Classifications

• • 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
  • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present disclosure relates generally to methods and compositions useful for modulating an inflammatory response.
• the present disclosure relates to methods and compositions useful for the treatment or prevention of an inflammatory condition, including but not limited to, inflammatory bowel disease, arthritis, and inflammatory respiratory conditions, such as chronic obstructive pulmonary disease (COPD), asthma, bronchitis, cystic fibrosis (CF) and acute respiratory distress syndrome (ARDS).
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• CF cystic fibrosis
• ARDS acute respiratory distress syndrome
• Inflammatory conditions are characterised by inflammation, the complex biological response to a noxious stimulus such as damage, auto-immunity, or an infection by a microbial pathogen and/or virus.
• a noxious stimulus such as damage, auto-immunity, or an infection by a microbial pathogen and/or virus.
• the clinical features of an inflammatory condition are likely to depend on the noxious stimulus (or stimuli), but are typically associated with heat, pain, redness and swelling of the affected organ or tissue.
• Inflammatory conditions are commonly associated with the upregulation of pro- inflammatory cytokines, such as interleukin- 1 beta (IL-I ⁇ ), interleukin-6 (IL-6), tumour- necrosis factor alpha (TNF- ⁇ ), interleukin-1 alpha (IL-1 ⁇ ), interleukin- 12 (IL-12(p70)), interferon gamma (IFN- ⁇ ) and/or macrophage inflammatory protein (MIP-1 ⁇ ), which modulate a range of signaling pathways to promote inflammatory reactions.
• pro-inflammatory cytokines such as interleukin- 1 beta (IL-I ⁇ ), interleukin-6 (IL-6), tumour- necrosis factor alpha (TNF- ⁇ ), interleukin-1 alpha (IL-1 ⁇ ), interleukin- 12 (IL-12(p70)), interferon gamma (IFN- ⁇ ) and/or macrophage inflammatory protein (MIP-1 ⁇ ), which modulate a range of signaling pathways to promote inflammatory reactions.
• Inflammatory conditions associated with the upregulation of pro-inflammatory cytokines include arthritis, inflammatory bowel disease, pain, gout, fibromyalgia, endometriosis, alcoholic liver disease, psoriasis/dermatitis, lupus and inflammatory respiratory conditions such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, sarcoidosis and pulmonary inflammation.
• ARDS acute respiratory distress syndrome
• COPD chronic obstructive pulmonary disease
• asthma bronchitis
• bronchiectasis sarcoidosis and pulmonary inflammation.
• Inflammatory respiratory conditions are among the most prevalent diseases globally. Although different inflammatory respiratory conditions express different inflammatory responses, there are some shared pathological features. For example, the innate neutrophilic inflammation shared by COPD and ARDS is also observed in some patients with severe asthma.
• ARDS is an inflammatory condition affecting pulmonary tissue, which is most commonly caused by sepsis. ARDS is characterised by poor oxygenation, pulmonary infiltrates, and acuity of onset (Diamond et al, 2020, Acute Respiratory Distress Syndrome (ARDS), in: StatPearls; Treasure Island (FL): StatPearls Publishing; 2020). ARDS typically begins within a week of the inciting event with a clinical presentation including capillary endothelial injury and diffuse alveolar damage, bilateral lung infiltrates and severe progressive hypoxemia in the absence of any evidence of cardiogenic pulmonary edema. Once ARDS develops, patients usually have varying degrees of pulmonary artery vasoconstriction and, subsequently, may develop pulmonary hypertension.
• ARDS has many risk factors. Besides pulmonary infection or aspiration, extra- pulmonary causes include sepsis, trauma, transfusion, near drowning, drug overdose, fat embolism, inhalation injury, and pancreatitis. These extra-thoracic illnesses and/or injuries trigger an inflammatory cascade culminating in pulmonary injury.
• Sepsis-associated ARDS is a complication arising from severe sepsis, being a systemic response to an infection of the blood. Any viable microbe, such as bacteria, fungi and viruses, can be the source of the infection. Sepsis is relatively common, occurring in approximately 750,000 adults annually in the United States, of which approximately 6% of patients develop ARDS. The mortality rate of patients diagnosed with ARDS is high, with an acute mortality rate exceeding 30% despite optimal critical care. [0009] The main pathophysiologic mechanism underlying ARDS is unrestrained and perpetual inflammation, resulting in edema. Respiratory failure leaves to multiple organ removal from the alveolar space, resulting in the accumulation of protein-rich fluid inside the alveoli.
• Edema produces diffuse alveolar damage, with the release of pro-inflammatory cytokines, including TNF- ⁇ , IL-I ⁇ , and IL-6.
• Neutrophils are recruited to the lungs by cytokines, become activated and release toxic mediators, such as reactive oxygen species and proteases. Extensive free radical production overwhelms endogenous anti-oxidants and causes oxidative cell damage.
• the initial phase of ARDS is the exudative phase, which is characterised by fluid accumulation in the pulmonary tissue, followed by a proliferation phase, which is characterised by resolution of pulmonary edema, proliferation of type II alveolar cells, fibroblasts, and myofibroblasts, and new matrix deposition.
• the proliferation phase starts within 72 hours after disease onset and lasts for more than 7 days. Patients who develop pulmonary fibrosis exhibit deterioration of pulmonary compliance, progressive hypoxia, and ventilator dependence, with mortality rate of nearly 60% (Pierrakos et al., 2012, Journal of Clinical Medicine Research, 4: 7-16).
• a method for the treatment or prevention of an inflammatory condition comprising administering to a subject in need thereof an effective amount of cannabidiol (CBD) or a pharmaceutically acceptable salt thereof, and an effective amount of hydroxychloroquine or a pharmaceutically acceptable salt thereof.
• CBD cannabidiol
• CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for the treatment or prevention of an inflammatory condition.
• composition comprising CBD or a pharmaceutically acceptable salt thereof, and hydroxychloroquine or a pharmaceutically acceptable salt thereof.
• composition comprising CBD or a pharmaceutically acceptable salt thereof, and hydroxychloroquine or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an inflammatory condition.
• kits comprising CBD or a pharmaceutically acceptable salt thereof, and hydroxychloroquine or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an inflammatory condition.
• a method of modulating an immune response comprising administering to a subject in need thereof CBD or a pharmaceutically acceptable salt thereof, and hydroxychloroquine or a pharmaceutically acceptable salt thereof.
• FIG. 1 shows that CBD or hydroxychloroquine can modulate key immune markers associated with sepsis-associated ARDS following intraperitoneal (IP) administration.
• A a graphical representation of mouse IL-I ⁇ (pg/mL; y-axis) following IP administration of CBD or hydroxychloroquine (x-axis);
• B a graphical representation of mouse IL-2 (pg/mL; y-axis) following IP administration of CBD or hydroxychloroquine (x- axis);
• C a graphical representation of mouse IL-10 (pg/mL; y-axis) following IP administration of CBD or hydroxychloroquine (x-axis);
• D a graphical representation of mouse IL-12(p70) (pg/mL; y-axis) following IP administration of CBD or hydroxychloroquine (x-axis);
• E a graphical representation of mouse IFN- ⁇ (pg/mL; y-axis
• FIG. 2 shows that CBD and/or hydroxychloroquine can modulate key immune markers associated with sepsis-associated ARDS following oral administration.
