Cannabidiol for use in the treatment or prevention of recurrent pericarditis

Abstract

Cannabidiol or its pharmaceutically acceptable prodrug, derivative, salt or solvate is disclosed for use in treating or preventing recurrent pericarditis.In an in vitro model, the effectiveness of cannabidiol in attenuating the levels of interleukin-1β (IL-1β) and IL-6, and the transcription of pro-IL-1β and NLRP3 mRNA is disclosed.Also disclosed is an experiment showing that cannabidiol is effective in preventing the increase of pericardial cavity (which is an indicator of pericardial effusion) and pericardial thickening in an in vivo mouse model of pericarditis.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Applications Nos. 63 / 399,881 and 63 / 422,226, filed August 22, 2022 and November 3, 2022, respectively, the entire contents of which are incorporated herein by reference.

[0002]

[0004] The present invention relates generally to therapeutic agents and methods for treating or preventing cardiovascular diseases, disorders or conditions, and more particularly to therapeutic agents and methods for treating or preventing pericarditis.

[0005] [Background technology]

[0003]

[0006] Pericarditis results from an intense inflammatory response in the pericardium, which involves the activation of an intracellular macromolecular complex called the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome. Upon sensing injury and stress, the NLRP3 inflammasome triggers an inflammatory process that results in the release of proinflammatory cytokines, such as interleukin-1β, which act as downstream mediators.

[0004]

[0007] Pericarditis can be classified as acute, frequent, recurrent, and chronic. Acute pericarditis is a clinical syndrome characterized by a single episode that resolves spontaneously or after treatment. Treatment usually consists of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, steroids, colchicine, and anakinra (4, 7, 8, 9). Acute pericarditis was reported at 27.7 cases per 100,000 person-years in metropolitan Italy, accounting for 0.1% of all hospitalizations for chest pain and 5% of emergency room admissions (2). Recurrent pericarditis (RP) is diagnosed when a symptom-free period of at least 4–6 weeks follows the index acute episode and is followed by a subsequent episode. RP occurs in 15–30% of patients with pericarditis, and some patients have been reported to experience multiple recurrences. Recurrence may be due to inadequate treatment of the initial attack, or due to an inadequate response to current treatment.

[0005]

[0008] The pathogenesis of pericarditis is not fully understood (3), but it is hypothesized that acute pericarditis is a typical response to acute injury to pericardial mesothelial cells (4). It is thought to be triggered by an "irritant" such as a virus or cellular debris after a viral infection (5, 6). It may also be triggered by cardiac procedures, such as cardiac surgery (especially coronary artery bypass grafting), pacemaker insertion, radiofrequency ablation, transcatheter aortic valve implantation, and, rarely, percutaneous coronary intervention (7).

[0006]

[0009] According to Klein et al. (12), the entire contents of which are incorporated herein by reference, there is a high unmet need for safe, available FDA-approved treatments that will reverse recurrent attacks and reduce the risk of recurrence without imposing excessive treatment burden on patients. Since the publication of Klein et al., the FDA has approved rilonacept (Arcalyst™), an interleukin-1 (IL-1) receptor blocker, as an orphan drug for the treatment of recurrent pericarditis (RP) and reduction of the risk of recurrence in adult and pediatric patients aged 12 years and older. (11)

[0007]

[0010] Cannabidiol is a small, lipophilic, non-psychoactive compound naturally occurring in the plant Cannabis sativa. Interest in this compound has grown in recent years due to its favorable safety profile and minimal side effects. Several in vitro and in vivo studies have demonstrated its anti-inflammatory properties, and its use in the treatment of various cardiac diseases has been suggested in the literature. However, the clinical efficacy of cannabidiol in the treatment of pericarditis remains unclear. Summary of the Invention [Problem to be solved by the invention]

[0008]

[0011] There continues to be a need for alternative therapeutic agents and methods for treating recurrent pericarditis, and the present invention is directed to addressing this need.

[0012] [Means for solving the problem]

[0009]

[0013] Through the following experiments, the inventors discovered that cannabidiol attenuates the increase in interleukin-1β (IL-1β) in an in vitro model of NLRP3 inflammasome activation. In separate experiments, the inventors discovered that the anti-inflammatory effects of cannabidiol are not limited to inhibition of the NLRP3 inflammasome pathway, as cannabidiol was found to reduce the level of interleukin-6 (IL-6), which is secreted independently of this pathway. In yet another experiment, cannabidiol was also found to attenuate the increase in transcription of pro-IL-1β mRNA and NLRP3 mRNA, components of the NLRP3 inflammasome. Furthermore, through in vivo experiments using a mouse model of pericarditis, the inventors discovered that cannabidiol is useful for reducing pericardial effusion and pericardial thickening, two hallmarks of pericarditis.

[0010]

[0014] Thus, a first aspect of the present invention provides the use of a pharmaceutically active agent selected from the group comprising cannabidiol and pharmaceutically acceptable prodrugs, derivatives, salts and solvates thereof in the treatment or prevention of recurrent pericarditis.

[0011]

[0015] A second aspect of the present invention provides the use of a pharmaceutically active agent selected from the group comprising cannabidiol and pharmaceutically acceptable prodrugs, derivatives, salts and solvates thereof in the preparation of a medicament for the treatment or prevention of recurrent pericarditis.

[0012]

[0016] According to a third aspect, the present invention provides a method of treating or preventing recurrent pericarditis in a subject in need thereof, the method comprising (optionally) identifying a subject suffering from or at risk of suffering from recurrent pericarditis, and administering to the subject an effective amount of a pharmaceutically active agent selected from the group comprising cannabidiol and pharmaceutically acceptable prodrugs, derivatives, salts, or solvates thereof.

[0013]

[0017] A fourth aspect of the present invention provides a pharmaceutically active agent selected from the group comprising cannabidiol and pharmaceutically acceptable prodrugs, derivatives, salts and solvates thereof for use in the treatment or prevention of recurrent pericarditis.

[0014]

[0018] According to a fifth aspect, the present invention provides a composition comprising an effective amount of a pharmaceutically active agent selected from the group comprising cannabidiol and pharmaceutically acceptable prodrugs, derivatives, salts and solvates thereof, and an effective amount of a delivery vehicle, wherein the composition is for use in the treatment or prevention of recurrent pericarditis.

[0015]

[0019] In some embodiments, the pharmaceutically active agent is synthetic. In the same or other embodiments, the pharmaceutically active agent is cannabidiol.

[0016]

[0020] Some embodiments of the uses and methods involve using a pharmaceutically active agent to prevent recurrent pericarditis, hi other embodiments, the pharmaceutically active agent is used to treat recurrent pericarditis.

[0017]

[0021] A pharmaceutically active agent (e.g., cannabidiol) can be used to reduce pericardial effusion and / or increased pericardial thickening in a subject (e.g., a subject suffering from or at risk of suffering from recurrent pericarditis) by, for example, at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or to reduce by up to about 100%, compared to the amount of pericardial effusion and / or pericardial thickening that would be present in the absence of administration of the pharmaceutically active agent.

[0018]

[0022] Furthermore, pharmaceutically active agents (such as cannabidiol) can also be used to attenuate inflammatory responses.For example, pharmaceutically active agents can be used to reduce the transcription of pro-IL-1βmRNA and / or NLRP3mRNA, which are components of NLRP3 inflammasome.Pharmaceutical active agents can also be used to reduce the release of at least one of IL-1β and / or IL-6 in a subject by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, compared with the release of IL-1β and / or IL-6 that would occur without administering the pharmaceutically active agent.

