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WO2024182882A1 - Bêta-caryophyllène destiné à être utilisé dans le traitement ou la prévention de la péricardite - Google Patents

Bêta-caryophyllène destiné à être utilisé dans le traitement ou la prévention de la péricardite Download PDF

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Publication number
WO2024182882A1
WO2024182882A1 PCT/CA2024/050156 CA2024050156W WO2024182882A1 WO 2024182882 A1 WO2024182882 A1 WO 2024182882A1 CA 2024050156 W CA2024050156 W CA 2024050156W WO 2024182882 A1 WO2024182882 A1 WO 2024182882A1
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bcp
pericarditis
composition
item
subject
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James Rhys BOLTON
Blagoja Ristevski
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Cardiol Therapeutics Inc
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Cardiol Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings

Definitions

  • the present invention relates generally to therapeutics and methods for treating or preventing cardiovascular diseases, disorders, or conditions and, more particularly, to therapeutics and methods for the treatment or prevention of pericarditis.
  • Pericarditis results from an intense inflammatory reaction of the pericardium. This reaction involves the activation of a macromolecular intracellular complex called the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome.
  • the NLRP3 inflammasome when it senses injury and stress, triggers an inflammatory process that involves the release of proinflammatory cytokines, such as interleukin- ip, that act as downstream mediators.
  • Pericarditis can be categorized into acute, inceimpuls, recurrent and chronic pericarditis.
  • Acute pericarditis is a clinical syndrome characterized by a single incident that resolves on its own or following treatment. The treatments mostly consist of nonsteroidal anti-inflammatory drugs, aspirin, steroids, colchicine, and anakinra (4, 7, 8, 9).
  • Episodes of acute pericarditis lasting more than 4 to 6 weeks but less than 3 months are called inceimpuls pericarditis, while episodes lasting more than three months are known as chronic pericarditis.
  • Recurrent pericarditis RP is defined as an episode of acute pericarditis that occurs at least 4-6 weeks after resolution of a prior episode.
  • RP has been reported to occur in 15-30% of pericarditis patients some of whom go on to experience multiple recurrences. In some cases, recurrences are due to inadequate treatment of the original episode, but, in other cases, they are due to inadequate response to current treatments.
  • pericarditis The pathogenesis of pericarditis is not completely understood (3); however, it has been hypothesized that acute pericarditis represents a stereotypical response to an acute injury of the mesothelial cells of the pericardium (4). It is believed to be triggered by an “irritant” such as a virus or cellular debris following a viral infection (5,6). It can 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).
  • an “irritant” such as a virus or cellular debris following a viral infection (5,6). It can 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).
  • BCP 0- caryophyllene
  • a first aspect of the invention provides the use of BCP in treating or preventing pericarditis.
  • a second aspect of the invention provides the use of BCP in the preparation of a medicament for the treatment or prevention of pericarditis.
  • the invention provides a method of treating or preventing pericarditis in a subject in need thereof, comprising (optionally) identifying a subject suffering from or at risk of suffering from pericarditis, and administering an effective amount of BCP to the subject.
  • a fourth aspect of the invention provides BCP for use in treating or preventing pericarditis.
  • the invention provides a composition comprising an effective amount of BCP and an effective amount of a pharmaceutically acceptable excipient, wherein the composition is for use in treating or preventing pericarditis.
  • the BCP is of natural origin. In other embodiments, the BCP is synthetic. In still other embodiments, the BCP is made by biotechnological processes.
  • Some embodiments of the present uses and methods entail using BCP to treat pericarditis.
  • BCP is used to prevent recurrence of pericarditis.
  • BCP can be used to attenuate an increase in pericardial effusion and/or pericardial thickness in a subject (e.g. a subject suffering from or at risk of suffering from pericarditis), for example, by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95, or up to about 100% as compared to the amount of pericardial effusion and/or pericardial thickness that would be present in the absence of administration of the BCP.
  • BCP can be used to decrease the release of IL-1 and IL-6, in a subject, e.g., by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%.