• A a graphical representation of mouse IL- 1 ⁇ (pg/mF; y-axis) following oral administration of CBD and/or hydroxychloroquine (x-axis);
• B a graphical representation of mouse IL-Ib (pg/mF; y-axis) following oral administration of CBD and/or hydroxychloroquine (x- axis);
• C a graphical representation of mouse IL-2 (pg/mF; y-axis) following oral administration of CBD and/or hydroxychloroquine (x-axis);
• D a graphical representation of mouse IL-3 (pg/mF; y-axis) following oral administration of CBD and/or hydroxychloroquine (x-axis);
• E a graphical representation of mouse IL-4 (pg/mF; y-axi
• FIG. 3 shows that CBD and hydroxychloroquine are effective for the treatment of mice with TNBS-induced colitis.
• a photographic representation of normal colon tissue in sham-treated control mice indicates regions of inflammatory cell infiltration in submucosal edema;
• B A photographic representation of colon tissue from vehicle control mice, indicates regions of inflammatory cell infiltration in submucosal edema;
• C A photographic representation of colon tissue from mice treated with CBD (1 mg/kg), indicates regions of inflammatory cell infiltration in submucosal edema;
• D A photographic representation of colon tissue from mice treated with hydroxychloroquine (2.5 mg/kg), indicates regions of mild abnormality, cyctic dilation and aberrant crypts;
• E A photographic representation of colon tissue from mice treated with CBD (1 mg/kg) and hydroxychloroquine (2.5 mg/kg), indicates regions of minimal cell infiltration. All images shown at 100X magnification, and stained with hematoxylin and eosin (
• FIG. 4 shows that CBD and hydroxychloroquine are effective for the treatment of mice with pulmonary inflammation.
• A A photographic representation of normal lung tissue in sham-treated control mice;
• B A photographic representation of lung tissue from vehicle control mice;
• C A photographic representation of lung tissue from mice treated with CBD (1 mg/kg);
• D A photographic representation of lung tissue from mice treated with hydroxychloroquine (2.5 mg/kg);
• E A photographic representation of lung tissue from mice treated with CBD (1 mg/kg) and hydroxychloroquine (2.5 mg/kg);
• F A photographic representation of lung tissue from mice treated with CBD (10 mg/kg);
• G A photographic representation of lung tissue from mice treated with hydroxychloroquine (25 mg/kg); and
• G A photographic representation of lung tissue from mice treated with CBD (10 mg/kg) and hydroxychloroquine (25 mg/kg). All images shown at 100X magnification, and stained with hematoxylin and eosin (H&E). Arrows indicate inflammatory cell
• FIG. 5 shows that CBD and hydroxychloroquine are effective for the treatment of rats with collagen-induced arthritis.
• A A photographic representation of normal hind paw ankle tissue in sham-treated control rats;
• B A photographic representation of hind paw ankle tissue from vehicle control rats;
• C A photographic representation of hind paw ankle tissue from rats treated with CBD (1 mg/kg);
• D A photographic representation of hind paw ankle tissue from rats treated with hydroxychloroquine (2.5 mg/kg);
• E A photographic representation of hind paw ankle tissue from rats treated with CBD (1 mg/kg) and hydroxychloroquine (2.5 mg/kg). All images shown at 50X magnification, and stained with hematoxylin and eosin (H&E).
• H&E hematoxylin and eosin
• phrases “consisting of” means including, and limited to, whatever follows the phrase “consisting of”. Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other elements may be present.
• the phrase “consisting essentially of” means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of” indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.
• CBD cannabidiol
• hydroxychloroquine can synergise to provide potent anti-inflammatory activity, useful for the treatment of arthritis, inflammatory bowel disease and inflammatory respiratory conditions including acute respiratory distress syndrome (ARDS), cystic fibrosis (CF), asthma, bronchitis and chronic obstructive pulmonary disease (COPD).
• ARDS acute respiratory distress syndrome
• CF cystic fibrosis
• COPD chronic obstructive pulmonary disease
• the synergistic effect between CBD and hydroxychloroquine enables a reduction in neutrophil infiltration into the pulmonary tissue to both reduce the proliferation phase of ARDS, and promote the clearance of alveolar fluid.
• the combination of CBD and hydroxychloroquine can reduce the formation and/or severity of colitis lesions and ameliorate symptoms of inflammatory bowel disease, including reduction in myeloperoxidase (MPO) levels in the colon, stool consistency score and reduction in macroscopic damage, thereby enabling the therapeutic use of this combination for patients with inflammatory bowel disease.
• MPO myeloperoxidase
• the combination of CBD and hydroxychloroquine has been shown to synergise to the extent that makes it possible to reduce the dose of hydroxychloroquine to a level that may minimise adverse effects associated with long-term use, while still eliciting a therapeutic effect.
• a method for the treatment or prevention of an inflammatory condition comprising administering to a subject in need thereof an effective amount of CBD or a pharmaceutically acceptable salt thereof, and an effective amount of hydroxychloroquine or a pharmaceutically acceptable salt thereof.
• inflammatory condition typically refers to a condition characterised by inflammation, or the complex biological response to a noxious stimulus such as damage, auto-immunity, or an infection by a microbial pathogen and/or virus.
• a noxious stimulus such as damage, auto-immunity, or an infection by a microbial pathogen and/or virus.
• the clinical features of an inflammatory condition are likely to depend on the noxious stimulus (or stimuli), but is typically characterised by heat, pain, redness and swelling of the affected organ or tissue.
• Tire inflammatory condition may be acute or chronic.
• the inflammatory condition is selected from the group consisting of an inflammatory respiratory condition, inflammatory bowel disease and arthritis. [0032] In an embodiment, the inflammatory condition is an inflammatory respiratory condition.
• Inflammatory respiratory conditions would be known to persons skilled in the art, illustrative examples of which include ARDS, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, sarcoidosis and cystic fibrosis (CF).
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• asthma bronchitis
• bronchiectasis bronchiectasis
• sarcoidosis and cystic fibrosis
• the inflammatory respiratory condition is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, bronchitis, cystic fibrosis (CF) and acute respiratory distress syndrome (ARDS).
• COPD chronic obstructive pulmonary disease
• CF cystic fibrosis
• ARDS acute respiratory distress syndrome
• the inflammatory respiratory condition is ARDS. In another embodiment, the inflammatory respiratory condition is sepsis-associated ARDS.
• the inflammatory condition is an inflammatory bowel disease.
• inflammatory bowel disease refers to diseases or disorders that involve chronic inflammation of the digestive tract. Such diseases or disorders would be known to persons skilled in the art, illustrative examples of which include ulcerative colitis, and Crohn's disease.
• the inflammatory condition is arthritis.
• arthritis typically refers to diseases that are characterised by inflammation of the joints that may also include the loss of cartilage. Such diseases would be known to persons skilled in the art, illustrative examples of which include rheumatoid arthritis, osteoarthritis, psoriatic arthritis and ankylosing spondylitis.
• the arthritis is rheumatoid arthritis.
• the inflammatory condition is associated with an increase or upregulation in the level of an inflammatory cytokine selected from the group consisting of IL-I ⁇ , IL-6, TNF- ⁇ , IL-1 ⁇ , IL-12(p70), IFN- ⁇ , CXCL-1, MCP-1 and MIP-1 ⁇ , or combinations thereof.
