering from or susceptible to one or more of reduced and/or slowed atrial conduction, reduced atrial conduction velocity, increased atrial conduction heterogeneity, atrial remodelling due to increased weight, atrial fibrosis and atrial inflammation.
  • the subject has an increased risk or likelihood of suffering from one or more of reduced and/or slowed atrial conduction, reduced atrial conduction velocity, increased atrial conduction heterogeneity, atrial remodelling due to increased weight, atrial fibrosis and atrial inflammation.
  • the subject has an increased body mass index.
  • the subject has a body mass index of 25 kgm "2 or greater. In certain embodiments, the subject has a body mass index of 25 to 29.9 kgm "2 . In certain embodiments, the subject is overweight.
  • the subject has a body mass index of 30 kgm "2 or greater.
  • the subject is obese. In certain embodiments, the subject is overweight. In certain embodiments, the subject is overweight or obese.
  • the subject has one or more of an increased level of intra-myocardial lipid, an increased level of inter-myocardial lipid and/or an increased pericardial fat or lipid volume. In certain embodiments, the subject has an increased level of intra-atrial myocardial lipid and/or an increased level of inter-atrial myocardial lipid.
  • the subject has one or more of the following characteristics: elevated ethnicity-specific waist circumference, type II diabetes, glucose intolerance, fasting hyperinsulinemia, increased cardiac MRI-determined atrial fibrosis by delayed enhancement, elevated high sensitivity CRP, low adiponectin levels and diabetic dyslipidemia.
  • the subject has one or more of the following characteristics: an increased body mass index; a body mass index of 25 kgm "2 or greater; a body mass index of 25 to 29.9 kgm "2 ; a body mass index of 30 kgm "2 or greater; overweight; obesity; an increased level of intra-myocardial lipid; an increased level of inter-myocardial lipid; an increased pericardial fat volume; an increased level of intra- atrial myocardial lipid; an increased level of inter-atrial myocardial lipid; reduced and/or slowed atrial conduction; reduced atrial conduction velocity; and increased atrial conduction heterogeneity; elevated ethnicity-specific waist circumference, type II diabetes, glucose intolerance, fasting hyperinsulinemia, increased cardiac MRI- determined atrial fibrosis by delayed enhancement, elevated high sensitivity CRP, low adiponectin levels and diabetic dyslipidemia picture.
  • the present disclosure provides a method of treating a subject, the method comprising:
  • an increased body mass index a body mass index of 25 kgm "2 or greater; a body mass index of 25 to 29.9 kgm "2 ; a body mass index of 30 kgm "2 or greater; overweight; obesity; an increased level of intra-myocardial lipid; an increased level of inter- myocardial lipid; an increased pericardial fat volume; an increased level of intra-atrial myocardial lipid; an increased level of inter-atrial myocardial lipid; reduced and/or slowed atrial conduction; reduced atrial conduction velocity; and increased atrial conduction heterogeneity; and
  • an endothelin receptor antagonist refers to an agent, treatment, or intervention that results directly or indirectly in a change in endothelin receptor activity so as to cause a decrease, an inhibition, a reduction, and/or an inability to be stimulated, in endothelin receptor activity, including for example a decrease in activity, an alteration in the timing and/or location of activity, or otherwise provide some form of negative control over activity.
  • an antagonist may (i) act directly to decrease the activity of an endothelin receptor, such as by altering the level of expression of the receptor, altering localisation of the receptor, altering signalling by the receptor, altering internationalisation of the receptor, and/or altering timing of receptor function; (ii) act to decrease the activity of a signalling pathway associated with an endothelin receptor, such as by altering the activity of a Gn protein; (iii) act to alter the level and/or the activity of a ligand that binds to an endothelin receptor, such as by competing with the binding of a ligand, or by altering the synthesis, breakdown, and/or localisation of the ligand.
  • Other forms of action are contemplated.
  • Examples of antagonists include a drug, a small molecule, a protein, a polypeptide, a lipid, a carbohydrate, a nucleic acid, an oligonucleotide, a ribozyme, a biologic, an aptamer, a peptide, a cofactor, a ligand, a receptor, an enzyme, a kinase, a phosphatase, a cytokine, a growth factor, a metal ion, a chelate, an antisense nucleic acid, a siRNA, an antibody, an amino acid, a ligand mimetic, a ligand antagonist, a dominant negative, a competitor, an inhibitor, and/or a suppressor.
  • activity refers to the function of a species and includes, for example, the level, the specificity, the ability to interact (directly and/or indirectly) with and/or modify other species, the ability to signal, and the ability to cause changes (directly and/or indirectly) in other cellular and/or non-cellular events.
  • Examples of modulating the activity of a species include, for example, a change in the level of the species, a change in the localisation of the species, a change in the synthesis and/or degradation rates of the species, a change in the timing of activity, a change in the ability to interact with other species (such as a change in the ability of a ligand and a receptor to interact), a change in the chemical composition of the species, a change in signalling, and a change in cellular and/or non-cellular events affected by the species.
  • Other forms of action are contemplated.
  • the endothelin receptor antagonist comprises one or more of A-186086, Ro-61-6612 (tezosentan), SB-209670, SB-217242 (enrasentan), SB- 217242, PD 142,893, PD 145,065, Ro 47-0203 (bosentan), R0 48-5033, macitentan, ACT-132577, A-127722, A-147627 (atrasentan), A-216546, BQ-123, BQ-610, FR 139317, Lu-135252 (darusentan), PD 151,242, PD 156,707, TBC-11251 (saitaxsentan), A-192621, BQ-788, RES-701-1, Ro 46-8443, and/or a pharmaceutically acceptable salt, hydrate, tautomer, isomer, pre-drug and/or derivative of any one or more of the aforementioned.
  • the aforementioned antagonists are either commercially available or may be synthethyl,
  • the antagonist is a selective antagonist. In certain embodiments, the antagonist is a non-selective antagonist.
  • the antagonist is a non-selective of endothelin receptor antagonist.
  • the antagonist is a selective endothelin receptor antagonist.
  • the antagonist is selected from one or more of an endothelin A receptor antagonist, an endothelin receptor B antagonist, an antagonist of synthesis of a ligand for an endothelin receptor, an antagonist of signalling via an endothelin receptor (such as a modulator of Gn protein coupled signalling), and an antagonist of endothelin receptor level or expression.
  • the antagonist is an endothelin receptor A antagonist and/or an endothelin receptor B antagonist. In certain embodiments, the antagonist is an endothelin receptor A antagonist and an endothelin receptor B antagonist.
  • the antagonist is a selective antagonist of endothelin receptor A activity. In certain embodiments, the antagonist is a non-selective antagonist of endothelin receptor A activity. In certain embodiments, the antagonist is a selective antagonist of endothelin receptor B activity. In certain embodiments, the antagonist is a non-selective antagonist of endothelin receptor B activity.
  • the antagonist is a non-selective endothelin receptor antagonist.
  • the non-selective antagonist comprises one or more of A- 186086, Ro-61-6612 (tezosentan), SB-209670, SB-217242 (enrasentan), SB- 217242, PD 142,893, PD 145,065, Ro 47-0203 (bosentan), R0 48-5033, macitentan, ACT- 132577 or a pharmaceutically acceptable salt, hydrate, tautomer, isomer, pre-drug and/or derivative of any one or more of the aforementioned.
  • the aforementioned antagonists are either commercially available or may be synthesized by a method known in the art.
  • the antagonist is a selective antagonist of endothelin receptor A activity.
  • the selective antagonist comprises one or more of A-127722, A-147627 (Atrasentan), A-216546, BQ-123, BQ-610, FR 139317, Lu-135252 (darusentan), PD 151,242, PD 156,707, TBC-11251 (saitaxsentan), and a pharmaceutically acceptable salt, hydrate, tautomer, isomer, pre-drug and/or derivative of any one or more of the aforementioned.
  • the aforementioned antagonists are either commercially available or may be synthesized by a method known in the art.
  • the antagonist is a selective antagonist of endothelin receptor B activity.
  • the selective antagonist comprises one or more of A-192621, BQ-788, RES-701-1, Ro 46-8443 and a pharmaceutically acceptable salt, hydrate, tautomer, isomer, pre-drug and/or derivative of any one or more of the aforementioned.
  • the aforementioned antagonists are either commercially available or may be synthesized by a method known in the art.
  • the endothelin receptor antagonist comprises bosentan and/or a pharmaceutically acceptable salt or hydrate thereof.
  • Bosentan is available commercially. Methods for synthesizing bosentan are known in the art, for example Kompella et al. (2014) Science Journal of Chemistry 2(6-1): 9-15.
