Methods and compositions for treating or preventing inflammatory conditions

Abstract

The present disclosure relates to compositions comprising cannabidiol (CBD) and hydroxychloroquine (HCQ) or pharmaceutically acceptable salts thereof, and their use in methods for treating inflammatory conditions or modulating immune responses. In one embodiment, the disclosure relates to methods and compositions useful for treating or preventing inflammatory conditions, 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).

Description

[Technical Field]

[0001] Related applications

[0001] This application claims priority to Australian Provisional Patent Application No. 2020901030 filed on 2 April 2020, No. 2020902432 filed on 14 July 2020, No. 2020903985 filed on 2 November 2020, No. 2020904264 filed on 18 November 2020, No. 2021900241 filed on 3 February 2021, and No. 2021900324 filed on 10 February 2021, the entire contents of which are incorporated herein by reference.

[0002]

[0002] The disclosure as a whole relates to methods and compositions useful for modulating inflammatory responses. In one embodiment, the disclosure relates to methods and compositions useful for treating or preventing inflammatory conditions, 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). [Background technology]

[0003]

[0003] Inflammatory states are characterized by complex biological responses to inflammation, harmful stimuli, such as injury, autoimmunity, or infection by microbial pathogens and / or viruses. The clinical features of an inflammatory state may depend on one or more harmful stimuli, but are typically associated with fever, pain, redness, and swelling of the affected organ or tissue.

[0004]

[0004] Inflammatory states are typically associated with the upregulation of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), interleukin-12 (IL-12(p70)), interferon-gamma (IFN-γ), and / or macrophage inflammatory protein (MIP-1α), which modulate the range of signaling pathways to promote inflammatory responses. Inflammatory states 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 states, such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, sarcoidosis, and pneumonia.

[0005]

[0005] Inflammatory respiratory conditions are among the most common diseases worldwide. Different inflammatory respiratory conditions exhibit different inflammatory responses, but share some common pathological features. For example, congenital neutrophilic inflammation, which is shared by COPD and ARDS, is also observed in some patients with severe asthma.

[0006]

[0006] ARDS is an inflammatory condition affecting lung tissue, most commonly caused by sepsis. ARDS is characterized by poor oxygenation, pulmonary infiltrates, and a severe onset (Diamond et al., 2020, Acute Respiratory Distress Syndrome (ARDS), in: StatPearls; Treasure Island (FL): StatPearls Publishing; 2020). ARDS typically develops within a week of an irritant event with clinically symptomatic presentations including capillary endothelial damage and diffuse alveolar damage, bilateral pulmonary infiltrates, and severe progressive hypoxemia, without any evidence of cardiogenic pulmonary edema. Upon developing ARDS, patients usually have varying degrees of pulmonary artery vasoconstriction and may subsequently develop pulmonary hypertension.

[0007]

[0007] ARDS has many risk factors. In addition to lung infection or aspiration, non-pulmonary causes include sepsis, trauma, blood transfusion, drowning, drug overdose, fat embolism, inhalation injury, and pancreatitis. These extrathoracic diseases and / or injuries trigger an inflammatory cascade that can lead to lung injury.

[0008]

[0008] Sepsis-associated ARDS is a complication resulting from severe sepsis and is a systemic response to a blood infection. Any living microorganism, such as bacteria, fungi, and viruses, can be the source of the infection. Sepsis is relatively common, affecting approximately 750,000 adults in the United States each year, with about 6% of patients developing ARDS. Mortality rates are high for patients diagnosed with ARDS, with acute mortality exceeding 30% despite optimal critical care.

[0009]

[0009] The primary pathophysiological mechanism underlying ARDS is unsuppressed, persistent inflammation, leading to edema. Respiratory failure removes numerous organs from the alveolar space, resulting in the accumulation of high-protein fluid within the alveoli. The edema leads to diffuse alveolar damage, accompanied by the release of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Neutrophils are recruited to the lungs by cytokines, activated, and release toxic mediators such as reactive oxygen species and proteases. The widespread generation of free radicals outnumbers endogenous antioxidants, causing oxidative cell damage. The initial phase of ARDS is an exudative phase characterized by fluid accumulation within the lung tissue, followed by a proliferative phase characterized by the resolution of pulmonary edema, proliferation of type II alveolar cells, fibroblasts, and myofibroblasts, and novel matrix deposition. The proliferative phase begins within 72 hours of disease onset and lasts longer than 7 days. Patients who develop pulmonary fibrosis exhibit deterioration of lung compliance, progressive hypoxia, and ventilator dependence, with a mortality rate of nearly 60% (Pierrakos et al., 2012, Journal of Clinical Medicine Research, 4:7-16).