[0019]

[0024] The present invention can be better understood with reference to the following detailed description and drawings.

[0023] [Brief explanation of the drawings]

[0020] [Figure 1A]

[0025] A bar graph showing the effect of a 10 μM dose of cannabidiol on IL-1β levels in an in vitro model of NLRP3 inflammasome activation. [Figure 1B]

[0026] A bar graph showing the effect of various doses of cannabidiol (10 μM, 1 μM, 0.1 μM, and 0.01 μM) on IL-1β levels in the same in vitro model of NLRP3 inflammasome activation. [Figure 1C]

[0027] Figure 1 is a bar graph showing the effect of a 10 μM dose of cannabidiol on IL-6 levels in another in vitro model. [Figure 1D]

[0028] Figure 1 is a bar graph showing the effect of a 10 μM dose of cannabidiol on the level of pro-IL-1β mRNA transcription in the same separate in vitro model. [Figure 1E]

[0029] Figure 1 is a bar graph showing the effect of a 10 μM dose of cannabidiol on the level of NLRP3 mRNA transcription in the same separate in vitro model. [Figure 2] 1 is a bar graph showing the effect of two doses (10 mg / kg and 1 mg / kg) of cannabidiol on the pericardial cavity (an indicator of pericardial effusion) in an in vivo model of pericarditis; and [Figure 3]

[0031] Figure 1 is a bar graph showing the effect of cannabidiol (10 mg / kg) on pericardial thickening in the same in vivo model of pericarditis. DETAILED DESCRIPTION OF THE INVENTION

[0021]

[0033] definition

[0034] For clarity and to avoid ambiguity, certain terms are defined herein as follows.

[0022]

[0035] As used herein, the term "pharmaceutical active agent" refers to a drug or agent that can be utilized as disclosed herein and is intended to be used in a subject to treat or prevent disease, illness, physical injury, or pathological symptoms, or to affect the state, pathology, or function of the body. Drugs that can be used can be found in references such as the Rote Liste or the Merck Index. Examples that can be mentioned include, for example, cannabidiol.

[0023]

[0036] When a composition is described as having "at least X% purity," this means that one or more impurities may be present in an amount up to 100-X% by weight, based on the total weight of the composition. The purity of a component can be determined by high performance liquid chromatography (HPLC) or other suitable means.

[0024]

[0037] The term "subject" refers to members of the animal kingdom, including humans and other mammals. In some embodiments, the subject is a human.

[0025]

[0038] As used herein, the terms "treat," "treatment," and similar phrases mean halting or slowing the progression of, or reducing the severity of, a condition, disorder, or disease. The terms "prevent," "prophylaxis," and similar phrases mean preventing, delaying, or reducing the occurrence and / or risk of developing a condition, disorder, or disease. These terms encompass "improving quality of life," "prolonging life," and "improving clinical outcome" of a subject suffering from or at risk of suffering from a condition, disorder, or disease, and do not necessarily mean, but do not exclude, "curing" the condition, disorder, or disease.

[0026]

[0039] "Pharmaceutically acceptable excipient," as used herein, means any substance that can be formulated with or present together with a pharmaceutically active agent to achieve one or more desired functions and that is not biologically or otherwise harmful when administered to a subject (e.g., a human). For example, the excipient should be non-toxic when administered and compatible with other ingredients in the formulation. One of ordinary skill in the art, given the teachings herein and information in the public domain, will know what compounds or components qualify as pharmaceutically acceptable excipients.

[0027]

[0040] The terms "at least one," "one or more," and "and / or" are open-ended expressions that are both conjunctive and disjunctive in operation. For example, the phrases "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," "one or more of A, B, or C," and "A, B, and / or C" each mean A alone, B alone, C alone, both A and B together, both A and C together, both B and C together, or both A, B, and C together.

[0028]

[0041] The term "a" or "an" means "one or more." Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein. It should also be noted that the term "or" is used in the sense of "and / or" unless the context clearly dictates otherwise. For the avoidance of doubt, reference herein to the use of cannabidiol to treat or prevent recurrent pericarditis refers to the use of cannabidiol to treat and / or prevent recurrent pericarditis.

[0029]

[0042] The term "comprising" means "including, but not limited to." Thus, for example, a composition that includes a list of compounds, ingredients, or elements may contain additional compounds, ingredients, or elements not expressly listed. It should also be noted that the terms "comprising," "including," "containing," and "having" can be used interchangeably.

[0030]

[0043] The term "consisting of" means including the recited integer and no additional integers, except that in the case of compounds or components, it does not exclude other compounds or components that may be present as natural or commercially available impurities or additives. Natural or commercially available impurities and additives will be apparent to those skilled in the art. For example, synthetic cannabidiol may contain up to about 0.5% w / w impurities, such as residual solvents and by-products of the manufacturing process.

[0031]

[0044] The term "consisting essentially of" means "including" the recited entities (e.g., compounds, steps, ingredients, etc.) as well as any additional entities that do not materially affect the basic novel property of the present invention, which is the beneficial effect of cannabidiol, pharmaceutically acceptable prodrugs, derivatives, salts, and solvates thereof, in the treatment and / or prevention of recurrent pericarditis.

[0032]

[0045] The terms "% w / w," "% wt.", "w / w%," "wt.%," and variations thereof refer to the amount of a substance obtained by dividing the weight of the substance by the total weight of the formulation containing that substance and multiplying by 100.

[0033]

[0046] The terms "% w / v," "w / v%," and variations thereof refer to the mass of a solute in grams divided by the volume in mL of solution in which the solute is dissolved, multiplied by 100. For example, a formulation containing 10 grams of a solvent per 25 mL of solution containing that solvent would have 40 wt / v% solvent, calculated as follows: (10 ÷ 25) × 100 = 40 wt / v%.

[0034]

[0047] The term "about" refers to variations in the stated quantity that may occur, for example, through measuring procedures and liquid handling procedures used to make the pharmaceutical formulation; differences in the manufacture, source, or purity of the components used to make the formulation; and / or differences in equilibrium conditions or reaction levels of components in the formulation obtained from an initial mixture. For clarity, the term "about" includes variations of up to ±5%, or ±10%, of the stated value. Whether or not a value is modified by the term "about," the claims include equivalents of that value.

[0035]

[0048] As used herein, the term "effective amount" refers to an amount that will produce a desired effect based on the purpose and function of the component in the context of the present invention as disclosed herein. A "desired effect" includes not causing toxicity. For example, an effective amount of a pharmaceutically active agent is an amount effective to produce a therapeutic effect while avoiding toxicity, such as may occur with long-term chronic administration. An effective amount of a solvent is an amount effective, alone or together with other components, to solubilize other or remaining components of the formulation. What constitutes an effective amount can be determined by one of ordinary skill in the art through routine experimentation, bearing in mind the teachings herein and / or information in the public domain.