• the inflammatory condition is associated with an increase or upregulation in the level of an inflammatory cytokine selected from the group consisting of IL-I ⁇ , IL-6 and TNF- ⁇ , or combinations thereof.
• Inflammatory conditions associated with an increase or upregulation in the level of IL-I ⁇ , IL-6, TNF- ⁇ , IL-1 ⁇ , IL-12(p70), IFN- ⁇ , CXCL-1, MCP-1 and/or MIP-1 ⁇ would be known to persons skilled in the art, illustrative examples of which include arthritis (as described by, e.g., Feldman et al, 1996, Annual Review of Immunology, 14: 397-440; Mclnnes et al, 2007, Nature Reviews Immunology, 7: 429-442; Tanaka et al., 2014, Cold Spring Harbor Perspectives in Biology, 6: a016292-a016295; Woo, 2002, Current Rheumatology Reports, 4: 452-457; Kapoor et ah, 2011, Nature Reviews Rheumatology, 7: 33-42), inflammatory bowel disease (as described by, e.g., Neurath, 2014, Nature Reviews Immunology, 14: 329-342; Papad
• ARDS Acute respiratory distress syndrome
• ARDS acute respiratory distress syndrome
• adult respiratory distress syndrome may be used interchangeably herein to refer to an inflammatory condition typically characterised by the disruption of the alveolar-capillary barrier, flooding of protein-rich edema fluid into the alveolar space, and cell recruitment due to immune system stimulation.
• ARDS can develop after direct lung injuries, e.g. , pneumonia, aspiration, inhalation injury, near drowning, pulmonary contusion, reperfusion pulmonary edema and fat embolism.
• ARDS can also occur during the course of indirect lung injuries, e.g., sepsis, severe trauma, acute pancreatitis, cardiopulmonary bypass, massive transfusions and drug overdose.
• “Sepsis-associated acute respiratory distress syndrome” or “sepsis-associated ARDS” typically refers to ARDS that is induced after lung infection or infection at extra- pulmonary sites. An aberrant host response to infection leads to disruption of the pulmonary alveolar-capillary barrier, resulting in lung injury characterised by hypoxemia, inflammation, and non-cardiogenic pulmonary edema.
• the ARDS is sepsis-associated ARDS.
• bacteria e.g., Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumanniv
• fungi e.g., Pneumocy
• the sepsis-associated ARDS is caused by a bacterial, fungal or viral infection.
• the bacterial infection is selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii infection.
• the viral infection is selected from the group consisting of cytomegalovirus, influenza, herpes simplex virus- 1, respiratory syncytial virus, parainfluenza, human metapneumovirus, enterovirus and coronavirus infection.
• the fungal infection is selected from the group consisting of Pneumocystis jirovecii, Candida albicans, Candida tropicalis and Candida glabrata infection.
• ARDS may be classified using the Berlin Criteria as described by, for example, The ARDS Definition Task Force (2012, American Medical Association, 307(23): 2526- 2234), which is based on the ration of arterial oxygen tension and fraction of inspired oxygen when measured at a minimum level of positive end-expiratory pressure (PEEP) of 5 cm H 2 O.
• PEEP positive end-expiratory pressure
• the severity of ARDS may be classified as mild, moderate or severe (Table 1).
• ARDS The classification of ARDS based on the Berlin Criteria may also be made in consideration of risk factors and period of exposure to risk factors (i.e., maximum period between exposure to risk factor and ARDS development is 7 days).
• Risk factors of ARDS include direct risk factors, i.e., pneumonia, aspiration of gastric contents, inhalation injury, pulmonary contusion, lung vasculitis and drowning, and indirect risk factors, i.e., non- pulmonary sepsis, multiple trauma, pancreatitis, non-cardiogenic shock, drug overdose and transfusion-associated acute lung injury (TRALI).
• direct risk factors i.e., pneumonia, aspiration of gastric contents, inhalation injury, pulmonary contusion, lung vasculitis and drowning
• indirect risk factors i.e., non- pulmonary sepsis, multiple trauma, pancreatitis, non-cardiogenic shock, drug overdose and transfusion-associated acute lung injury (TRALI).
• TRALI transfusion-associated acute lung injury
• Imaging the lung pathobiology in ARDS patients and measurement of inflammatory markers or other biomarkers for ARDS may also be used in the classification of ARDS.
• Suitable imaging methods would be known to persons skilled in the art, illustrative examples of which include computed tomography (CT), as described by, for example, Puybasset et al. (1998, American Journal of Respiratory and Critical Care Medicine, 158(5): 1644-1655).
• CT computed tomography
• suitable inflammatory markers and other biomarkers for ARDS would be known to persons skilled in the art, illustrative examples of which include the biomarkers reviewed by, for example, Blondonnet et al. (2016, Disease Markers, 2016: 35101373).
• CBD and hydroxychloroquine act synergistically to inhibit the production of inflammatory cytokines in response to a noxious stimulus.
• administration of CBD and hydroxychloroquine can treat conditions associated with pulmonary inflammation, including COPD, asthma, CF and ARDS (e.g., by reducing or alleviating symptoms or severity of ARDS, in particular, by reducing the acute pulmonary inflammatory response, reversing edema, and limiting damage to the lung).
• CBD Cannabidiol
• CBD cannabinoid produced by plants of the genus Cannabis.
• CBD has antagonist activity on agonists of the CB 1 and CB2 receptors and acts as an inverse agonist of the CB1 and CB2 receptors.
• CBD is synthesised in cannabis plants as cannabidiolic acid (CBDA), which decarboxylates to CBD (Table 2). While some decarboxylation may occur in the plant, decarboxylation typically occurs post-harvest and is increased by exposing plant material to heat (Sanchez and Verpoote, 2008, Plant Cell Physiology, 49(12): 1767-82).
• CBD cannabidiolic acid
• Decarboxylation is usually achieved by drying and/or heating the plant material. Persons skilled in the art would be familiar with methods by which decarboxylation of CBDA can be promoted, illustrative examples of which include air-drying, combustion, vaporisation, curing, heating and baking.
• the decarboxylated CBD will typically bind to and/or stimulate, directly or indirectly, cannabinoid receptors including CB1 and/or CB2.
• CBD may be extracted from any suitable plant parts including leaves, flowers or stems and may be produced by any suitable means known to those skilled in the art.
• CBD extracts may be produced by extraction with supercritical or subcritical CO 2 , or by volatilisation of plant material with a heated gas.
• Illustrative examples of methods used the extract CBD and other cannabinoids from plant material include the methods described in US Patent No. 10189762 and WO 2004/016277.
• the CBD described herein is a synthetic compound.
• Synthesised CBD is particularly useful for pharmaceutical development it is largely free from contaminants.
• a number of methods for the synthesis of CBD are known in the art, illustrative examples of which include methods for the synthesis of CBD as described in US Patent No. 10,059,682.
• the present disclosure further contemplates the use of pharmaceutically acceptable salts of CBD.
• Suitable pharmaceutically acceptable salts of CBD would be known to persons skilled in the art, illustrative examples of which include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, which would be known to persons skilled in the art.
• “Hydroxychloroquine” is a chemical derivative of chloroquine, which features a hydroxyethyl group instead of an ethyl group.