  • Figure 1 A is a bar graph showing the effect of BCP at a dose of 10 pM on the level of IL- 10 in an in vitro model of NLRP3 inflammasome activation;
  • Figure IB is a bar graph showing the effect of BCP at a dose of 10 pM on the level of IL-6 in another in vitro model
  • Figure 2 is a bar graph showing the effect of BCP at a dose of 10 mg/kg on the pericardial space (an indicator of pericardial effusion) in an in vivo model of pericarditis; and [00025]
  • Figure 3 is a bar graph showing the effect of BCP (10 mg/kg) on the pericardial thickness in the same in vivo model of pericarditis.
  • the term “pharmaceutically active agent” means a drug or agent which can be employed as disclosed herein and is intended to be used in a subject to treat or prevent diseases, ailments, physical damage, or pathological symptoms; or to influence the state, the condition or the functions of the body. Drugs in use can be found in reference works such as, for example, the Rote Liste or the Merck Index. Examples which may be mentioned, include, for example, BCP.
  • composition of matter is described as having a “purity of at least X %” 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 of matter.
  • the purity of an ingredient can be determined by high performance liquid chromatography (HPLC) or other suitable means.
  • subject means members of the animal kingdom including humans and other mammals. In some embodiments, the subject is a human.
  • the terms “treat,” “treatment,” and the like expression mean stopping, delaying the progression of a condition, disorder, or disease, or reducing the symptoms or severity of the symptoms thereof.
  • the terms “prevent,” “prevention,” and the like expression mean preventing, delaying, or reducing the incidence and/or risk of the onset of a condition, disorder, or disease.
  • the terms are intended to encompass “improving quality of life,” “extending the life,” and “improving clinical outcomes” of a subject suffering from, or at risk of suffering from, the condition, disorder, or disease, and do not necessarily mean “curing” the condition, disorder, or disease, though such is not precluded.
  • “Pharmaceutically acceptable excipient” when used herein means any substance which can be formulated with or that is present alongside a pharmaceutically active agent to achieve a desired function or functions and that is not biologically or otherwise undesirable when administered to a subject (e.g., human).
  • the excipient should be non-toxic when administered and compatible with the other ingredients in the formulation.
  • the person skilled in the art will appreciate what compounds or ingredients would qualify as a pharmaceutically acceptable excipient given the teachings of the present specification and information in the public domain.
  • 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", “one or more of A, B, or 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.
  • references herein to the use of BCP to treat or prevent pericarditis are references to the use of BCP to treat and/or prevent pericarditis.
  • composition comprising a list of compounds, ingredients, or elements, may include additional compounds, ingredients, or elements not expressly recited. It is also to be noted that the terms “comprising,” “including,” “containing,” and “having” can be used interchangeably.
  • the C of A specifies atarget purity of 80%, though the actual purity was 92.9%.
  • commercial sources of BCP may contain impurities up to about 20, 17.5, 15, 12.5, 10, 7.5, or 5%, comprising other plant components, in the case of botanically sourced BCP.
  • the term "consisting essentially of means "including the listed integers (e.g., compounds, steps, ingredients, etc.) and any additional integers that do not materially affect the basic and novel properties of the invention.
  • the basic and novel properties of the invention is the beneficial effect of BCP in treating and/or preventing pericarditis in any form, namely, acute pericarditis, incessant pericarditis, chronic pericarditis, and recurrent pericarditis.
  • % w/w mean the amount of a substance in terms of the weight of that substance divided by the total weight of the formulation containing that substance, and multiplied by 100.
  • % w/v means the mass of a solute in grams divided by the volume of the solution in which the solute is dissolved in mL, and multiplied by 100.
  • the term "about” refers to variations in an expressed numerical quantity that can occur, for example, through measuring and liquid handling procedures used for making pharmaceutical formulations, differences in the manufacture, source, or purity of the ingredients used to make the formulations, and/or differences due to different equilibrium conditions or different reaction levels of ingredients in a formulation resulting from an initial mixture.
