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]

[0001] Cross - reference to Related Applications

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

[0002]

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

[0005]

Background Art

[0003]

[0006] Pericarditis is caused by an intense inflammatory reaction of the pericardium. This reaction involves the activation of an intracellular macromolecular complex called the NLRP3 (NACHT, leucine - rich repeat, and pyrin domain - containing protein 3) inflammasome. The NLRP3 inflammasome triggers an inflammatory process that, upon sensing damage and stress, results in the release of inflammatory cytokines that act as downstream mediators such as interleukin - 1β.

[0004]

[0007] Pericarditis can be classified into acute pericarditis, frequent pericarditis, recurrent pericarditis, and chronic pericarditis. Acute pericarditis is a clinical syndrome characterized by a single episode that resolves spontaneously or after treatment. Treatment typically consists of nonsteroidal anti-inflammatory drugs, aspirin, steroids, colchicine, and anakinra (4, 7, 8, 9). Acute pericarditis was reported at a rate of 27.7 cases per 100,000 person-years in Italian metropolitan areas, accounting for 0.1% of all hospitalizations for chest pain and 5% of emergency room admissions (2). Recurrent pericarditis (RP) is diagnosed when there is an asymptomatic period of at least 4-6 weeks after an indicative acute episode, followed by a subsequent episode. RP occurs in 15-30% of patients with pericarditis, and some patients have been reported to experience multiple relapses thereafter. The cause of recurrence can be inappropriate treatment of the initial attack, or it can be due to an insufficient 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 damage to the mesothelial cells of the pericardium (4). It is thought to be triggered by a “stimuli” such as viruses or cell fragments after viral infection (5, 6). It may also be triggered by cardiac procedures, such as cardiac surgery (especially coronary artery bypass grafting), pacemaker implantation, radiofrequency ablation, transcatheter aortic valve implantation, and rarely percutaneous coronary intervention (7).

[0006]

[0009] According to Klein et al. (12), whose entire content is incorporated herein by reference, there remains a high but unmet need for FDA-approved, safe, and available treatments that can restore recurrent attacks and reduce the risk of recurrence without imposing an excessive procedural burden on patients. Since the publication of Klein et al., the FDA has approved lilonacept (Arcalyst®), an interleukin-1 (IL-1) receptor blocker, as an orphan drug for the treatment of recurrent pericarditis (RP) and for reducing the risk of recurrence in adult patients and children aged 12 years and older (11).

[0007]

[0010] Cannabidiol is a low-molecular-weight, lipophilic, non-psychoactive compound naturally occurring in the plant Cannabis sativa. Due to its favorable safety profile and minimal side effects, interest in this compound has been growing in recent years. Several in vitro and in vivo studies have demonstrated its anti-inflammatory properties, and its use in the treatment of various heart conditions has been suggested in the literature. However, the clinical efficacy of cannabidiol in the treatment of pericarditis remains unclear. [Overview of the project] [Problems that the invention aims to solve]

[0008]

[0011] There is a continuing need for alternative therapeutic substances and methods for treating recurrent pericarditis. This invention aims to address this need.

[0012] [Means for solving the problem]

[0009]

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

[0010]

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

[0012]

[0016] According to a third aspect, the present invention provides a method for treating or preventing recurrent pericarditis in a subject requiring treatment or prevention of recurrent pericarditis, comprising: identifying a subject (optionally) who has or is at risk of developing 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 cannabidiol and a pharmaceutically active agent selected from the group comprising pharmaceutically acceptable prodrugs, derivatives, salts, and solvates thereof, and a pharmaceutically active amount of a delivery vehicle, the composition being used for 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 this use and method involve the use of a pharmaceutically active agent to prevent recurrent pericarditis. In other embodiments, the pharmaceutically active agent is used to treat recurrent pericarditis.

[0017]

[0021] A pharmaceutically active agent (e.g., cannabidiol) can be used in subjects (e.g., subjects with or at risk of developing recurrent pericarditis) to reduce pericardial effusion and / or increased pericardial thickness by at least approximately 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or up to approximately 100%, compared to the amount of pericardial effusion and / or pericardial thickness that would be present without the administration of the pharmaceutically active agent.

[0018]

[0022] Furthermore, pharmaceutically active agents (e.g., cannabidiol) can also be used to reduce inflammatory responses. For example, pharmaceutically active agents can be used to reduce the transcription of pro-IL-1β mRNA and / or NLRP3 mRNA, which are components of the NLRP3 inflammasome. Pharmacologically 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 approximately 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% compared to the release of IL-1β and / or IL-6 that would occur without administration of the pharmaceutically active agent.

