WO2025107042A1

WO2025107042A1 - Compositions and methods for the treatment or prevention of cardiovascular diseases or disorders

Info

Publication number: WO2025107042A1
Application number: PCT/AU2024/051253
Authority: WO
Inventors: David HAINSWORTH; Brad DILKES; James Mckenna
Original assignee: Algorae Pharmaceuticals Ltd
Current assignee: Algorae Pharmaceuticals Ltd
Priority date: 2023-11-22
Filing date: 2024-11-22
Publication date: 2025-05-30
Anticipated expiration: 2026-05-22

Abstract

The present disclosure relates generally to compositions and methods for the treatment or prevention of cardiovascular diseases or disorders (eg., cardiac inflammation, endothelial dysfunction, aberrant angiogenesis and cardiotoxicity)

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OR PREVENTION OF CARDIOVASCULAR DISEASES OR DISORDERS

Related Applications

[0001] This application claims priority from Australian Provisional Patent Application No. 2023903761 filed on 22 November 2023, the entire content of which is incorporated by reference.

Field

[0002] The present disclosure relates generally to compositions and methods for the treatment or prevention of cardiovascular diseases or disorders (e.g., cardiac inflammation, endothelial dysfunction, aberrant angiogenesis and cardiotoxicity).

Background

[0003] Cardiovascular diseases (CVDs) encompass a range of conditions affecting the heart and blood vessels, including coronary artery disease, heart failure, arrhythmias, hypertension, cardiac inflammation (e.g., myocarditis, pericarditis) and aberrant angiogenesis. CVDs are a leading cause of morbidity, mortality and healthcare expenditure, such that these diseases are collectively acknowledged to represent a significant global health burden.

[0004] Current standard of care for CVDs includes long-term or continuous use of multiple drugs, such as aspirin, statins, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. While these drugs, often coupled with lifestyle changes, can be effective in the management of the symptoms associated with CVDs, there are currently no curative treatments available. It is recognized that one of the limitations associated with the development of such curative treatments is due to the pathophysiology of CVDs, including the permanent physiological changes that occur during the development of CVDs. For example, in coronary heart disease, irreversible atherosclerosis restricts arterial blood flow. While further plaque deposition may be slowed or inhibited by therapeutic or lifestyle interventions, there is no way to reverse existing atherosclerosis. Moreover, long-term use or misuse of drugs for the treatment of CVDs can impact on a patient's quality of life, prolong hospital stays and increase the overall burden of healthcare expenditures. Therefore, there remains an urgent need for the development of new pharmacological approaches that are effective for the treatment or prevention of CVDs or disorders.

Summary

[0005] In an aspect of the present disclosure, there is provided a method for the treatment or prevention of a cardiovascular disease or disorder, the method comprising administering to a subject in need thereof a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0006] In another aspect of the present disclosure, there is provided a use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a betablocker or a pharmaceutically acceptable salt thereof; or (b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder.

[0007] In another aspect of the present disclosure, there is provided a use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0008] In another aspect of the present disclosure, there is provided a use of a betablocker or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with a cannabinoid or a pharmaceutically acceptable salt or derivative thereof.

[0009] In another aspect of the present disclosure, there is provided a use of an antiinflammatory agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with a cannabinoid or a pharmaceutically acceptable salt or derivative thereof.

[0010] In another aspect of the present disclosure, there is provided a kit comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a betablocker or a pharmaceutically acceptable salt thereof; or (b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0011] In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an antiinflammatory agent or a pharmaceutically acceptable salt thereof.

Brief Description of the Drawings

[0012] Embodiments of the disclosure are described herein, by way of non-limiting example only, with reference to the accompanying drawings.

[0013] Figure 1 shows that combinations of CBD + beta blocker can rescue HUVEC cells from the anti-proliferative effects of Angiotensin-II (Angll). (A-D) A series of graphical representations of fold change in cell proliferation (fold change from TO; y-axis) and time (hours; x-axis) following treatment with single agents (1 pM CBD, 1 pM beta blocker) or combinations of 1 pM CBD with (A) 1 pM metoprolol; (B) 1 pM carvedilol; (C) 1 pM bisoprolol and (D) 1 pM atenolol. Error bars representative of standard error of the mean, n = 3.

[0014] Figure 2 shows that synergistic combinations of CBD + beta blockers are effective for treating chemotherapy-induced cardiotoxicity. (A) A graphical representation of H9C2(2-1) cell viability (% relative viability; y-axis) following treatment with 0.1 pM doxorubicin together with 1 pM CBD + 1 pM bisoprolol, 1 pM CBD + 1 pM metoprolol and 1 pM CBD + 1 pM carvedilol (x-axis). (B) A graphical representation of H9C2(2-1) cell proliferation (proliferation from TO; y-axis) following treatment with 0.1 pM doxorubicin, 1 pM CBD, 1 pM carvedilol and 1 pM CBD + 1 pM carvedilol (x-axis). [0015] Figure 3 shows that the synergistic combination of CBD + metoprolol reduces expression of immunogenic modulators of cardiovascular disease following stimulation with TNF-a. (A-B) A graphical representation of (A) caspase- 1 ; or (B) VCAM expression relative to GAPDH (y-axis) following treatment with 10 ng/mL TNF-a together with 1 pM CBD, 1 pM metoprolol and a combination 1 pM CBD + 1 pM metoprolol (x-axis).

[0016] Figure 4 shows that the synergistic combination of CBD + bisoprolol reduces PDGF-mediated cell proliferation and AKT phosphorylation. (A) A graphical representation of cell proliferation (fold change from TO; y-axis) following treatment with PDGF alone or the combination of CBD + bisoprolol (x-axis). (B) A graphical representation of AKT phosphorylation (y-axis) as measured by immunoblot at 24 hours post-treatment with PDGF alone or the combination of CBD + bisoprolol (x-axis).

[0017] Figure 5 shows that the combination of CBD and dexamethasone potently reduces expression of immunogenic modulators of cardiovascular disease following exposure to lipopolysaccharide (LPS). A graphical representation of caspase- 1 expression relative to P-actin (y-axis) following exposure to LPS and treatment with CBD, dexamethasone, or a combination of CBD + dexamethasone (x-axis).

Detailed Description

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Any materials and method similar or equivalent to those described herein can be used to practice the present invention.

[0019] Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of the stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0020] The phrase "consisting of" means including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. The phrase "consisting essentially of" means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0021] As used herein the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound, as well as two or more compounds; reference to "an agent" includes one agent, as well as two or more agents; and so forth.

[0022] The term “about”, as used herein, means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%. Therefore, about 50% means in the range of 44%-55%. Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.9, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about”.

[0023] In an aspect disclosed herein, there is provided a method for the treatment or prevention of a cardiovascular disease or disorder, the method comprising administering to a subject in need thereof a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an antiinflammatory agent or a pharmaceutically acceptable salt thereof.

Cardiovascular diseases or disorders

[0024] The term “cardiovascular disease or disorder" as used herein refers to any disease or disorder associated with the heart and blood vessels.

[0025] In an embodiment, the cardiovascular disease or disorder is selected from the group consisting of hypertension, cardiac inflammation, endothelial dysfunction, aberrant angiogenesis and cardiotoxicity. [0026] The term "hypertension" as used herein refers to a condition characterized by persistent elevation in arterial pressure. The current definition of hypertension is systolic blood pressure values of 130 mm Hg or more and/or diastolic blood pressure of more than 80 mm Hg. Methods for the diagnosis of hypertension would be known to persons skilled in the art, illustrative examples of which include ambulatory blood pressure measurement.

[0027] The term "cardiac inflammation" as used herein refers to any inflammation of the heart tissue, including endocarditis (z.e., inflammation of the endocardium), myocarditis (z.e., inflammation of the heart muscle) and pericarditis (z.e., inflammation of the pericardium). These inflammatory conditions may be associated with infection (e.g., bacterial or viral infection), injury to the chest and cancer. Methods for the diagnosis of cardiac inflammation would be known to persons skilled in the art, illustrative examples of which include blood tests to identify infection, cardiac enzymes or antibody markers, electrocardiogram, imaging (e.g., x-ray and cardiac MRI), echocardiogram, cardiac catheterization and tissue biopsy.

[0028] The term "endothelial dysfunction" as used herein refers to a non-obstructive coronary artery disease (CAD) in which there are no arterial blockages, rather the large blood vessels on the heart's surface constrict instead of dilating. Methods for the diagnosis of endothelial dysfunction would be known to persons skilled in the art, illustrative examples of which include imaging, electrocardiogram and acetylcholine-induced dilation assessment.

[0029] The term "aberrant angiogenesis" as used herein refers to any condition associated with the abnormal stimulation or inhibition of angiogenesis. As used herein, the term "angiogenesis" refers to the process of formation of new vessels from the existing microvasculature. The mechanism of angiogenesis involves either sprouting from preexisting vessels or splitting due to intussusception.

[0030] In an embodiment, aberrant angiogenesis is associated (z.e., co-morbid) with another disease or condition selected from the group consisting of cancer, diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, arteriosclerosis and vasculopathies.

[0031] In an embodiment, the condition associated with aberrant angiogenesis is cancer. [0032] The term "cardiotoxicity" as used herein refers to an adverse effect associated with cancer treatment. Acute or subacute cardiotoxicity is characterized by sudden changes in ventricular polarization, changes in the chemotherapy interval, supraventricular and ventricular arrhythmias, acute coronary syndromes, pericarditis and myocarditis. Types of cardiotoxicity have been defined with reference to the pathophysiology associated with the use of specific drugs, for example, anthracyclines are capable of irreversible cardiac damage and are thus characterized as "type I" toxins, whereas drugs that have the potential to cause reversible cardiac damage, such as monoclonal antibodies, are characterized as "type II" toxins (see, e.g., Suter et al., 2013, European Heart Journal, 34: 1102-1111; and Ewer et al., 2005, Journal of Clinical Oncology, 23: 2900-2902). Methods for the diagnosis of cardiotoxicity would be known to persons skilled in the art, illustrative examples of which include measuring left ventricular ejection fraction (LVEF) using multi-gated acquisition (MUGA) scan, echocardiogram, two dimensional (2D) and three dimensional (3D) contrast imaging and cardiac MRI.