  • the term “about” includes variations in the expressed value up to ⁇ 5% or up to ⁇ 10%. Whether or not a value is modified by the term "about,” the claims include equivalents to the values.
  • an effective amount means an amount that would bring about the desired effect, based on the purpose and function of the ingredient in the context of the invention disclosed herein. Implicit in “desired effect” is that toxicity does not arise.
  • an effective amount of a pharmaceutically active agent is that amount which would be effective to provide a therapeutic effect while avoiding toxicity, such as may occur via long-term chronic administration.
  • An effective amount of a solvent is that amount which, alone or together with other ingredients, would be effective to solubilize the other or remaining ingredients of the formulation. What constitutes an effective amount will be determinable by the person of ordinary skill in the art by routine experimentation, having regard to the teachings herein and/or information in the public domain.
  • the expression “free of Y” means that “Y” is not deliberately added but may be present as an impurity or due to other factors.
  • a formulation that is “free ofY” will not contain Y or contain only up to 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, or 0.5 % w/v ofY, based on the total formulation.
  • the present invention contemplates using BCP, as well as compositions (e.g., medicaments) comprising same.
  • BCP is a natural bicyclic sesquiterpene that is widely distributed in the plant kingdom (14). It can be found in the essential oils of black pepper (Piper nigrum), melissa (Melissa officinalis), guava leaf (Psidium guajava), hemp (Cannabis saliva), clove (Eugenia caryophyllata), ylang ylang (Cananga odor ata), and copaiba (Copaifera spp.) (17).
  • BCP is a non-psychotropic, selective phytocannabinoid agonist of type 2 receptors (CB2-R) and of peroxisome proliferator-activated receptor gamma (PPAR-Y) receptors (15, 17, 18).
  • BCP may be useful in treating anxiety, chronic pain, inflammation, cancer, depression, diabetes, neuroinflammatory conditions (e.g., Alzheimer's disease), endometriosis, interstitial cystitis, seizures, and nonalcoholic fatty liver disease (17, 18).
  • BCP As generally regarded as safe (GRAS) and have approved it for use as a food additive and flavoring.
  • GRAS general regarded as safe
  • BCP is classified according to OECD (Organization for Economic Co-operation and Development) guideline 423 as a category five substance (toxic at doses greater than 2000 mg/kg) (15).
  • beta-caryophyllene “P-caryophyllene”, and “BCP” are used interchangeably herein and refer to the compound, (1 S,4E,9R)-4, 11,11 -trimethyl-8- methylidenebicyclo[7.2.0]undec-4-ene.
  • BCP mainly occurs as trans-caryophyllene ((E)-BCP) (1) mixed with small amounts of the isomers (Z) — caryophyllene ((Z)-BCP) (2) and a-humulene (a- caryophyllene) (3) and its oxidation derivative, -caryophyllene oxide (BCPO) (4) shown below (15, 17):
  • BCP is intended to include all stereoisomers.
  • the most commonly occurring form of BCP is one wherein the stereocentre adjacent to the exocyclic double bond has the S configuration while the remaining stereocentre has the R configuration.
  • BCP can also be made by synthetic and biotechnological processes.
  • the chemical synthesis of BCP is described, for example, in Corey, E. J. et al. J. Am. Chem. Soc. 1964 86 (3), 485-492, and also in Larionov et al., An unconventional approach to the enantioselective synthesis of caryophylloids. J. Am. Chem. Soc. 2008, 130, 2954-2955.
  • Biotechnological techniques using microbial fermentation methods can also be used.
  • obtaining BCP from natural sources is (at present) more convenient and less expensive than by chemical synthesis and microbial fermentation (17).
  • the BCP used in the context of the present invention has a purity of at least 80%, 85%, 90%, 95%, 95.5%, 96% 96.5%, 97%, 97.5%, 98%, 98.5%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.
  • Impurities that may be present in BCP of natural origin are other C15H24 terpene hydrocarbons (e.g., isocaryophyllene and a-humulene, formerly called a- caryophyllene).