• Hydroxychloroquine commonly referred to by the trade name “Plaquenil®” is known to be effective for the treatment of malaria, and has shown efficacy for the treatment of systemic lupus erythematosus, rheumatoid arthritis and Sjogren’s Syndrome.
• hydroxychloroquine increases lysosomal pH in antigen presenting cells, and has been demonstrated to inhibit or block the activation of toll- like receptors on plasmacytoid dendritic cells.
• hydroxychloroquine includes the racemic hydroxychloroquine, which is 2-[[4-[(7-chloro-4-quinolmyl)ammo]pentyl]ethylaniino]- ethanol as disclosed in US Patent No. 2,546,658, or any of the single enantiomers “(S)-(+) hydroxychloroquine” or “(R)-(-) hydroxychloroquine” as disclosed in US Patent No. 5,314,894, This term may relate either to the free form of hydroxychloroquine or to any pharmaceutically acceptable salt thereof, such as hydroxychloroquine sulfate.
• Suitable pharmaceutically acceptable salts would be known to person skilled in the art, illustrative examples of which include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, which would be well known to person skilled in the art.
• the pharmaceutically acceptable salt is hydroxychloroquine sulfate.
• treat means relieving, reducing, alleviating, ameliorating or otherwise inhibiting the severity of one or more symptoms of an inflammatory condition in a subject. It is to be understood that the terms “treat”, “treating”, “treatment” and the like, as used herein, do not imply that a subject is treated until the inflammatory condition has been eliminated or are no longer evident. Said treatment may also reduce the severity of the one or more symptoms of an inflammatory condition.
• prevent means preventing the establishment of a condition of a disease, or to otherwise prevent, hinder, retard, abrogate or reverse the onset or progression of a condition or disease or other undesirable symptoms in any way whatsoever.
• subject refers to any mammal, including livestock and other farm animals (such as cattle, goats, sheep, horses, pigs and chickens), performance animals (such as racehorses), companion animals (such as cats and dogs), laboratory test animals and humans.
• livestock and other farm animals such as cattle, goats, sheep, horses, pigs and chickens
• performance animals such as racehorses
• companion animals such as cats and dogs
• laboratory test animals such as cats and dogs
• the CBD or a pharmaceutically acceptable salt thereof, and the hydroxychloroquine or a pharmaceutically acceptable salt thereof will be administered to the subject in need thereof in a therapeutically effective amount.
• therapeutically effective amount typically refer to an amount of CBD and an amount of hydroxychloroquine that is sufficient to affect one or more beneficial or desired therapeutic outcomes (e.g., reduction in inflammatory mediators, reduction in white blood cell count and/or neutrophil infiltration, reduction in acute pulmonary inflammatory response, reversal of edema, and limiting damage to the lung).
• Said beneficial or desired therapeutic outcomes may be quantified by measuring clinical parameters, illustrative examples of which include the measurement of oxygenation index (OI[F IO2 X mean airway pressure x 100)/Pao2]) or oxygenation saturation index (OSI[F IO2 x mean airway pressure x 100)/oxygen saturation by pulse oximetry (Spo2] as described by Des Prez et al.
• Subjective measures of said beneficial or desired therapeutic outcomes can also be made using clinical instruments known in the art, illustrative examples of this include the Lung Injury Score (LIS) (Murray et al., 1988, American Review of Respiratory Disease, 138(3): 720) the American-European Consensus Conference (AECC) Definition (Bernard et al., 1994, American Journal of Respiratory and Critical Care Medicine, 149: 818-824), illness severity scores (e.g ., Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Index Score II), the Berlin Criteria (The ARDS Definition Task Force, 2012, supra), Crohn's Disease Activity Index (CDAI; Best et al, 1976, Gastroenterology, 70: 439- 444) and Mayo Score for Ulcerative Colitis (UC; Lewis et al., 2008, Inflammatory Bowel Disease, 14: 1660-1666)
• LIS Lung Injury Score
• AECC American-European Consensus Conference
• Changes in the symptoms or severity of an inflammatory condition as measured by any of the quantitative methods or clinical instruments described elsewhere herein may be expressed using any appropriate statistical measure to demonstrate the magnitude of the reduction in the symptoms or severity of an inflammatory condition.
• the methods disclosed herein reduce in the symptoms or severity of an inflammatory condition by at least 10%, preferably at least 20%, preferably at least 30%, preferably at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, or more preferably at least 100% as compared to a subject with the same inflammatory condition who has not been administered CBD and hydroxychloroquine .
• an effective amount can be provided in one or more administrations. The exact amount required may vary depending on factors such as the nature and severity of the inflammatory condition to be treated, the age and general health of the subject, and the form in which the active agents are to be administered.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 1000 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg,
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 1000 mg, preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a dose of at least about 1 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a dose from about 1 mg to about 500 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a dose of from about 200 mg to about 400 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a loading dose of at least about 1 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a loading dose of from about 1 mg to about 500 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a loading dose of about 400 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a maintenance dose of at least about 1 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a maintenance dose from about 1 mg to about 500 mg, twice per day.
• the hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered at a maintenance dose of about 200 mg, twice per day.
• the CBD or a pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 1500 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg,
• the CBD or a pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 1500 mg, preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37
• the CBD or a pharmaceutically acceptable salt thereof is administered at a dose of at least about 1 mg, twice per day.
• the CBD or a pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 500 mg, twice per day.
• the CBD or a pharmaceutically acceptable salt thereof is administered at a dose of from about 500 mg to about 1000 mg, twice per day.
• the CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof may be administered orally, topically, parenterally, transdermally, by inhalation, intranasally, by irrigation, by implant, by insufflation, topically to the eye, or aurally.
• compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof may be administered in dosage unit and in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
• Formulations include liposomal, nanoparticle, microparticle, polymer-based, dispersion, suspension, coated on a device, powder, microspheres, carrier-mediated, implant and encapsulation.
• the CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered orally.
• the CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered parenterally.
• parenteral includes subcutaneous injections, aerosol for administration to lungs or nasal cavity, intravenous, intramuscular, intrathecal, intracranial, injection or infusion techniques.
• the present disclosure also provides suitable topical, oral and parenteral pharmaceutical formulations for use in the novel methods of treatment described herein.
• the CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered intraperitoneally.
• the CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are formulated for oral administration.
• Suitable dosage forms for oral administration would be known to persons skilled in the art, illustrative examples of which include tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, liquids, syrups or elixirs.
• the CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof is in liquid, oil, tablet or capsule form.
• the CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof may be co-administered with one or more other agents suitable for the amelioration of symptoms associated with an inflammatory condition, such as sepsis-associated ARDS, illustrative examples of which include antibiotics, antiviral agents and antifungal agents.
• a composition comprising CBD or a pharmaceutically acceptable salt thereof, and hydroxychloroquine or a pharmaceutically acceptable salt thereof.
• the composition comprises from about 1 mg to about 1000 mg hydroxychloroquine or a pharmaceutically acceptable salt thereof per dose. In another embodiment, the composition comprises from about 200 mg to about 400 mg hydroxychloroquine or a pharmaceutically acceptable salt thereof per dose.