[0033] In an embodiment, the cardio toxicity is chemotherapy-induced cardiotoxicity.

[0034] The term "chemotherapy" as used herein refers to any agent that is administered to inhibit the growth of cells (e.g., cancer cells) or induce cell death. Suitable chemotherapies would be known to persons skilled in the art, illustrative examples of which include methotrexate, paclitaxel, ado -trastuzumab emtansine, fluorouracil, everolimus, anastrozole, panidronate disodium, exemestane, capecitabine, cyclophosphamide, docetaxel, doxorubicin, epirubicin, eribulin, everolimus, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, trastuzumab, ixabepilone, lapatinib, megestrol, pamidronate, pertuzumab, docetaxel, thiotepa, toremifene, vinblastine, and capecitabine.

[0035] In an embodiment, the cardiotoxicity is anthracycline-induced cardio toxicity.

[0036] The term "anthracy cline" as used herein refers to a class of chemotherapeutic agents that are derived from Streptomyces spp., which are used for the treatment of both solid and hematological malignancies (e.g., acute lymphocytic leukemia, acute myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, bladder cancer, breast cancer, ovarian cancer, osteogenic sarcoma, Ewing sarcoma, soft tissue sarcoma, thyroid cancer, neuroblastoma, Wilm's tumor and small cell lung cancer), including metastatic disease. [0037] In an embodiment, the anthracycline is selected from the group consisting of danorubicin, doxorubicin, epirubicin, mitoxantrone, valrubicin and idarubicin.

[0038] In an embodiment, the anthracycline-induced cardio toxicity is doxorubicin- induced cardiotoxicity.

Cannabinoids

[0039] The term "cannabinoid", as used herein, refers to a family of terpeno -phenolic compounds, of which more than 100 compounds are known to exist in nature. Cannabinoids will be known to persons skilled in the art, illustrative examples of which are provided in Table 1, below, including acidic and decarboxylated forms thereof.

[0040] Cannabinoids are synthesized in cannabis plants as carboxylic acids. While some decarboxylation may occur in the plant, decarboxylation typically occurs post-harvest and is increased by exposing plant material to heat (Sanchez and Verpoote, 2008, Plant Cell Physiology, 49(12): 1767-82). Decarboxylation is usually achieved by drying and/or heating the plant material. Persons skilled in the art would be familiar with methods by which decarboxylation of carboxylic acids can be promoted, illustrative examples of which include air-drying, combustion, vaporization, curing, heating and baking. The decarboxylated cannabinoid will typically bind to and/or stimulate, directly or indirectly, cannabinoid receptors including CB1 and/or CB2.

[0041] Cannabinoids may be extracted from any suitable plant parts including leaves, flowers or stems and may be produced by any suitable means known to those skilled in the art. For example, cannabinoid extracts may be produced by extraction with supercritical or subcritical CO2, or by volatilization of plant material with a heated gas. Illustrative examples of methods used to extract cannabinoids from plant material include the methods described in US Patent No. 10189762 and WO 2004/016277.

[0042] In an embodiment, the cannabinoid is a naturally-occurring molecule, e.g., produced by a plant.

[0043] In an embodiment, the cannabinoid is a synthetic cannabinoid, i.e., man-made, etc. [0044] In an embodiment, the cannabinoid is a non-naturally occurring molecule.

[0045] In an embodiment, the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabidivarin (CBDV) and cannabichromene (CBC).

[0046] In an embodiment, the cannabinoid is CBD.

[0047] The terms "cannabidiol" or "CBD" are used interchangeably herein to refer to a cannabinoid produced by plants of the genus Cannabis. CBD has antagonist activity on agonists of the CB 1 and CB2 receptors and acts as an inverse agonist of the CB1 and CB2 receptors. CBD is produced in cannabis plants as cannabidiolic acid (CBDA), which decarboxylates to CBD.

[0048] CBD is a chiral compound, although only the (-) CBD enantiomer is present in cannabis plants.

[0049] The term “enantiomer” as used herein refers to asymmetric molecules that can exist in two different isomeric forms, which have different configurations in space. An enantiomer can rotate plane-polarized light and is, therefore, optically active. Two different enantiomers of the same compound will rotate plane -polarized light in the opposite direction, thus the light can be rotated to the left or counterclockwise for a hypothetical observer (z.e., “levorotatory” or “-”) or it can be rotated to the right or clockwise (z.e., “dextrorotatory” or “+”).

[0050] In an embodiment, the CBD is a racemic mixture, comprising the (-) CBD enantiomer and the (+) CBD enantiomer.

[0051] In an embodiment, the CBD consists of the (-) CBD enantiomer.

[0052] The terms "cannabinol" or "CBN" are used interchangeably herein to refer to a cannabinoid produced by plants of the genus Cannabis. CBN acts as a low affinity partial agonist on the CB 1 and CB2 receptors. Unlike other cannabinoids, CBN is generated in cannabis plants through the oxidation of tetrahydrocannabinol (THC). [0053] The terms "cannabigerol" or "CBG" are used interchangeably herein to refer to a cannabinoid produced by plants of the genus Cannabis. CBG relatively weak agonistic effect on the CB1 and CB2 receptors. However, CBG acts as an AEA uptake inhibitor, a-2 adrenoceptor agonist and a moderate 5-HT1A antagonist. CBG is produced in cannabis plants as cannabigerolic acid (CBGA), which decarboxylates to CBG.

[0054] The terms "cannabidivarin" or "CBDV" are used interchangeably herein to refer to a cannabinoid produced by plants of the genus Cannabis. CBDV is produced in cannabis plants as cannabidivarinic acid (CBDVA), which decarboxylates to CBDV.

[0055] The terms "cannabichromene" or "CBC" are used interchangeably herein to refer to a cannabinoid produced by plants of the genus Cannabis. CBC is a CB2 receptor agonist, which can also recruit CB2 receptor regulatory mechanisms. CBC is produced in cannabis plants as cannabichromenic acid (CBCA), which decarboxylates to CBC.

[0056] The present disclosure contemplates the use of pharmaceutically acceptable salts of cannabinoids. Suitable pharmaceutically acceptable salts of cannabinoids would be known to persons skilled in the art, illustrative examples of which include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, which would be known to persons skilled in the art.

[0057] The present disclosure further contemplates the use of functional derivatives of cannabinoids. Suitable functional derivatives of cannabinoids would be known to persons skilled in the art, illustrative examples of which include 7-OH-CBD (7-hydroxycannabidiol), methoxylated CBD derivatives (e.g., CBDM, or 2-methoxycannabidiol and CBDD, or 2,6- dimethoxycannabidiol), cannabidiorcol (CBD-Ci) and the CBD derivatives described by Morales et al. (2017, Frontiers in Pharmacology, 8: 422).

[0058] Illustrative examples of the structures of cannabinoids or pharmaceutically acceptable salts or derivatives thereof are shown in Table 1. Beta-blockers

[0059] As used herein, the terms “beta-blocker” or "beta-adrenergic blocking agents" refers to a class of agents that inhibit the activity of adrenaline (epinephrine) and related hormones on beta receptors. Beta-blockers are use in the treatment of cardiovascular diseases or disorders, e.g., hypertension, angina, arrhythmia and heart failure. Suitable betablockers would be known to persons skilled in the art, illustrative examples of which include non-selective beta-blockers (e.g., carteolol, labetalol, nadolol, pindolol, propranolol, timolol and nadolol), selective beta-1 blockers (e.g., acebutolol, betaxolol, esmolol, penbutolol, sotalol, metoprolol, atenolol and bisoprolol), beta-blockers with vasodilator properties (e.g., carvedilol and labetalol), beta-blockers with intrinsic sympathomimetic activity (e.g., pindolol), beta-blockers with membrane-stabilizing activity (e.g., propranolol), cardioselective beta-blockers with nitric oxide-donating properties (e.g., nebivolol) and beta-blockers with lipophilic properties (e.g., acebutolol and metoprolol succinate), or pharmaceutically acceptable salts thereof. In an embodiment, the beta-blocker is a non- naturally occurring molecule, e.g., man-made, synthetic, etc.

[0060] In an embodiment, the beta-blocker is a non-selective beta-blocker.

[0061] In an embodiment, the beta-blocker is a selective beta-1 blocker.

[0062] In an embodiment, the beta-blocker is a beta-blocker with vasodilator properties.

[0063] In an embodiment, the beta-blocker is a cardioselective beta-blocker with nitric oxide-donating properties.

[0064] In an embodiment, the beta-blocker is selected from the group consisting of carteolol, labetalol, nadolol, pindolol, propranolol, timolol, cebutolol, betaxolol, esmolol, penbutolol, sotalol, metoprolol, atenolol, bisoprolol, carvedilol, nebivolol, acebutolol, and pharmaceutically acceptable salts of the foregoing.

[0065] In an embodiment, the beta-blocker is selected from the group consisting of propranolol, metoprolol, atenolol, carvedilol, nebivolol and bisoprolol.

[0066] In an embodiment, the beta-blocker is selected from the group consisting of metoprolol, atenolol, carvedilol and bisoprolol. [0067] In an embodiment, the beta-blocker is propranolol.

[0068] In an embodiment, the beta-blocker is metoprolol.

[0069] In an embodiment, the beta-blocker is atenolol.

[0070] In an embodiment, the beta-blocker is carvedilol.

[0071] In an embodiment, the beta-blocker is nebivolol.

[0072] In an embodiment, the beta-blocker is bisoprolol.

[0073] "Propranolol" is a non-selective beta-blocker with the structure of formula (I).

[0074] "Metoprolol" is a selective beta-1 blocker with the structure of formula (II).

[0075] Atenolol" is a selective beta-1 blocker with the structure of formula (III).

[0076] Carvedilol" is a beta-blocker with vasodilator properties with the structure of formula (IV).

[0077] Nebivolol" is a cardioselective beta-blocker with nitric oxide-donating properties with the structure of formula (V).

[0078] "Bisoprolol" is a selective beta-1 blocker with the structure of formula (VI).