  • Synthetic BCP may include impurities consisting of residual organic solvents and/or by-products or residues of manufacture.
  • compositions can be in any dosage form known in the art, including, without limitation, oral solutions, injectable or other parenteral formulations, tablets, gummies, gel capsules, chewing gum formulations, and more.
  • Oral solutions and elixir formulations can be simple, or they can be quite complex, involving many types of excipients including water-soluble organic solvents, water-insoluble organic solvents, surfactants, buffers, sugars, flavors, sweeteners, aromatics, dyes, antioxidants, and preservatives.
  • the solutions can include water or be free of water.
  • Organic cosolvents are normally used to solubilize poorly water-soluble drugs, including BCP, to the desired concentration in oral solutions, as is known in the art.
  • Embodiments of oral solutions include formulations comprising BCP dissolved in a water insoluble solvent, such as long-chain triglycerides, peanut oil, com oil, soybean oil, sesame oil, olive oil, peppermint oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides.
  • a water insoluble solvent such as long-chain triglycerides, peanut oil, com oil, soybean oil, sesame oil, olive oil, peppermint oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides.
  • Medium-chain triglycerides can be synthetic or derived from coconut oil and palm seed oil.
  • Other water-insoluble solvents include beeswax, dl-a- tocopherol (Vitamin E), and oleic acid.
  • BCP can be present in a concentration of from about 50, 75, 100, 150, or 200 mg/mL. Additionally, or alternatively, the oral solution can contain BCP in a concentration of up to about 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, or 250 mg/mL. In one embodiment, the oral solution contains BCP in an amount of about 100 mg/mL. In another embodiment, the oral solution contains BCP in an amount of about 250 mg/mL. In yet another embodiment, the oral solution contains BCP in an amount of about 500 mg/mL.
  • BCP can be present at a concentration as high as 500, 450, 400, 350, 300, or 250 mg/mL and/or as low as 200, 150, 100 or 50 mg/mL.
  • the injectable/parenteral solution contains BCP in an amount of about 100 mg/mL.
  • the injectable/parenteral solution contains BCP in an amount of about 250 mg/mL.
  • the injectable/parenteral solution contains BCP in an amount of about 500 mg/mL.
  • the term “subject” or “patient” refers to mammals and includes, without limitation, human and veterinary animals. In a preferred embodiment, the subject is human.
  • BCP does not preclude combination therapies involving other pharmaceutically active agents. It also does not preclude compositions that comprise additional pharmaceutically active agents. However, in some embodiments, only BCP is used to treat or prevent pericarditis. For example, other terpenes or terpenoids that may be present in essential oils containing BCP are expressly excluded.
  • a-caryophyllene now called a-humulene
  • D-limonene linalool
  • terpineol terpinene
  • terpinene a-pinene
  • BCP is administered in combination with a therapeutic dose of another pharmaceutically active agent, e.g., nonsteroidal anti-inflammatory drugs, aspirin, steroids, colchicine, and/or anakinra.
  • another pharmaceutically active agent e.g., nonsteroidal anti-inflammatory drugs, aspirin, steroids, colchicine, and/or anakinra.
  • Any desired combination of pharmaceutically active agents can be delivered simultaneously or sequentially (e.g., within a 24 hour period). Suitable therapeutically effective dosages for each agent may be lowered due to additive or synergistic effects resulting from the combination therapy.
  • compositions according to the present invention can contain BCP together with at least one pharmaceutically acceptable excipient that do not undermine the basic and novel properties of the invention.
  • oral and injectable solutions according to the invention may contain a solvent for BCP (e.g., medium chain triglycerides) and an effective amount of at least one lipophilic antioxidant for improved shelflife.
  • Benzyl alcohol may be included in injectable solutions for its anaesthetic properties.
  • the at least one antioxidant can be selected from the group consisting of vitamin E (also referred to as a-tocopherol), carotenoids (xanthophylls and carotenes), propyl gallate, lecithin, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), and monothioglycerol tert-butylhydroquinone (TBHQ).