• the composition comprises from about 1 mg to about 1500 mg CBD or a pharmaceutically acceptable salt thereof per dose. In another embodiment, the composition comprises from about 500 mg to about 1000 mg CBD or a pharmaceutically acceptable salt thereof per dose.
• the composition is formulated for oral administration.
• the composition is formulated for intraperitoneal administration.
• Compositions comprising CBD and hydroxychloroquine for oral administration may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
• Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
• Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
• Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavoring.
• Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
• Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
• Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
• the composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.
• suitable pharmaceutically acceptable carriers, diluents or excipients would be known to persons skilled in the art, illustrative examples of which include inert diluents (e.g., calcium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia), lubricating agents (e.g., magnesium stearate, stearic acid or talc) and material to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period (e.g., glyceryl monostearate or glyceryl distearate). Coating may also be performed using techniques described in the US Patent Nos. 4,256,108, 4,160,
• compositions disclosed herein may be prepared according to conventional methods well known in the pharmaceutical and nutraceutical industries, such as those described in Remington’s Pharmaceutical Handbook (Mack Publishing Co., NY, USA) using suitable excipients, diluents and fillers.
• compositions suitable for oral administration may be presented as discrete units (i.e., dosage forms), each containing a predetermined amount of each component of the composition as a powder, tablet, capsule, granules, as a solution or a suspension in an aqueous liquid or non-aqueous liquid, or as an emulsion.
• compositions may be formulated for administration as separate unit dosage forms for administration.
• the unit dosage form may be suitable for a capsule, tablet, oil or liquid solution.
• the composition is for use in the treatment or prevention of an inflammatory condition.
• the composition is for use in the treatment or prevention of an inflammatory respiratory condition.
• the composition is for use in the treatment or prevention of an inflammatory respiratory condition selected from the group consisting of ARDS, COPD, asthma, bronchitis, and CF.
• the composition is for use in the treatment or prevention of ARDS.
• the composition is for use in the treatment or prevention of sepsis-associated ARDS.
• the composition is for use in the treatment or prevention of sepsis-associated ARDS caused by a bacterial, fungal, or viral infection, as described elsewhere herein.
• the composition is for use in the treatment or prevention of inflammatory bowel disease.
• the composition is for use in the treatment or prevention of arthritis. In another embodiment, the composition is for use in the treatment or prevention of rheumatoid arthritis.
• CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of an inflammatory condition.
• the inflammatory condition is an inflammatory respiratory condition.
• the inflammatory respiratory condition is selected from the group consisting of ARDS, COPD, asthma, bronchitis and CF. [0118] In an embodiment, the inflammatory condition is ARDS. In another embodiment, the ARDS is sepsis-associated ARDS.
• the inflammatory condition is inflammatory bowel disease.
• the inflammatory condition is arthritis.
• the arthritis is rheumatoid arthritis.
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof may be administered as a single composition or co-administered as separate compositions.
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered sequentially.
• sequential administration it is meant there is an interval between the administration of the CBD and hydroxychloroquine.
• the interval between sequential administrations may be seconds, minutes, hours or days.
• the interval between sequential administrations of the CBD and hydroxychloroquine is less than an hour, preferably less than 30 minutes, most preferably less than 1 minute.
• Sequential administration may be in any order (i.e., administration of CBD prior to the administration of the hydroxychloroquine, or administration of the hydroxychloroquine prior to the administration of CBD).
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered simultaneously.
• the CBD and hydroxychloroquine are administered at the same time.
• the CBD and hydroxychloroquine may be administered simultaneously in a single composition or dosage form.
• the CBD and hydroxychloroquine may be administered simultaneously as two separate compositions or dosage forms.
• periodic re-administration of the active agents may be required to achieve a desirable therapeutic effect.
• CBD and hydroxychloroquine will depend on a number of factors, examples of which are described elsewhere herein, such as the subject’s age, body weight, general health, sex and dietary requirements, as well as any drugs or agents used in combination or coincidental with the administration of the composition. Where multiple divided doses are required, these may be administered hourly, daily, weekly, monthly or at other suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation.
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered twice per day.
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered for a period of at least one week.
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered to the subject for a period of between 1 to 10 weeks (e.g., for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks).
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered to the subject for a period of between 1 to 10 weeks, preferably for about 1 week, preferably about 2 weeks, preferably about 3 weeks, preferably about 4 weeks, preferably about 5 weeks, preferably about 6 weeks, preferably about 7 weeks, preferably about 8 weeks, preferably about 9 weeks, or more preferably for about 10 weeks.
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or compositions comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered to the subject for a period of between 3 to 4 weeks.
• the subject is administered a loading dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof on the first day of treatment followed by a maintenance dose for each day thereafter, wherein the loading dose is from about 1 mg to about 1000 mg, twice per day, and wherein the maintenance dose is from about 1 mg to about 1000 mg, twice per day.
• the subject is administered a loading dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof on the first day of treatment followed by a maintenance dose for each day thereafter, wherein the loading dose is from about 1 mg to about 500 mg, twice per day, and wherein the maintenance dose is from about 1 mg to about 500 mg, twice per day.
• the subject is administered a loading dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof on the first day of treatment followed by a maintenance dose for each day thereafter, wherein the loading dose is from about 1 mg, twice per day, and wherein the maintenance dose is from about 1 mg, twice per day.
• the subject is administered from about 1 mg to about 1500 mg CBD or a pharmaceutically acceptable salt thereof with the loading dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof, twice per day.
• the subject is administered from about 1 mg to about 1000 mg CBD or a pharmaceutically acceptable salt thereof with the loading dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof, twice per day.
• the subject is administered from about 1 mg to about 1500 mg CBD or a pharmaceutically acceptable salt thereof with the maintenance dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof, twice per day.
• the subject is administered from about 500 mg to about 1000 mg CBD or a pharmaceutically acceptable salt thereof with the maintenance dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof, twice per day.
• loading dose refers to an initial higher dose of a drug that is to be given at the commencement of a course of treatment before dropping down to a lower maintenance dose.
• maintenance dose refers to the maintenance rate (mg/h) of a drug following administration, which is equal to the rate of elimination at steady state.
• the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are formulated as separate unit dosage forms for administration.
• the unit dosage form may be suitable for oral solution, capsule or tablet form.
• unit dosage forms comprising CBD or a pharmaceutically acceptable salt thereof and/or hydroxychloroquine or a pharmaceutically acceptable salt thereof need not be of the same type.
• methods of the present disclosure contemplate the administration of, for example, CBD in a liquid form and the hydroxychloroquine as a capsule or tablet
• kits comprising CBD or a pharmaceutically acceptable salt thereof, and hydroxychloroquine or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an inflammatory condition.
• the kit comprises the CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof in separate unit dosage forms for the loading dose and maintenance dose, as described elsewhere herein.
• CBD cannabidiol
• hydroxychloroquine or a pharmaceutically acceptable salt thereof.
• modulation of the immune response in accordance with the methods disclosed herein can be determined by a variety of methods known in the art, illustrative examples of which include measuring changes in cytokine production (e.g., levels, concentrations, ratios) in the subject such as before and after treatment or during the course of treatment.
• modulation is to be understood to mean a reduction or an increase in the immune response, as determined, for example, by a decrease or increase in the level, concentration and/or ratio of inflammatory mediators, such as cytokines.