Anti-inflammatory agents

[0079] As used herein, the term "anti-inflammatory agents" refers to a class of agents the decrease inflammation, reduce pain and decrease fever. Suitable anti-inflammatory agents would be known to persons skilled in the art, illustrative examples of which include steroids, specific anti-inflammatory cytokines and chemokines, autoimmune agents and nonsteroidal anti-inflammatory drug (NSAIDs). In an embodiment, the anti-inflammatory agent is a non-naturally occurring molecule, e.g., man-made, synthetic, etc.

[0080] In an embodiment, the anti-inflammatory agent is a non-steroidal antiinflammatory drug (NS AID).

[0081] Non-steroidal anti-inflammatory drugs" or "NSAIDs" are a class of agents that are used to treat pain, fever and other inflammatory processes. Suitable NSAIDs would be known to persons skilled in the art, illustrative examples of which include acetylated salicylates (e.g., aspirin), non-acetylated salicylates (e.g., difhmisal, salsalate), propionic acids (e.g., naproxen, ibuprofen, acetic acids (e.g., diclofenac, indomethacin), enolic acids (e.g., meloxicam, piroxicam), anthranilic acids (e.g., meclofenamate, mefenamic acid), naphthylalanine (e.g., nabumetone), and selective COX-2 inhibitors (e.g., celecoxib, etoricoxib). NSAIDs can also be categorized based on the selectivity of the drug, for example, "non- selective NSAIDs" include diclofenac, difhmisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; whereas the "COX-2 selective NSAIDs" include celecoxib, rofecoxib and valdecoxib.

[0082] In an embodiment, the NSAID is a non-selective NSAID.

[0083] In an embodiment, the NSAID is a COX-2 selective NSAID.

[0084] In an embodiment, the anti-inflammatory agent is a corticosteroid.

[0085] Corticosteroids" are a class of steroid hormones that are synthetic analogs of the natural steroid hormones produced by the adrenal cortex, including glucocorticoids and mineralocorticoids. Suitable corticosteroids would be known to persons skilled in the art, illustrative examples of which include dexamethasone, cortisone, hydrocortisone and prednisone.

[0086] In an embodiment, the corticosteroid is dexamethasone.

Methods for the treatment or prevention of a cardiovascular disease or disorder

[0087] The terms “treat”, "treating", “treatment” and the like are used interchangeably herein to mean relieving, reducing, alleviating, ameliorating or otherwise inhibiting the severity of one or more symptoms of a cardiovascular disease or disorder in a subject. The terms "prevent", "preventing", “prophylaxis”, “prophylactic”, “preventative” and the like are used interchangeably herein to mean preventing or delaying the onset of a cardiovascular disease or disorder, or reducing the risk of developing a cardiovascular disease or disorder.

[0088] It is to be understood that the terms “treat”, "treating", “treatment” and the like, as used herein, do not imply that a subject is treated until the cardiovascular disease or disorder has been eliminated or are no longer evident. Said treatment may also reduce the severity of the one or more symptoms of the cardiovascular disease or disorder.

[0089] The term “subject” as used herein refers to any mammal, including livestock and other farm animals (such as cattle, goats, sheep, horses, pigs and chickens), performance animals (such as racehorses), companion animals (such as cats and dogs), laboratory test animals and humans for whom treatment or prophylaxis of a cardiovascular disease or disorder is desired. In an embodiment, the subject is a human.

[0090] It is to be understood that the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof will be administered to the subject in need thereof in a therapeutically effective amount. As used herein, the term “therapeutically effective amount” typically refers to an amount of the cannabinoid and an amount of (a) the beta-blocker; or (b) the anti-inflammatory agent that is sufficient to affect one or more beneficial or desired therapeutic outcomes (e.g., reduction in blood pressure, decreased levels of inflammatory markers or mediators, e.g., VCAM-1, ICAM-1, E-selectin, P-selectin, L-selectin, B2-integrin, MCP-1, TNF-a, IL-ip, IL-6, Cox- 2, caspase- 1, and NFKB; reduction in oxidative stress, reduction in pro-angiogenic markers (e.g., VEGF, Akt, ERK), reduction in fibrosis or fibrotic lesions and improved endothelial cell function. Said beneficial or desired therapeutic outcomes may be quantified by using clinical instruments or experimental techniques known in the art.

[0091] Changes in the symptoms or severity of a cardiovascular disease or disorder as measured by any of the quantitative methods or clinical instruments described elsewhere herein may be expressed using any appropriate statistical measure to demonstrate the magnitude of the reduction in the symptoms or severity of a cardiovascular disease or disorder. In an embodiment, the methods disclosed herein reduce in the symptoms or severity of a cardiovascular disease or disorder by at least 10%, preferably at least 20%, preferably at least 30%, preferably at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, or more preferably at least 100% as compared to a subject with the same cardiovascular disease or disorder who has not been administered a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0092] In an embodiment, the methods disclosed herein slow the progression of a cardiovascular disease or disorder. [0093] In an embodiment, the methods disclosed herein slow the progression of a cardiovascular disease or disorder by >10% as compared to a subject with the same cardiovascular disease or disorder who has not been administered a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0094] In an embodiment, the methods disclosed herein prevent the development of a cardiovascular disease or disorder.

[0095] In an embodiment, the subject is administered from about 1 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg,

35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg,

47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg,

59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg,

71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg,

83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg,

95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day).

[0096] Thus, in an embodiment, the subject is administered from about 1 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day, preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably about 64 mg, preferably about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, preferably about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg, preferably about 84 mg, preferably about 85 mg, preferably about 86 mg, preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 110 mg, preferably about 120 mg, preferably about 130 mg, preferably about 140 mg, preferably about 150 mg, preferably about 160 mg, preferably about 170 mg, preferably about 180 mg, preferably about 190 mg, preferably about 200 mg, preferably about 210 mg, preferably about 220 mg, preferably about 230 mg, preferably about 240 mg, preferably about 250 mg, preferably about 260 mg, preferably about 270 mg, preferably about 280 mg, preferably about 290 mg, preferably about 300 mg, preferably about 310 mg, preferably about 320 mg, preferably about 330 mg, preferably about 340 mg, preferably about 350 mg, preferably about 360 mg, preferably about 370 mg, preferably about 380 mg, preferably about 390 mg, preferably about 400 mg, preferably about 410 mg, preferably about 420 mg, preferably about 430 mg, preferably about 440 mg, preferably about 450 mg, preferably about 460 mg, preferably about 470 mg, preferably about 480 mg, preferably about 490 mg, preferably about 500 mg, preferably about 510 mg, preferably about 520 mg, preferably about 530 mg, preferably about 540 mg, preferably about 550 mg, preferably about 560 mg, preferably about 570 mg, preferably about 580 mg, preferably about 590 mg, preferably about 600 mg, preferably about 610 mg, preferably about 620 mg, preferably about 630 mg, preferably about 640 mg, preferably about 650 mg, preferably about 660 mg, preferably about 670 mg, preferably about 680 mg, preferably about 690 mg, preferably about 700 mg, preferably about 710 mg, preferably about 720 mg, preferably about 730 mg, preferably about 740 mg, preferably about 750 mg, preferably about 760 mg, preferably about 770 mg, preferably about 780 mg, preferably about 790 mg, preferably about 800 mg, preferably about 810 mg, preferably about 820 mg, preferably about 830 mg, preferably about 840 mg, preferably about 850 mg, preferably about 860 mg, preferably about 870 mg, preferably about 880 mg, preferably about 890 mg, preferably about 900 mg, preferably about 910 mg, preferably about 920 mg, preferably about 930 mg, preferably about 940 mg, preferably about 950 mg, preferably about 960 mg, preferably about 970 mg, preferably about 980 mg, preferably about 990 mg, preferably about 1000 mg, preferably about 1100 mg, preferably about 1200 mg, preferably about 1300 mg, preferably about 1400 mg, or more preferably about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day.

[0097] In an embodiment, the subject is administered from about 20 mg to about 50 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day.

[0098] In an embodiment the subject is administered from about 50 mg to about 500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day.

[0099] In an embodiment, the subject is administered from about 500 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day. [0100] In an embodiment, the cannabinoid is selected from the group consisting of CBD, CBN, CBG, CBDV and CBC.

[0101] In an embodiment, the cannabinoid is CBD.

[0102] In an embodiment, the method comprises administering a cannabinoid or a pharmaceutically acceptable salt or derivative thereof and a beta-blocker or a pharmaceutically acceptable salt thereof to the subject.

[0103] In an embodiment, the subject is administered from about 0.1 mg to about 500 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per day (e.g., 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg,

30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg,

42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg,

54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg,

66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg,

78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg,

90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per day).

[0104] Thus, in an embodiment the subject is administered from about 0.1 mg to about 500 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per day, preferably about 0.1 mg, preferably about 0.2 mg, preferably about 0.3 mg, preferably about 0.4 mg, preferably about 0.5 mg, preferably about 0.6 mg, preferably about 0.7 mg, preferably about 0.8 mg, preferably about 0.9 mg. preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably about 64 mg, preferably about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, preferably about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg, preferably about 84 mg, preferably about 85 mg, preferably about 86 mg, preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 110 mg, preferably about 120 mg, preferably about 130 mg, preferably about 140 mg, preferably about 150 mg, preferably about 160 mg, preferably about 170 mg, preferably about 180 mg, preferably about 190 mg, preferably about 200 mg, preferably about 210 mg, preferably about 220 mg, preferably about 230 mg, preferably about 240 mg, preferably about 250 mg, preferably about 260 mg, preferably about 270 mg, preferably about 280 mg, preferably about 290 mg, preferably about 300 mg, preferably about 310 mg, preferably about 320 mg, preferably about 330 mg, preferably about 340 mg, preferably about 350 mg, preferably about 360 mg, preferably about 370 mg, preferably about 380 mg, preferably about 390 mg, preferably about 400 mg, preferably about 410 mg, preferably about 420 mg, preferably about 430 mg, preferably about 440 mg, preferably about 450 mg, preferably about 460 mg, preferably about 470 mg, preferably about 480 mg, preferably about 490 mg, or more preferably about 500 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per day.