  • Bosentan has the formula C 27 H 29 N 5 0 6 S » H 2 0 and is designated chemically as 4-tert-butyl-N- [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidin-4- yl]- benzenesulfonamide monohydrate, and has the following structural formula:
  • the endothelin receptor antagonist comprises macitentan and/or a pharmaceutically acceptable salt or hydrate thereof.
  • Macitentan is available commercially. Methods for synthesizing macitentan are known in the art, for example Bolli et al. (2012) J. Med Chem. 55(17): 7849-7861.
  • Macitentan has the formula Ci H 2 oBr 2 N60 4 S and is designated chemically as N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'- propylsulfamide, and has the following structural formula:
  • the antagonist comprises an antagonist of a ligand of an endothelin receptor.
  • the antagonist comprises an antagonist of one or more of endothelin-1, endothelin-2, and endothelin-3. In certain embodiments, the antagonist comprises an antagonist of endothelin-1.
  • the antagonist inhibits the binding of a ligand of an endothelin receptor.
  • the antagonist inhibits the synthesis of a ligand for an endothelin receptor.
  • the antagonist inhibits the processing of a species that forms a ligand for an endothelin receptor.
  • the antagonist inhibits processing of a precursor of one or more of endothelin-1, endothelin-2, and endothelin-3.
  • the antagonist is an inhibitor of an endothelin converting enzyme.
  • the method further comprises administering a further active agent to the subject.
  • the method further comprises administering to the subject an effective amount of an inhibitor of the renin-angiotensin-aldosterone axis.
  • the inhibitor of the renin-angiotensin-aldosterone axis is selected from one or more of a Renin inhibitor, an Angiotensin converting enzyme inhibitor, an Angiotensin II receptor antagonist, an Aldosterone receptor antagonist and a selective aldosterone synthase inhibitor.
  • Inhibitors of the renin-angiotensin-aldosterone axis are known in the art and commercially available.
  • the method further comprises administering to the subject an effective amount of a TGF- ⁇ antagonist.
  • TGF- ⁇ antagonists are known in the art and commercially available
  • the method further comprises administering to the subject an effective amount of another agent, such as an anti-fibrotic agent or anti- fibrogenic agent, such as tranilast.
  • another agent such as an anti-fibrotic agent or anti- fibrogenic agent, such as tranilast.
  • the method of preventing and/or treating atrial fibrillation further comprises a weight reduction intervention. Examples of weight loss interventions are known in the art.
  • the weight reduction intervention comprises administering to the subject an effective amount of a weight loss agent.
  • the method comprises identifying a subject suffering from or susceptible to atrial fibrillation and treating the subject with an endothelin receptor antagonist.
  • Methods for identifying a subject suffering from or susceptible to atrial fibrillation are known in the art.
  • the method comprises identifying a subject suffering from or susceptible to atrial fibrillation and having one or more characteristics.
  • the one or more characteristics comprise an increased body mass index; a body mass index of 25 kgm "2 or greater; a body mass index of 25 to 29.9 kgm "2 ; a body mass index of 30 kgm "2 or greater; overweight; obesity; an increased level of intra-myocardial lipid; an increased level of inter-myocardial lipid; an increased pericardial fat volume; an increased level of intra-atrial myocardial lipid; an increased level of inter-atrial myocardial lipid; reduced and/or slowed atrial conduction; reduced atrial conduction velocity; and increased atrial conduction heterogeneity; atrial fibrosis; atrial inflammation; elevated ethnicity-specific waist circumference, type II diabetes, glucose intolerance, fasting hyperinsulinemia, increased cardiac MRI-determined atrial fibrosis by delayed enhancement, elevated high sensitivity CRP, low adiponectin levels and diabetic dyslipidemia picture.
  • Certain embodiments of the present disclosure provide a method of treating a subject, the method comprising:
  • identifying a subject suffering from or susceptible to atrial fibrillation and administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • the method comprises identifying a subject suffering from or susceptible to atrial fibrillation and having one or more characteristics, and treating the subject with an endothelin receptor antagonist on the basis of the one or more characteristics.
  • the one or more characteristics comprise one or more of an increased body mass index; a body mass index of 25 kgm-2or greater; a body mass index of 25 to 29.9 kgm-2; a body mass index of 30 kgm "2 or greater; overweight; obesity; an increased level of intra-myocardial lipid; an increased level of inter- myocardial lipid; an increased pericardial fat volume; an increased level of intra-atrial myocardial lipid; an increased level of inter-atrial myocardial lipid; reduced and/or slowed atrial conduction; reduced atrial conduction velocity; and increased atrial conduction heterogeneity; atrial fibrosis, atrial inflammation, elevated ethnicity-specific waist circumference, type II diabetes, glucose intolerance, fasting hyperinsulinemia, increased cardiac MRI-determined atrial fibrosis by delayed enhancement, elevated high sensitivity CRP, low adiponectin levels and diabetic dyslipidemia picture.
  • Certain embodiments of the present disclosure provide a method of identifying a subject suffering from or susceptible to atrial fibrillation and suitable for treatment with an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method of identifying a subject suffering from or susceptible to atrial fibrillation and suitable for treatment with an endothelin receptor antagonist, the method comprising identifying a subject with one or more of the following characteristics: an increased body mass index; a body mass index of 25 kgm- 2 or greater; a body mass index of 25 to 29.9 kgm "2 ; a body mass index of 30 kgm "2 or greater; overweight; obesity; an increased level of intra-myocardial lipid; an increased level of inter-myocardial lipid; an increased pericardial fat/lipid volume; an increased level of intra-atrial myocardial lipid; an increased level of interatrial myocardial lipid; reduced and/or slowed atrial conduction; reduced atrial conduction velocity; increased atrial conduction heterogeneity, atrial fibrosis and atrial inflammation.
  • Endothelin receptor antagonists are as described herein.
  • the term "therapeutically effective amount” as used herein refers to that amount of an agent that is sufficient to effect prevention and/or treatment, when administered to a subject.
  • the therapeutically effective amount will vary depending upon a number of factors, including for example the specific activity of the agent being used, the severity of the disease, condition or state in the subject, the age, physical condition, existence of other disease states, and nutritional status of the subject. A suitable amount may be readily selected by a medical practitioner.
  • the antagonist is administered to the subject in an amount ranging from one of the following selected ranges: 1 ⁇ g/kg to 1000 mg/kg, 1 ⁇ g/kg to 100 mg/kg; 1 ⁇ g/kg to 10 mg/kg; 1 ⁇ g/kg to 1 mg/kg; 1 ⁇ g/kg to 100 ⁇ g/kg; 1 ⁇ g/kg to ⁇ g/kg; 10 ⁇ g/kg to 1000 mg/kg, 10 ⁇ g/kg to 100 mg/kg; 10 ⁇ g/kg to 10 mg/kg; 10 ⁇ g/kg to 1 mg/kg; 10 ⁇ g/kg to 100 ⁇ g/kg; 10 ⁇ g/kg to 1000 mg/kg, 100 ⁇ g/kg to 100 mg/kg; 100 ⁇ g/kg to 10 mg/kg; 100 ⁇ g/kg to 10 mg/kg; 100 ⁇ g/kg to 1 mg/kg; 1 mg/kg to 10 mg/kg; 10 mg/kg to 1000 mg/kg;
  • the antagonist is administered to the subject in an amount ranging from one of the following selected ranges: 0.1 mg/kg to 10 mg/kg, 0.5 mg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg. 0.1 mg/kg to 5 mg/kg, 0.5 mg/kg to 5 mg/kg, 1 mg/kg to 5 mg/kg, 0.1 mg/kg to 1 mg/kg or 0.5 mg/kg to 1 mg/kg.
  • the antagonist is administered to the subject in an amount ranging from one of the following selected ranges: 1 ⁇ g/kg/day to 1000 mg/kg/day, 1 ⁇ g/kg/day to 100 mg/kg/day; 1 ⁇ g/kg/day to 10 mg/kg/day; 1 ⁇ g/kg/day to 1 mg/kg/day; 1 ⁇ g/kg/day to 100 ⁇ g/kg/day; 1 ⁇ g/kg/day to 10 ⁇ g/kg/day; 10 ⁇ g/kg/day to 1000 mg/kg/day, 10 ⁇ g/kg/day to 100 mg/kg/day; 10 ⁇ g/kg/day to 10 mg/kg/day; 10 ⁇ g/kg/day to 1 mg/kg/day; 10 ⁇ g/kg/day to 100 ⁇ g/kg/day; 10 ⁇ g/kg/day to 1000 mg/kg/day, 100 ⁇ g/kg/day; 100 ⁇ g/kg/day; 10 ⁇ g/kg/day to 1000 mg/kg/day, 100
  • the antagonist is administered to the subject in an amount ranging from one of the following selected ranges: 0.1 mg/kg/day to 10 mg/kg/day, 0.5 mg/kg/day to 10 mg/kg/day, 1 mg/kg/day to 10 mg/kg/day, 5 mg/kg/day to 10 mg/kg/day, 0.1 mg/kg/day to 5 mg/kg/day, 0.5 mg/kg/day to 5 mg/kg/day, 1 mg/kg/day to 5 mg/kg/day, 0.1 mg/kg/day to 1 mg/kg/day, or 0.5 mg/kg/day to 1 mg/kg/day.