[0019]

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

[0023] [Brief explanation of the drawing]

[0020] [Figure 1A]

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

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

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

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

[0029] Bar graph showing the effect of a 10 μM dose of cannabidiol on the level of NLRP3 mRNA transcription in the same another in vitro model. [Figure 2]

[0030] Bar graph showing the effects of two doses (10 mg / kg and 1 mg / kg) of cannabidiol on the pericardial cavity (an indicator of pericardial fluid retention) in an in vivo model of pericarditis. And [Figure 3]

[0031] Bar graph showing the effect of cannabidiol (10 mg / kg) on pericardial hypertrophy in the same in vivo model of pericarditis.

[0032]

Mode for Carrying Out the Invention

[0021]

[0033] Definitions

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

[0022]

[0035] As used herein, the term “pharmaceutically active agent” means a drug or activator intended for use in a subject to treat or prevent a disease, illness, physical injury, or pathological condition, or to affect the state, condition, or function of the body, and which can be used as disclosed herein. Drugs used can be found in references such as the Rote List or the Merck Index. An example that can be cited is 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 amounts up to 100-X% by weight, based on the total weight of the composition. The purity of the components can be determined by high-performance liquid chromatography (HPLC) or by 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 human.

[0025]

[0038] As used herein, the terms “to treat” and similar expressions mean to halt, delay, or reduce the progression of a condition, disorder, or disease, or to reduce the symptoms or severity of such symptoms. The terms “to prevent” and similar expressions mean to prevent, delay, or reduce the onset of a condition, disorder, or disease, and / or the risk of developing them. These terms encompass, but do not necessarily exclude, “improving the quality of life,” “extending life,” and “improving clinical outcomes” for individuals who have or are at risk of developing a condition, disorder, or disease.

[0026]

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

[0027]

[0040] The phrases "at least one," "one or more," and "and / or" are open-ended expressions that can be both associative and associative in their usage. For example, each of the expressions "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," and "A, B, and / or C" means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together.

[0028]

[0041] The terms “one (a)” or “one (an)” mean “one or more.” Therefore, the terms “one (a)” (or “one (an)”), “one or more,” and “at least one” are interchangeable in this specification. It should also be noted that the term “or” is used to mean “and / or” unless the context explicitly negates it. To avoid ambiguity, in this specification, when we refer to the use of cannabidiol to treat or prevent recurrent pericarditis, we mean the use of cannabidiol to treat and / or prevent recurrent pericarditis.

[0029]

[0042] The term "comprising" means "including indefinitely." Therefore, for example, a composition containing a list of compounds, components, or elements may contain additional compounds, components, or elements not explicitly listed. It should also be noted that the terms "comprising," "including," "containing," and "having" can be used interchangeably.

[0030]

[0043] The term "consists of" means that it includes the integers listed but does not include any additional integers, however, in the case of compounds or components, other compounds or components that may be present as natural or commercial impurities or additives are not excluded. Natural or commercial impurities and additives are obvious to those skilled in the art. For example, synthetic cannabidiol may contain impurities of up to about 0.5% w / w, such as residual solvents and by-products of the manufacturing process.

[0031]

[0044] The term "becomes substantial from" means 「 The complete sets listed (e.g., compounds, processes, components, etc.) and any additional complete sets that do not substantially affect the fundamental novel properties of the present invention. of include 」 This means that the fundamental novel properties of the present invention are the beneficial effects of cannabidiol, its pharmaceutically acceptable prodrugs, derivatives, salts, and solvates in the treatment and / or prevention of recurrent pericarditis.

[0032]

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

[0033]

[0046] The terms "%w / v" and "w / v%" and their variations mean that the mass in grams of a solute is divided by the volume in milliliters of the solution in which it is dissolved, and then multiplied by 100. For example, a certain solute quality that dissolve quality A formulation containing 10 grams per 25 mL of solution containing 40 w / v% quality This will result in a value that can be calculated as follows: (10 ÷ 25) × 100 = 40 w / v%.

[0034]

[0047] The term "approximately" refers to variations in expressed quantities that may occur, for example, through measurement and liquid handling procedures used to prepare a pharmaceutical formulation, variations due to differences in the manufacture, source, or purity of the components used to prepare the formulation, and / or differences in equilibrium conditions or reaction levels of the components in the formulation obtained from the initial mixture. For clarity, the term "approximately" includes variations of up to ±5% or ±10% of the expressed value. Whether or not a value is modified with the term "approximately," the claims include equivalents of that value.