[0105] In an embodiment, the subject is administered from about 10 mg to about 400 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per day.

[0106] In an embodiment, the subject is administered from about 1 mg to about 100 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per day.

[0107] In an embodiment, the subject is administered from about 0.1 mg to about 50 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per day.

[0108] In an embodiment, the beta-blocker is selected from the group consisting of propranolol, metoprolol, carvedilol, atenolol, nebivolol and bisoprolol.

[0109] In an embodiment, the beta-blocker is selected from the group consisting of metoprolol, carvedilol, atenolol, and bisoprolol.

[0110] In an embodiment, the beta-blocker is propranolol.

[0111] In an embodiment, the beta-blocker is metoprolol.

[0112] In an embodiment, the beta-blocker is carvedilol.

[0113] In an embodiment, the beta-blocker is atenolol.

[0114] In an embodiment, the beta-blocker is nebivolol.

[0115] In an embodiment, the beta-blocker is bisoprolol.

[0116] In an embodiment, the method comprises administering a cannabinoid or a pharmaceutically acceptable salt or derivative thereof and an anti-inflammatory agent or a pharmaceutically acceptable salt thereof to the subject.

[0117] In an embodiment, the subject is administered from about 100 mg to about 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per day (e.g. , 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg,

2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg,

3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg.

4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, or 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per day).

[0118] Thus, in an embodiment the subject is administered from about 0.1 mg to about 500 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per day, preferably about 100 mg, preferably about 110 mg, preferably about 120 mg, preferably about 130 mg, preferably about 140 mg, preferably about 150 mg, preferably about 160 mg, preferably about 170 mg, preferably about 180 mg, preferably about 190 mg, preferably about 200 mg, preferably about 210 mg, preferably about 220 mg, preferably about 230 mg, preferably about 240 mg, preferably about 250 mg, preferably about 260 mg, preferably about 270 mg, preferably about 280 mg, preferably about 290 mg, preferably about 300 mg, preferably about 310 mg, preferably about 320 mg, preferably about 330 mg, preferably about 340 mg, preferably about 350 mg, preferably about 360 mg, preferably about 370 mg, preferably about 380 mg, preferably about 390 mg, preferably about 400 mg, preferably about 410 mg, preferably about 420 mg, preferably about 430 mg, preferably about 440 mg, preferably about 450 mg, preferably about 460 mg, preferably about 470 mg, preferably about 480 mg, preferably about 490 mg, preferably about 500 mg, preferably about 510 mg, preferably about 520 mg, preferably about 530 mg, preferably about 540 mg, preferably about 550 mg, preferably about 560 mg, preferably about 570 mg, preferably about 580 mg, preferably about 590 mg, preferably about 600 mg, preferably about 610 mg, preferably about 620 mg, preferably about 630 mg, preferably about 640 mg, preferably about 650 mg, preferably about 660 mg, preferably about 670 mg, preferably about 680 mg, preferably about 690 mg, preferably about 700 mg, preferably about 710 mg, preferably about 720 mg, preferably about 730 mg, preferably about 740 mg, preferably about 750 mg, preferably about 760 mg, preferably about 770 mg, preferably about 780 mg, preferably about 790 mg, preferably about 800 mg, preferably about 810 mg, preferably about 820 mg, preferably about 830 mg, preferably about 840 mg, preferably about 850 mg, preferably about 860 mg, preferably about 870 mg, preferably about 880 mg, preferably about 890 mg, preferably about 900 mg, preferably about 910 mg, preferably about 920 mg, preferably about 930 mg, preferably about 940 mg, preferably about 950 mg, preferably about 960 mg, preferably about 970 mg, preferably about 980 mg, preferably about 990 mg, preferably about 1000 mg, preferably about 1100 mg, preferably about 1200 mg, preferably about 1300 mg, preferably about 1400 mg, preferably about 1500 mg, preferably about 1600 mg, preferably about 1700 mg, preferably about 1800 mg, preferably about 1900 mg, preferably about 2000 mg, preferably about 2100 mg, preferably about 2200 mg, preferably about 2300 mg, preferably about 2400 mg, preferably about 2500 mg, preferably about 2600 mg, preferably about 2700 mg, preferably about 2800 mg, preferably about 2900 mg, preferably about 3000 mg, preferably about 3100 mg, preferably about 3200 mg, preferably about 3300 mg, preferably about 3400 mg, preferably about 3500 mg, preferably about 3600 mg, preferably about 3700 mg, preferably about 3800 mg, preferably about 3900 mg, preferably about 4000 mg. 4100 mg, preferably about 4200 mg, preferably about 4300 mg, preferably about 4400 mg, preferably about 4500 mg, preferably about 4600 mg, preferably about 4700 mg, preferably about 4800 mg, preferably about 4900 mg, or more preferably about 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per day.

[0119] In an embodiment, the anti-inflammatory agent is selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID) and a corticosteroid.

[0120] In an embodiment, the subject is administered the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and/or (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof as escalating daily doses comprising a first daily dose and a second daily dose, wherein the amount of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and/or (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof administered as the second daily dose is greater than the effective amount of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and/or (a) the betablocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof administered as the first daily dose.

[0121] The amount and frequency of administration of escalating daily doses may be determined in accordance with methods of “empiric therapy” or “empirical administration.” The person skilled in the art would appreciate that empirical administration of escalating daily doses (e.g., first daily dose, second daily dose, third daily dose, fourth daily dose, fifth daily dose, and so on) will be determined by an appropriate medically trained professional overseeing the methods of treatment or prevention of a cardiovascular disease or disorder, as disclosed herein.

[0122] The cannabinoid or a pharmaceutically acceptable salt or derivative thereof and

(a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the antiinflammatory agent or a pharmaceutically acceptable salt thereof disclosed herein may be administered to the subject by any suitable route that allows for delivery of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof to the subject at a therapeutically effective amount, as described herein. Suitable routes of administration will be known to persons skilled in the art, illustrative examples of which include enteral routes of administration (e.g., oral and rectal), parenteral routes of administration, typically by injection or microinjection (e.g., intramuscular, subcutaneous, intravenous, epidural, intra-articular, intraperitoneal, intracistemal or intrathecal) and topical (transdermal or trans mucosal) routes of administration (e.g., buccal, sublingual, vaginal, intranasal or by inhalation).

[0123] In an embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or

(b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof are orally administered to the subject. [0124] Suitable dosage forms for oral administration would be known to persons skilled in the art, illustrative examples of which include tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, liquids, syrups or elixirs.

[0125] In an embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof is in liquid, oil, tablet or capsule form. In another embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof is in liquid form.

[0126] In an embodiment, the beta-blocker or a pharmaceutically acceptable salt thereof is in liquid, oil, tablet or capsule form. In another embodiment, the beta-blocker or a pharmaceutically acceptable salt thereof is in tablet or capsule form.

[0127] In an embodiment, the anti-inflammatory agent or a pharmaceutically acceptable salt thereof is in liquid, oil, tablet or capsule form. In another embodiment, the antiinflammatory agent or a pharmaceutically acceptable salt thereof is in tablet or capsule form.

[0128] It is further contemplated herein that the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof may be co-administered with one or more other appropriate therapeutic agents.

[0129] In accordance with the methods disclosed herein, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof may be co-administered as separate compositions.

[0130] In an embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof are administered sequentially.

[0131] By “sequential” administration it is meant there is an interval between the administration of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the antiinflammatory agent or a pharmaceutically acceptable salt thereof. The interval between sequential administrations may be seconds, minutes, hours or days. In a preferred embodiment, the interval between sequential administrations of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof is less than an hour, preferably less than 30 minutes, most preferably less than 1 minute. Sequential administration may be in any order (z.e., administration of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof prior to the administration of (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof, or administration of (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof prior to the administration of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof).

[0132] In another embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0133] By “simultaneous” administration it is meant that the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof are administered at the same time. In accordance with the methods disclosed herein, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof may be administered simultaneously as two separate compositions or dosage forms. Alternatively, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the betablocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof are administered simultaneously as a single composition or dosage form.

[0134] In some embodiments, periodic re-administration of the active agents (either sequentially or simultaneously) may be required to achieve a desirable therapeutic effect. The exact amounts and rates of administration of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof will depend on a number of factors, examples of which are described elsewhere herein, such as the subject’s age, body weight, general health, sex and dietary requirements, as well as any drugs or agents used in combination or coincidental with the administration of the composition. Where multiple divided doses are required, these may be administered hourly, daily, weekly, monthly or at other suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation.

[0135] In an embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof is administered as a single daily dose with (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0136] In other embodiments disclosed herein, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof are formulated as separate unit dosage forms for administration. The unit dosage form may be suitable for oral administration, e.g., solution, capsule or tablet form. Those skilled in the art will appreciate that unit dosage forms comprising the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof need not be of the same type. Thus, methods of the present disclosure contemplate the administration of, for example, the cannabinoid in oil form and the beta-blocker or anti-inflammatory agent in capsule or tablet form.

[0137] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof to the subject.

[0138] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof to the subject. [0139] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof to the subject.

[0140] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof to the subject.

[0141] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof to the subject.

[0142] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0143] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof to the subject.

[0144] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0145] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof to the subject.

[0146] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof to the subject.

[0147] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof to the subject. [0148] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0149] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof to the subject.

[0150] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0151] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof to the subject.

[0152] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof to the subject.

[0153] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof to the subject.

[0154] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0155] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof to the subject.

[0156] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof to the subject. [0157] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof to the subject.

[0158] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof to the subject.

[0159] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof to the subject.

[0160] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0161] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof to the subject.

[0162] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0163] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof to the subject.

[0164] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof to the subject.

[0165] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof to the subject. [0166] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof to the subject.

[0167] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof to the subject.

[0168] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof to the subject.

[0169] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof to the subject.

[0170] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof to the subject.

[0171] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof to the subject.

[0172] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof to the subject.

[0173] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof to the subject.

[0174] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof to the subject. [0175] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof to the subject.

[0176] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof to the subject.

[0177] In an embodiment, the method comprises administering CBD or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof to the subject.