• level and “amount” are used interchangeably herein to refer to a quantitative amount (e.g., moles or number), a semi-quantitative amount, a relative amount (e.g., weight %, or mole % within a class, or a ratio), a concentration, and the like. Thus, these terms encompass absolute or relative amounts or concentrations, including of inflammatory mediators, in a sample.
• Inflammatory mediators such as cytokines
• nucleic acid-based assays nucleic acid is isolated from cells contained in a biological sample according to standard methodologies (Sambrook, et al., 1989, Molecular Cloning: A Laboratory Manual ⁇ , and Ausubel et al., 1994, Current Protocols in Molecular Biology).
• protein levels of inflammatory mediators can be measured using protein-based assays known in the art.
• an antibody-based technique may be employed to determine the level of an autoantibody in a sample, illustrative examples of which include immunoassays, such as the enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and the radioimmunoassay (RIA).
• ELISA enzyme-linked immunosorbent assay
• IHC immunohistochemistry
• RIA radioimmunoassay
• protein expression is measured using a multiplexed protein expression analysis method.
• the multiplexed protein expression analysis method is a protein microarray or Luminex bead array.
• Protein-capture arrays that permit simultaneous detection and/or quantification of a large number of proteins may also be employed.
• low-density protein arrays on filter membranes such as the universal protein array system allow imaging of arrayed antigens using standard ELISA techniques and a scanning charge-coupled device (CCD) detector.
• Exemplary protein capture arrays include protein function arrays comprising spatially addressed protein-binding molecules (i.e., antigens), which can facilitate extensive parallel analysis of autoantibodies with specificity for the antigens that comprise the protein function array. Central to this type of analysis is the retention of the correctly folded protein confirmation of the arrayed antigen.
• Protein function arrays have been shown to have the required properties of specificity and acceptable background, and are available commercially (e.g ., Sengenics). Various methods for the preparation of protein function arrays have been reported (see, e.g., Gnjatic etal., 2009, Journal of Immunological Methods, 341(50): 1-2; PCT/GBOl/00395, PCT/GB02/05499, PCT/GB03/00362). Individual spatially distinct functional proteins are typically attached to a support surface, which is generally planar or contoured. Common physical supports include glass slides, silicon, microwells, nitrocellulose or PVDF membranes, and magnetic and other microbeads.
• Particles in suspension can also be used as the basis of arrays, providing they are coded for identification; systems include colour coding for microheads (e.g., available from Luminex, Bio-Rad and Nanomics Biosystems) and semiconductor nanocrystals (e.g., QDotsTM, available from Quantum Dots), and barcoding for beads (UltraPlexTM, available from Smartbeads) and multimetal microrods (NanobarcodesTM particles, available from Surromed). Beads can also be assembled into planar arrays on semiconductor chips (e.g., available from LEAPS technology and BioArray Solutions).
• colour coding for microheads e.g., available from Luminex, Bio-Rad and Nanomics Biosystems
• semiconductor nanocrystals e.g., QDotsTM, available from Quantum Dots
• barcoding for beads UltraPlexTM, available from Smartbeads
• NanobarcodesTM particles available from Surromed
• individual protein-capture agents e.g., antibodies to inflammatory mediators or inflammatory mediator-binding fragments thereof
• the particles may then be assayed separately, but in parallel, in a compartmentalised way, for example in the wells of a microtiter plate or in separate test tubes.
• a patient or control sample is delivered to a protein function array under conditions suitable for protein or peptide binding, and the array is washed to remove unbound or non-specifically bound components of the sample from the array.
• the array is incubated with fluorescently-Iabelled antibody to detect the interaction between array antigens and inflammatory mediator(s) present in the sample.
• the presence or amount of protein or peptide bound to each feature of the array is detected using a suitable fluorescence detection system.
• the amount of protein bound to a feature of the array is proportional to the intensity of fluorescence.
• local background fluorescence obtained from control features of the array are automatically subtracted and relative fluorescent units (rfu) for each feature of the array is recorded.
• the protein function array is a Luminex-based multiplex assay, which is a bead-based multiplexing assay, where beads are internally dyed with fluorescent dyes to produce a specific spectral address.
• Biomolecules such as an oligo or antibody
• Biomolecules can be conjugated to the surface of beads to capture analytes of interest; that is, inflammatory markers, e.g., cytokines.
• Flow cytometric or other suitable imaging technologies known to persons skilled in the art can then be used for characterisation of the beads, as well as for detection of analyte presence.
• Luminex technology enables are large number of proteins, genes or other gene expression products (e.g., 100 or more, 200 or more, 300 or more, 400 or more) to be detected using very small sample volume (e.g., in a 96 or 384-weII plate).
• the level of an inflammatory mediator can be normalised against a housekeeping biomarker.
• housekeeping biomarker refers to a biomarker or group of biomarkers (e.g., polynucleotides and/or polypeptides), which are typically found at a constant level in the cell type(s) or tissue(s) being analysed and across the conditions being assessed.
• the level of an inflammatory mediator measured using a protein array can be normalised by both intra- and inter-array data normalisation.
• the overall median value of all median relative fluorescent units (rfu) of each protein in a protein function array (excluding data from control proteins) is calculated and intra-array normalisation achieved by dividing the median of the quadruplicate spots of each protein on the array, by the overall median value of all the proteins on the array in each sample.
• Inter-array normalisation can be achieved using bioinformatics software packages that are known in the art.
• inter-array normalisation can be achieved using the normalize. quantiles package in R (Bolstad et al., 2003, Bioinformatics, 19(2): 185-193).
• the method of analysing the level of an inflammatory mediator in a sample can be quantitative, semi-quantitative or qualitative in nature.
• quantitative analyses will typically provide a concentration or number of an inflammatory mediator nucleic acid molecule or protein in the sample within an appropriate error margin (e.g., mean +/- standard deviation).
• semi-quantitative or qualitative analyses will typically provide an indication of the relative amount of an inflammatory mediator in a sample. This may involve a comparison of an amount of an inflammatory mediator in a first sample with an amount of an inflammatory mediator in a second sample and making a determination as to the relative amount of the inflammatory mediator between the first and second samples.
• the method of modulating an immune response comprises decreasing the level of an inflammatory mediator relative to a reference level.
• the inflammatory mediator is a cytokine.
• cytokine refers to factors that exert a variety of effects on cells, for example, inducing growth or proliferation, illustrative examples of which include IL-I ⁇ , IL-2, IL-10, IL-12 (p70), IFN- ⁇ , TNF- ⁇ , IL-1 ⁇ , IL-3, IL-4, IL-5, IL-6, IL- 9, IL-12(p40), IL-13, IL-17A, Eotaxin, G-CSF, GM-CSF, IFN- ⁇ , KC, MCP-l(MCAF), MIR-1 ⁇ , MIR-1 ⁇ , RANTES and CXCL-1.
• the method of modulating an immune response comprises decreasing the level of an inflammatory cytokine selected from the group consisting of IL- 1b, IL-6, TNF- ⁇ , IL-1 ⁇ , IL-12(p70), IEN-g, CXCL-1, MCP-1 and MIP-1 ⁇ , relative to a reference level.