  • the antagonist may be administered to the subject in a suitable form.
  • administering or “providing” includes administering the antagonist, or administering a prodrug of the antagonist, or a derivative of the antagonist that will form an effective amount of the antagonist within the body of the subject.
  • routes of administration that are systemic (e.g., via injection such as intravenous injection, orally in a tablet, pill, capsule, or other dosage form useful for systemic administration of pharmaceuticals), and topical (e.g., creams, solutions, pastes, ointment, including solutions such as mouthwashes, for topical oral administration). Other routes of administration are contemplated.
  • the antagonist is administered orally. In certain embodiments, the antagonist is administered intravenously. In certain embodiments, the antagonist is administered via injection such as intravenous injection. In certain embodiments, the antagonist is administered by nebulized administration, by aerosolized administration or by being instilled into the lung. Other forms of administration are contemplated.
  • the antagonist may be administered alone or may be delivered in a mixture with other therapeutic agents and/or agents that, for example, enhance, stabilise or maintain the activity of the antagonist.
  • an administration vehicle e.g., pill, tablet, implant, injectable solution, etc.
  • the methods as described herein may also include combination therapy.
  • the subject may be treated or given another drug or treatment modality in conjunction with the antagonist as described herein. This combination therapy can be sequential therapy where the subject is treated first with one and then the other, or the two or more treatment modalities are given simultaneously.
  • Co-administering or “co-administration” refers to the administration of two or more therapeutic agents together at one time.
  • the two or more therapeutic agents can be co-formulated into a single dosage form or “combined dosage unit”, or formulated separately and subsequently combined into a combined dosage unit, typically for intravenous administration or oral administration.
  • the therapeutically effective dosage of an agent may vary depending upon the particular agent utilized, the mode of administration, the condition, and severity thereof, as well as the various physical factors related to the subject being treated.
  • the daily dosages are expected to vary with route of administration, and the nature of the antagonist administered and any other agents administered.
  • the methods comprise administering to the subject escalating doses of antagonist and/or repeated doses.
  • the antagonist is administered orally.
  • the antagonist is administered via injection, such as intravenous injection.
  • the antagonist is administered parenterally.
  • the antagonist is administered by direct introduction to the lungs, such as by aerosol administration, by nebulized administration, and by being instilled into the lung.
  • the antagonist is administered by implant.
  • the antagonist is administered by subcutaneous injection, intra- articularly, rectally, intranasally, intraocularly, vaginally, or transdermally. Methods of administration are known in the art.
  • Oral administration is a route of administration where a substance is taken through the mouth, and includes buccal, sublabial and sublingual administration, as well as enteral administration.
  • Typical forms for the oral administration of therapeutic agents includes the use of tablets or capsules.
  • the antagonist is administered as an immediate release formulation.
  • immediate release formulation is a formulation which is designed to quickly release a therapeutic agent in the body over a shortened period of time. Immediate release formulations are known in the art.
  • the antagonist is administered as a sustained release formulation.
  • sustained release formulation is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time. Sustained release formulations are known in the art.
  • the antagonist may be used in a pharmaceutical composition.
  • the antagonist may be used in a pharmaceutical composition for use in the methods of the present disclosure as described herein.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition
  • the pharmaceutical composition comprises a pharmaceutical composition for use to prevent and/or treat a condition as described herein. In certain embodiments, the pharmaceutical composition comprises a pharmaceutical composition for use to prevent and/or treat atrial fibrillation.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition when used to prevent and/or treat atrial fibrillation, the pharmaceutical composition comprising a therapeutically effective amount of an endothelin receptor antagonist.
  • Endothelin receptor antagonists are as described herein.
  • the pharmaceutical composition comprises a further agent as described herein.
  • a pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or suitable excipients.
  • the present disclosure provides use of an endothelin receptor antagonist in the preparation of a medicament for preventing and/or treating a condition as described herein.
  • the present disclosure provides use of an endothelin receptor antagonist in the preparation of a medicament for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition when used to prevent and/or treat atrial fibrillation, the pharmaceutical composition comprising a therapeutically effective amount of bosentan and/or a pharmaceutically acceptable salt and/or hydrate thereof.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition when used to prevent and/or treat atrial fibrillation, the pharmaceutical composition comprising a therapeutically effective amount of macitentan and/or a pharmaceutically acceptable salt and/or hydrate thereof.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition when used to prevent and/or treat atrial fibrillation, the pharmaceutical composition comprising a therapeutically effective amount of bosentan and/or macitentan, and/or a pharmaceutically acceptable salt and/or hydrate thereof.
  • the antagonist is present in a composition or medicament so as to provide an amount of antagonist for administration to the subject in an amount ranging from one of the following selected ranges: 1 ⁇ g/kg to 1000 mg/kg, 1 ⁇ g/kg to 100 mg/kg; 1 ⁇ g/kg to 10 mg/kg; 1 ⁇ g/kg to 1 mg/kg; 1 ⁇ g/kg to 100 ⁇ g/kg; 1 ⁇ g/kg to ⁇ g/kg; 10 ⁇ g/kg to 1000 mg/kg, 10 ⁇ g/kg to 100 mg/kg; 10 ⁇ g/kg to 10 mg/kg; 10 ⁇ g/kg to 1 mg/kg; 10 ⁇ g/kg to 100 ⁇ g/kg; 10 ⁇ g/kg to 1000 mg/kg, 100 ⁇ g/kg to 100 mg/kg; 100 ⁇ g/kg to 10 mg/kg; 100 ⁇ g/kg to 10 mg/kg; 100 ⁇ g/kg to 10 mg/kg; 100 ⁇ g/kg to 10 mg/kg; 100 ⁇ g/kg to 10
  • the antagonist is present in a composition or a medicament to provide an amount of antagonist for administration to the subject in an amount ranging from one of following selected ranges: 0.1 mg/kg to 10 mg/kg, 0.5 mg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg. 0.1 mg/kg to 5 mg/kg, 0.5 mg/kg to 5 mg/kg, 1 mg/kg to 5 mg/kg, 0.1 mg/kg to 1 mg/kg or 0.5 mg/kg to 1 mg/kg.
  • the antagonist is present in a composition or medicament so as to provide an amount of antagonist for administration to the subject in an amount ranging from one of the following selected ranges: 1 ⁇ g/kg/day to 1000 mg/kg/day, 1 ⁇ g/kg/day to 100 mg/kg/day; 1 ⁇ g/kg/day to 10 mg/kg/day; 1 ⁇ g/kg/day to 1 mg/kg/day; 1 ⁇ g/kg/day to 100 ⁇ g/kg/day; 1 ⁇ g/kg/day to 10 ⁇ g/kg/day; 10 ⁇ g/kg/day to 1000 mg/kg/day, 10 ⁇ g/kg/day to 100 mg/kg/day; 10 ⁇ g/kg/day to 10 mg/kg/day; 10 ⁇ g/kg/day to 1 mg/kg/day; 10 ⁇ g/kg/day to 100 ⁇ g/kg/day; 10 ⁇ g/kg/day to 1000 mg/kg/day, 100 ⁇ g/kg/day; 10 ⁇ g/kg/day to 1000 mg
  • the antagonist is present in a composition or medicament so as to provide an amount of antagonist for administration to the subject in an amount ranging from one of the following selected ranges: 0.1 mg/kg/day to 10 mg/kg/day, 0.5 mg/kg/day to 10 mg/kg/day, 1 mg/kg/day to 10 mg/kg/day, 5 mg/kg/day to 10 mg/kg/day, 0.1 mg/kg/day to 5 mg/kg/day, 0.5 mg/kg/day to 5 mg/kg/day, 1 mg/kg/day to 5 mg/kg/day, 0.1 mg/kg/day to 1 mg/kg/day, or 0.5 mg/kg/day to 1 mg/kg/day.
  • the composition or medicament is suitable for delivery to the subject by one or more of intravenous administration, intratracheal administration, by nebulized administration, by aerosolized administration, by instillation into the lung, by oral administration, by parenteral administration, by implant, by subcutaneous injection, intraarticularly, rectally, intranasally, intraocularly, vaginally, or transdermally.
  • Other routes of administration are contemplated.
  • the antagonist is provided with a pharmaceutically acceptable carrier suitable for administering the pharmaceutical composition to a subject.