[0178] In an embodiment, the method comprises administering CBN or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof to the subject.

[0179] In an embodiment, the method comprises administering CBG or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof to the subject.

[0180] In an embodiment, the method comprises administering CBDV or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof to the subject.

[0181] In an embodiment, the method comprises administering CBC or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof to the subject.

[0182] In an aspect disclosed herein, there is provided a use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder.

[0183] In an aspect disclosed herein, there is provided a use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof and a beta-blocker or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder.

[0184] In another aspect disclosed herein, there is provided a use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with a beta-blocker or a pharmaceutically acceptable salt thereof.

[0185] In another aspect disclosed herein, there is provided a use of a beta-blocker or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with a cannabinoid or a pharmaceutically acceptable salt or derivative thereof.

[0186] In an aspect disclosed herein, there is provided a use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof and an anti-inflammatory agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder.

[0187] In another aspect disclosed herein, there is provided a use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0188] In another aspect disclosed herein, there is provided a use of an antiinflammatory agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with a cannabinoid or a pharmaceutically acceptable salt or derivative thereof.

Pharmaceutical compositions [0189] In an aspect disclosed herein, there is provided a pharmaceutical composition comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a beta-blocker or a pharmaceutically acceptable salt or derivative thereof; or (b) an antiinflammatory agent or a pharmaceutically acceptable salt thereof.

[0190] In an aspect disclosed herein, there is provided a pharmaceutical composition comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and a beta-blocker or a pharmaceutically acceptable salt or derivative thereof.

[0191] In an aspect disclosed herein, there is provided a pharmaceutical composition comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0192] In an embodiment, the composition comprises from about 1 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg,

95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose). [0193] Thus, in an embodiment, the pharmaceutical composition comprises from about 1 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose, preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably about 64 mg, preferably about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, preferably about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg, preferably about 84 mg, preferably about 85 mg, preferably about 86 mg, preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 110 mg, preferably about 120 mg, preferably about 130 mg, preferably about 140 mg, preferably about 150 mg, preferably about 160 mg, preferably about 170 mg, preferably about 180 mg, preferably about 190 mg, preferably about 200 mg, preferably about 210 mg, preferably about 220 mg, preferably about 230 mg, preferably about 240 mg, preferably about 250 mg, preferably about 260 mg, preferably about 270 mg, preferably about 280 mg, preferably about 290 mg, preferably about 300 mg, preferably about 310 mg, preferably about 320 mg, preferably about 330 mg, preferably about 340 mg, preferably about 350 mg, preferably about 360 mg, preferably about 370 mg, preferably about 380 mg, preferably about 390 mg, preferably about 400 mg, preferably about 410 mg, preferably about 420 mg, preferably about 430 mg, preferably about 440 mg, preferably about 450 mg, preferably about 460 mg, preferably about 470 mg, preferably about 480 mg, preferably about 490 mg, preferably about 500 mg, preferably about 510 mg, preferably about 520 mg, preferably about 530 mg, preferably about 540 mg, preferably about 550 mg, preferably about 560 mg, preferably about 570 mg, preferably about 580 mg, preferably about 590 mg, preferably about 600 mg, preferably about 610 mg, preferably about 620 mg, preferably about 630 mg, preferably about 640 mg, preferably about 650 mg, preferably about 660 mg, preferably about 670 mg, preferably about 680 mg, preferably about 690 mg, preferably about 700 mg, preferably about 710 mg, preferably about 720 mg, preferably about 730 mg, preferably about 740 mg, preferably about 750 mg, preferably about 760 mg, preferably about 770 mg, preferably about 780 mg, preferably about 790 mg, preferably about 800 mg, preferably about 810 mg, preferably about 820 mg, preferably about 830 mg, preferably about 840 mg, preferably about 850 mg, preferably about 860 mg, preferably about 870 mg, preferably about 880 mg, preferably about 890 mg, preferably about 900 mg, preferably about 910 mg, preferably about 920 mg, preferably about 930 mg, preferably about 940 mg, preferably about 950 mg, preferably about 960 mg, preferably about 970 mg, preferably about 980 mg, preferably about 990 mg, preferably about 1000 mg, preferably about 1100 mg, preferably about 1200 mg, preferably about 1300 mg, preferably about 1400 mg, or more preferably about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose.

[0194] In an embodiment, the pharmaceutical composition comprises from about 20 mg to about 50 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose. [0195] In an embodiment, the pharmaceutical composition comprises from about 50 mg to about 500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose.

[0196] In an embodiment, the pharmaceutical composition comprises from about 500 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose.

[0197] In an embodiment, the pharmaceutical composition comprises from about 0.1 mg to about 500 mg of the beta-blocker per dose (e.g., 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg of the beta-blocker per dose).

[0198] Thus, in an embodiment, the pharmaceutical composition comprises from about 0.1 mg to about 500 mg of the beta-blocker per dose, preferably about 0.1 mg, preferably about 0.2 mg, preferably about 0.3 mg, preferably about 0.4 mg, preferably about 0.5 mg, preferably about 0.6 mg, preferably about 0.7 mg, preferably about 0.8 mg, preferably about 0.9 mg. preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably about 64 mg, preferably about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, preferably about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg, preferably about 84 mg, preferably about 85 mg, preferably about 86 mg, preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 110 mg, preferably about 120 mg, preferably about 130 mg, preferably about 140 mg, preferably about 150 mg, preferably about 160 mg, preferably about 170 mg, preferably about 180 mg, preferably about 190 mg, preferably about 200 mg, preferably about 210 mg, preferably about 220 mg, preferably about 230 mg, preferably about 240 mg, preferably about 250 mg, preferably about 260 mg, preferably about 270 mg, preferably about 280 mg, preferably about 290 mg, preferably about 300 mg, preferably about 310 mg, preferably about 320 mg, preferably about 330 mg, preferably about 340 mg, preferably about 350 mg, preferably about 360 mg, preferably about 370 mg, preferably about 380 mg, preferably about 390 mg, preferably about 400 mg, preferably about 410 mg, preferably about 420 mg, preferably about 430 mg, preferably about 440 mg, preferably about 450 mg, preferably about 460 mg, preferably about 470 mg, preferably about 480 mg, preferably about 490 mg, or more preferably about 500 mg of the beta-blocker per dose.

[0199] In an embodiment, the pharmaceutical composition comprises from about 10 mg to about 400 mg of the beta-blocker per dose.

[0200] In an embodiment, the pharmaceutical composition comprises from about 1 mg to about 100 mg of the beta-blocker per dose.

[0201] In an embodiment, the pharmaceutical composition comprises from about 0.1 mg to about 50 mg of the beta-blocker per dose.

[0202] In an embodiment, the pharmaceutical composition comprises from about 100 mg to about 5000 mg of the anti-inflammatory agent or pharmaceutically acceptable salt thereof per dose (e.g., 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg. 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, or 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per dose)

[0203] Thus, in an embodiment, the pharmaceutical composition comprises from about 0.1 mg to about 500 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per dose, preferably about 100 mg, preferably about 110 mg, preferably about 120 mg, preferably about 130 mg, preferably about 140 mg, preferably about 150 mg, preferably about 160 mg, preferably about 170 mg, preferably about 180 mg, preferably about 190 mg, preferably about 200 mg, preferably about 210 mg, preferably about 220 mg, preferably about 230 mg, preferably about 240 mg, preferably about 250 mg, preferably about 260 mg, preferably about 270 mg, preferably about 280 mg, preferably about 290 mg, preferably about 300 mg, preferably about 310 mg, preferably about 320 mg, preferably about 330 mg, preferably about 340 mg, preferably about 350 mg, preferably about 360 mg, preferably about 370 mg, preferably about 380 mg, preferably about 390 mg, preferably about 400 mg, preferably about 410 mg, preferably about 420 mg, preferably about 430 mg, preferably about 440 mg, preferably about 450 mg, preferably about 460 mg, preferably about 470 mg, preferably about 480 mg, preferably about 490 mg, preferably about 500 mg, preferably about 510 mg, preferably about 520 mg, preferably about 530 mg, preferably about 540 mg, preferably about 550 mg, preferably about 560 mg, preferably about 570 mg, preferably about 580 mg, preferably about 590 mg, preferably about 600 mg, preferably about 610 mg, preferably about 620 mg, preferably about 630 mg, preferably about 640 mg, preferably about 650 mg, preferably about 660 mg, preferably about 670 mg, preferably about 680 mg, preferably about 690 mg, preferably about 700 mg, preferably about 710 mg, preferably about 720 mg, preferably about 730 mg, preferably about 740 mg, preferably about 750 mg, preferably about 760 mg, preferably about 770 mg, preferably about 780 mg, preferably about 790 mg, preferably about 800 mg, preferably about 810 mg, preferably about 820 mg, preferably about 830 mg, preferably about 840 mg, preferably about 850 mg, preferably about 860 mg, preferably about 870 mg, preferably about 880 mg, preferably about 890 mg, preferably about 900 mg, preferably about 910 mg, preferably about 920 mg, preferably about 930 mg, preferably about 940 mg, preferably about 950 mg, preferably about 960 mg, preferably about 970 mg, preferably about 980 mg, preferably about 990 mg, preferably about 1000 mg, preferably about 1100 mg, preferably about 1200 mg, preferably about 1300 mg, preferably about 1400 mg, preferably about 1500 mg, preferably about 1600 mg, preferably about 1700 mg, preferably about 1800 mg, preferably about 1900 mg, preferably about 2000 mg, preferably about 2100 mg, preferably about 2200 mg, preferably about 2300 mg, preferably about 2400 mg, preferably about 2500 mg, preferably about 2600 mg, preferably about 2700 mg, preferably about 2800 mg, preferably about 2900 mg, preferably about 3000 mg, preferably about 3100 mg, preferably about 3200 mg, preferably about 3300 mg, preferably about 3400 mg, preferably about 3500 mg, preferably about 3600 mg, preferably about 3700 mg, preferably about 3800 mg, preferably about 3900 mg, preferably about 4000 mg. 4100 mg, preferably about 4200 mg, preferably about 4300 mg, preferably about 4400 mg, preferably about 4500 mg, preferably about 4600 mg, preferably about 4700 mg, preferably about 4800 mg, preferably about 4900 mg, or more preferably about 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per dose.