[0010]

[0010] Current standard treatment for sepsis-associated ARDS is limited to supportive therapies such as mechanical ventilation and oxygen supplementation, which are typically delivered concurrently with treatment for potential infections causing severe sepsis, if any such treatments are available. However, despite decades of efforts to improve the prognosis of ARDS, therapeutic treatments are currently unavailable. Conventional attempts to develop treatments for ARDS have aimed to reduce the acute pulmonary inflammatory response, reverse edema, and limit lung damage by using, for example, glucocorticoids (Steinberg et al., 2006, The New England Journal of Medicine, 354(16):1671-1684), surfactant replacement therapy, neutrophil elastase inhibitors, anticoagulants, nonsteroidal anti-inflammatory drugs and statins (e.g., Boyle et al., 2013, BMC Medicine, 11:166, review). Unfortunately, however, pharmacological interventions have not proven effective in treating ARDS. [Overview of the initiative] [Problems that the invention aims to solve]

[0011]

[0011] Therefore, there remains an urgent need for the development of pharmacological approaches to treat or prevent inflammatory conditions, including inflammatory bowel disease, arthritis, and inflammatory respiratory conditions, such as COPD, asthma, bronchitis, CF, and ARDS. [Means for solving the problem]

[0012]

[0012] In one aspect of the present disclosure, a method is provided for treating or preventing an inflammatory condition, comprising the step of administering to a subject in need of such treatment or prevention an effective amount of cannabidiol (CBD) or a pharmaceutically acceptable salt thereof, and an effective amount of hydroxychloroquine or a pharmaceutically acceptable salt thereof.

[0013]

[0013] In another aspect of the present disclosure, the use of 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 is provided.

[0014]

[0014] In another aspect of the present disclosure, compositions comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are provided.

[0015] In another aspect of this disclosure, compositions comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are provided for use in the treatment or prevention of inflammatory conditions.

[0015]

[0016] In another aspect of this disclosure, a kit is provided comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of inflammatory conditions.

[0016]

[0017] In another aspect of the present disclosure, a method is provided for modulating an immune response, comprising the step of administering to a subject in need of such modification CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawing]

[0017] [Figure 1-1]

[0018] Figure 1 shows that CBD or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following intraperitoneal (IP) administration. (A) Graph of mouse IL-1β (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (B) Graph of mouse IL-2 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (C) Graph of mouse IL-10 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (D) Graph of mouse IL-12 (p70) (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (E) (F) Graph showing mouse IFN-γ (pg / mL; y axis) following IP administration of hydroxychloroquine (x axis); (G) Graph showing mouse TNF-α (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (X) Graph showing D-dimer levels (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); +p<0.05 vs. pseudo; *p<0.05 vs. CBD vehicle (group 2); #p<0.05 vs. hydroxychloroquine vehicle (group 10); One-way ANOVA and Dunnett's test. [Figure 1-2]

[0018] Figure 1 shows that CBD or hydroxychloroquine can modulate important immunomarkers associated with sepsis-related ARDS following intraperitoneal (IP) administration. (A) Graph of mouse IL-1β (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (B) Graph of mouse IL-2 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (C) Graph of mouse IL-10 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (D) Graph of mouse IL-12 (p70) (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (E) CBD or hydroxychloroquine (F) Graph showing mouse IFN-γ (pg / mL; y axis) following IP administration of hydroxychloroquine (x axis); (G) Graph showing mouse TNF-α (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (X) Graph showing D-dimer levels (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); +p<0.05 vs. pseudo; *p<0.05 vs. CBD vehicle (group 2); #p<0.05 vs. hydroxychloroquine vehicle (group 10); One-way ANOVA and Dunnett's test. [Figure 1-3]