[0036]

[0049] As used herein, the phrase "Y-free" means that "Y" is not intentionally added, but may be present as an impurity or due to other factors. For clarity, a "Y-free" formulation will either contain no Y or only up to 0.01% w / v, only up to 0.02% w / v, only up to 0.03% w / v, only up to 0.04% w / v, only up to 0.05% w / v, only up to 0.06% w / v, only up to 0.07% w / v, only up to 0.08% w / v, only up to 0.09% w / v, only up to 0.1% w / v, only up to 0.2% w / v, only up to 0.3% w / v, only up to 0.4% w / v, or only up to 0.5% w / v of Y, based on the total formulation.

[0037]

[0050] Values recited herein are intended to include all values meeting the stated parameters, including values not explicitly recited. For example, a value less than 1.0 is intended to include less than 0.99, less than 0.98, less than 0.97, less than 0.90, less than 0.84, less than 0.56, less than 0.01, etc. Accordingly, all ranges disclosed herein should be understood to encompass any and all subranges subsumed therein. For example, a recited range of "1 to 10" should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10 (and inclusive), such as 1 to 6.3, 5.5 to 10, 2.7 to 6.1, etc.

[0038]

[0051] This specification allows that any ingredient may be omitted even if not expressly named herein as being included or excluded.

[0039]

[0052] Cannabidiol

[0053] As used herein, the terms "cannabidiol" and "CBD" refer to the compound 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol, which has the following chemical structure:

[0040] [ka]

[0041]

[0054] Cannabidiol can be of natural origin or synthetic origin.Cannabidiol can be derived from various cannabis plants, including hemp, and can be purified using conventional means.The synthesis of cannabidiol is described, for example, in Petilka et al., Helv.Chim.Acta, 52:1102 (1969) and Mechoulam et al., J.Am.Chem.Soc., 87:3273 (1965), and U.S. Patent Nos. 10,059,683 and 10,844,035.

[0042]

[0055] Pharmaceutically acceptable prodrugs, derivatives, salts, and solvates of cannabidiol known in the art can also be used in addition to or in place of cannabidiol to treat and / or prevent recurrent pericarditis.

[0043]

[0056] Cannabidiol prodrugs can include, for example, compounds that are chemically converted into an active form with medical effects by metabolic or other processes in the body of a mammal to which the compound is administered. Exemplary cannabidiol prodrugs of the present invention include, but are not limited to, cannabidiol esters prepared by functionalizing one or more of the hydroxyl groups present in the molecular structure of cannabidiol. Exemplary cannabidiol prodrugs are described in U.S. Patent No. 8,293,786.

[0044]

[0057] Salt forms of cannabidiol can include any cannabidiol salt suitable for mammalian administration, including those prepared from formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acid, beta-hydroxybutyric acid, galactaric acid and galacturonic acid.

[0045]

[0058] Preferably, the cannabidiol has a purity of at least 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. Impurities that may be present in synthetic cannabidiol include residual solvents (e.g., methanol, n-heptane, dichloromethane, and triethylamine) and / or manufacturing by-products or residues, such as olivetol, monobromo-cannabidiol, and tetrahydrocannabinol. Cannabidiol from plant sources may contain small amounts of other cannabinoids (e.g., cannabidivarin (CBDV) and the butyl analog of cannabidiol (cannabidibutol)), terpenes, and solvents or ingredients used in the purification process, as well as pesticide residues.

[0046]

[0059] Tetrahydrocannabinol (also known as THC, delta-9-tetrahydrocannabinol, and delta-9-THC) is the compound having the structure shown below.

[0047] [ka]

[0048]

[0060] In some embodiments, the composition according to the present invention does not contain THC. This means that THC is absent or present in an amount of less than 0.5% w / w, preferably less than 0.4% w / w, more preferably less than 0.3% w / w, and even more preferably less than 0.2% w / w, based on the weight of the formulation. To avoid psychotropic or intoxicating effects, it may be desirable to reduce the level of THC to as low a level as possible, for example, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm, based on the total composition.

[0049]

[0061] The compositions can be in any dosage form known in the art, including, but not limited to, oral solutions, injectable formulations, tablets, gel capsules, chewing gum formulations, and other dosage forms.

[0050]

[0062] Oral solution and elixir formulations can be simple or quite complex, requiring a wide variety of additives, such as water-soluble organic solvents, water-insoluble organic solvents, surfactants, buffers, sugars, flavorings, sweeteners, fragrances, colorings, antioxidants, and preservatives. Solutions may or may not contain water. Organic cosolvents are typically used to solubilize poorly water-soluble drugs, including cannabidiol, to achieve the desired concentration in the oral solution, as known in the art. Oral solution embodiments include formulations containing cannabidiol dissolved in water-insoluble solvents, such as long-chain triglycerides, peanut oil, corn oil, soybean oil, sesame oil, olive oil, peppermint oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides. Medium-chain triglycerides may be synthetic or derived from coconut oil and palm kernel oil. Other water-insoluble solvents include beeswax, dl-α-tocopherol (vitamin E), and oleic acid.

[0051]

[0063] When in the form of an oral solution, cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof can be present in a concentration of from about 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL. Additionally or alternatively, the oral solution can contain cannabidiol in a concentration of up to about 350 mg / mL, up to 300 mg / mL, or up to 250 mg / mL. In some embodiments, the oral solution contains cannabidiol in an amount of 50 to 125 mg / mL, for example, about 100 mg / mL.

[0052]

[0064] When in the form of an injectable formulation, cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof may be present in a concentration of at most 350 mg / mL, 300 mg / mL, or 250 mg / mL and / or at least 200 mg / mL, 150 mg / mL, or 100 mg / mL. In one embodiment, the pharmaceutically active agent is present in a concentration of about 250 mg / mL.

[0053]

[0065] The compositions contemplate using one or more pharmaceutically active agents selected from the group including cannabidiol and pharmaceutically acceptable prodrugs, derivatives, salts and solvates thereof.

[0054]

[0066] Additional pharmaceutically active agents and excipients

[0067] The description of cannabidiol and / or its pharmaceutically acceptable prodrugs, derivatives, salts, and solvates herein does not exclude combination therapy involving other pharmaceutically active agents. The description also does not exclude compositions containing additional pharmaceutically active agents. However, in some embodiments, cannabidiol alone is used to treat or prevent recurrent pericarditis. In some embodiments, cannabidiol is administered in combination with a therapeutic dose of another active agent, such as a nonsteroidal anti-inflammatory drug, aspirin, steroid, colchicine, and / or anakinra. In some embodiments, cannabidiol is used to treat recurrent pericarditis that is not adequately controlled by other agents.

[0055]

[0068] The composition may also contain additional pharmaceutically acceptable additives, provided that these ingredients do not impair the basic novel properties of the present invention. For example, oral solutions according to the present invention may contain an effective amount of at least one lipophilic antioxidant to improve shelf life. The at least one antioxidant may be selected from the group consisting of vitamin E (also known as α-tocopherol), carotenoids (xanthophylls and carotenes), propyl gallate, lecithin, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and monothioglycerol tert-butylhydroquinone (TBHQ). What constitutes an "effective amount" depends on the identity of the compound. Generally, the total amount of antioxidants will be greater than about 0.01% w / v and less than about 1.5% w / v. In some embodiments, the amount is greater than about 0.1% w / v and less than about 1% w / v.

[0056]

[0069] Additional additives contemplated for use in the practice of the present disclosure are those available to one of skill in the art, such as those found in the United States Pharmacopeia, Volume II and the National Formulary, Volume XVII, US Pharmacopeia Convention, Inc., Rockville, Md. (1989).