  • vitamin E also referred to as a-tocopherol
  • carotenoids xanthophylls and carotenes
  • propyl gallate lecithin
  • ascorbyl palmitate butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), and monothioglycerol tert-butylhydroquinone (TBHQ).
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxy toluene
  • TBHQ monothi
  • the “therapeutically effective amount” will vary depending on the compound administered as well as the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated. In general, the total amount of antioxidant(s) will be 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.
  • excipients which are contemplated for use in the practice of the disclosure are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. II and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, Md. (1989).
  • BCP can be administered in a variety of ways known in the art, including orally and parenterally.
  • parenteral is meant to include, without limitation, administration via intravenous (IV), subcutaneous (SC), intraperitoneal (IP), and intramuscular (IM) injection, and is used interchangeably with the term “injectable” herein.
  • IV intravenous
  • SC subcutaneous
  • IP intraperitoneal
  • IM intramuscular
  • the dose of BCP when administered parenterally will be lower than the dose when administered orally, given that orally administered BCP is expected to have lower bioavailability.
  • compositions can be administered at least once weekly, or at least once every 6, 5, 4, 3, or 2 days.
  • the composition can also be administered at least once daily, or at least twice daily.
  • compositions at least about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg BCP per kg body weight can be administered per dose.
  • compositions at least about 0.1, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 mg BCP per kg body weight can be administered per dose.
  • the treatment period can be for 6, 5, 4, 3, or 2 months, or for 8, 7, 6, 5, 4, 3, 2, or 1 week(s).
  • chronic conditions e.g., chronic pericarditis and/or recurrent pericarditis
  • the treatment period can also be indefinite.
  • BCP is administered twice daily. In another embodiment, BCP is administered once daily. In still another embodiment, BCP is administered twice weekly. In yet another embodiment, BCP is administered at least once a week.
  • One example dosage regime entails administering up to 8 mg/kg body weight, by subcutaneous injection, daily, for 5, 6, 7, 14, 21, or 28 days.
  • the administration can entail dividing the dose and administering each half dose every 12 hours.
  • Another example dosage regime entails administering up to 18 mg/kg body weight, orally, daily, for 5, 6, 7, 14, 21, or 28 days.
  • the administration can entail dividing the dose and administering each half dose every 12 hours.
  • LPS Lipopolysaccharide
  • ATP Adenosine Triphosphate
  • BCP beta-caryophyllene
  • NaCl normal saline or saline
  • Veh vehicle
  • Example 1A Effect of 10 uM BCP on level of IL-10 in in vitro NLRP3 Inflammasome Activation Model
  • J774A.1 mouse macrophages were cultured in 96-well plates (15,000 cells/well) and divided into the following groups to which various treatments described below were administered during a period of six hours:
  • Group 1 (CONTROL) - cells received nothing during the 6-hour treatment period.
  • Group 3 (BCP) - cells received BCP solubilized in methanol (10 pM) for 6 hours.
  • Group 4 (LPS+ATP+BCP) - cells received BCP solubilized in methanol (10 pM) and LPS (1 pg/mL) for 5.5 hours and ATP (5 mM) for the last 30 minutes.
  • Figure 1A shows that the cells of Group 2 (LPS+ATP) had significantly higher concentrations of IL-10 compared to the cells of Group 1 (CONTROL).
  • the cells of Group 4 (LPS+ATP+BCP) had significantly lower concentrations of IL- 10 than the cells of Group 2 (LPS+ATP).
  • J774A.1 mouse macrophages were cultured in 96-well plates (15,000 cells/well) and divided into the following groups to which various treatments described below were administered during a period of six hours:
  • Group 1 (CNT) - cells received nothing during the 6 hours treatment period.
  • Group 3 (BCP) - cells received BCP solubilized in methanol (MetOH) (10 pM) for 6 hours.
  • Group 4 (LPS+BCP) - cells received BCP solubilized in methanol (10 pM) and LPS (1 pg/mL) for 6 hours.