[0018] Figure 1 shows that CBD or hydroxychloroquine can modulate important immunomarkers associated with sepsis-related ARDS following intraperitoneal (IP) administration. (A) Graph of mouse IL-1β (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (B) Graph of mouse IL-2 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (C) Graph of mouse IL-10 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (D) Graph of mouse IL-12 (p70) (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (E) CBD or hydroxychloroquine (F) Graph showing mouse IFN-γ (pg / mL; y axis) following IP administration of hydroxychloroquine (x axis); (G) Graph showing mouse TNF-α (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (X) Graph showing D-dimer levels (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); +p<0.05 vs. pseudo; *p<0.05 vs. CBD vehicle (group 2); #p<0.05 vs. hydroxychloroquine vehicle (group 10); One-way ANOVA and Dunnett's test. [Figure 1-4]

[0018] Figure 1 shows that CBD or hydroxychloroquine can modulate important immunomarkers associated with sepsis-related ARDS following intraperitoneal (IP) administration. (A) Graph of mouse IL-1β (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (B) Graph of mouse IL-2 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (C) Graph of mouse IL-10 (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (D) Graph of mouse IL-12 (p70) (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (E) CBD or hydroxychloroquine (F) Graph showing mouse IFN-γ (pg / mL; y axis) following IP administration of hydroxychloroquine (x axis); (G) Graph showing mouse TNF-α (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); (X) Graph showing D-dimer levels (pg / mL; y axis) following IP administration of CBD or hydroxychloroquine (x axis); +p<0.05 vs. pseudo; *p<0.05 vs. CBD vehicle (group 2); #p<0.05 vs. hydroxychloroquine vehicle (group 10); One-way ANOVA and Dunnett's test. [Figure 2-1]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-2]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-3]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);Graphical representation of mouse GM-CSF (pg / mL; y-axis) following oral administration of (P)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse IFN-γ (pg / mL; y-axis) following oral administration of (Q)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse keratinocyte chemoattractant (KC) (pg / mL; y-axis) following oral administration of (R)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse MCP-1 (pg / mL; y-axis) following oral administration of (S)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse MIP-1α (pg / mL; y-axis) following oral administration of (T)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse MIP-1β (pg / mL; y-axis) following oral administration of (U)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse RANTES (pg / mL; y-axis) following oral administration of (V)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse TNF-α (pg / mL; y-axis) following oral administration of (W)CBD and / or hydroxychloroquine (x-axis); p<0.05, vs vehicle control; one-way analysis of variance and Dunnett's test.; [Figure 2-4]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-5]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-6]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-7]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);Graphical representation of mouse GM-CSF (pg / mL; y-axis) following oral administration of (P)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse IFN-γ (pg / mL; y-axis) following oral administration of (Q)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse keratinocyte chemoattractant (KC) (pg / mL; y-axis) following oral administration of (R)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse MCP-1 (pg / mL; y-axis) following oral administration of (S)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse MIP-1α (pg / mL; y-axis) following oral administration of (T)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse MIP-1β (pg / mL; y-axis) following oral administration of (U)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse RANTES (pg / mL; y-axis) following oral administration of (V)CBD and / or hydroxychloroquine (x-axis); Graphical representation of mouse TNF-α (pg / mL; y-axis) following oral administration of (W)CBD and / or hydroxychloroquine (x-axis); p<0.05, vs vehicle control; one-way analysis of variance and Dunnett's test. ; [Figure 2-8]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-9]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-10]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-11]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 2-12]