  • a pharmaceutically acceptable carrier suitable for administering the pharmaceutical composition to a subject.
  • the carriers may be chosen based on various considerations including the route of administration, the agent(s) being delivered and the time course of delivery of the agents.
  • pharmaceutically acceptable carrier refers to a substantially inert solid, semi-solid or liquid filler, diluent, excipient, encapsulating material or formulation auxiliary of any type.
  • An example of a pharmaceutically acceptable carrier is physiological saline.
  • Other physiologically acceptable carriers and their formulations are known in the art.
  • materials which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as TWEEN 80; buffering agents such as magnesium hydroxide and aluminium hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such
  • the antagonist is provided with a pharmaceutically acceptable excipient.
  • suitable excipients for use with an antagonist in the form of a tablet include a tablet with a tablet core and a film coat as follows: tablet core - maize starch, pregelatinised starch, sodium starch glycollate, povidone, glycerol dibehenate, magnesium stearate; film coat - hypromellose, glycerol triacetate, talc, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), ethylcellulose. Other excipients are contemplated.
  • a tablet with the endothelin receptor antagonist bosentan may include an amount of the agent as a monohydrate and a tablet core with maize starch, pregelatinised starch, sodium starch glycollate, povidone, glycerol dibehenate, and magnesium stearate, and a film coat with hypromellose, glycerol triacetate, talc, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), and ethylcellulose.
  • the antagonist may be administered, or present in a pharmaceutical composition, as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to acid addition salts or metal complexes which are commonly used in the pharmaceutical industry.
  • acid addition salts include organic acids such as acetic, lactic, palmoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like.
  • Metal complexes include zinc, iron, and the like. Other pharmaceutically acceptable salts are contemplated.
  • the antagonist may be administered, or present in a pharmaceutical composition, as a pharmaceutically acceptable hydrate.
  • a hydrate is a solid adduct containing both the parent compound (e.g., the anhydrate of a drug or excipient) and water.
  • compositions or medicaments as described herein comprise other therapeutic agents and/or agents that enhance, stabilise or maintain the activity of the active.
  • Oral formulations as described herein may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
  • Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
  • pharmaceutically acceptable diluents including binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium
  • Surface modifying agents include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminium silicate, and triethanolamine.
  • Oral formulations may utilize standard delay or time-release formulations to alter the absorption of the peptides.
  • the oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed.
  • Oral formulation are known in the art and may be formulated by a skilled person. .
  • Formulations for the administration of aerosol forms are known in the art and may be formulated by a skilled person. .
  • the antagonist may also be administered parenterally (such as directly into the joint space) or intraperitoneally.
  • solutions or suspensions of agents in a non-ionised form or as a pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to prevent the growth of microorganisms.
  • Parenteral formulations are known in the art and may be formulated by a skilled person.
  • the antagonist may also be administered by injection.
  • Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersion medium containing, for example, water, isotonic saline, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • injectable formulations are known in the art and may be formulated by a skilled person.
  • the antagonist may also be administered intravenously.
  • Compositions suitable for intravenous administration are known in the art and may be formulated by a skilled person.
  • isotonic saline may be used in an intravenous composition containing an antagonist.
  • the antagonist may also be administered transdermally.
  • Transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using an antagonist as described herein, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • Transdermal administration may also be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient.
  • Transdermal formulations are known in art and may be formulated by a skilled person.
  • the antagonist may also be administered by way of a suppository.
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used. Suppository formulations are known in the art and may be formulated by a skilled person.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition comprising a therapeutically effective amount of bosentan and/or a pharmaceutically acceptable salt and/or hydrate thereof for use for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide bosentan and/or a pharmaceutically acceptable salt and/or hydrate thereof for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide use of bosentan and/or a pharmaceutically acceptable salt and/or hydrate thereof in the preparation of a medicament for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition comprising a therapeutically effective amount of macitentan and/or a pharmaceutically acceptable salt and/or hydrate thereof for use for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide macitentan and/or a pharmaceutically acceptable salt and/or hydrate thereof for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide use of macitentan and/or a pharmaceutically acceptable salt and/or hydrate thereof in the preparation of a medicament for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition comprising a therapeutically effective amount of an endothelin receptor antagonist and an inhibitor of the renin-angiotensin-aldosterone axis.
  • the inhibitor of the renin-angiotensin-aldosterone axis is selected from one or more of a renin inhibitor, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, an aldosterone receptor antagonist and a selective aldosterone synthase inhibitor.
  • Certain embodiments of the present disclosure provide a pharmaceutical composition comprising a therapeutically effective amount of an endothelin receptor antagonist and an anti-fibrotic agent and/or an anti-fibrogenic agent, such as tranilast.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating a condition as described herein, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or medicament as described herein.
  • Certain embodiments of the present disclosure provide a method of preventing and/or treating atrial fibrillation, the method comprising administering to the subject of a therapeutically effective amount of a pharmaceutical composition or medicament as described herein.
  • an endothelin receptor antagonist is used to reduce the frequency and/or duration of episodes of atrial fibrillation and/or reducing the severity and/or effects of atrial fibrillation, to prevent and/or treat atrial remodelling due to weight gain, to prevent and/or treat atrial remodelling due to obesity, to prevent and/or treat one or more of reduced and/or slowed atrial conduction, to prevent and/or treat reduced atrial conduction velocity, to prevent and/or treat increased atrial conduction heterogeneity, to modulate atrial rhythm, to prevent and/or treat atrial fibrosis, to prevent and/or treat atrial inflammation, to reduce the likelihood of stroke, to reduce the probability of a subject developing atrial fibrillation, making an arrhythmia in a subject more responsive to pharmacological intervention, and to reduce the dose of another agent for preventing and/
  • Certain embodiments of the present disclosure provide a method of reducing the frequency and/or duration of episodes of atrial fibrillation and/or reducing the severity and/or effects of atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method of reducing the frequency and/or duration of episodes of atrial fibrillation and/or reducing the severity and/or effects of atrial fibrillation in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial remodelling due to weight gain.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial remodelling due to weight gain in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced and/or slowed atrial conduction.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced and/or slowed atrial conduction in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist. [00184] Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced atrial conduction velocity.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced atrial conduction velocity in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced atrial conduction heterogeneity.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating reduced atrial conduction heterogeneity in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial fibrosis.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial inflammation.
  • Certain embodiments of the present disclosure provide a method for preventing and/or treating atrial inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method for reducing the likelihood of stroke in a subject suffering from or susceptible to atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method for reducing the likelihood of stroke in a subject suffering from or susceptible to atrial fibrillation, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method of reducing the probability of a subject developing atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method of reducing the probability of a subject developing atrial fibrillation, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist.
  • Certain embodiments of the present disclosure provide a method of reducing the dose of an agent administered for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method of reducing the dose of an agent administered to a subject for preventing and/or treating atrial fibrillation, the method comprising administering to the subject an effective amount of an endothelin receptor antagonist, and thereby reduce the dose of the agent for preventing and/or treating atrial fibrillation.
  • beta blockers such as metoprolol, atenolol, bisoprolol, nebivolol
  • non-dihydropyridine calcium channel blockers such as diltiazem or verapamil
  • cardiac glycosides such as digoxin
  • amiodarone diltiazem
  • amiodarone dronedarone
  • procainamide dofetilide
  • ibutilide propafenone, flecainide, and vernakalant.
  • an endothelin receptor antagonist may be used to reduce the dose of another agent for preventing and/or treating stroke associated with atrial fibrillation.
  • agents include warfarin, vitamin-K epoxide reductase inhibitors (such as tecarfarin), direct thrombin inhibitors (such as AZD-0837; dabigatran etexilate, dabigatran, ximelagatran; melagatran, and argatroban), Factor Xa inhibitors (such as apixaban, rivaroxaban, YM466, betrixaban, and edoxaban).
  • Certain embodiments of the present disclosure provide a product comprising an endothelin receptor antagonist.
  • a product comprising an endothelin receptor antagonist is provided for use in the methods as described herein.
  • Certain embodiments of the present disclosure provide a combination product comprising:
  • Certain embodiments of the present disclosure provide a combination product comprising:
  • the combination product may optionally further comprise an inhibitor of the renin-angiotensin-aldosterone axis and/or instructions for weight loss intervention.
  • kits for performing a method as described herein provide a kit for performing a method as described herein.
  • the kit may comprise one or more antagonists, agents, reagents, components, compositions, formulations, products and instructions, as described herein.
  • kits for preventing and/or treating atrial fibrillation comprising an endothelin receptor antagonist and optionally comprising one or more of instructions for administering the antagonist to a subject.