  • mice (average age 10 weeks) supplied by Harlan Laboratories (Harlan Sprague Dawley Inc.) were used and divided into the following treatment groups, with each group consisting of 4-5 mice: 1.
  • Group 1 (Saline + Veh) - mice received normal saline (0.9 % w/v NaCl) in the surgical procedure described below and were subsequently treated for seven days with a vehicle consisting of ethanol :Cremophor EL:water (1:1:18).
  • Group 2 mice received normal saline (0.9 % w/v NaCl) in the surgical procedure described below and were subsequently treated for seven days with BCP at a dose of 10 mg/kg.
  • the BCP was dissolved in the same vehicle as the vehicle used for Group 1.
  • Group 3 (Zym + Veh) - mice received Zymosan A in the surgical procedure described below and were subsequently treated for seven days with the same vehicle as the vehicle used for Group 1.
  • Group 4 (Zym + BCP) - mice received Zymosan A in the surgical procedure described below and were subsequently treated for seven days with BCP at a dose of 10 mg/kg.
  • the BCP was dissolved in the same vehicle as the vehicle used for Group 1.
  • mice of all four treatment groups were anesthetized, intubated orotracheally, and placed in the right lateral decubitus position. A left thoracotomy was then performed. Under direct visualization and using a 30 Gauge needle, 1 mg of Zymosan A (referred to herein also as “zymosan”) dissolved in 50 pl of sterile normal saline (0.9 % w/v NaCl) was delivered into the pericardial space of the mice of Groups 3 and 4 by carefully lifting the pericardial sac with forceps until a complete distribution of the solution into the pericardium was achieved. Sham procedures were performed vis-a-vis the mice of Groups 1 and 2 by injecting an equal volume of sterile normal saline instead of the Zymosan A solution. All mice received analgesia for the peri-operative period.
  • Zymosan A sterile normal saline
  • mice Following echocardiography, and on day seven, the mice were sacrificed, and their hearts were explanted and processed for pathology. Formalin -fixed paraffin- embedded transverse sections of the hearts were stained with hematoxylin and eosin. An investigator blinded to group allocation measured the pericardial thickness with the aid of computer morphometry using Image-ProTM Plus 6.0 software (Media Cybernetics, Silver Spring, MD).
  • mice The human equivalent dose of 10 mg/kg used above in mice is 0.81 mg/kg (13). This dose would be applicable to parenteral formulations since BCP was administered parenterally in the above in vivo mouse model.
  • Item 1 Use of beta-caryophyllene (BCP) in treating pericarditis.
  • Item 2 Use of BCP to prevent pericarditis.
  • Item 3 The use of item 1 or 2, wherein the BCP is effective to attenuate an increase in pericardial effusion in a subject.
  • Item 4 The use of item 3, wherein the BCP is effective to attenuate an increase in pericardial effusion by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%, compared to the amount of pericardial effusion that would be present if the BCP was not administered.
  • Item 5 The use of item 1 or 2, wherein the BCP is effective to prevent an increase in pericardial effusion in a subject.
  • Item 6 The use of any one of items 1 to 5, wherein the BCP is effective to attenuate an increase in pericardial thickness in a subject.
  • Item 7 The use of item 6, wherein the BCP is effective to attenuate an increase in pericardial thickness by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%, compared to the pericardial thickness that would be present if the BCP was not administered.
  • Item 8 The use of any one of items 1 to 5, wherein the BCP is effective to prevent an increase in pericardial thickness in a subject.
  • Item 9 The use of any one of items 1 to 8, wherein the BCP is effective to attenuate an increase in the level of at least one of interleukin- 1 (IL- 10) and interleukin-6 (IL-6) in a subject.
  • IL- 10 interleukin- 1
  • IL-6 interleukin-6
  • Item 10 The use of item 9, wherein the level of at least one of interleukin- 10 (IL-10) and interleukin-6 (IL-6) is attenuated by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%.