[0057]

[0070] Methods of Treatment and Administration

[0071] To treat or prevent recurrent pericarditis, cannabidiol and / or its pharmaceutically acceptable prodrugs, derivatives, salts and solvates can be administered in various ways, including orally and parenterally, as known in the art. The term "parenteral" includes, but is not limited to, intravenous (IV) injection, subcutaneous (SC) injection, intraperitoneal (IP) injection, and intramuscular (IM) injection. The dose of cannabidiol administered parenterally can be lower than the dose administered orally, because orally administered cannabidiol usually has lower bioavailability.

[0058]

[0072] The parenteral composition can be administered at least once a month, at least once every two weeks, at least once a week, or at least once every 6, 5, 4, 3, 2, or 1 day. The parenteral composition can also be administered at least twice a day. The oral composition can be administered at least once a week, at least once every 2 days, or 1 day, or at least twice a day.

[0059]

[0073] For parenteral compositions, at least about 0.01 mg, 0.1 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of cannabidiol per kg body weight, and / or up to about 30 mg, 28 mg, 26 mg, 24 mg, 22 mg, or 20 mg of cannabidiol per kg body weight may be administered per dose. Preferably, the dose is at least 1 mg of cannabidiol per kg body weight.

[0060]

[0074] For oral compositions, at least about 0.1 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of cannabidiol per kg body weight can be administered per dose.

[0061]

[0075] The duration of treatment can be 6, 5, 4, 3, or 2 months, or 8, 7, 6, 5, 4, 3, 2, or 1 week. It is also contemplated that in the case of chronic conditions (e.g., recurrent pericarditis), the duration of treatment can be indefinite.

[0062]

[0076] In one embodiment, the pharmaceutically active agent is administered orally, twice daily at a dose of from about 10 mg / kg body weight, hi another embodiment, the pharmaceutically active agent is administered subcutaneously, at least once weekly at a dose of from about 5 to 10 mg / kg body weight per dose.

[0077] [Example]

[0063]

[0078] The following experiments were carried out using synthetic cannabidiol (Cas number 13956-29-1) with a purity of 100%±2%.

[0064]

[0079] The following abbreviations are used in the experimental and / or figure descriptions that follow:

[0080] CNT = control

[0081] LPS = lipopolysaccharide

[0082] ATP = adenosine triphosphate

[0083] CBD = Cannabidiol (synthetic, pharmaceutical grade)

[0084] NaCl = normal saline or saline

[0085] Veh = vehicle

[0065]

[0086] Example 1A - Effect of 10 μM CBD on IL-1β levels in an in vitro NLRP3 inflammasome activation model

[0087] Experiments were performed as follows to determine the effect of 10 μM cannabidiol on NLRP3 inflammasome activation in an in vitro model.

[0066]

[0088] J774A.1 mouse macrophages were cultured in 96-well plates (15,000 cells / well) and divided into the following groups, each of which received various treatments described below for 6 hours: 1. Group 1 (CNT) - Cells received nothing during the 6 hour treatment period. 2. Group 2 (LPS) - Cells were treated with LPS (1 μg / ml) for 6 hours. 3. Group 3 (ATP) - Cells were left untreated for 5.5 hours, then treated with ATP (5 mM) for the last 30 minutes. 4. Group 4 (LPS+ATP)—Cells were treated with LPS (1 μg / mL) for 5.5 hours and ATP (5 mM) for the last 30 minutes. 5. Group 5 (CBD) - Cells were treated with cannabidiol (10 μM) solubilized in methanol for 6 hours. 6. Group 6 (CBD+LPS+ATP) - Cells were treated with cannabidiol (10 μM) solubilized in methanol and LPS (1 μg / mL) for 5.5 hours, with ATP (5 mM) administered for the last 30 minutes.

[0067]

[0089] After 6 hours, 100 µL samples of cells were collected from each well and loaded as single points in a specific ELISA assay. This assay was used to measure the amount of IL-1β secreted by macrophages in each sample. IL-1β is an indicator of NLRP3 inflammasome activation and positively correlates with NLRP3 inflammasome activation. The results are summarized in Table 1A.1 and Figure 1A.

[0068]

[0090] [Table 1]

[0069]

[0091] Figure 1A shows that cells in Group 4 (LPS + ATP) had significantly higher IL-1β levels compared to cells in Group 1 (CNT). Cells in Group 6 (CBD + LPS + ATP) had significantly lower IL-1β levels than cells in Group 4 (LPS + ATP). These results indicate that cannabidiol was effective in attenuating the increase in IL-1β induced by administration of LPS and ATP in this in vitro model of NLRP3 inflammasome activation in J774A.1 mouse macrophages.

[0070]

[0092] Table 1A.1 shows that cannabidiol attenuated the increase in IL-1β by more than 70%, calculated as follows:

[0093] 449.13[LPS+ATP]-6.38[CNT]=442.75

[0094] 118.73[LPS+ATP+CBD]-6.38[CNT]=112.35

[0095] [(442.75-112.35)÷442.75]×100=74.62%

[0071]

[0096] The experiment was repeated and the results are shown in Tables 1A.2 and 1A.3 below.

[0072]

[0097] [Table 2]

[0073]

[0098] [Table 3]

[0074]

[0099] The mean and SEM values for the data in Tables 1A.2 and 1A.3 are presented below in Table 1A.4.

[0075] [000100] [Table 4]

[0076] [000101] Table 1A.4 shows that cannabidiol attenuated the increase in IL-1β by approximately 97.65%, or greater than 97%, calculated as follows: [000102] 464.65[LPS+ATP]-8.72[CNT]=455.93 [000103] 19.44[LPS+ATP+CBD]-8.72[CNT]=10.72 [000104] [(455.93-10.72)÷455.93]×100=97.65%

[0077] [000105] Example 1B - Effect of various concentrations of cannabidiol on IL-1β levels in an in vitro NLRP3 inflammasome activation model [000106] Experiments were performed using the in vitro model of Example 1A to evaluate the effects of various doses of cannabidiol (10 μM, 1 μM, 0.1 μM, and 0.01 μM). In these experiments, J774A.1 mouse macrophages were cultured in 96-well plates (15,000 cells / well) and divided into the following groups, which received various treatments described below for 6 hours: 1. Group 1 (control) - Cells received nothing during the 6 hour treatment period. 2. Group 2 (LPS+ATP) - Cells were treated with LPS (1 μg / mL) for 5.5 hours and ATP (5 mM) for the last 30 minutes. 3. Group 3 (LPS+ATP+CBD10) - Cells were treated with cannabidiol (10 μM) solubilized in methanol and LPS (1 μg / mL) for 5.5 hours, with ATP (5 mM) administered for the last 30 minutes. 4. Group 4 (LPS+ATP+CBD1)—Cells were treated with cannabidiol (1 μM) solubilized in methanol and LPS (1 μg / mL) for 5.5 hours, with ATP (5 mM) administered for the last 30 minutes. 5. Group 5 (LPS+ATP+CBD0.1)—Cells were treated with cannabidiol (0.1 μM) solubilized in methanol and LPS (1 μg / mL) for 5.5 hours, with ATP (5 mM) administered for the last 30 minutes. 6. Group 6 (LPS+ATP+CBD0.01)—Cells were treated with cannabidiol (0.01 μM) solubilized in methanol and LPS (1 μg / mL) for 5.5 hours, with ATP (5 mM) administered for the last 30 minutes.