  • kits for administration to a subject contains the active agent (ie an endothlin receptor antagonist) in a form suitable for administration to the subject and one or more instructions, data sheets, and information on dosages, side effects, contraindications, and drug monitoring.
  • active agent ie an endothlin receptor antagonist
  • Certain embodiments of the present disclosure provide a method of identifying active agents.
  • methods may be used to identify an agent for preventing and/or treating atrial fibrillation, to identify an agent suitable to reduce the frequency and/or duration of episodes of atrial fibrillation and/or reducing the severity and/or effects of atrial fibrillation, to prevent and/or treat atrial remodelling due to weight gain, to prevent and/or treat atrial remodelling due to obesity, to prevent and/or treat one or more of reduced and/or slowed atrial conduction, to prevent and/or treat reduced atrial conduction velocity, to prevent and/or treat increased atrial conduction heterogeneity, to modulate atrial rhythm, to prevent and/or treat atrial fibrosis, to prevent and/or treat atrial inflammation, to reduce the likelihood of stroke, to reduce the probability of a subject developing atrial fibrillation, to identify an agent for making an arrhythmia in a subject more responsive to pharmacological intervention, and to reduce the dose of another agent needed for preventing and/or treating a condition as described herein, such as atrial
  • Certain embodiments of the present disclosure provide a method of identifying an agent for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method for identifying an agent for preventing and/or treating atrial fibrillation, the method comprising:
  • test agents include a drug, a small molecule, a protein, a polypeptide, a lipid, a carbohydrate, a nucleic acid, an oligonucleotide, a ribozyme, a biologic, an aptamer, a peptide, a cofactor, a ligand, a receptor, an enzyme, a kinase, a phosphatase, a cytokine, a growth factor, a metal ion, a chelate, an antisense nucleic acid, a siRNA, an antibody, an amino acid, aa ligand antagonist, a ligand mimetic, a dominant negative, a competitor, an inhibitor, and/or a suppressor.
  • Other types of agents are contemplated.
  • the test agent may be a candidate drug agent.
  • Determination of the ability of a test agent to antagonise endothelin receptor activity may be accomplished in an appropriate system.
  • the ability of the test agent to modulate endothelin receptor activity may be determined in one or more of an in vitro cell free system, an in vitro cell system, an animal model and a human subject.
  • Methods for assessing endothelin receptor activity in vitro and/or in vivo are known in the art, for example as described in Ihara et al. (1991) Biochem Biophys Res Commun. 178(1): 132-7, Miyata et al. (1992) J. Antibiotics 45:74-82, and Urade et al. (1992) FEBS Lett. 311(1): 12-6.
  • test agent may be tested in a suitable animal model.
  • animal models include a horse, a cow, a sheep, a goat, a pig, a dog, a cat, a primate, a monkey, a rabbit, a mouse and laboratory animals.
  • Determination of the ability of a test agent to modulate endothelin receptor activity may also be accomplished (independently or after testing in an animal model) in a human subject in an appropriate clinical trial. Examples of human subjects are as described herein.
  • test agent is as an agent for preventing and/or treating atrial fibrillation
  • Identification that the test agent is as an agent for preventing and/or treating atrial fibrillation may be accomplished using a method known in the art, for example using an animal model as described herein and/or in a human clinical trial.
  • the test agent comprises a derivative of a molecule that is an endothelin receptor antagonist as described herein.
  • the test agent comprises a derivative of A-186086, Ro- 61-6612 (tezosentan), SB-209670, SB-217242 (enrasentan), SB-217242, PD 142,893, PD 145,065, Ro 47-0203 (bosentan), R0 48-5033, macitentan, ACT-132577, A-127722, A- 147627 (atrasentan), A-216546, BQ-123, BQ-610, FR 139317, Lu- 135252 (darusentan), PD 151,242, PD 156,707, TBC-11251 (saitaxsentan), A-192621, BQ-788, RES-701-1, or Ro 46-8443.
  • the test agent comprises a derivative of bosentan.
  • the test agent comprises a derivative of macitentan.
  • Certain embodiments of the present disclosure provide a method of screening endothelin receptor antagonists for their ability to provide a therapeutic effect as described herein.
  • Certain embodiments of the present disclosure provide a method of screening endothelin receptor antagonists for their ability to provide a therapeutic effect for one or more of the following: to reduce the frequency and/or duration of episodes of atrial fibrillation and/or reducing the severity and/or effects of atrial fibrillation, to prevent and/or treat atrial remodelling due to weight gain, to prevent and/or treat atrial remodelling due to obesity, to prevent and/or treat one or more of reduced and/or slowed atrial conduction, to prevent and/or treat reduced atrial conduction velocity, to prevent and/or treat increased atrial conduction heterogeneity, to modulate atrial rhythm, to prevent and/or treat atrial fibrosis, to prevent and/or treat atrial inflammation, to reduce the likelihood of stroke, to reduce the probability of a subject developing atrial fibrillation, making an arrhythmia in a subject more responsive to pharmacological intervention, and to reduce the dose of another agent for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method of identifying an agent for preventing and/or treating of atrial fibrillation, the method comprising identifying an endothelin receptor antagonist, and/or a derivative thereof, as an agent for preventing and/or treating atrial fibrillation.
  • Certain embodiments of the present disclosure provide a method for identifying an agent for preventing and/or treating atrial fibrillation, the method comprising:
  • an endothelin receptor antagonist and/or a derivative thereof providing an endothelin receptor antagonist and/or a derivative thereof; and identifying the endothelin receptor antagonist and/or a derivative thereof as an agent for preventing and/or treating atrial fibrillation.
  • Endothelin receptor antagonists are as described herein.
  • the endothelin receptor antagonist to be screened/tested is a derivative of an endothelin receptor antagonist as described herein. In certain embodiments, the endothelin receptor antagonist to be screened/tested is a derivative of bosentan. In certain embodiments, the endothelin receptor antagonist to be screened/tested is a derivative of macitentan.
  • Certain embodiments of the present disclosure provide a method for identifying an agent for preventing and/or treating atrial fibrillation, the method comprising:
  • Certain embodiments of the present disclosure provide a method for identifying an agent for preventing and/or treating atrial fibrillation, the method comprising:
  • Certain embodiments of the present disclosure provide an agent identified by a method as described herein.
  • Certain embodiments of the present disclosure provide a method of treating a condition or disorder as described herein, the method comprising administering to the subject a therapeutically effective amount of an endothelin receptor antagonist and/or tranilast. Methods for administering agents to a subject are as described herein.
  • Subjects suitable for treatment are as described herein.
  • the subject is obese.
  • a method for preventing and/or treating atrial fibrillation in a subject comprising administering to the subject a therapeutically effective amount of tranilast, for example for preventing and/or treating atrial fibrillation in obese patients.
  • EXAMPLE 1 Progressive weight gain results in abnormal Endothelin Receptor expression, atrial fibrosis and the substrate for atrial fibrillation
  • a previously characterized ovine model of progressive weight gain utilizing an ad-libitum regimen of hay and high energy pellets, was used to induce progressive weight gain. This model has shown an approximate increase of 10kg monthly up to 36 weeks during which weight gain plateaued (terminal obesity).
  • 30 healthy animals were commenced on a high caloric diet of unlimited supply of energy-dense soybean oil (2.2%) and molasses fortified grain and maintenance hey with weekly weight measurement. Excess voluntary intake was predominantly of grass alfalfa silage and hay.
  • pellets were gradually introduced at 8% excess basal energy requirements, and rationed to >70% of total dry matter intake.
  • Cardiac MRI was performed to assess bi-atrial and bi -ventricular volumes and ejection fractions (Siemens Sonata 1.5 Telsa, MR Imaging Systems, Siemens Medical Solutions, Erlangen Germany) with 6 mm slices through the atria and 10 mm through the ventricles without inter-slice gaps. Animals were placed and secured in the dorsal recumbent position for scanning. Mechanical ventilation was maintained to facilitate ECG-gated image acquisition with periodic breath holding. All analyses were performed offline by blinded operators using proprietary software, QMass MR (Medis medical imaging systems, Leiden, Netherlands).
  • Chamber size, ventricular mass and pericardial fat volumes were measured using previously described methods (Wong CX, Abed HS, Molaee P, Nelson AJ, Brooks AG, Sharma G, et al. "Pericardial fat is associated with atrial fibrillation severity and ablation outcome” J Am Coll Cardiol. 2011 Apr 26;57(17): 1745-51)
  • MAP mean arterial pressure
  • LAP LA pressure
  • Electrophysiology study was performed under general anesthesia. Midline sternotomy was used to facilitate cardiac exposure, pericardial cradle formation and epicardial application of the multi-electrode plaques. Custom designed 128-electrode plaques with 5mm spacing were applied over the right and left atria spanning the appendage and free wall on each chamber as previously described (Lau DH, Mackenzie L, Kelly DJ, Psaltis PJ, Worthington M, Rajendram A, et al. "Short-term hypertension is associated with the development of atrial fibrillation substrate: a study in an ovine hypertensive model.” Heart Rhythm.