[0204] In an embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents and excipients.

[0205] Suitable pharmaceutically acceptable carriers, diluents or excipients would be known to persons skilled in the art, illustrative examples of which include inert diluents (e.g., calcium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia), lubricating agents (e.g., magnesium stearate, stearic acid or talc) and material to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period (e.g., glyceryl monostearate or glyceryl distearate). Coating may also be performed using techniques described in the US Patent Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.

[0206] The pharmaceutical composition disclosed herein may be for administration by any suitable route that allows for delivery of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof to a subject at a therapeutically effective amount, as described herein. Suitable administrative forms will be known to persons skilled in the art, illustrative examples of which include enteral administration (e.g., oral and rectal), parenteral administration, typically injectable or micro-injectable forms e.g., intramuscular, subcutaneous, intravenous, epidural, intra-articular, intraperitoneal, intracisternal or intrathecal) and topical (transdermal or trans mucosal) administration (e.g., buccal, sublingual, vaginal, intranasal or by inhalation).

[0207] In an embodiment, the pharmaceutical composition is for oral administration. [0208] Oral administration of cannabinoids has been demonstrated to be an effective administration route (reviewed by Millar et al., 2018, Frontiers in Pharmacology, 9: 1365). Similarly, oral administration of beta-blockers (e.g., propranolol and metoprolol) and antiinflammatory agents e.g., NSAIDs), has been demonstrated to be effective for absorption with sufficient bioavailability (see. e.g., Corbo et al., 1990, Journal of Pharmaceutical Sciences, 79(7): 584-587; de Stoppelaar et al., 1999, Pharmacy World and Science, 21(5): 233-238; Vergin et al., 1989, The Journal of International Medical Research, 17(5): 417- 425; and Dewland et al., 2009, BMC Clinical Pharmacology, 9: 19).

[0209] Suitable dosage forms for oral administration would be known to persons skilled in the art, illustrative examples of which include tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, liquids, syrups or elixirs.

[0210] In an embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof is in liquid, oil, tablet or capsule form. In another embodiment, the cannabinoid or a pharmaceutically acceptable salt or derivative thereof is in liquid form.

[0211] In an embodiment, the beta-blocker or a pharmaceutically acceptable salt thereof is in liquid, oil, tablet or capsule form. In another embodiment, the beta-blocker or a pharmaceutically acceptable salt thereof is in tablet or capsule form.

[0212] In an embodiment, the anti-inflammatory agent or a pharmaceutically acceptable salt thereof is in liquid, oil, tablet or capsule form. In another embodiment, the antiinflammatory agent or a pharmaceutically acceptable salt thereof is in tablet or capsule form.

[0213] Dosage forms for oral administration may comprise one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavoring. Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0214] Pharmaceutical compositions suitable for oral administration may be presented as discrete units (z.e., dosage forms), each containing a predetermined amount of each component of the pharmaceutical composition as a powder, tablet, capsule, granules, as a solution or a suspension in an aqueous liquid or non-aqueous liquid, or as an emulsion.

[0215] As described elsewhere herein, the pharmaceutical compositions may be formulated for administration as separate unit dosage forms for administration. The unit dosage form may be suitable for a capsule, tablet, oil or liquid solution.

[0216] In an embodiment, the pharmaceutical composition comprises a cannabinoid is selected from the group consisting of CBD, CBN, CBG, CBDV and CBC.

[0217] In an embodiment, the pharmaceutical composition comprises CBD.

[0218] In an embodiment, the pharmaceutical composition comprises a beta-blocker or a pharmaceutically acceptable salt thereof.

[0219] In an embodiment, the pharmaceutical composition comprises a beta-blocker selected from the group consisting of propranolol, metoprolol, carvedilol, atenolol, nebivolol and bisoprolol.

[0220] In an embodiment, the beta-blocker is selected from the group consisting of metoprolol, carvedilol, atenolol, and bisoprolol.

[0221] In an embodiment, the beta-blocker is propranolol.

[0222] In an embodiment, the beta-blocker is metoprolol.

[0223] In an embodiment, the beta-blocker is carvedilol.

[0224] In an embodiment, the beta-blocker is atenolol.

[0225] In an embodiment, the beta-blocker is nebivolol.

[0226] In an embodiment, the beta-blocker is bisoprolol. [0227] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof.

[0228] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof.

[0229] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof.

[0230] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof.

[0231] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof.

[0232] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof.

[0233] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof.

[0234] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof.

[0235] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof. [0236] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof.

[0237] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof.

[0238] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof.

[0239] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof.

[0240] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof.

[0241] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof.

[0242] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof.

[0243] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof.

[0244] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof. [0245] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof.

[0246] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof.

[0247] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof.

[0248] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof.

[0249] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof.

[0250] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof.

[0251] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and propranolol or a pharmaceutically acceptable salt thereof.

[0252] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and metoprolol or a pharmaceutically acceptable salt thereof.

[0253] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and atenolol or a pharmaceutically acceptable salt thereof. [0254] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and carvedilol or a pharmaceutically acceptable salt thereof.

[0255] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and nebivolol or a pharmaceutically acceptable salt thereof.

[0256] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and bisoprolol or a pharmaceutically acceptable salt thereof.

[0257] In an embodiment, the pharmaceutical composition comprises an antiinflammatory agent or a pharmaceutically acceptable salt thereof.

[0258] In an embodiment, the pharmaceutical composition comprises an antiinflammatory agent selected from the group consisting of a NSAID and a corticosteroid.

[0259] In an embodiment, the corticosteroid is dexamethasone.

[0260] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof.

[0261] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof.

[0262] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof.

[0263] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof. [0264] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and a NSAID or a pharmaceutically acceptable salt thereof.

[0265] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof.

[0266] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof.

[0267] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof.

[0268] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof.

[0269] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof.

[0270] In an embodiment, the pharmaceutical composition comprises CBD or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof.

[0271] In an embodiment, the pharmaceutical composition comprises CBN or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof.

[0272] In an embodiment, the pharmaceutical composition comprises CBG or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof. [0273] In an embodiment, the pharmaceutical composition comprises CBDV or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof.

[0274] In an embodiment, the pharmaceutical composition comprises CBC or a pharmaceutically acceptable salt or derivative thereof, and dexamethasone or a pharmaceutically acceptable salt thereof.

[0275] Pharmaceutical compositions disclosed herein may be prepared according to conventional methods well known in the pharmaceutical and nutraceutical industries, such as those described in Remington’s Pharmaceutical Handbook (Mack Publishing Co., NY, USA).

[0276] In an embodiment, the pharmaceutical composition is for use in the treatment or prevention of a cardiovascular disease or disorder.

[0277] In an embodiment, the pharmaceutical composition is for use in the treatment or prevention of a cardiovascular disease or disorder selected from the group consisting of hypertension, cardiac inflammation, endothelial dysfunction, aberrant angiogenesis and cardiotoxicity.

Kits

[0278] The present disclosure further contemplates a kit comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

[0279] In an embodiment, the kit comprises the cannabinoid or a pharmaceutically acceptable salt or derivative thereof in a dosage form comprising from about 1 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose.

[0280] In an embodiment, the kit comprises a cannabinoid selected from the group consisting of CBD, CBN, CBG, CBDV and CBC. [0281] In an embodiment, the kit comprises the beta-blocker or a pharmaceutically acceptable salt thereof in a dosage form comprising from about 0.1 mg to about 500 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per dose.

[0282] In an embodiment, the kit comprises a beta-blocker selected from the group consisting of propranolol, metoprolol, carvedilol, atenolol, nebivolol and bisoprolol.

[0283] In an embodiment, the kit comprises the anti-inflammatory agent or a pharmaceutically acceptable salt thereof in a dosage form comprising from about 100 mg to about 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof per dose.

[0284] In an embodiment, the kit comprises an anti-inflammatory agent selected from the group consisting of a non-steroidal anti-inflammatory drug (NS AID) and a corticosteroid.

[0285] In an embodiment, the corticosteroid is dexamethasone.

[0286] In an embodiment, the kit is for use in the treatment or prevention of a cardiovascular disease or disorder.

[0287] In an embodiment, the kit is for use in the treatment or prevention of a cardiovascular disease or disorder selected from the group consisting of hypertension, cardiac inflammation, endothelial dysfunction, aberrant angiogenesis and cardiotoxicity.

[0288] All essential materials and reagents required for treating a cardiovascular disease or disorder in a subject may be assembled together in a kit. In an embodiment, the kit comprises two separate pharmaceutical compositions: one containing the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and the second containing (a) the betablocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof. In another embodiment, the kit comprises a containing or containing the separate compositions such as a divided bottle or a divided foil packet. In an embodiment, the kit further comprises directions for the use of the components.

[0289] In an embodiment, the kit comprises the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof in a blister pack. The term “blister pack” as used herein refers to a commonly used packaging of pharmaceutical unit dosage forms (.e.g., tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0290] In an embodiment, the kit further comprises a memory aid, e.g., in the form of numbers or a code next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . " etc. Other variations of memory aids will be readily apparent to persons skilled in the art.

[0291] The kit may also optionally include appropriate therapeutic agents to be administered in combination with the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt or derivative thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof, illustrative examples of which include analgesics.

[0292] The present disclosure also contemplates a commercial package, also referred to as a “treatment pack” comprising the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof, together with instructions for use for the treatment or prevention of a cardiovascular disease or disorder. [0293] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

[0294] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0295] All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entireties.

[0296] The various embodiments enabled herein are further described by the following non-limiting examples.

EXAMPLES

Example 1

Exemplary pharmaceutical compositions for the treatment or prevention of a cardiovascular disease or disorder

[0297] Exemplary combinations according to the present disclosure are presented in Table 2.

Example 2

Exemplary methods for the treatment or prevention of a cardiovascular disease or disorder

[0298] An exemplary method for the treatment or prevention of a cardiovascular disease or disorder according to the present disclosure is as follows:

Composition of Example 1 : oral administration or co-administration of active agents to the subject daily.