[0035]

[0048] As used herein, the term “effective amount” means the amount that will produce the desired effect based on the purpose and function of the components in the present invention as disclosed herein. “Desired effect” includes the absence of toxicity. For example, an effective amount of a pharmaceutically active agent is the amount that is effective in producing a therapeutic effect while avoiding the toxicity that may occur with long-term chronic administration. An effective amount of a solvent is the amount that is effective in solubilizing the other or remaining components of a formulation, either alone or in combination with other components. What constitutes an effective amount can be determined by a person skilled in the art through routine experimentation, taking into account the teachings herein and / or public domain information.

[0036]

[0049] As used herein, the expression “Y-free” means that “Y” is not intentionally added, but may be present as an impurity or due to other factors. For clarification, “Y-free” formulations either contain no Y, or contain Y in amounts up to 0.01% w / v, 0.02% w / v, 0.03% w / v, 0.04% w / v, 0.05% w / v, 0.06% w / v, 0.07% w / v, 0.08% w / v, 0.09% w / v, 0.1% w / v, 0.2% w / v, 0.3% w / v, 0.4% w / v, or 0.5% w / v relative to the formulation as a whole.

[0037]

[0050] The values ​​described herein include all values ​​that conform to the stated parameters, including values ​​not expressly stated. For example, values ​​less than 1.0 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. Therefore, all ranges disclosed herein should be understood to include all subranges contained therein. For example, the stated range "1 to 10" should be considered to include all subranges between the minimum value of 1 and the maximum value of 10 (including upper and lower limits), such as 1 to 6.3, 5.5 to 10, 2.7 to 6.1, etc.

[0038]

[0051] This specification acknowledges that any component may be omitted, even if it is not expressly named as included or excluded herein.

[0039]

[0052] Cannabidiol

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

[0040] [ka]

[0041]

[0054] Cannabidiol may be of natural or synthetic origin. Cannabidiol is derived from various hemp plants, including hemp, and can be purified using conventional methods. 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 in 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 may also be used in addition to or instead of cannabidiol to treat and / or prevent recurrent pericarditis.

[0043]

[0056] Cannabidiol prodrugs may include, for example, compounds that are chemically converted into an active form with medicinal effects by metabolic or other processes within 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 hydroxyl groups present in the molecular structure of cannabidiol. Exemplary cannabidiol prodrugs are described in U.S. Patent No. 8,293,786.

[0044]

[0057] The salt forms of cannabidiol may include any cannabidiol salt suitable for administration to mammals, 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, pyruvate, 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 the synthetic cannabidiol include residual solvents (e.g., methanol, n-heptane, dichloromethane, and triethylamine) and / or by-products or residues of the manufacture, such as olivetol, monobromo-cannabidiol, and tetrahydrocannabinol. Cannabidiol from plant sources may contain small amounts of other cannabinoids (e.g., cannabidivarin (CBDV) and butyl analogs of cannabidiol (cannabidibutol)), terpenes, solvents or components used in the purification process, and pesticide residues.

[0046]

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

[0047] [ka]

[0048]

[0060] In some embodiments, the compositions according to the present invention are THC-free. This means that THC is either 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 psychoactive or toxic effects, it would be desirable to reduce the level of THC to the lowest possible level, 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 entire composition.

[0049]

[0061] The composition may be in any dosage form known in the art, including, but not limited to, oral solutions, injections, tablets, gel capsules, chewing gums, and other dosage forms.

[0050]

[0062] Oral solutions and elixir formulations can be simple or quite complex and require many types of additives, such as water-soluble organic solvents, water-insoluble organic solvents, surfactants, buffers, sugars, flavoring agents, sweeteners, fragrances, colorants, antioxidants, and preservatives. Solutions may or may not contain water. To solubilize poorly water-soluble drugs, including cannabidiol, organic cosolvents are usually used to achieve the desired concentration in the oral solution, as is known in the art. Embodiments of oral solutions 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 seed oil. Other water-insoluble solvents include beeswax, dl-α-tocopherol (vitamin E), and oleic acid.

[0051]

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

[0052]

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

[0053]

[0065] This composition is intended to use one or more pharmaceutically active agents selected from the group comprising cannabidiol and pharmaceutically acceptable prodrugs, derivatives, salts, and solvates thereof.