  • Atrial ERP was measured at twice the diastolic threshold (tissue capture threshold) at CL (SI) of 500, 400, 300 and 200ms from four sites (right atrial appendage [RAA], right atrial free wall [RAFW], left atrial appendage [LAA] and left atrial free wall [LAFW]). Eight basic (SI) stimuli were followed by a premature (S2) Stimulus in 10 ms decrements. Atrial ERP was defined as the longest S1-S2 interval not resulting in a propagated response. Each measurement was repeated three times. If there was greater than 10ms variability, two further measurements were taken and the total averaged.
  • SI tissue capture threshold
  • Conduction velocity was calculated from each site in both atria, during stable capture of SI pacing train and the shortest coupled S2 that captures the atria at each CL.
  • Activation maps were created using semi-automated custom designed software (Nucleus Medical, Sydney, Australia; Lau DH, Mackenzie L, Kelly DJ, Psaltis PJ, Worthington M, Rajendram A, et al. "Short-term hypertension is associated with the development of atrial fibrillation substrate: a study in an ovine hypertensive model.” Heart Rhythm. 2010 Mar; 7(3):396-404.
  • Each annotation was manually verified with the local activation time annotated to the peak of the largest amplitude deflection on bipolar electrograms.
  • Local conduction velocity was calculated from the local vectors within each triangle of electrodes. Mean CV was then derived for each map.
  • Conduction heterogeneity was assessed using established phase mapping techniques during SI and S2 pacing (Lammers WJ, Schalij MJ, Kirchhof CJ, Allessie MA. "Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias.” Am J Physiol. 1990 Oct;259 (4 Pt 2):H1254-63). In brief, the largest activation time difference between every four adjacent electrodes was first determined and divided by inter-electrode distances. The largest value at each site was then used to create a phase map, with values also displayed as histograms. Absolute conduction phase delay was calculated as the difference between the 5th and 95th percentile of the phase difference distribution. Conduction heterogeneity index is then determined by dividing the absolute phase delay by the median (P50).
  • Spontaneous and induced AF was recorded.
  • Spontaneous AF was defined as episodes of irregular atrial rhythm lasting >5sec occurring during the electrophysiology study in the absence of pacing after stable plaque application. Inducibility of AF was determined by ramp burst pacing commencing at CL 250 msec with progressive 5 ms decrements until AF was induced or there was no longer 1 : 1 conduction. This manoeuvre was repeated 5 times from each of the 4 per-determined pacing sites and undertaken after the completion of electrophysiologic evaluation. When AF was induced and persisted for >5sec, the episode and its duration was recorded. Electrical cardioversion was performed only when hemodynamic compromise occurred or if AF became sustained (>5mins). If cardioversion was required or arrhythmia sustained, no further electrophysiologic recordings were made.
  • Western blot analyses were performed with polyclonal antibodies to the ETA receptor (ab30536; 1 :500 dilution; Abeam) and ETB receptor (AF4496; 1 :300 dilution; R&D Systems), in addition to a goat anti-sheep secondary antibody.
  • a monoclonal antibody to the house keeping protein, a-tubulin (1 :8000 dilutiuon; Millipore Corp.) was used to demonstrate equivalent loading of protein samples.
  • Densitometry of ETA (63kDa) and ETB ( ⁇ 30kDa) receptor bands was performed using Bio-Rad GS710 Calibrated Imaging Densitometer and Quantity-OneTM software (Bio-Rad Laboratories). The density of each receptor was then corrected for corresponding a-tubulin and expressed as an absolute optical density (arbitrary units).
  • Figure 3 shows representative examples of activation maps during pacing from the LAA at baseline, overweight and obese animals. Note the progressive conduction slowing demonstrated by the progressive isochronal crowding and delayed activation. In addition, evolution of circuitous wavefront propagation is observed with increasing weight.
  • Figure 5 demonstrates the differences in CV at baseline, overweight and obese animals in terms of SI and S2.
  • the S2 coupling interval demonstrated slower conduction.
  • the extent of the conduction slowing with S2 compared to SI was greater (P ⁇ 0.001).
  • Figure 8 shows the changes in ET receptor subtype expression with increasing weight.
  • the bars represent the optical density of the western blot analysis of the ET receptor proteins and comparison internal control a-tubulin.
  • ETA panel A
  • ETB receptor expression panel B
  • ETA there was a 4-fold and 2-fold increase in receptor density, relative to baseline in the overweight and obese groups, respectively.
  • ETB there was a 5-fold and 4-fold increase in receptor density, relative to baseline in the overweight and obese groups, respectively.
  • EXAMPLE 2 The role of endothelin-receptor blockade in the prevention of the substrate for atrial fibrillation - an interventional study in an obese ovine model
  • Atrial fibrillation is the most common heart rhythm disorder in adults with its prevalence reaching epidemic proportions. Patients are often highly symptomatic and notable complications include stroke, cardiomyopathy and dementia. This has resulted in significant increase in hospitalization and cost to the community. Several factors have been implicated for the burgeoning frequency of AF. In addition to the classical risk factors such as aging and hypertension, obesity has more recently emerged as an independent association with both the development and progression of the disease. Obesity is also at epidemic levels and confers a 49% increased risk of developing AF, the risk increasing in parallel with increasing BMI.4
  • Bosentan is an orally active non-peptide endothelin receptor antagonist (ERA) of both receptor subtypes, with an affinity for ET-A. It is used clinically in the management of patients with primary pulmonary hypertension. With the progressive upregulation of ET receptors associated with weight gain as demonstrated in Example 1, we hypothesized that intervention to block this pathway would prevent the development of the substrate for AF. Therefore, the present study investigated the effect of ERA on the electrophysiological and structural atrial abnormalities associated with obesity in an ovine model.
  • ERA non-peptide endothelin receptor antagonist
  • Study Protocol [00295] The study design is shown in Figure 9. The obese model and intervention are described below. Animals underwent sequential percutaneous endocardial electrophysiological and electroanatomical evaluation at baseline, 30 and 60 weeks. In addition at each time point, cardiac MRI and DEXA scans were performed. To allow more detailed electrophysiological characterization, at the terminal study a high density plaque was utilized to perform epicardial mapping. Following the terminal study, tissue was harvested to characterize the degree of atrial fibrosis, inflammation and pro-fibrotic protein expression.
  • Electroanatomical maps were created in sinus rhythm using the Carto XP system (Biosense Webster, Diamond Bar, CA, USA) as described in Sanders P, Morton JB, Davidson NC, Spence SJ, Vohra JK, Sparks PB, Kalman JM. Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation Sep 23 2003; 108: 1461-1468. Both right and left atria were mapped using a 3.5-mm tip catheter ablation catheter (Navistar, Biosense Webster, Diamond Bar, CA, USA), with a minimum of 100 equally distributed points collected in each chamber.
  • atria was divided as follows: Septal right atrium (RA); High lateral RA; Low lateral RA; Posterior left atrium (LA); Lateral LA; and Inferior LA. The following were determined:
  • Signal fractionation defined as a signal greater than 50ms duration with at least four deflections
  • Atrial voltage Low voltage was defined as an area with three contiguous points with a bipolar voltage of ⁇ 0.5mV. Scar was an area with three contiguous points ⁇ 0.05mV.
  • Effective refractory period was measured at three times the tissue capture threshold at a pulse width of 2ms. This was performed from the following 8 sites: Septal RA; High lateral RA; Low lateral RA; Posterior LA; Lateral LA; Inferior LA; Proximal coronary sinus (CS); and Distal CS. Eight SI stimuli were delivered with SI cycle lengths of 400 and 200ms, with incremental S2 (5ms increments) commencing at a coupling interval of 100ms using a Micropace EPS 320 stimulator (Micropace, Surrey, Australia). The ERP was the longest S1-S2 interval without atrial capture. The mean of two attempts was recorded. An additional attempt was made if the difference between attempts was greater than 10ms.
  • Inducibility of AF was determined using a burst pacing protocol from the left atrial appendage, performed at the terminal study. Twenty impulses were delivered at the lowest cycle length with 1 : 1 atrial capture. An AF episode was defined as irregular atrial activity lasting >2 seconds. This protocol was repeated five times and the number of episodes and total duration were recorded. Sustained AF was defined as an episode lasting >20 minutes. In the event of sustained AF, no further testing was performed.