[0078] [000107] After 6 hours, 100 μL of cell samples were collected from each well and loaded as a single point in a specific ELISA assay, which was used to measure the amount of IL-1β in each sample. The results are summarized in Figure 1B, which shows that cannabidiol was effective in attenuating the increase in IL-1β in a dose-dependent manner, i.e., the higher the cannabidiol concentration, the greater the level of attenuation of IL-1β secretion. In this experiment, groups corresponding to Groups 2, 3, and 5 (LPS alone, ATP alone, and CBD alone) in Example 1A were not tested. This is because they were already tested in Example 1A and found to be indistinguishable from the control group. This was expected, since LPS alone, ATP alone, and CBD alone were not expected to activate the NLRP3 inflammasome.

[0079] [000108] Example 1C - Effect of 10 μM cannabidiol on IL-6, pro-IL-1β mRNA, and NLRP3 mRNA in an in vitro model of inflammation [000109] Experiments were performed to evaluate the anti-inflammatory activity and mechanism of action of cannabidiol. IL-6 secretion and transcription of pro-IL-1β mRNA and NLRP3 mRNA, components of the NLRP3 inflammasome, are regulated by the NF-κβ pathway and activated by LPS.

[0080] [000110] In the first experiment, J774A.1 mouse macrophages were cultured in 96-well plates (15,000 cells / well) and divided into the following groups, each of which received various treatments described below for 6 hours: 1. Group 1 (control) - Cells received nothing during the 6 hour treatment period. 2. Group 2 (LPS) - Cells were treated with LPS (1 μg / ml) for 6 hours. 3. Group 3 (CBD) - Cells were treated with cannabidiol (10 μM) solubilized in methanol (MetOH) for 6 hours. 4. Group 4 (LPS+CBD) - Cells were treated with cannabidiol (10 μM) solubilized in methanol and LPS (1 μg / mL) for 6 hours.

[0081] After 6 hours, 100 μL samples of cells were collected from each well and loaded as single points in a specific ELISA assay, which was used to measure the amount of IL-6 in each sample. The results, summarized in Figure 1C, show that LPS significantly increased the levels of IL-6 secreted by macrophages, and that cannabidiol completely attenuated this increase. Without wishing to be bound by theory, it is possible that the anti-inflammatory effects of cannabidiol extend beyond inhibition of the NLRP3 inflammasome pathway, as IL-6 secretion has been shown to be independent of the NLRP3 inflammasome pathway. A second experiment was performed to evaluate the effects of cannabidiol on the transcription of components of the NLRP3 inflammasome, namely, pro-IL-1β mRNA and NLRP3 mRNA. In this second experiment, J774A.1 mouse macrophages were cultured in individual plates (1,000,000 cells / well) and divided into the following groups, each of which received various treatments described below for 6 hours: 1. Group 1 (control) - Cells received nothing during the 6 hour treatment period. 2. Group 2 (LPS) - Cells were treated with LPS (1 μg / ml) for 6 hours. 3. Group 3 (LPS+CBD) - Cells were treated with cannabidiol (10 μM) solubilized in methanol and LPS (1 μg / mL) for 6 hours.

[0082] At the end of the 6-hour treatment period, samples were collected from each group and processed using polymerase chain reaction (PCR) to measure the levels of pro-IL-1B mRNA and NLRP3 mRNA transcription in the samples. The results are summarized in Figure 1D and Figure 1E. As shown in these figures, LPS increased the levels of transcription of these NLRP3 inflammasome components, and cannabidiol (10 μM) significantly attenuated these increases. These results further support the efficacy of cannabidiol in alleviating inflammation and explain its effect on the NLRP3 inflammasome. Because pericarditis involves activation of (at least) the NLRP3 inflammasome, the suppression of transcription of its components indicates that cannabidiol may be useful in treating or preventing pericarditis, including recurrent pericarditis.

[0083] [000113] Example 2 - In Vivo Testing of Cannabidiol [000114] Experiments were performed using a mouse model of pericarditis described in Mauro et al. (10), which is incorporated herein by reference for its disclosure of the mouse model.

[0084] [000115] Institute of Cancer Research (IRC) adult mice (10 weeks old) supplied by Harlan Laboratories (Harlan Sprague Dawley Inc.) were used and divided into the following treatment groups, each consisting of 4-5 mice: 1. Group 1 (NaCl+Veh) - Mice received normal saline (0.9% w / v NaCl) following surgical procedures and were subsequently treated with a vehicle consisting of ethanol:Cremophor EL:water (1:1:18) for 7 days. 2. Group 2 (NaCl+) - Mice received normal saline (0.9% w / v NaCl) following the surgical procedure and were subsequently treated with cannabidiol at a dose of 10 mg / kg for 7 days. The cannabidiol was dissolved in the same vehicle used for Group 1. 3. Group 3 (Zym+Veh) - Mice received Zymosan A at the surgical procedure described below, followed by 7 days of treatment with a vehicle identical to that used in Group 1. 4. Group 4 (Zym+CBD 10 mg / kg) - Mice were administered Zymosan A at the surgical procedure described below and subsequently treated with cannabidiol at a dose of 10 mg / kg for 7 days. The cannabidiol was dissolved in the same vehicle used in Group 1. 5. Group 5 (Zym+CBD 1 mg / kg) - Mice were administered Zymosan A at the surgical procedure described below, followed by treatment with cannabidiol at a dose of 1 mg / kg for 7 days. The cannabidiol was dissolved in the same vehicle used in Group 1.

[0085] [000116] Surgical preparation of mice [000117] Mice in all four treatment groups were anesthetized, orally intubated, and placed in the right lateral position. A left thoracotomy was then performed. Under direct visualization, 1 mg of zymosan A (also referred to herein as "zymosan") dissolved in 50 μl of sterile normal saline (0.9% w / v NaCl) was delivered using a 30-gauge needle into the pericardial cavity of mice in Groups 3 and 4 by carefully lifting the pericardial sac with forceps to ensure complete distribution of the solution into the pericardium. For mice in Groups 1 and 2, a sham surgery was performed by injecting an equal volume of sterile normal saline instead of zymosan A solution. All mice were administered analgesics perioperatively.

[0086] [000118] All groups were treated intraperitoneally (IP) with either cannabidiol dissolved in vehicle or vehicle alone daily for 7 days, with the first treatment administered approximately 30 minutes after surgery.

[0087] [000119] Transthoracic echocardiography On day 7, all mice underwent echocardiography under light anesthesia using a Prospect™ T1 ultrasound imaging system (Scintica, London, Canada). This procedure visualized the left ventricle in a two-dimensional (B-mode) image at the midventricular level in a parasternal short-axis view. Images were optimized for the anterior wall and gradually enlarged to visualize the anterior pericardial structures. After image optimization, monodimensional (M-mode) images were acquired at optimal temporal and spatial resolution. An examiner blinded to group assignment measured the maximum pericardial space between the two layers of the pericardium in both M-mode and B-mode. The pericardial space is a unidimensional measure of pericardial effusion.

[0088] [000121] The results for Groups 1 to 4 are summarized in Table 2.