[0054]

[0066] Additional pharmaceutically active drugs and excipients

[0067] The descriptions herein of cannabidiol and / or pharmaceutically acceptable prodrugs, derivatives, salts, and solvates thereof do not preclude combination therapies requiring other pharmaceutically active agents. The descriptions also do not preclude 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 another active agent in a therapeutic dose, such as a nonsteroidal anti-inflammatory drug, aspirin, a 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 components do not impair the fundamental novel properties of the present invention. For example, the oral solution according to the present invention may contain an effective amount of at least one lipophilic antioxidant to improve the shelf life. The at least one antioxidant may be vitamin E (also known as α-tocopherol), carotenoids (xanthophyll and carotene), propyl gallate, lecithin, ascorbyl palmitate, butylated hydroxyanisole (BHA), or butylated hydroxytoluene (BHT). 、 Monothioglycerol , and The compounds can be selected from the group consisting of tert-butylhydroquinone (TBHQ). What constitutes an "effective amount" depends on the compound. Generally, the total amount of antioxidant is more than about 0.01% w / v and less than about 1.5% w / v. In some embodiments, the amount is more than about 0.1% w / v and less than about 1% w / v.

[0056]

[0069] Additional additives intended for use in the implementation of this disclosure are available to those skilled in the art, for example, those found in United States Pharmacopeia Volume II and National Formulary Volume XVII, US Pharmacopeia Convention, Inc., Rockville, Md. (1989).

[0057]

[0070] Treatment and administration methods

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

[0058]

[0072] Parenteral compositions may be administered at least once a month, at least once every two weeks, at least once a week, or once every six, five, four, three, two, or one day. Parenteral compositions may also be administered at least twice a day. Oral compositions may be administered at least once a week, at least once every two days or one 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 of 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 20 mg of cannabidiol per kg of body weight can be administered per single dose. Preferably, the dose is at least 1 mg of cannabidiol per kg of 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 of body weight can be administered per single dose.

[0061]

[0075] The treatment period can be 6 months, 5 months, 4 months, 3 months, or 2 months, or 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week. In cases of chronic conditions (e.g., recurrent pericarditis), the treatment period may be uncertain.

[0062]

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

[0077] [Examples]

[0063]

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

[0064]

[0079] The following abbreviations are used in the descriptions of the experiments and / or drawings below.

[0080] CNT = Contrast

[0081] LPS = Lipopolysaccharide

[0082] ATP = Adenosine triphosphate

[0083] CBD = Cannabidiol (synthetically produced, pharmaceutical grade)

[0084] NaCl = normal physiological saline or physiological 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] The experiment was conducted 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), divided into the following groups, and each group was subjected to the various treatments described below over a period of 6 hours. 1. Group 1 (CNT) cells received no treatment during a 6-hour treatment period. 2. Group 2(LPS)- cells were administered LPS (1 μg / ml) over 6 hours. 3. Group 3(ATP)-cells were left untreated for 5.5 hours, and then ATP (5 mM) was administered for the last 30 minutes. 4. Group 4 (LPS+ATP) - Cells were administered LPS (1 μg / mL) for 5.5 hours, followed by ATP (5 mM) administration during the last 30 minutes. 5. Group 5(CBD)- cells were administered cannabidiol (10 μM) solubilized in methanol over a period of 6 hours. 6. Group 6(CBD+LPS+ATP)- cells were administered methanol-solubilized cannabidiol (10 μM) and LPS (1 μg / mL) over 5.5 hours, and ATP (5 mM) was administered during the last 30 minutes.

[0067]

[0089] After 6 hours, 100 μL of cell sample was collected from each well and loaded as a single point 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 is positively correlated 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 concentrations compared to cells in group 1 (CNT). Cells in group 6 (CBD+LPS+ATP) had significantly lower IL-1β concentrations than cells in group 4 (LPS+ATP). These results indicate that in this in vitro model of NLRP3 inflammasome activation in J774A.1 mouse macrophages, cannabidiol was effective in attenuating the LPS and ATP-induced increase in IL-1β.

[0070]

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

[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. The results are shown in Tables 1A.2 and 1A.3 below.