  • IL-10 interleukin- 10
  • IL-6 interleukin-6
  • Item 11 The use of any one of items 1 to 8, wherein the BCP is effective to prevent an increase in the level of at least one of interleukin- 10 (IL- 10) and interleukin-6 (IL-6) in a subject.
  • IL- 10 interleukin- 10
  • IL-6 interleukin-6
  • Item 13 Use of BCP in the preparation of a medicament for the prevention of pericarditis.
  • Item 14 A method of treating pericarditis in a subject in need thereof, comprising administering an effective amount of BCP to the subject.
  • Item 15 A method of preventing pericarditis in a subject in need thereof, comprising administering an effective amount of BCP to the subject.
  • Item 16 The method of items 14 or 15, wherein the BCP is effective to attenuate or prevent an increase in pericardial effusion in the subject.
  • Item 17 The method of item 16, wherein the BCP is effective to attenuate an increase in pericardial effusion by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%, compared to the amount of pericardial effusion that would be present in the absence of said administration.
  • Item 18 The method of any one of items 14 to 17, wherein the BCP is effective to attenuate or prevent an increase in pericardial thickness in the subject.
  • Item 19 The method of item 18, wherein the BCP is effective to attenuate an increase in pericardial thickness by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%, compared to the pericardial thickness that would be present in the absence of said administration.
  • Item 20 The method of any one of items 14 to 19, wherein the BCP is effective to attenuate or prevent an increase in the level of at least one of interleukin- 1 [3 (IL-ip) and interleukin-6 (IL-6) in the subject.
  • IL-ip interleukin- 1 [3 (IL-ip)
  • IL-6 interleukin-6
  • Item 21 The method of item 20, wherein the level of at least one of interleukin- ip (IL-0) and interleukin-6 (IL-6) is attenuated by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%.
  • IL-0 interleukin-ip
  • IL-6 interleukin-6
  • Item 22 The method of any one of items 14 to 21, further comprising the step of identifying a subject suffering from or at risk of suffering from pericarditis, prior to said administration.
  • Item 23 BCP for use in the treatment or prevention of pericarditis.
  • Item 24 BCP for use in preventing pericarditis.
  • Item 25 BCP for use in treating pericarditis.
  • Item 26 BCP for use in attenuating an increase in pericardial effusion in a subject.
  • Item 27 BCP for use in preventing an increase in pericardial effusion in a subject.
  • Item 28 BCP for use in attenuating an increase in pericardial thickness in a subject.
  • Item 29 BCP for use in preventing an increase in pericardial thickness in a subject.
  • Item 30 A composition comprising an effective amount of BCP and a pharmaceutically acceptable excipient, wherein the composition is for use in treating pericarditis.
  • Item 31 A composition comprising an effective amount of BCP and a pharmaceutically acceptable excipient, wherein the composition is for use in preventing pericarditis.
  • Item 32 The composition of item 30 or 31, wherein the composition is effective to attenuate an increase in pericardial effusion in a subject.
  • Item 33 The composition of item 32, wherein the composition is effective to attenuate an increase in pericardial effusion by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%, compared to the amount of pericardial effusion that would be present if the composition was not administered.
  • Item 34 The composition of item 30 or 31, wherein the composition is effective to prevent an increase in pericardial effusion in a subject.
  • Item 35 The composition of any one of items 30 to 34, wherein the composition is effective to attenuate an increase in pericardial thickness in a subject.
  • Item 36 The composition of item 35, wherein the composition is effective to attenuate an increase in pericardial thickness by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%, compared to the pericardial thickness that would be present if the composition was not administered.
  • Item 37 The composition of any one of items 30 to 34, wherein the composition is effective to prevent an increase in pericardial thickness in a subject.
  • Item 38 The composition of any one of items 30 to 37, wherein the composition is effective to attenuate an increase in the level of at least one of interleukin- ip (IL-1 ) and interleukin-6 (IL-6) in a subject.