[0089] [000122] [Table 5]

[0090] [000123] These results show that mice in Group 3 (Zym + Veh) had significantly larger pericardial cavities than mice in Group 1 (Saline + Veh). Mice in Group 2 (Saline + CBD) and Group 4 (Zym + CBD) did not have larger pericardial cavities than mice in Group 1 (Saline + Veh), and the differences between these groups were not statistically significant.

[0091] [000124] Cannabidiol attenuated the increase in pericardial space measurements by at least 85%, calculated as follows: [000125] 0.26125[Zym+Veh]-0.0982[Saline+Veh]=0.16305 [000126] 0.11775[Zym+CBD]-0.0982[Saline+Veh]=0.01955 [000127] [(0.16305)-(0.01955)]÷[0.16305]×100=approx. 88.01%

[0092] [000128] The above experiment was repeated using a lower dose of 1 mg / kg cannabidiol (group 5 mice). In this later experiment, cannabidiol was found to attenuate the increase in pericardial cavity measurements at this lower dose to the same extent as the 10 mg / kg dose of cannabidiol in the previous experiment. The results of both experiments are shown in Figure 2, and show no statistical difference between the pericardial cavity measurements of control group 1 (saline + Veh) and those of groups 4 (Zym + CBD 10 mg / kg) and 5 (Zym + CBD 1 mg / kg). Thus, these results indicate that cannabidiol was effective in attenuating the increase in pericardial cavity caused by administration of zymosan in this mouse model of pericarditis.

[0093] [000129] Histochemical examination [000130] On day 7 after echocardiography, mice were sacrificed, and hearts were removed and processed for pathological examination. Transverse sections of formalin-fixed, paraffin-embedded hearts were stained with hematoxylin and eosin. An examiner blinded to group assignment measured pericardial thickening using computerized morphometry with Image-Pro™ Plus 6.0 software (Media Cybernetics, Silver Spring, MD).

[0094] [000131] The results are summarized in Figure 3.

[0095] [000132] These results indicate that mice in Group 3 (Zym + Veh) had significantly increased pericardial thickening compared to mice in Group 1 (NaCl + Veh). Mice in Groups 2 (NaCl + CBD), 4 (Zym + CBD 10 mg / kg), and 5 (Zym + CBD 1 mg / kg) did not differ in pericardial thickening from mice in Group 1 (NaCl + Veh), and the differences between these groups were not statistically significant. These results indicate that cannabidiol was effective in both attenuating and preventing the increase in pericardial thickening caused by zymosan administration in this mouse model of pericarditis.

[0096] [000133] Human equivalent dose [000134] The human equivalent doses of 10 mg / kg and 1 mg / kg used above in mice are 0.81 mg / kg and 0.081 mg / kg, respectively. (21) This dose is likely applicable to parenteral formulations, since cannabidiol was administered parenterally in the in vivo mouse model above.

[0097] [000135] Statistical significance [000136] In the above experiments, data are expressed as continuous variables, mean and standard error, and comparisons were made between three or more groups at each time point using one-way ANOVA, followed by Sidak's test for multiple comparisons. P values less than 0.05 are indicated using a single asterisk (*). P values less than 0.01 are indicated using two asterisks (**). P values less than 0.001 are indicated using three asterisks (***). P values less than 0.0001 are indicated using four asterisks (****).

[0098] [000137] List of items [000138] The following is a non-exhaustive list of items provided by the present invention.

[0099] [000139] Item 1. Use of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, in the treatment or prevention of recurrent pericarditis, or in the preparation of a medicament for the treatment or prevention of recurrent pericarditis.

[0100] [000140] Item 2. Use of cannabidiol in the treatment or prevention of recurrent pericarditis or in the preparation of a medicament for the treatment or prevention of recurrent pericarditis.

[0101] [000141] Item 3. The use according to Items 1 or 2, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical product is used to prevent recurrent pericarditis.

[0102] [000142] Item 4. The use according to items 1 or 2, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical product is used to treat recurrent pericarditis.

[0103] [000143] Item 5. The use of any one of items 1 to 4, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical agent is effective to attenuate increased pericardial effusion in a subject.

[0104] [000144] Item 6. The use of any one of Items 1 to 4, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical product, is effective in preventing an increase in pericardial effusion in a subject.

[0105] [000145] Item 7. The use of any one of items 1 to 6, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical agent is effective in attenuating increased pericardial thickening in a subject.

[0106] [000146] Item 8. The use of any one of Items 1 to 6, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical agent is effective in preventing increased pericardial thickening in a subject.

[0107] [000147] Item 9. The use of any one of Items 1 to 8, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or pharmaceutical agent is effective in attenuating or preventing an increase in the level of at least one of interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA transcription, and NLRP3 mRNA transcription in a subject.

[0108] [000148] Item 10. The use of item 9, wherein the level of at least one of interleukin-1β (IL-1β) and interleukin-6 (IL-6) is reduced by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% compared to the level that would be present if cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or pharmaceutical agent is not administered to the subject.

[0109] [000149] Item 11. The use of any one of items 1-10, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is effective to reduce an increase in pericardial effusion by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by up to about 100%, compared to the amount of pericardial effusion that would be present if the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament were not administered to the subject.

[0110] [000150] Item 12. The use of any one of items 1 to 11, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is effective in reducing the increase in pericardial thickening by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by up to about 100%, compared to the pericardial thickening that would be present if the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament were not administered to the subject.

[0111] [000151] Item 13. The use according to any one of Items 1 to 12, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is synthetic.

[0112] [000152] Item 14. A method for treating or preventing recurrent pericarditis in a subject in need thereof, comprising administering to the subject an effective amount of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof.

[0113] [000153] Item 15. A method for treating or preventing recurrent pericarditis in a subject in need thereof, comprising administering to the subject an effective amount of cannabidiol.

[0114] [000154] Item 16. The method of items 14 or 15, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is administered orally.

[0115] [000155] Item 17. The method of item 16, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is administered at least once a week, at least every two days or once a day, or at least twice a day.

[0116] [000156] Item 18. The method of item 16 or 17, wherein at least about 0.1 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of cannabidiol per kg body weight is administered per dose.

[0117] [000157] Item 19. The method of any one of Items 16 to 18, wherein cannabidiol is administered twice daily at a dose from about 10 mg / kg body weight.

[0118] [000158] Item 20. The method of items 14 or 15, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is administered parenterally.

[0119] [000159] Item 21. The method of item 20, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is administered at least once a month, at least once every two weeks, at least once a week, or at least once every 6, 5, 4, 3, 2, or 1 day.

[0120] [000160] Item 22. The method of item 21, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is administered at least twice a day.

[0121] [000161] Item 23. The method of any one of Items 20-22, wherein at least about 0.01 mg, 0.1 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of cannabidiol per kg body weight and / or up to about 30 mg, up to 28 mg, up to 26 mg, up to 24 mg, up to 22 mg, or up to 20 mg of cannabidiol per kg body weight is administered per dose.

[0122] [000162] Item 24. The method of item 23, wherein the dose is at least 1 mg of cannabidiol per kg of body weight.

[0123] [000163] Item 25. The method of Item 20, wherein cannabidiol is administered subcutaneously at least once a week at a dose of about 5 to 10 mg / kg body weight.

[0124] [000164] Item 26. The method of any one of Items 14 to 25, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in preventing recurrent pericarditis.