[0072]

[0097] [Table 2]

[0073]

[0098] [Table 3]

[0074]

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

[0075] [000100] [Table 4]

[0076] [000101] Table 1A.4 shows that cannabidiol reduced the increase in IL-1β by approximately 97.65%, or more than 97%, as calculated below. [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 - Effects of various concentrations of cannabidiol on IL-1β levels in an in vitro NLRP3 inflammasome activation model [000106] The experiment was 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 this experiment, J774A.1 mouse macrophages were cultured in 96-well plates (15,000 cells / well) and divided into the following groups, each group receiving the various treatments described below over 6 hours. 1. Group 1 (control) - No treatment was administered to the cells during a 6-hour treatment period. 2. Group 2 (LPS+ATP) - Cells were administered LPS (1 μg / mL) for 5.5 hours, followed by ATP (5 mM) administration during the last 30 minutes. 3. Group 3 (LPS+ATP+CBD10)-cells were administered methanol-soluble cannabidiol (10 μM) and LPS (1 μg / mL) over 5.5 hours, and ATP (5 mM) was administered during the last 30 minutes. 4. Group 4(LPS+ATP+CBD1)- cells were administered methanol-solubilized cannabidiol (1 μM) and LPS (1 μg / mL) for 5.5 hours, and ATP (5 mM) was administered during the last 30 minutes. 5. Group 5(LPS+ATP+CBD0.1)- cells were administered methanol-solubilized cannabidiol (0.1 μM) and LPS (1 μg / mL) over 5.5 hours, and ATP (5 mM) was administered during the last 30 minutes. 6. Group 6(LPS+ATP+CBD0.01)- cells were administered methanol-soluble cannabidiol (0.01 μM) and LPS (1 μg / mL) over 5.5 hours, and ATP (5 mM) was administered during the last 30 minutes.

[0078] [000107] After 6 hours, 100 μL of cell sample was collected from each well and loaded as a single point in a specific ELISA assay, and the amount of IL-1β in each sample was measured using this assay. The results are summarized in Figure 1B, which shows that cannabidiol was dose-dependently effective in attenuating the increase in IL-1β, i.e., the higher the concentration of cannabidiol, the greater the level of attenuation of IL-1β secretion. In this experiment, groups 2, 3, and 5 (LPS alone, ATP alone, and CBD alone) from Example 1A were not tested because they had already been tested in Example 1A and were found to be no different from the control group. This was expected because 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. The secretion of IL-6, as well as the transcription of pro-IL-1β mRNA and NLRP3 mRNA, which are 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), divided into the following groups, and each group was subjected to the various treatments described below over a period of 6 hours. 1. Group 1 (control) - No treatment was administered to the cells during a 6-hour treatment period. 2. Group 2(LPS)- cells were administered LPS (1 μg / ml) over 6 hours. 3. Group 3 (CBD) cells were administered cannabidiol (10 μM) solubilized in methanol (MetOH) for 6 hours. 4. Group 4 (LPS+CBD)- cells were administered methanol-solubilized cannabidiol (10 μM) and LPS (1 μg / mL) over a period of 6 hours.

[0081] [000111] After 6 hours, 100 μL of cell sample was collected from each well and loaded as a single point in a specific ELISA assay, and the amount of IL-6 in each sample was measured using this assay. The results are summarized in Figure 1C, which shows that LPS significantly increased the level of IL-6 secreted by macrophages, and that cannabidiol completely attenuated this increase. While we do not wish to be bound by theory, since IL-6 secretion has been shown to be independent of the NLRP3 inflammasome pathway, the anti-inflammatory effect of cannabidiol may not be limited to the inhibition of the NLRP3 inflammasome pathway. A second experiment was performed to evaluate the effect 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), divided into the following groups, and each group was subjected to the various treatments described below over a period of 6 hours. 1. Group 1 (control) - No treatment was administered to the cells during a 6-hour treatment period. 2. Group 2(LPS)- cells were administered LPS (1 μg / ml) over 6 hours. 3. Group 3 (LPS+CBD) cells were administered methanol-solubilized cannabidiol (10 μM) and LPS (1 μg / mL) over a period of 6 hours.

[0082] [000112] At the end of the 6-hour treatment period, samples were collected from each group and processed using polymerase chain reaction (PCR) to determine the presence of pro-IL-1 in the samples. βThe levels of mRNA and NLRP3 mRNA transcription were measured. The results are summarized in Figures 1D and 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. This result further supports the efficacy of cannabidiol in alleviating inflammation and further explains its effect on the NLRP3 inflammasome. Since pericarditis involves (at least) activation of the NLRP3 inflammasome, the suppression of transcription of its components suggests that cannabidiol may be useful in the treatment or prevention of pericarditis, including recurrent pericarditis.

[0083] [000113] Example 2 - Testing of cannabidiol in vivo [000114] The experiments were conducted using a mouse model of pericarditis described by Mauro et al. (10). This mouse model is incorporated herein by reference with respect to the disclosure of that mouse model.