Example 3 General materials and methods

Cell culture

[0299] Human umbilical vein endothelial cells (HUVECs, #C2519A) and pulmonary artery smooth muscle cells (PASMC) were purchased from Lonza, Australia. H9C2(2-1) myoblast cells (a subclone of the original clonal cell line derived from embryonic BD1X rat heart tissue) were purchased from ATCC (Lot #70040766; In Vitro Technologies).

[0300] HUVECs were cultured using standard cell culture techniques under aseptic conditions using complete endothelial cell growth medium-2 (EGM-2; #CC3156 and #CC- 4176) containing 0.04% hydrocortisone, 2% fetal bovine serum (FBS), 0.1% vascular endothelial growth factor (VEGF), 0.4% human basic fibroblast growth factor, 0.1% hEGF, 0.1% R3-IGF, 0.1% GA- 1000, 0.1% ascorbic acid and 0.1% heparin. [0301] PASMCs were cultured using standard cell culture techniques under aseptic conditions using complete smooth muscle cell growth media (5% fetal bovine serum (FBS), SGM2, Lonza).

[0302] H9C2(2-1) cells were cultured using ATCC-formulated Dulbecco’s Modified

Eagle’s Medium (DMEM; #30-2002) supplemented with 10% fetal bovine serum (Moregate FBS, sterile filtered; #MORFBSFAU).

[0303] Cryopreserved HUVECs, PASMCs and H9C2(2-1) cells were retrieved from liquid nitrogen and thawed in a water bath set at 37°C. The cell suspension was pipetted into a sterile 15 mL conical tube contain 5 mL of complete media and centrifuged at 300 x g for 5 minutes (HUVECs and PASMCs) or 125 x g for 5-7 minutes (H9C2(2-1) cells). Supernatant containing cryopreserved media was removed carefully without disturbing the pellet and the pellet was re-suspended in 2-3 mL of complete growth media. This cell suspension was pipetted into a 75 cm² cell culture flask containing 15 mL of complete medium and the flask was placed in a humidified incubator set at 37°C and 5% CO2. Medium was replaced every 48 hours until cells reached 70-80% confluency.

Angiotensin II (Angll) perturbation assay

[0304] Cells were seeded in 96 well plates. After 24 hours of incubation at 37°C and 5% CO2, medium was aspirated from each well and cells were treated in media with 0.5% serum with media only (non-treated control); 1 pM Angll alone (Angll treated control); 1 pM CBD with 1 pM Angll; 1 pM beta-blocker with 1 pM Angll; and 1 pM of CBD and a beta-blocker in combination with 1 pM Angll. CBD and a beta-blocker were dissolved in DMSO to working stocks before dilution to the final assay concentrations. The final DMSO concentration of all treatments was 0.02%. Cell viability was determined at 0 hour, 24 hours and 48 hours.

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay

[0305] MTT cell proliferation assays were performing using the MTT kit containing MTT reagent and MTT solvent purchased from Sigma- Aldrich (Roche #11465007001) in accordance with the manufacturer's instructions. Trypan blue cell viability assay

[0306] The trypan blue exclusion method was used to assess cell viability following trypsinisation of cells. The number of live cells (i.e., cells that exclude trypan blue) were counted manually using a hemocytometer.

RNA extraction

[0307] Cells were harvested for RNA extraction using the Mini RNeasy kit (Qiagen, #74104) in accordance with the manufacturer's instructions. RNA concentration (ng/ pL) as well as A260/A280 and A260/A230 were measured by loading 2 pF of each sample onto a Nanodrop. Extracted RNA samples were stored at -80°C. cDNA synthesis

[0308] cDNA synthesis was performed by the QuantiTect Reverse Transcription Kit (Qiagen, #205311). The template RNA was diluted to a final concentration of 1 pg in 12 pL of RNase free water before cDNA synthesis was performed in accordance with the manufacturer’s instructions.

Real time PCR (RT-PCR)

[0309] RT-PCR was performed on the QuantStudio 7 Real-Time PCR system (ThermoFisher Scientific) after setting up a reaction using KicqStart Primer Pairs (Sigma), QuantiTECT SYBR Green Master Mix and SYBR Green I. For each sample, a reaction was made up on a 96 well plate as follows, 2 pL Water, 5 pL SYBR green dye, 4 pL each forward/reverse primers (300 nM final concentration), 5 pL cDNA (5 ng/well).

[0310] Primers used for this analysis are shown in Table 3.

[0311] CT values were calculated by the Design and Analysis 2 (DA2) PCR software (ThermoFisher) and were used to quantify the relative gene expression of the gene of interest (VC AM or Caspase 1) relative to the internal housekeeping gene GAPDH. Having defined the reference gene, the software also calculates the ACT (Target CT - Reference Gene CT). The average change in CT for the control group was then subtracted from each CT to determine the AACT. Consequently, gene expression was expressed relative to the control group, by substituting the AACT into the equation 2-AACT.

Immunobloting

[0312] Protein was extracted from plates by lysing cells using protein lysis buffer (RIPA buffer: NaCl 150 mmol/L; Tris-Hcl 50 mmol/L; Triton X 1%; Na deoxycholate 0.5%, sodium dodecyl sulphate 0.1%) containing protease (cOmplete protease inhibitor cocktail, Roche) and phosphatase inhibitors (PhosSTOP, Roche). Each well was scraped, removed and incubated in lysis buffer on ice for 30 mins, before centrifugation at 20,000 x g for 20 mins at 4°C. For each sample, the supernatant containing the extracted proteins was collected. Protein concentration was determined following the manufacturer's protocol using the Pierce™ BCA protein assay kit (Thermo Fisher Scientific). After quantification, the protein extracts were stored 10 pg of protein was prepared with 1 x EDS sample buffer (Bolt, Invitrogen) and 50 mmol/L dithiothreitol. Samples were denatured at 70°C for 10 minutes, before being transferred to ice for 2 minutes. Samples were then loaded onto pre-cast BisTris 4-12% gradient gels for separation through gel electrophoresis (Thermo Scientific Bolt™) at 200V for 22 minutes.

[0313] Proteins were transferred onto a PVDF at 25V for 7 minutes. To verify the successful transfer of proteins, membranes were stained with Ponceau Red. Following staining, the membranes were washed with Tris-buffered saline with 0.01% Tween-20 (TBS-T) and were then blocked using a 5% skim milk powder solution dissolved in lx TBS- T for one hour. Membranes were probed with the primary antibodies phospho-Akt [Ser473], #9271; Akt #9272; Cell Signalling Technologies), prepared in 5% skim milk/TBS-T, overnight at 4°C. Subsequently, the membranes were washed with TBS-T and were then exposed to goat anti-rabbit or goat anti-mouse IgG HRP secondary antibodies (Abeam, 1:5000) in 5% milk for one hour. The membranes underwent development using a high- sensitivity ECE substrate kit (Abeam), and protein bands were visualised using iBright imaging system (Thermo Fisher Scientific) and quantified using ImageJ. Phosphorylation is measured in ratio of non-phosphorylated to phosphorylated AKT.

[0314] Example 4

Combinations of CBD and a beta-blocker synergise to rescue cells following exposure to Angiotensin II

[0315] Angiotensin II (Angll) is the primary effector hormone of the renin-angiotensin system, which mediates the cardiovascular physiological effects of vasoconstriction and blood pressure regulation. Excessive production of Angll is closely associated with a series of pathological events that can impair endothelial cell function and drive vascular dysfunction. Angll has also been implicated in diverse cardiovascular diseases, including atherosclerosis, hypertension, and congestive heart failure. As such, Angll inhibitors (e.g., Angiotensin-Converting Enzyme Inhibitors (ACE inhibitors)) are widely used for the treatment of hypertension, which is a significant risk factor for coronary disease, heart failure, stroke, and other cardiovascular conditions.

[0316] Under normal conditions, Angll has an anti-proliferative effect on HUVECs. To assess if CBD can synergize with a beta-blocker to modulate the effects of Angll activity, and restore normal proliferation, CBD, beta-blocker (i.e., metoprolol, carvedilol, bisoprolol, and atenolol) and combinations thereof were assessed for changes in cell proliferation by MTT assay following exposure to Angll.

[0317] As shown in Figure 1, CBD, metoprolol, carvedilol, bisoprolol, and atenolol had negligible single agent activity, with little to no restoration of normal cell proliferation at 24 or 48 hours following exposure to Angll. However, when CBD was used in combination with any one of metoprolol, carvedilol, bisoprolol, or atenolol, significant improvements in cell proliferation were observed. In fact, CBD in combination with metoprolol, bisoprolol, or atenolol restored cell proliferation to normal levels notwithstanding their exposure to Angll.

[0318] Given the significant improvements to cell proliferation, synergy calculations were performed on the MTT absorbance data (average absorbance of all background corrected (T24 replicates or T48 replicates, - TO) technical replicates) and the predicted combinatorial effects of CBD + metoprolol, CBD + carvedilol, CBD + bisoprolol, and CBD + atenolol using the Bliss independence principle and the following equation:

Epred A + B = (E^ + Eg) — (E^Eg) [0319] In the context of the Angll perturbation assay, the activity of the combination using this equation was calculated as (X -Angll) / (Control - Angll), where control is the non-treated control, Angll is Angll treated control, and X is treatment with single agent CBD, single agent metoprolol, single agent carvedilol, single agent bisoprolol, and single agent atenolol, or CBD + metoprolol, CBD + carvedilol, CBD + bisoprolol, and CBD + atenolol. Synergism was observed for each of the combinations CBD + metoprolol, CBD + carvedilol, CBD + bisoprolol, and CBD + atenolol at both 24 hours (Table 4) and 48 hours (Table 5) post-exposure to Angll.