  • Conduction velocity was determined using activation maps using custom software, as described in Lau DH, Mackenzie L, Kelly DJ, et al. Hypertension and atrial fibrillation: evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model. Heart Rhythm Sep 2010; 7: 1282-1290. The peak of the largest amplitude deflection on each bipolar electrogram was automatically annotated and manually verified. Local conduction velocity was calculated for each point from triangulated local vectors, allowing subsequent calculation of mean velocity for each map.
  • Conduction heterogeneity was calculated using established phase mapping techniques integrated into the software, as described in Lau DH, Mackenzie L, Kelly DJ, et al. Hypertension and atrial fibrillation: evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model. Heart Rhythm Sep 2010; 7: 1282-1290. Absolute conduction phase delay was calculated by subtracting the 5th from the 95th percentile of the phase difference distribution (P5.95). Conduction heterogeneity index was derived from dividing P5.95 by the median (P 50 ).
  • Chamber volumes were measured using MRI (Siemens Sonata 1.5 Tesla, MR Imaging Systems, Siemens Medical Solutions, Erlangen, Germany). 6-mm slices were taken through the left atrium and ventricle. Images were taken using electrocardiogram- gating and periodic breath holding. Analyses were performed offline using CVI42 (Circle Cardiovascular Imaging Inc., Calgary, Canada).
  • Scans were acquired using a GE-Lunar Prodigy Vision DXA bone densitometer using Encore 13.60.033 software (GE-Lunar, Madison, WI, USA). Scans were performed using Total Body scan protocol in standard or thick mode to allow for variation in tissue depth.
  • TGF beta polyclonal antibodies to TGF beta (Sigma-Aldrich, St Louis, MO, USA, Cat #SAB4502954), Angiotensin II (Abbiotec, San Diego, CA, USA, Cat#251229), CTGF (Abbiotec, San Diego, CA, USA, Cat#251261), IL-6 (Abbiotec, San Diego, CA, USA, Cat#250717) and PDGF (Abeam, Cambridge, UK, Cat#ab61219) were used at dilutions of 1 :500, 1 :250, 1 :400, 1 :500 and 1 :6400, respectively, in a standard streptavidin-biotinylated immunoperoxidase technique.
  • Table 2 presents that changes in anthropometry, hemodynamic and cardiac structure in the two groups. Both groups increased in weight and body fat equally over 60 weeks. Left and right atrial pressures significantly increased with increasing weight, accompanied by a non-significant increase in systolic blood pressure and RV systolic pressure. There was no increase in chamber volumes with increasing weight and a trend to increased LV mass with weight gain. There was no significant difference in hemodynamics, chamber volumes, LV mass or function between treatment and control groups at any timepoint.
  • Figure 14 shows the AF burden at endpoint study.
  • Three (1 ERA treated, 2 control) animals had sustained AF (>20 mins) and were excluded from inducibility and duration analysis.
  • Endothelin receptor blockade prevented the development of atrial substrate in an obese ovine model. Treatment with bosentan during weight gain was associated with:
  • Intervention using an endothelin receptor blockade partially prevented the development of these abnormalities with reduced collagen staining on Masson's trichrome, reduced inflammation and increased connexin 43 expression associated with resolution of the conduction abnormalities associated with obesity. Importantly, it reduced the atrial vulnerability to AF. Notably, there was no significant difference in haemodynamic parameters between the groups, suggesting that endothelin receptor blockade in obesity may prevent atrial fibrosis directly, without an effect on either systemic or intracardiac pressures.
  • TGF- ⁇ transforming growth factor beta
  • CGF connective tissue growth factor
  • PDGF platelet derived growth factor
  • TGF- ⁇ is directly involved cardiac fibrosis. Fibroblasts exposed to TGF- ⁇ had a dose and time dependent increase in collagen production. In a canine heart failure model, atrial TGF- ⁇ was significantly upregulated in association with atrial fibrosis and blockade of TGF- ⁇ receptors resulted in reduced fibrosis and propensity to AF.
  • TGF- ⁇ antagonism may represent an alternative therapeutic option for obesity related atrial fibrosis, potentially in combination with ERA treatment.
  • CTGF has previously been found to be a regulator of the effects of endothelin- 1 in cardiac tissue. Our results showed a significant downregulation of CTGF with ERA treatment. This is strongly suggestive that CTGF acts downstream to endothelin in the fibrotic cascade.
  • PDGF is associated with atrial fibrosis and AF, as previously demonstrated by a pressure overloaded mouse model. Previous studies have also shown that administration of endothelin has no significant effect on PDGF in rat aortic tissue, but blockade of endothelin receptors reduced PDGF expression in the coronary arteries of rats undergoing cardiac transplantation. We have demonstrated reduced expression in the atrial tissue of animals treated with ERA than in controls. This offers new insight into the mechanisms of fibrosis in obesity, and is suggestive that PDGF acts downstream to endothelin.
  • IL-6 exposure is associated with cardiac fibrosis and hypertrophy in a mouse model and serum IL-6 has been shown to correlate with human AF more than several other inflammatory markers, including c-reactive protein.
  • ET-1 induces IL-6 release from human vascular smooth muscle cells.
  • ERA treatment was associated with reduction in IL-6 expression, suggestive of an antiinflammatory action.
  • Endothelin receptor pathways are important determinants of the substrate for AF in obesity. Blockade of endothelin receptors partially prevents the development of atrial substrate due to weight gain. This may represent a unique therapeutic target in AF associated with obesity.
  • a patent suffering from atrial fibrillation and suitable for treatment with an endothelin receptor antagonist may be identified by a suitably qualified medical practitioner.
  • bosentan or macitentan may be selected as a suitable endothelin receptor antagonist.
  • bosentan For administration of bosentan to the patient, film coated tablets or dispersible tables containing a suitable amount of bosentan may be used. Typical dosages of bosentan (as a monohydrate) in tablet form include 32 mg in a dispersible tablet, or 62.5 mg or 125 mg in film coated tablets. For example a suitable dose of bosentan for a human may be in the range from 30 to 125 mg per day.
  • Tablets may be taken orally at a suitable frequency, for example morning and evening, with or without food.
  • the frequency of administration may be selected by a qualified practitioner. For example, a dose of 62.5 mg to 125 mg may be administered twice daily. Suitable doses and frequency of administration for paediatric patients may be selected.
  • Excipients - Tablet core maize starch, pregelatinised starch, sodium starch glycollate, povidone, glycerol dibehenate, magnesium stearate.
  • Excipients - Film coat hypromellose, glycerol triacetate, talc, titanium dioxide (El 71), iron oxide yellow (E172), iron oxide red (E172), ethylcellulose.
  • niacitentan Another endothelin receptor antagonist is niacitentan.
  • a suitable dose of niacitentan for a human may be in the range from 1 to 30 mg per day, and administered by way of a film coated, immediate release tablet.
  • Effectiveness of the endothelin receptor antagonist as a treatment for atrial fibrillation may be assessed by a medical practitioner, and any modification to dose, frequency, efficacy, side effects, and co-morbidities assessed by the practitioner.
  • EXAMPLE 4 The role of endothelin-receptor blockade in the prevention of the substrate for atrial fibrillation - an interventional study in an obese ovine model
  • Endothelin-1 has been implicated in the pathogenesis of atrial fibrillation (AF), with upregulation of endothelin receptors in atrial tissue following weight gain. We hypothesised that direct inhibition with an endothelin receptor antagonist (ERA) would prevent the substrate for AF.
  • AF atrial fibrillation
  • ERA endothelin receptor antagonist
  • Obesity was induced in 20 sheep over 60 weeks using a high-calorie diet. Animals were randomized in equal groups to be: 1. treated with an ERA (bosentan 125mg bd) during this period; or 2. as controls. Endocardial EP studies and CMR were performed at 0, 30 and 60 weeks to determine conduction (CV), refractoriness (ERP), AF inducibility and cardiac structure. Following terminal epicardial EP studies, tissue was harvested to determine fibrosis and protein expression.
  • Intervention with an endothelin receptor antagonist prevented atrial electrical remodelling due to obesity.
  • EXAMPLE 5 Treatment with tranilast prevents atrial remodelling and AF in an obese ovine model
  • Tranilast N-(3,4-dimethoxycinnamoyl) anthranilic acid
  • Tranilast is an anti-inflammatory/anti-fibrotic compound, predominantly affecting TGF- ⁇ .
  • Obesity was induced in sixteen Merino Cross sheep using a diet of high fat pellets consisting of wheat, barley and canola seed. Excess voluntary intake was of grass alfalfa silage and hay. The pellets were gradually introduced at 8% excess basal energy requirements and rationed to 70% of the total dry matter intake. This was continued for the duration of the study, to allow gradual increase in weights in all animals over 64 weeks. Weights were recorded weekly and reported weights were those taken in a shorn and fasted state immediately prior to electrophysiological procedures. Plasma samples were collected at intervals to ensure stability of haematological and biochemical indices.