[0084] [000115] Provided by Harlan Laboratories (Harlan Sprague Dawley Inc.) Institute of Cancer Research ICR Adult mice (10 weeks old) were used and divided into the following treatment groups, with each group consisting of 4-5 mice. 1. Group 1 (NaCl+Veh) mice were administered normal physiological saline (0.9% w / v NaCl) by the following surgical procedure, and subsequently treated for 7 days with a vehicle consisting of ethanol:cremofor EL:water (1:1:18). 2. Group 2 (NaCl+ CBD Mice were administered normal physiological saline (0.9% w / vNaCl) by the following surgical procedure, followed by treatment with cannabidiol at a dose of 10 mg / kg for 7 days. Cannabidiol was dissolved in the same vehicle used in Group 1. 3. Group 3 (Zym+Veh) mice were administered zymosan A by the following surgical procedure, and subsequently treated for 7 days with the same vehicle used in Group 1. 4. Group 4 (Zym + CBD 10 mg / kg) - Mice were administered zymosan A by the following surgical procedure, followed by treatment with cannabidiol at a dose of 10 mg / kg for 7 days. Cannabidiol was dissolved in the same vehicle used in Group 1. 5. Group 5 (Zym + CBD 1 mg / kg) mice were administered zymosan A by the following surgical procedure, followed by treatment with cannabidiol at a dose of 1 mg / kg for 7 days. Cannabidiol was dissolved in the same vehicle used in Group 1.

[0085] [000116] Surgical preparation of mice [000117] All mice in the four treatment groups were anesthetized, orally intubated endotracheally, and placed in the right lateral decubitus position. Left thoracotomy was then performed. Under direct visualization, 1 mg of zymosan A (hereinafter also referred to as "zymosan") dissolved in 50 μl of sterile normal saline (0.9% w / v NaCl) was delivered to the pericardial cavity of mice in groups 3 and 4 using a 30-gauge needle, by carefully lifting the pericardial sac with forceps to achieve complete distribution of the solution to the pericardium. For mice in groups 1 and 2, 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 received intraperitoneal (IP) treatment daily for 7 days with either cannabidiol dissolved in a vehicle or the vehicle alone. The first treatment was administered approximately 30 minutes after surgery.

[0087] [000119] Transthoracic echocardiography [000120] On day 7, echocardiography was performed on all mice under light anesthesia using a Prospect® T1 ultrasound imaging system (Scintica, London, Canada). In this procedure, the left ventricle was visualized in two-dimensional mode (B-mode) at the mid-ventricular level in a parasternal short-axis view. The image was optimized for the anterior wall, and the image was gradually magnified to visualize the anterior pericardial structure. After optimizing the image, mono-dimensional mode (M-mode) was acquired with optimal temporal and spatial resolution. Blinded examiners measured the maximum pericardial cavity between the two layers of the pericardium in both M-mode and B-mode. Pericardial cavity is a one-dimensional 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 indicate that the pericardial cavity was significantly larger in mice in group 3 (Zym + Veh) compared to mice in group 1 (saline + Veh). Mice in group 2 (saline + CBD) and group 4 (Zym + CBD) did not show a larger pericardial cavity than mice in group 1 (saline + Veh), and the difference between these groups was not statistically significant.

[0091] [000124] Cannabidiol attenuated the increase in pericardial cavity measurements by at least 85%, calculated as follows: [000125] 0.26125[Zym+Veh]-0.0982[physiological saline+Veh]=0.16305 [000126] 0.11775[Zym+CBD]-0.0982[Saline solution+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 of cannabidiol (group 5 mice). In this subsequent experiment, it was found that cannabidiol, even at this lower dose, attenuated the increase in pericardial cavity measurements to the same extent as cannabidiol at a dose of 10 mg / kg in the previous experiment. The results of both experiments are shown in Figure 2, and no statistically significant difference was observed between the pericardial cavity measurements of control group 1 (saline + Veh) and the respective pericardial cavity measurements of groups 4 (Zym + CBD 10 mg / kg) and 5 (Zym + CBD 1 mg / kg). Therefore, these results indicate that cannabidiol was effective in attenuating the increase in pericardial cavity induced by zymosan administration in this mouse model of pericarditis.

[0093] [000129] Histochemical examination [000130] On day 7 after echocardiography, the mice were disposed of, their hearts were removed and processed for pathological examination. Transverse sections of the formalin-fixed and paraffin-embedded hearts were stained with hematoxylin and eosin. Blinded examiners measured pericardial thickness using Image-Pro® Plus 6.0 software (Media Cybernetics, Silver Spring, MD), utilizing computer-aided morphometry.