Example 5

Synergistic combinations of CBD and a beta blocker are effective for the treatment of chemotherapy-induced cardiotoxicity

[0320] To assess the effect of the synergistic combinations of CBD and beta blockers on treating or preventing chemotherapy -induced cardiotoxicity, H9C2 cells were subjected to doxorubicin treatment for 24 hours before treatment with 1 pM CBD + 1 pM bisoprolol, 1 pM CBD + 1 pM metoprolol and 1 pM CBD + 1 pM carvedilol for a further 24 hours. As shown in Figure 2A, treatment with each 1 pM CBD + 1 pM bisoprolol, 1 pM CBD + 1 pM metoprolol and 1 pM CBD + 1 pM carvedilol improved the viability of cells exposed to doxorubicin, as measured by trypan blue exclusion assay.

[0321] To further assess the effect of the synergistic combination of CBD + beta blocker in treating cardiotoxicity, H9C2 cells were subjected to doxorubicin treatment for 24 hours before treatment with 1 pM CBD + 1 pM carvedilol for a further 24 hours. The combination of CBD + carvedilol significantly increased cell proliferation relative to the vehicle only (i.e., dox treated) control, as measured by MTT assay (Figure 2B).

Example 6

Synergistic combination of CBD + metoprolol reduces expression of immunogenic modulators of cardiovascular disease

[0322] There is increasing evidence that cytokines, such as tumor necrosis factor alpha (TNF-a), play a role in cardiovascular disease. For example, under normal conditions, TNF- a modulates both cardiac contractility and peripheral resistance, which are essential determinants of cardiac function. Increased levels of TNF-a (or its soluble receptors) have been associated with ischemia-reperfusion injury, myocarditis, cardiac allograft and congestive heart failure. The pathology of TNF-a in the context of cardiac dysfunction is at least partially mediated by the activation of proapoptotic caspases, such as caspase- 1, and the upregulation of adhesion molecules, such as vascular cell adhesion molecule- 1 (VCAM- 1).

[0323] To investigate the effect of the synergistic combinations of CBD + beta blocker in mediating the response to TNF-a, H9C2 cells were stimulated with TNF-a (10 ng/mL) and measured for expression of caspase-1 and VCAM-1. The synergistic combination of CBD + metoprolol significantly reduced the expression of caspase- 1 in response to TNF-a relative to controls, as measured by RT-QPCR (Figure 3A), whereas the effect of CBD + metoprolol on the expression of VCAM-1 was more muted (Figure 3B).

[0324] In addition, using the Angll model described above in Example 4, it was shown that the synergistic combination of CBD + metoprolol also reduced the expression of NFKB and VC AMI in HUVECs relative to controls.

Example 7

Synergistic combination of CBD + bisoprolol reduces dysregulated proliferation mediated by PDGF

[0325] AKT is an important member of the PI3K/AKT signalling pathway which plays a crucial role in cardiac health and disease. The dysregulation of the AKT pathway can lead to adverse remodelling of the heart which can affect both its structure and function, which can result in cardiac diseases characterised by hypertrophy and heart failure.

[0326] To investigate the effect of the synergistic combination of CBD + bisoprolol in mediating the dysregulated proliferation of smooth muscle cells (PASMCs) caused by PDGF, PASMCs were treated with PDGF and measured for change in growth after 48 hours and phosphorylation of AKT after 24 hours. The synergistic combination of CBD + bisoprolol significantly reduced PDGF-mediated cell proliferation (Figure 4A) and the phosphorylation of AKT relative to the controls. Moreover, it is known that PDGF stimulation of smooth muscle cells results in AKT phosphorylation which in turn leads to an increase in cell proliferation. This is consistent with the data presented in Figure 4B, which shows that AKT phosphorylation was reduced in cells treated with the combination of CBD + bisoprolol.

Example 8

Combination of CBD and dexamethasone synergises to modulate LPS -induced inflammation

[0327] Lipopolysaccharide (LPS) is a potent activator of the innate immune system. It binds to Toll-like receptor 4 (TLR4) on immune cells and triggers a cascade of signalling pathways that lead to the production of pro-inflammatory cytokines and chemokines. It has been widely used in biological research to study the inflammatory response in cells. In the context of cardiovascular diseases and disorders, LPS is known to induce cardiac hypertrophy and apoptosis in the heart.

[0328] To investigate if cannabinoids can be combined with an anti-inflammatory agent to provide a synergistic effect for the treatment of a cardiovascular disease or disorder, H9C2 cells were treated with 10 pg/mL LPS for 6 hours and the inflammatory response was assessed with reference to induction of caspase- 1 expression as measured by RT-PCR. As shown in Figure 5, the combination of 1 pM CBD + 1 pM dexamethasone potently down- regulated caspase- 1 expression. In fact, the level of caspase- 1 expression was less than that observed in the non-treated control cells. This result is particularly surprising, as CBD as a single agent significantly upregulated caspase- 1 expression. Accordingly, the combination of CBD + dexamethasone was able to mediate the inflammatory response induced by both LPS and CBD.

[0329] Given the significant down regulation of caspase- 1, synergy calculations were performed on the RT-PCR data and the predicted combinatorial effects of CBD + dexamethasone using the Bliss independence principle and the following equation:

Epred A + B = (E_A + E_B) — (E_AE_B)

[0330] In the context of the LPS inflammation assay, the activity of the combination using this equation was calculated as 1- ((X / (LPS- Control)), where control is the nontreated control, LPS is vehicle control, and X is treatment with single agent CBD, single agent dexamethasone, or CBD + dexamethasone. Synergism was observed for the combination CBD + dexamethasone after 6 hours of exposure to LPS (Table 6).

Table 1. Exemplary structures of cannabinoids or pharmaceutically acceptable salts or derivatives thereof

Table 2. Exemplary pharmaceutical compositions for the treatment or prevention of a cardiovascular disease or disorder

Table 3. RT-PCR Primers

Table 4. Synergistic restoration of Angll-induced growth inhibition 24 hours postexposure to Angll

All treatments are in the presence of 1 pM of Angll with the exception of the “control”

Table 5. Synergistic restoration of Angll-induced growth inhibition 48 hours postexposure to Angll

Table 6. Synergistic modulation of Caspase-1 expression in response to LPS-induced inflammation

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A method for the treatment or prevention of a cardiovascular disease or disorder, the method comprising administering to a subject in need thereof a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and:

(a) a beta-blocker or a pharmaceutically acceptable salt thereof; or

(b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the subj ect is administered from about 1 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per day.

3. The method of claim 1 or claim 2, wherein the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabidivarin (CBDV) and cannabichromene (CBC).

4. The method of claim 3, wherein the cannabinoid is CBD.

5. The method of any one of claims 1 to 4, wherein the cannabinoid or a pharmaceutically acceptable salt or derivative thereof is administered sequentially with (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1 to 4, wherein the cannabinoid is administered simultaneously with (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 4, wherein the cannabinoid or a pharmaceutically acceptable salt or derivative thereof is administered as a single daily dose with (a) the beta-blocker or a pharmaceutically acceptable salt thereof; or (b) the antiinflammatory agent or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the cardiovascular disease or disorder is selected from the group consisting of hypertension, cardiac inflammation, endothelial dysfunction, aberrant angiogenesis and cardiotoxicity.

9. The method of any one of claims 1 to 8, wherein the subject is administered the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and the beta-blocker or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the subject is administered from about 0.1 mg to about 500 mg of the beta-blocker or pharmaceutically acceptable salt thereof per day.

11. The method of claim 9 or claim 10, wherein the beta-blocker is selected from the group consisting of propranolol, metoprolol, carvedilol, atenolol, nebivolol and bisoprolol.

12. The method of any one of claims 1 to 8, wherein the subject is administered the cannabinoid or a pharmaceutically acceptable salt or derivative thereof and the antiinflammatory agent or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein the subject is administered from about 100 mg to about 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the anti-inflammatory agent is selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID) and a corticosteroid.

15. The method of claim 14, wherein the corticosteroid is dexamethasone.

16. Use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and(a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an antiinflammatory agent or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for the treatment or prevention of a cardiovascular disease or disorder.

17. Use of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with (a) a beta-blocker or a pharmaceutically acceptable salt thereof; or (b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

18. Use of a beta-blocker or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with a cannabinoid or a pharmaceutically acceptable salt or derivative thereof.

19. Use of an anti-inflammatory agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease or disorder, wherein the medicament is to be co-administered with a cannabinoid or a pharmaceutically acceptable salt or derivative thereof.

20. A kit comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and

(a) a beta-blocker or a pharmaceutically acceptable salt thereof; or

(b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

21. The kit of claim 20 for use in the treatment or prevention of a cardiovascular disease or disorder.

22. A pharmaceutical composition comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, and:

(a) a beta-blocker or a pharmaceutically acceptable salt thereof;

(b) an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition of claim 22, further comprising one or more pharmaceutically acceptable carriers, diluents and excipients.

24. The pharmaceutical composition of claim 22 or claim 23, comprising from about 1 mg to about 1500 mg of the cannabinoid or a pharmaceutically acceptable salt or derivative thereof per dose.

25. The pharmaceutical composition of any one of claims 22 to 24, wherein the cannabinoid is selected from the group consisting of CBD, CBN, CBG, CBDV and CBC.

26. The pharmaceutical composition of claim 25, wherein the cannabinoid is CBD.

27. The pharmaceutical composition of any one of claims 22 to 26, comprising from about 0.1 mg to about 500 mg of the beta-blocker or a pharmaceutically acceptable salt thereof per dose.

28. The pharmaceutical composition of claim 27, wherein the beta-blocker is selected from the group consisting of propranolol, metoprolol, carvedilol, atenolol, nebivolol and bisoprolol.

29. The pharmaceutical composition of any one of claims 22 to 26, comprising from about 100 mg to about 5000 mg of the anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition of claim 29, wherein the anti-inflammatory agent is selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID) and a corticosteroid.

31. The pharmaceutical composition of claim 30, wherein the corticosteroid is dexamethasone.

32. The pharmaceutical composition of any one of claims 22 to 31, which is for oral administration.

33. The pharmaceutical composition of any one of claims 22 to 32 for use in the treatment or prevention of a cardiovascular disease or disorder.

34. The kit for use of claim 20, or the pharmaceutical composition for use of claim 33, wherein the cardiovascular disease or disorder is selected from the group consisting of hypertension, cardiac inflammation, endothelial dysfunction, aberrant angiogenesis and cardiotoxicity.