  • Electroanatomical maps were created in sinus rhythm using the Carto XP system (Biosense Webster, Diamond Bar, CA). Right and left atrial maps were recorded using a 3.5-mm tip catheter ablation catheter (Navistar, Biosense Webster, Diamond Bar, CA) with a minimum of 80 equally distributed points collected in each chamber. Endocardial contact was confirmed with a combination of electrogram stability, fluoroscopy and the Carto point stability criteria ( ⁇ 6mm stability in space, ⁇ 5ms in local activation time). Location, voltage and activation timing were recorded at each point. For analysis the atria was divided as follows: Septal right atrium (RA); High lateral RA; Low lateral RA; Posterior left atrium (LA); Lateral LA; and Inferior LA. The following parameters were determined:
  • the direction of conduction was determined from examination of isochronal maps. 3-5 pairs of points were taken in the direction of conduction, with velocity being calculated using the distance and timing as reported by the mapping system.
  • Low voltage was defined as an area with three contiguous points with a bipolar voltage of ⁇ 0.5mV.
  • Scar was an area with three contiguous points ⁇ 0.05mV.
  • Effective refractory periods were defined as an area with three contiguous points with a bipolar voltage of ⁇ 0.5mV.
  • Effective refractory period was measured at three times the tissue capture threshold at a pulse width of 2ms, using a Micropace EPS 320 stimulator (Micropace, Canterbury, Australia). This was performed from the following 8 sites: Septal RA; High lateral RA; Low lateral RA; Posterior LA; Lateral LA; Inferior LA; Proximal coronary sinus (CS); and Distal CS. Eight SI stimuli were delivered with SI cycle lengths of 400 and 200ms, with incremental S2 impulses (10ms increments), commencing at a coupling interval of 100ms. The ERP was the longest S1-S2 interval without atrial capture. The mean of two attempts was recorded. An additional attempt was made if the difference between attempts was greater than 10ms.
  • Inducibility of AF was determined using a burst pacing protocol from the left atrial appendage, performed at the terminal study. Twenty impulses were delivered at the lowest cycle length with 1 : 1 atrial capture. An episode was defined as irregular atrial activity lasting greater than or equal to 3 seconds. This protocol was repeated five times and the total duration was recorded. Sustained AF was defined as an episode lasting >10 minutes. In the event of sustained AF, no further testing was performed.
  • Conduction velocity was determined using activation maps analysed by custom software. The peak of the largest amplitude deflection on each bipolar electrogram was automatically annotated and manually verified. Local conduction velocity was calculated for each point from triangulated local vectors, allowing subsequent calculation of mean velocity for each map.
  • Conduction heterogeneity was calculated using established phase mapping techniques integrated into the software. Absolute conduction phase delay was calculated by subtracting the 5th from the 95th percentile of the phase difference distribution (P5- 95). Conduction heterogeneity index was derived from dividing P5-95 by the median (P50).
  • Chamber volumes were measured using MRI (Siemens Sonata 1.5 Tesla, MR Imaging Systems, Siemens Medical Solutions, Erlangen, Germany). 6-mm slices were taken through the left atrium and ventricle. Images were taken using electrocardiogram- gating and periodic breath holding. Analyses were performed offline using CVI42 (Circle Cardiovascular Imaging Inc., Calgary, Canada).
  • Scans were acquired using a GE-Lunar Prodigy Vision DXA bone densitometer using Encore 13.60.033 software (GE-Lunar, Madison, WI, USA). Scans were performed using Total Body scan protocol in standard or thick mode to allow for variation in tissue depth.
  • Table 4 presents the changes in anthropometry, hemodynamic and cardiac structure in the two groups. Both groups increased in weight equally over 64 weeks. Left and right atrial pressures significantly increased with increasing weight, accompanied by a non-significant increase in systolic blood pressure and RV systolic pressure. There was a non-significant increase in left atrial volume and left ventricular mass with increasing weight but no change in LV volume or function.
  • Two animals (1 tranilast treated, 1 control) had sustained AF (>10mins) during testing and were excluded from inducibility analysis.
  • TGF- ⁇ has long been recognised to be a central mediator of the fibrotic pathway. Its effect on infarcted, hypertrophic and cardiomyopathic ventricular tissue has been well characterised. More recent work has investigated its relationship with atrial fibrosis. Overexpression of TGF- ⁇ in a transgenic mouse model induced heterogeneous conduction in the left atrium, slowed conduction in the right atrium and increased susceptibility to AF. The cardiac profibrotic effects of TGF- ⁇ may be enhanced in atrial tissue. Previous studies have demonstrated TGF- ⁇ inhibition to have a disease- modifying role.
  • Tranilast was found, in conjunction with TGF- ⁇ mRNA downregulation, to reduce ventricular fibrosis in one study of hypertensive rats, 12 along with reduced mortality. It also prevented cardiac fibrosis in rats with diabetic cardiomyopathy, despite persistent hypertension and hyperglycaemia. Although initial human studies of its effect on coronary restenosis were encouraging, a subsequent multicentre, randomised trial reported no significant effect. Recent investigation has found that it reduces both atrial fibrosis and AF inducibility when used in a canine heart failure model. Our study is in keeping with these findings. Atrial remodelling was prevented by tranilast, as demonstrated by significantly improved endocardial and epicardial atrial conduction velocities in the treatment group. This corresponded with a reduced susceptibility to AF with tranilast treatment.
  • TGF- ⁇ receptors in atrial tissue during weight gain, in both the intermediate and long term. This was associated with both increased atrial fibrosis and an increased susceptibility to AF. TGF- ⁇ is expressed in adipose tissue and the degree of expression correlates with BMI in human subjects.
  • a recent study used an original atrial organo-culture model to demonstrated that TGF- ⁇ was secreted by human epicardial fat in small amounts and this was less than by subcutaneous fat.
  • Activin A a member of the TGF superfamily, was secreted by epicardial fat significantly more than in non-cardiac fat, and its presence induced TGF- ⁇ expression.
  • Tranilast Although the effect of Tranilast is predominantly on the TGF- ⁇ pathway, it has several other potentially anti-fibrotic and anti-inflammatory effects that may account for some of the observed effects. Macrophages exposed to tranilast demonstrated upregulation of the anti-inflammatory molecule heme oxygenase- 1, downregulation of the pro-inflammatory substance cyclooxygenase-2. This resulted in inhibition of prostaglandins, tumour necrosis factor and interleukin-lb and demonstrates the potential confounding effects of tranilast treatment. It also acts antagonistically on angiotensin II, inhibiting the its effects in vascular smooth muscle. In a hypertensive rat model, it inhibited PDGF as well as TGF- ⁇ induced collagen synthesis.

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  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
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Abstract

La présente divulgation concerne des méthodes et des produits destinés à prévenir et/ou à traiter la fibrillation auriculaire. Certains modes de réalisation selon la présente divulgation concernent une méthode destinée à prévenir et/ou à traiter la fibrillation auriculaire chez un sujet, la méthode comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un antagoniste du récepteur d'endothéline.
PCT/AU2017/050393 2016-04-29 2017-04-28 Méthode destinée à prévenir et/ou à traiter la fibrillation auriculaire Ceased WO2017185142A1 (fr)

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AU2016901586A AU2016901586A0 (en) 2016-04-29 Method for preventing and or treating atrial fibrillation
AU2016901586 2016-04-29

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WO2017185142A1 true WO2017185142A1 (fr) 2017-11-02

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US20200061061A1 (en) 2017-02-27 2020-02-27 Idorsia Pharmaceuticals Ltd Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
WO2023107640A1 (fr) * 2021-12-09 2023-06-15 Incarda Therapeutics, Inc. Thérapie inhalée pour arythmie cardiaque

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200061061A1 (en) 2017-02-27 2020-02-27 Idorsia Pharmaceuticals Ltd Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
US11174247B2 (en) 2017-02-27 2021-11-16 Idorsia Pharmaceuticals Ltd Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
US11680058B2 (en) 2017-02-27 2023-06-20 Idorsia Pharmaceuticals Ltd Crystalline forms of a 4-pyrimidinesulfamide derivative aprocitentan
US11787782B2 (en) 2017-02-27 2023-10-17 Idorsia Pharmaceuticals Ltd Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
US12297189B2 (en) 2017-02-27 2025-05-13 Idorsia Pharmaceuticals Ltd Crystalline forms of a 4-pyrimidinesulfamide derivative aprocitentan
WO2023107640A1 (fr) * 2021-12-09 2023-06-15 Incarda Therapeutics, Inc. Thérapie inhalée pour arythmie cardiaque

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