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

[0095] [000132] These results indicate that pericardial thickening was significantly greater in mice of group 3 (Zym + Veh) compared to mice of group 1 (NaCl + Veh). Mice of group 2 (NaCl + CBD), group 4 (Zym + CBD 10 mg / kg ) The mice in group 1 and group 5 (Zym + CBD 1 mg / kg) showed no difference in pericardial thickening compared to the 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 in mice above are 0.81 mg / kg and 0.081 mg / kg, respectively (21). These doses appear applicable to parenteral formulations because cannabidiol was administered parenterally in the in vivo mouse model above.

[0097] [000135] Statistical significance [000136] In the above experiment, data were presented as continuous variables, with mean and standard error. Three or more groups were compared at each time point using one-way ANOVA, followed by multiple comparisons using the Sidak test. P-values ​​less than 0.05 are indicated with one asterisk (*). P-values ​​less than 0.01 are indicated with two asterisks (**). P-values ​​less than 0.001 are indicated with three asterisks (***). P-values ​​less than 0.0001 are indicated with 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 prophylaxis of recurrent pericarditis, or in the preparation of a drug for the treatment or prophylaxis of recurrent pericarditis.

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

[0101] [000141] Item 3. The use of cannabidiol, or any pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicinal product, as described in item 1 or 2, for the purpose of preventing recurrent pericarditis.

[0102] [000142] Item 4. The use of cannabidiol, or any pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicinal product, as described in item 1 or 2, for the treatment of recurrent pericarditis.

[0103] [000143] Item 5. The use described in any one of items 1 to 4, in which cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicinal product is effective in reducing the increase in pericardial effusion in a subject.

[0104] [000144] Item 6. Uses of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical product, that are effective in preventing an increase in pericardial effusion in a subject, as described in any one of items 1 to 4.

[0105] [000145] Item 7. Uses of any one of items 1 to 6 in which cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical product is effective in reducing the increase in pericardial thickening in a subject.

[0106] [000146] Item 8. Uses of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or a pharmaceutical product, that are effective in preventing increased pericardial thickening in a subject, as described in any one of items 1 to 6.

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

[0108] [000148] Item 10. Use as described in Item 9, wherein at least one level of interleukin-1β (IL-1β) 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 cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or drug were not administered to the subject.

[0109] [000149] Item 11. Uses of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicinal product, that are effective in attenuating an increase in pericardial effusion by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or 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, or medicinal product were not administered to the subject, as described in any one of items 1 to 10.

[0110] [000150] Item 12. Uses of cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicinal product, as described in any one of items 1 to 11, in which the cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicinal product thereof, is effective in attenuating an increase in pericardial thickening by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or is effective in attenuating it by about 100%, compared to the pericardial thickening that would be present if cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, or medicinal product thereof were not administered to the subject.

[0111] [000151] Item 13. Uses of cannabidiol, or any pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, which is synthetic, as described in any one of items 1 to 12.

[0112] [000152] Item 14. A method for treating or preventing recurrent pericarditis in a subject requiring treatment or prevention of recurrent pericarditis, 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 requiring treatment or prevention of recurrent pericarditis, comprising administering an effective amount of cannabidiol to the subject.

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

[0115] [000155] Item 17. The method according to 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, once a day, or at least twice a day.

[0116] [000156] Item 18. The method according to 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 of body weight is administered per single dose.

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

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

[0119] [000159] Item 21. The method according to 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 six days, five days, four days, three days, two days, or one day.

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

[0121] [000161] Item 23. The method according to any one of items 20 to 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 of 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 20 mg of cannabidiol per kg of body weight is administered per single dose.

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

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

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

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

[0126] [000166] Item 28. The method according to any one of items 14 to 27, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in reducing an increase in pericardial effusion in a subject.

[0127] [000167] Item 29. The method according to 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 a subject.

[0128] [000168] Item 30. The method according to any one of items 14-29, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in attenuating an increase in pericardial thickening in a subject.

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

[0130] [000170] Item 32. The method according to 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 transcription of at least one of the following in a subject: interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA, and NLRP3 mRNA.

[0131] [000171] Item 33. The method according to Item 32, wherein the level of at least one of interleukin-1β (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 cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof were not administered to the subject.