• an inflammatory cytokine selected from the group consisting of IL- 1b, IL-6, TNF- ⁇ , IL-1 ⁇ , IL-12(p70), IEN-g, CXCL-1, MCP-1 and MIP-1 ⁇
• the method of modulating an immune response comprises decreasing the level of an inflammatory cytokine selected from the group consisting of IL- 1b, IL-6 and TNF- ⁇ relative to a reference level.
• CBD Cannabidiol
• HCQ hydroxychloroquine
• LPS Lipopolysaccharide
• mice Male C57BL/B6 mice weighing 10-20 g were used. Vehicle and active agents ⁇ i.e., CBD and hydroxychloroquine) alone or in combination were administered intraperitoneally (IP) at 1 hour before LPS ( ⁇ 80 mg/kg) was administered intratracheally. 24 hours after LPS injection, mice were anaesthetized with pentoparbital and 0.5 mL of PBS was administered twice through a tracheal cannula after which approximately 0.6 mL of broncheoalveolar lavage fluid (BALF) was obtained. The BALF was assayed for IL-I ⁇ , TNF- ⁇ , MCP-l(MCAF) and CXCL-1 by Luminex. ANOVA followed by Dunnett's test was applied for comparison between vehicle and treatment groups. p ⁇ 0.05 was considered significant.
• Vehicle and active agents ⁇ i.e., CBD and hydroxychloroquine
• IP intraperitoneally
• mice 24 hours after LPS injection, mice were anaesthetized
• lungs were harvested at termination (five lobes per lung) and fixed in 10% neutral buffered formalin for histopathology. Samples were sectioned at 4-6 pm and stained with hematoxylin and eosin (H&E) to examine inflammatory lesions as described by Shackleford et al. (2002, Toxicologic Pathology, 30(1): 93-96). Briefly, a score of 0 corresponds to not present, and a score of 5 indicates a severe/high number of lesions. Scores were averaged across lobes for each animal and then across animals for each treatment group.
• H&E hematoxylin and eosin
• TNBS 2,4,6-trinitrobenzene sulfonic acid
• Male BALB/c were used as an in vivo model of colitis, induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in 50% ethanol, as previously described by Antoniou et al. (2016, Annals of Medicine and Surgery, 11: 9-15). Briefly, the ethanol disrupts the intestinal barrier, permitting TNBS to interact with colon proteins. Interaction of TNBS with high-molecular weight proteins renders them immunogenic, leading to Thl mediated inflammation, which is causative of symptoms include inconsistent stool formation and blood in the faeces.
• TNBS 2,4,6-trinitrobenzene sulfonic acid
• Vehicle and active agents i.e., CBD and hydroxychloroquine
• IP intraperitoneally
• test articles and vehicle were given 2 hrs before TNBS.
• Colon tissues were harvested in all animals at termination. Colon samples were taken at 0.5, 2, and 3.5 cm from the anus, fixed in formalin, and then embedded in paraffin blocks. Four-micrometer tissue sections were cut and stained with H&E for histological analysis in accordance with the method of Dieleman et al. (1998, Clinical Experimental Immunology, 114: 385-391). Histological criteria included: abnormalities of mucosal architecture, extent of inflammation, erosion or ulceration, epithelial regeneration, and the percentage involvement by the disease process. The scoring was based on the findings of the observers by examining three sections from each colon per animal. Total score for colitis (Total Colitis Index) were added, resulting in a combined histological score range from 0 to 60.
• Total Colitis Index Total Colitis Index
• Vehicle and active agents ⁇ i.e., CBD and hydroxychloroquine
• IP intraperitoneally
• the anti-inflammatory activity the combination of CBD and hydroxychloroquine was assessed by determining cytokine release from human peripheral blood mononuclear cells (PBMCs) stimulated with bacterial lipopolysaccharide (LPS) using a Luminex based assay.
• PBMCs peripheral blood mononuclear cells
• LPS bacterial lipopolysaccharide
• a 96-well microtitre plate-based checkerboard assay with seven concentrations (including the no drug control) of CBD and hydroxychloroquine were assessed in combination was used to determine the drug-drug interaction. Briefly, frozen PMBCs from two independent donors were thawed, diluted in culture medium, seeded into 96-well microtitre plates and incubated at 37°C, 5% CO 2 for 1 hour prior to the addition of test compounds.
• E pred A+B (E A +E B )-(E A E B )
• Doses of CBD and hydroxychloroquine used in in vivo models of the inflammatory conditions exemplified herein may be converted (i.e., theoretically extrapolated) to an appropriate human starting dose using methods known in the art, illustrative examples of which include the U.S. Department of Health and Human Services, Food and Drug Administration (FDA) Guidance for Industry - Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (2005, available at http://www.fda.gov/72309/download).
• the derived starting dose can be tested for safety and efficacy using routine methods, such as first-in-human clinical trials for new therapeutic modalities in adult healthy volunteers.
• Example 1 Exemplary composition for the treatment of sepsis-associated ARDS
• Exemplary loading dose compositions according to the present disclosure comprise the following ingredients:
• Exemplary maintenance dose compositions according to the present disclosure comprise the following ingredients:
• Both the loading dose and maintenance dose compositions according to the present disclosure are formulated for oral administration according to a twice daily dosage regimen.
• Example 2 Exemplary methods for the in vitro treatment of sepsis-associated ARDS
• ARDS The in vitro treatment of ARDS according to the present disclosure will be assessed using classic rodent model systems of sepsis-associated ARDS (e.g., as reviewed by Matute-Bello et al., 2008, American Journal of Physiology - Lung Cellular and Molecular Physiology, 295: L379-L399) to evaluate the pharmacodynamics of CBD and hydroxychloroquine, or compositions comprising CBD and/or hydroxychloroquine. Plasma concentration of the active agents, reduction in markers of acute inflammation and increased pulmonary function are the key experimental endpoints for these methods.
• Example 3 Exemplary methods for the treatment of sepsis-associated ARDS
• An exemplary method for the treatment of sepsis-associated ARDS according to the present disclosure is as follows:
• Composition of Example 1 Loading dose - oral administration or co-administration of active agents to the subject twice per day on the first day of treatment.
• the duration of therapy is acute, expected to be between 3-4 weeks.
• CBD and hydroxychloroquine or compositions comprising CBD and/or hydroxychloroquine for the treatment of sepsis-associated ARDS as follows:
• Group 1 Loading dose: 500 mg - 1000 mg CBD + 400 mg hydroxychloroquine, twice per day.
• Group 2 Loading dose: 500 mg - 1000 mg CBD + placebo, twice per day. Maintenance dose: 500 mg - 1000 mg CBD + placebo, twice per day.
• Group 3 Loading dose: Placebo + 400 mg hydroxychloroquine, twice per day.
• Efficacy of each trial group is assessed based on a target efficacy for clinical significance (i.e., reduction in markers of acute inflammation/ reduction of LIS > 20%).
• ARDS is an inflammatory disorder associated with the release of pro- inflammatory cytokines, together with accumulation of immune cells within the pulmonary tissues.
• pro-inflammatory transcription factors e.g., NF-k ⁇
• NF-k ⁇ pro-inflammatory transcription factors
• CBD and hydroxychloroquine will simultaneously reduce inflammation and promote immune system regulatory pathways that may reverse pulmonary tissue damage in patients with ARDS to effectively treat ARDS and ameliorate associated symptoms.