[0125] [000165] Item 27. The method of any one of Items 14 to 25, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in treating recurrent pericarditis.

[0126] [000166] Item 28. The method of any one of Items 14 to 27, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to attenuate increased pericardial effusion in the subject.

[0127] [000167] Item 29. The method of any one of Items 14 to 27, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in preventing an increase in pericardial effusion in the subject.

[0128] [000168] Item 30. The method of any one of Items 14 to 29, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to attenuate increased pericardial thickening in the subject.

[0129] [000169] Item 31. The method of any one of Items 14 to 29, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in preventing increased pericardial thickening in the subject.

[0130] [000170] Item 32. The method of any one of Items 14 to 31, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in attenuating or preventing an increase in the level of at least one of interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA transcription, and NLRP3 mRNA transcription in a subject.

[0131] [000171] Item 33. The method of item 32, wherein the level of at least one of interleukin-1β (IL-β) and interleukin-6 (IL-6) is reduced by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% compared to the level that would be present if cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, were not administered to the subject.

[0132] [000172] Item 34. The method of any one of items 14 to 33, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to reduce the increase in pericardial effusion by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by up to about 100%, compared to the amount of pericardial effusion that would be present if cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, were not administered to the subject.

[0133] Item 35. The method of any one of items 14 to 34, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to reduce the increase in pericardial thickening by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or is effective to reduce by up to about 100%, compared to the amount of pericardial effusion that would be present if cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, were not administered to the subject.

[0134] [000174] Item 36. The method of any one of Items 14 to 35, further comprising the step of identifying a subject suffering from or at risk of suffering from recurrent pericarditis prior to said administering.

[0135] [000175] Item 37. The method of any one of Items 14 to 36, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is synthetic.

[0136] [000176] Item 38. Cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in the treatment or prevention of recurrent pericarditis.

[0137] [000177] Item 39. Cannabidiol for use in the treatment or prevention of recurrent pericarditis.

[0138] [000178] Item 40. Cannabidiol according to item 38 or 39, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in preventing recurrent pericarditis.

[0139] [000179] Item 41. Cannabidiol according to item 38 or 39, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in treating recurrent pericarditis.

[0140] [000180] Item 42. Cannabidiol according to any one of items 38 to 41, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in attenuating increased pericardial effusion in a subject.

[0141] [000181] Item 43. Cannabidiol according to any one of Items 38 to 41, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in preventing increased pericardial effusion in a subject.

[0142] [000182] Item 44. Cannabidiol according to any one of items 38 to 43, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in attenuating increased pericardial thickening in a subject.

[0143] [000183] Item 45. Cannabidiol according to any one of Items 38 to 43, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in preventing increased pericardial thickening in a subject.

[0144] [000184] Item 46. Cannabidiol according to any one of Items 38 to 45, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in attenuating or preventing an increase in the level of at least one of interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA transcription, and NLRP3 mRNA transcription in a subject.

[0145] [000185] Item 47. The cannabidiol according to any one of Items 38 to 46, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, which is synthetic.

[0146] [000186] Item 48. A composition comprising an effective amount of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, and an effective amount of a delivery vehicle, the composition being for use in treating or preventing recurrent pericarditis in a subject in need thereof.

[0147] [000187] Item 49. A composition comprising an effective amount of cannabidiol and an effective amount of a delivery vehicle, the composition being for use in treating or preventing recurrent pericarditis in a subject in need thereof.

[0148] [000188] Item 50. The composition of Item 48 or 49, for use in treating recurrent pericarditis in a subject in need thereof.

[0149] [000189] Item 51. The composition of Item 48 or 49, for use in preventing recurrent pericarditis in a subject in need thereof.

[0150] [000190] Item 52. The composition of any one of Items 48 to 51, wherein the composition is an oral solution and the cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof is present in a concentration of from about 50 mg / mL, from 75 mg / mL, from 100 mg / mL, from 150 mg / mL, or from 200 mg / mL, and / or up to about 350 mg / mL, 300 mg / mL, or 250 mg / mL.

[0151] [000191] Item 53. The composition of Item 52, wherein the oral solution contains cannabidiol in an amount of 50 to 125 mg / mL.

[0152] [000192] Item 54. The composition of item 53, wherein the oral solution contains cannabidiol in an amount of about 100 mg / mL.

[0153] [000193] Item 55. The composition of any one of Items 48 to 51, wherein the composition is an injectable formulation and the cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof is present in a concentration of up to about 350 mg / mL, up to 300 mg / mL, or up to 250 mg / mL, and / or from about 200 mg / mL, from 150 mg / mL, or from 100 mg / mL.

[0154] [000194] Item 56. The composition of item 55, wherein the cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof is present in a concentration of about 250 mg / mL.

[0155] [000195] The above experiments demonstrate that cannabidiol may be a novel strategy for the treatment and prevention of recurrent pericarditis. The above embodiments are intended for illustrative purposes only and are not intended to limit the scope of the invention as described herein and as defined by the following claims.

[0156] References 1. Adler Y, Charron P, Imazio M, et al., 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: the Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015;36:2921-64. 2. Imazio M, Gaita F, LeWinter M., Evaluation and treatment of pericarditis: a systematic review. JAMA 2015; 314:1498-506. 3. Bonaventura A, Montecucco F., Inflammation and pericarditis: are neutrophils actors behind the scenes? J Cell Physiol 2019; 234:5390-8. 4. Buckley LF, Viscusi MM, Van Tassell BW, Abbate A., Interleukin-1 blockade for the treatment of pericarditis. Eur Heart J Cardiovasc Pharmacother 2018; 4:46-53. 5. Toldo S, Abbate A., The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol 2018; 15:203-14. 6. Mauro AG, Bonaventura A, Mezzaroma E, Quader M, Toldo S., NLRP3 Inflammasome in Acute Myocardial Infarction. J Cardiovasc Pharmacol 2019; 74:175-87. 7. Chiabrando JG, Bonaventura A, Vecchie A, et al., Management of acute and recurrent pericarditis: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 75:76-92. 8. Bayes-Genis A, Adler Y, de Luna AB, Imazio M., Colchicine in pericarditis. Eur Heart J 2017;38: 1706-9. 9. Brucato A, Imazio M, Gattorno M, et al., Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA 2016; 316: 1906-12. 10. Mauro et al., The Role of NLRP3 Inflammasome in Pericarditis. JACC: BASIC TO TRANSLATIONAL SCIENCE Vol. 6, No. 2, 2021, pp. 137-150; doi.org / 10.1016 / j.jacbts.2020.11.016 11. "FDA Approves First Treatment for Disease That Causes Recurrent Inflammation in Sac Surrounding Heart". U.S. Food and Drug Administration (FDA). 18 March 2021 (fda.gov / drugs / news-events-human-drugs / fda-approves-first-treatment-disease-causes-recurrent-inflammation-sac-surrounding-heart). 12. Klein et al. Clinical Burden and Unmet Need in Recurrent Pericarditis: A Systematic Literature Review. Cardiology in Review; Vol. 30, No. 2, March / April 2022. 13. Liu et al. Inhibitory Effect of Cannabidiol on the Activation of NLRP3 Inflammasome Is Associated with Its Modulation of the P2X7 Receptor in Human Monocytes. J. Nat. Prod. 2020, 83, 6, 2025-2029 Publication Date:May 6, 2020. doi.org / 10.1021 / acs.jnatprod.0c00138. 14. Libro et al., (2016) Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front. Physiol.7:559. doi: 10.3389 / fphys.2016.00559. 15. Suryavanshi, S.V.; Zaiachuk, M.; Pryimak, N.; Kovalchuk, I.; Kovalchuk, O., Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro. Cells 2022, 11, 1391. doi.org / 10.3390 / cells11091391. 16. Suryavanshi SV, Kovalchuk I and Kovalchuk O, (2021) Cannabinoids as Key Regulators of Inflammasome Signaling: A Current Perspective. Front. Immunol. 11:613613. doi: 10.3389 / fimmu.2020.613613. 17. Stanley Christopher P., Hind William H., O’Sullivan Saoirse E., Is the cardiovascular system a therapeutic target for cannabidiol? Br J Clin Pharmacol / 75:2 / 313-322. doi: 10.1111 / j.1365-2125.2012.04351.x 18. Atalay Sinemyiz, Jarocka-Karpowicz Iwona, and Skrzydlewska Elzbieta, Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants 2020, 9, 21; doi:10.3390 / antiox9010021. 19. Sunda Falone, Arowolo Afolake, A molecular basis for the anti-inflammatory and anti-fibrosis properties of cannabidiol. The FASEB Journal. 2020;00:1-10. doi: 10.1096 / fj.202000975R. 20. Garza-Cervantes J.A., Ramos-Gonzalez M, Lozano O, Jerjes-Sanchez C, Garcia-Rivas G., Therapeutic Applications of Cannabinoids in Cardiomyopathy and Heart Failure. Hindawi Oxidative Medicine and Cellular Longevity Volume 2020, Article ID 4587024, 17 pages. doi.org / 10.1155 / 2020 / 4587024. 21. Nair Anroop B., Jacob Shery, A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. March 2016-May 2016; 7(2): 27-31. doi: 10.4103 / 0976-0105.177703