[0132] [000172] Item 34. The method according to any one of items 14 to 33, wherein cannabidiol, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, is effective in attenuating an increase in pericardial effusion by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or 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] [000173] Item 35. Cannabidiol, or any pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, increases pericardial thickening, which would be present in the pericardium if cannabidiol, or any pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof were not administered to the subject. thickening The method described in any one of items 14-34, which is effective in reducing the amount by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or is effective in reducing it by about 100%.

[0134] [000174] Item 36. The method according to any one of items 14 to 35, further comprising the step of identifying subjects who have recurrent pericarditis or are at risk of developing recurrent pericarditis prior to the administration.

[0135] [000175] Item 37. The method according to any one of items 14 to 36, wherein 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 prophylaxis of recurrent pericarditis.

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

[0138] [000178] Item 40. Cannabidiol as described in item 38 or 39, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in the prevention of recurrent pericarditis.

[0139] [000179] Item 41. Cannabidiol as described in Item 38 or 39, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in the treatment of recurrent pericarditis.

[0140] [000180] Item 42. Cannabidiol as described in any one of items 38-41, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in reducing the increase in pericardial effusion in a subject.

[0141] [000181] Item 43. Cannabidiol as described in any one of items 38-41, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in preventing increased pericardial effusion in subjects.

[0142] [000182] Item 44. Cannabidiol as described in any one of items 38-43, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in reducing the increase of pericardial thickening in subjects.

[0143] [000183] Item 45. Cannabidiol as described in any one of items 38-43, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in preventing increased pericardial thickening in subjects.

[0144] [000184] Item 46. Cannabidiol as described in any one of items 38-45, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof, for use in a subject to attenuate or prevent an increase in the transcription of at least one of the following: interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA, and NLRP3 mRNA.

[0145] [000185] Item 47. Cannabidiol as described in any one of items 38-46, which is synthetic, or a pharmaceutically acceptable prodrug, derivative, salt, or solvate thereof.

[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 used for the treatment or prevention of recurrent pericarditis in subjects requiring treatment or prevention of recurrent pericarditis.

[0147] [000187] Item 49. A composition comprising an effective amount of cannabidiol and an effective amount of a delivery vehicle, wherein the composition is intended for use in the treatment or prevention of recurrent pericarditis in subjects requiring treatment or prevention of recurrent pericarditis.

[0148] [000188] Item 50. The composition according to item 48 or 49, for use in the treatment of recurrent pericarditis in subjects requiring treatment for recurrent pericarditis.

[0149] [000189] Item 51. The composition according to item 48 or 49, for use in the prevention of recurrent pericarditis in subjects requiring prevention of recurrent pericarditis.

[0150] [000190] Item 52. A composition according to any one of items 48 to 51, wherein the composition is an oral solution and contains cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof in concentrations 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, up to 300 mg / mL, or up to 250 mg / mL.

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

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

[0153] [000193] Item 55. A composition according to any one of items 48 to 51, wherein the composition is an injectable preparation, and cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof is present in concentrations 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 according to item 55, wherein cannabidiol or a pharmaceutically acceptable prodrug, derivative, salt or solvate thereof is present at 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 for illustrative purposes only and do not limit the scope of the invention as described herein and 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. Cannabidiol for use in the treatment or prevention of recurrent pericarditis.

2. Cannabidiol for use according to Claim 1, wherein the use is (a) To reduce or prevent the increase in pericardial effusion in the subject; (b) To reduce or prevent the increase in pericardial thickening in the subject; (c) Attenuating or preventing an increase in the level of at least one of the following in the subjects: interleukin-1β (IL-1β), interleukin-6 (IL-6), pro-IL-1β mRNA transcription, and NLRP3 mRNA transcription; or (d) Any combination of (a), (b), and (c) above Cannabidiol for use, including

3. Cannabidiol for use according to Claim 2, wherein the use includes attenuating or preventing an increase in pericardial effusion in a subject.

4. Cannabidiol for use according to Claim 2, wherein the use includes attenuating or preventing an increase in pericardial thickening in a subject.

5. A composition comprising an effective amount of cannabidiol and an effective amount of a delivery vehicle, wherein the composition is intended for use in the treatment or prevention of recurrent pericarditis.

6. The composition according to claim 5, wherein the composition is an oral solution, and the cannabidiol is present in concentrations from about 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL, and / or up to about 350 mg / mL, up to 300 mg / mL, or up to 250 mg / mL.

7. The composition according to claim 5, wherein the composition is an injectable formulation, and the cannabidiol is present in concentrations 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.

8. Cannabidiol for use according to any one of Claims 1 to 4, or a composition according to any one of Claims 5 to 7, wherein the cannabidiol is synthesized.

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