• the anti-inflammatory activity of CBD likely synergises with the anti-inflammatory activity and promotion of the resolution of inflammation mediated by the hydroxychloroquine to reduce the acute pulmonary inflammatory response to treat ARDS.
• Example 4 Intraperitoneal administration of CBD or hydroxychloroquine modulates the immune response to LPS-induced sepsis in vivo
• CBD and hydroxychloroquine were evaluated for their ability to modulate the immune response to LPS-induced sepsis in mice at five different dose levels following intraperitoneal administration.
• hydroxychloroquine also showed a dose-dependent increase on D-dimer level and significant (p ⁇ 0.05) increase on IL-10 levels compared to the vehicle group. Moreover, when compared to the vehicle group, hydroxychloroquine given at 50 and 100 mg/kg produced significant (p ⁇ 0.05) decreases in IL-I ⁇ and IL-2 levels and a moderate decrease on IL-12(p70), TNF- ⁇ and IFN- ⁇ levels in the in vivo model of LPS-induced sepsis (Figure 1, Table 9).
• dexamethasone at 10 mg/kg PO significantly ( p ⁇ 0.05) reduced the levels of levels of IL-I ⁇ , IL-2, IL-12(p70) and TNF- ⁇ compared to the vehicle group in the study ( Figure 1, Table 10).
• Example 5 Oral administration of a combination of CBD and hydroxychloroquine modulates the immune response to LPS-induced sepsis in vivo
• CBD and hydroxychloroquine were evaluated for their ability to modulate the immune response to LPS-induced sepsis in mice at two different dose levels following oral administration.
• CBD given at 10 mg/kg or hydroxychloroquine given at 20 mg/kg by oral gavage (PO) alone showed moderate suppression on the LPS-induced IL- 1 ⁇ , IL-I ⁇ , IL-2, IL-4, IL-5, and IL-9 release compared to the vehicle group.
• CBD at 1 mg/kg or hydroxychloroquine at 2 mg/kg PO alone had little or no effect on biomarker levels (Figure 2; Tables 13 and 14).
• CBD given at 1 mg/kg in combination with hydroxychloroquine given at 2 mg/kg by PO showed significant (p ⁇ 0.05) reduction in IL-1 ⁇ , IL-2, IL-4 and GM-CSF levels and moderate effect in IL-I ⁇ , IL-5, IL-9, IL-13 and IFN- ⁇ compared to the vehicle group ( Figure 2; Tables 15 and 17).
• CBD given at 10 mg/kg in combination with hydroxychloroquine given at 2 mg/kg by PO showed significant (p ⁇ 0.05) effect on IL-1 ⁇ level and moderate effect on IL-4, IL-5, IL-9 and IL-13 levels compared to the vehicle group (Tables 16 and 18).
• CBD at 10 mg/kg in combination with hydroxychloroquine at 20 mg/kg PO produced significant (p ⁇ 0.05) effect on IL-4 level and moderate effect on IL-1 ⁇ , IL-I ⁇ , IL-5, IL-9, IL-13 and IFN- ⁇ in LPS-induced sepsis model (Figure 2; Tables 16 and 18).
• dexamethasone at 10 mg/kg PO significantly ( p ⁇ 0.05) reduced the levels of levels of IL-I ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p40), IL-12(p70), IL-17A, Eotaxin, GM-CSF, MCP-1, MIR-1 ⁇ , MIR-1 ⁇ , RANTES, and TNF- ⁇ compared to the vehicle group in the study ( Figure 2; Tables 11 and 12).
• Example 6 Combination of CBD and hydroxychloroquine synergise to modulate an inflammatory response in vitro
• CBD and hydroxychloroquine act synergistically to inhibit LPS-induced production of the inflammatory cytokines IL-I ⁇ , IL-6, TNF- ⁇ , IL-1 ⁇ , and MIP-1 ⁇ at multiple drug concentrations.
• PBMCs from Donor 1 were treated with 5 ⁇ g/mL CBD in combination with 0.63, 1.25, 2.5, 5 and 10 ⁇ g/mL hydroxychloroquine, the results of which are shown in Table 19.
• PBMCs from Donor 2 were treated with 5 ⁇ g/mL CBD in combination with 0.63, 1.25, 2.5, 5, 10 and/or 20 ⁇ g/mL hydroxychloroquine, the results of which are shown in Table 20.
• Example 7 Combination of CBD and hydroxychloroquine synergise to modulate an inflammatory response in vivo
• CBD and hydroxychloroquine act synergistically to inhibit the LPS-induced production of inflammatory cytokines IL-I ⁇ , IL-6, IL-12(p70), IFN- ⁇ , and/or TNF- ⁇ at multiple drug concentrations (Tables 21-24).
• Example 8 Combination of CBD and hydroxychloroquine synergise to modulate the immune response in an in vivo model of pulmonary inflammation
• mice were challenged with LPS intratracheally to trigger pulmonary inflammation in a manner recapitulates clinical aspects of pulmonary inflammation observed inflammatory respiratory conditions such as COPD (see, e.g., Flakannsson et al., 2012, Pulmonary Pharmacology & Therapeutics, 25: 399-406).
• CBD and hydroxychloroquine act synergistically to inhibit the production of inflammatory cytokines IL-I ⁇ , IL-6, TNF- ⁇ , CXCL-1 and MCP-1 at multiple concentrations, as measured from the BALF of mice with LPS-induced pulmonary inflammation (Tables 25-26).
• CBD and hydroxychloroquine act synergistically to reduce the myeloperoxidase
• Example 10 Combination of CBD and hydroxychloroquine synergise to treat arthritis in vivo
• the Excess Over Bliss scores for clinical score, paw volume, pannus formation and total histological score were 0.05, 0.26, 0.30 and 0.03, respectively (Table 35).
• Hydroxychloroquine has been used for the treatment of rheumatoid arthritis in the form of hydroxychloroquine sulfate.
• long-term use of hydroxychloroquine has been associated with ocular toxicity and cardiac effects (e.g ., cardiomyopathy and QT prolongnation).
• ocular toxicity and cardiac effects e.g ., cardiomyopathy and QT prolongnation.
• Clinically, the most important predictor of ocular toxicity and cardiac effects in rheumatoid arthritis patients is the cumulative dose of hydroxychloroquine.
• the combination of CBD and hydroxychloroquine can be used to modulate inflammatory mediators of sepsis-induced ARDS and pulmonary inflammation, including a reduction in IL-I ⁇ , which is known to be elevated in both the bronchoalveolar lavage fluid and in the circulating plasma ARDS patients (see, e.g., Meduri et al., 2009, Chest, 136: 1631-1643).
• the combination of CBD and hydroxychloroquine has been shown to synergise to the extent that makes it possible to reduce the dose of hydroxychloroquine to a level that may minimise adverse effects associated with long-term use, while still eliciting a therapeutic effect.
• Vehicle and TAs are administered orally (PO) at 1 hr before LPS (100 ⁇ g/mouse) injected intravenously (IV).
• IV intravenously
• Table 33 Cartilage and bone destruction by pannus formation scoring matrix in vivo model of arthritis
• Table 34 Mononuclear cell infiltration scoring matrix for in vivo model of arthritis
• Table 37 Comparison of high dose HCQ with low dose HCQ in combination with 1 mg/kg CBD in reducing disease severity in an in vivo model of arthritis

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