  • IL-1 interleukin- ip
  • IL-6 interleukin-6
  • Item 39 The composition item 38, wherein the level of at least one of interleukin- ip (IL-1 P) 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 composition was not administered.
  • Item 40 The composition of any one of items 30 to 37, wherein the composition is effective to prevent an increase in the level of at least one of interleukin- 1 [3 (IL-ip) and interleukin-6 (IL-6) in a subject.
  • Item 41 The use of any one of items 1-13, the method of any one of items 14-22, the BCP of any one of items 23-29, or the composition of any one of items 30-40, wherein the pericarditis is acute pericarditis.
  • Item 42 The use of any one of items 1-13, the method of any one of items 14-22, the BCP of any one of items 23-29, or the composition of any one of items 30-40, wherein the pericarditis is recurrent pericarditis.
  • Item 43 The use of any one of items 1-13, the method of any one of items 14-22, the BCP of any one of items 23-29, or the composition of any one of items 30-40, wherein the BCP does not contain impurities.
  • Item 44 The composition of any one of items 30-40, wherein the composition is free of other pharmaceutically active agents.
  • Item 45 The composition of any one of items 30-40, wherein the composition is free of compounds selected from the group comprising a-caryophyllene, a- humulene, D-limonene, linalool, terpineol, terpinene, a-pinene, P-pinene, P-elemene, P- ocimene, camphene, nerolidol, euphol, citral, celatrol, falcarinol, salvinorin A, and pristimerin.
  • a-caryophyllene a- humulene, D-limonene, linalool, terpineol, terpinene, a-pinene, P-pinene, P-elemene, P- ocimene, camphene, nerolidol, euphol, citral, celatrol, falcarinol, salvinorin A, and pristimerin.
  • Item 46 The composition of any one of items 30-40, wherein the composition further comprises at least one additional pharmaceutically active agent.
  • Item 47 The composition of item 46, wherein the at least one additional pharmaceutically active agent is cannabidiol.
  • BCP may represent a novel strategy for treating and preventing pericarditis, including acute and recurrent pericarditis.
  • the embodiments described above are by way of example only and are not intended to limit the scope of the invention as described herein and defined by the following claims.

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Abstract

L'invention concerne un bêta-caryophyllène (BCP) destiné à être utilisé dans le traitement ou la prévention de la péricardite. L'efficacité du BCP dans l'atténuation des taux d'interleukine -1β(IL-1β) et d'IL-6 dans des modèles in vitro est décrite. L'invention concerne également des expériences révélant que le BCP est efficace dans l'atténuation ou la prévention d'une augmentation de l'espace péricardique (qui est un indicateur d'épanchement péricardique) et de l'épaisseur péricardique dans un modèle de péricardite de souris in vivo.
PCT/CA2024/050156 2023-03-03 2024-02-08 Bêta-caryophyllène destiné à être utilisé dans le traitement ou la prévention de la péricardite Pending WO2024182882A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2024232899A AU2024232899A1 (en) 2023-03-03 2024-02-08 Beta-caryophyllene for use in treating or preventing pericarditis

Applications Claiming Priority (2)

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US202363449799P 2023-03-03 2023-03-03
US63/449,799 2023-03-03

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WO2024182882A1 true WO2024182882A1 (fr) 2024-09-12

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021077211A1 (fr) * 2019-10-25 2021-04-29 Cardiol Therapeutics Inc. Compositions de cannabidiol destinées à être utilisées dans le traitement de pathologies cardiaques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021077211A1 (fr) * 2019-10-25 2021-04-29 Cardiol Therapeutics Inc. Compositions de cannabidiol destinées à être utilisées dans le traitement de pathologies cardiaques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAYA N ET AL.: "BETA-CARYOPHYLLENE REDUCES PERICARDIAL INFLAMMATION IN A MOUSE MODEL OF ACUTE PERICARDITIS", J. AM. COLL. CARDIOL, 8 March 2023 (2023-03-08), pages 809, XP087281289, DOI: 10.1016/S0735-1097(23)01253-6 *

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