Claims

1. 10. Use of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, in the treatment or prevention of recurrent pericarditis, or in the preparation of a medicament for the treatment or prevention of recurrent pericarditis.

2. 10. Use of cannabidiol in the treatment or prevention of recurrent pericarditis or in the preparation of a medicament for the treatment or prevention of recurrent pericarditis.

3. 3. The use according to claim 1 or 2, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or pharmaceutical product is used to prevent recurrent pericarditis.

4. 3. The use according to claim 1 or 2, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or pharmaceutical product is used to treat recurrent pericarditis.

5. 5. The use of any one of claims 1 to 4, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is effective in attenuating or preventing an increase in pericardial effusion in a subject.

6. 6. The use of claim 5, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or pharmaceutical product is effective in preventing an increase in pericardial effusion in a subject.

7. 7. The use of any one of claims 1 to 6, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is effective in attenuating or preventing increased pericardial thickening in a subject.

8. 8. The use of claim 7, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or pharmaceutical product is effective in preventing increased pericardial thickening in a subject.

9. 9. The use of any one of claims 1 to 8, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is effective to attenuate or prevent an increase in the level of at least one of interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA transcription, and NLRP3 mRNA transcription in a subject.

10. 10. The use of claim 9, wherein the level of at least one of interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) is reduced by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% compared to the level that would be present if the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or pharmaceutical agent is not administered to the subject.

11. 11. The use of any one of claims 1 to 10, wherein the cannabidiol, or pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is effective to attenuate an increase in pericardial effusion by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or is effective to attenuate by up to about 100%, compared to the amount of pericardial effusion that would be present if the cannabidiol, or pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament were not administered.

12. 12. The use of any one of claims 1 to 11, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is effective to attenuate an increase in pericardial thickening by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or is effective to attenuate by up to about 100%, compared to the pericardial thickening that would be present if the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicament is not administered.

13. The use according to any one of claims 1 to 12, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is synthetic.

14. A method for treating or preventing recurrent pericarditis in a subject in need thereof, comprising administering to the subject an effective amount of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof.

15. 1. A method of treating or preventing recurrent pericarditis in a subject in need thereof, comprising administering to said subject an effective amount of cannabidiol.

16. 16. The method of claim 14 or 15, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in preventing recurrent pericarditis.

17. 16. The method of claim 14 or 15, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in treating recurrent pericarditis.

18. 18. The method of any one of claims 14 to 17, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to attenuate or prevent an increase in pericardial effusion in the subject.

19. 19. The method of claim 18, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to prevent an increase in pericardial effusion in the subject.

20. 20. The method of any one of claims 14 to 19, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to attenuate or prevent increased pericardial thickening in the subject.

21. 21. The method of claim 20, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to prevent increased pericardial thickening in the subject.

22. 22. The method of any one of claims 14-21, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to attenuate an increase in the level of at least one of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA transcription, and NLRP3 mRNA transcription in the subject.

23. 23. The method of claim 22, wherein the level of at least one of interleukin-1 beta (IL-β) and interleukin-6 (IL-6) is attenuated by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% compared to the level that would be present if the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, were not administered to the subject.

24. 24. The method of any one of claims 14-23, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to attenuate an increase in pericardial effusion by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or is effective to attenuate by up to about 100%, compared to the amount of pericardial effusion that would be present if the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, were not administered to the subject.

25. 25. The method of any one of claims 14-24, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective to attenuate an increase in pericardial thickening by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or is effective to attenuate by up to about 100%, compared to the pericardial thickening that would be present if the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is not administered to the subject.

26. 26. The method of any one of claims 14 to 25, further comprising the step of identifying a subject suffering from or at risk of suffering from recurrent pericarditis prior to said administering.

27. 27. The method of any one of claims 14 to 26, wherein the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is synthetic.

28. 1. Cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in the treatment or prevention of recurrent pericarditis.

29. Cannabidiol for use in the treatment or prevention of recurrent pericarditis.

30. 30. Cannabidiol according to claim 28 or 29, or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof, for use in the prevention of recurrent pericarditis.

31. 30. Cannabidiol according to claim 28 or 29, or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof, for use in the treatment of recurrent pericarditis.

32. 32. Cannabidiol according to any one of claims 28 to 31, or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof, for use in attenuating or preventing increased pericardial effusion in a subject.

33. 33. Cannabidiol as described in claim 32, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in preventing increased pericardial effusion in a subject.

34. 34. Cannabidiol according to any one of claims 28 to 33, or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof, for use in attenuating or preventing increased pericardial thickening in a subject.

35. 35. Cannabidiol as described in claim 34, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in preventing increased pericardial thickening in a subject.

36. 36. Cannabidiol according to any one of claims 28 to 35, or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof, for use in attenuating an increase in the level of at least one of interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA transcription, and NLRP3 mRNA transcription in a subject.

37. 37. Cannabidiol according to any one of claims 28 to 36, or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof, which is synthetic.

38. A composition comprising an effective amount of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, and an effective amount of a delivery vehicle, said composition being for use in treating or preventing recurrent pericarditis.

39. 1. A composition comprising an effective amount of cannabidiol and an effective amount of a delivery vehicle, said composition being for use in treating or preventing recurrent pericarditis.

40. 40. The composition of claim 38 or 39 for use in treating recurrent pericarditis.

41. 40. The composition of claim 38 or 39 for use in the prevention of recurrent pericarditis.

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