[0019] Figure 2 shows that CBD and / or hydroxychloroquine can modulate key immunomarkers associated with sepsis-related ARDS following oral administration. (A) Graph of mouse IL-1α (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (B) Graph of mouse IL-1β (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (C) Graph of mouse IL-2 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (D) Graph of mouse IL-3 (pg / mL) following oral administration of CBD and / or hydroxychloroquine (x axis). (L; y axis) graph display; (E) Graph display of mouse IL-4 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (F) Graph display of mouse IL-5 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (G) Graph display of mouse IL-6 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (H) Mouse IL-6 following oral administration of CBD and / or hydroxychloroquine (x axis) Graph display of IL-9 (pg / mL; y axis); (I) Graph display of mouse IL-10 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (J) Graph display of mouse IL-12 (p40) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (K) Graph display of mouse IL-12 (p70) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (L) CBD and / or hydroxychloroquine (M) Graph showing mouse IL-13 (pg / mL; y axis) following oral administration of roxychloroquine (x axis); (N) Graph showing mouse IL-17A (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (O) Graph showing mouse G-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis);(P) Graph showing mouse GM-CSF (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (Q) Graph showing mouse IFN-γ (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (R) Graph showing mouse keratinocyte chemoattractant (KC) (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (S) Graph showing mouse MCP-1 (pg / mL; y axis) following oral administration of CBD and / or hydroxychloroquine (x axis); (T) CBD and / or hydroxychloroquine (U) Graph showing mouse MIP-1α (pg / mL; y axis) followed by oral administration of hydroxychloroquine (x axis); (V) Graph showing mouse RANTES (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); (W) Graph showing mouse TNF-α (pg / mL; y axis) followed by oral administration of CBD and / or hydroxychloroquine (x axis); p<0.05, vs. vehicle control; one-way ANOVA and Dunnett's test. [Figure 3-1]

[0020] Figure 3 shows that CBD and hydroxychloroquine are effective in treating mice with TNBS-induced colitis. (A) Photographs of normal colon tissue from simulated-treated control mice; (B) Photographs of colon tissue from vehicle control mice, * indicates areas of inflammatory cell infiltration in submucosal edema; (C) Photographs of colon tissue from mice treated with CBD (1 mg / kg), * indicates areas of inflammatory cell infiltration in submucosal edema; (D) Photographs of colon tissue from mice treated with hydroxychloroquine (2.5 mg / kg), * indicates areas of mild abnormalities, cyctic dilation, and abnormal crypts; (E) Photographs of colon tissue from mice treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg), * indicates areas of minimal cell infiltration. All images are shown at 100x magnification and stained with hematoxylin and eosin (H&E). [Figure 3-2]

[0020] Figure 3 shows that CBD and hydroxychloroquine are effective in treating mice with TNBS-induced colitis. (A) Photograph of normal colon tissue from a simulated-treated control mouse; (B) Photograph of colon tissue from a vehicle control mouse, * indicates areas of inflammatory cell infiltration in submucosal edema; (C) Photograph of colon tissue from a mouse treated with CBD (1 mg / kg), * indicates areas of inflammatory cell infiltration in submucosal edema; (D) Photograph of colon tissue from a mouse treated with hydroxychloroquine (2.5 mg / kg), * indicates areas of mild abnormalities, cyctic dilation, and abnormal crypts; (E) Photograph of colon tissue from a mouse treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg), * indicates areas of minimal cell infiltration. All images are shown at 100x magnification and stained with hematoxylin and eosin (H&E). [Figure 3-3]

[0020] Figure 3 shows that CBD and hydroxychloroquine are effective in treating mice with TNBS-induced colitis. (A) Photograph of normal colon tissue from a simulated-treated control mouse; (B) Photograph of colon tissue from a vehicle control mouse, * indicates areas of inflammatory cell infiltration in submucosal edema; (C) Photograph of colon tissue from a mouse treated with CBD (1 mg / kg), * indicates areas of inflammatory cell infiltration in submucosal edema; (D) Photograph of colon tissue from a mouse treated with hydroxychloroquine (2.5 mg / kg), * indicates areas of mild abnormalities, cyctic dilation, and abnormal crypts; (E) Photograph of colon tissue from a mouse treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg), * indicates areas of minimal cell infiltration. All images are shown at 100x magnification and stained with hematoxylin and eosin (H&E). [Figure 4-1]

[0021] Figure 4 shows that CBD and hydroxychloroquine are effective in treating mice with pneumonia. (A) Photographs of normal lung tissue from simulated-treated control mice; (B) Photographs of lung tissue from vehicle control mice; (C) Photographs of lung tissue from mice treated with CBD (1 mg / kg); (D) Photographs of lung tissue from mice treated with hydroxychloroquine (2.5 mg / kg); (E) Photographs of lung tissue from mice treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg); (F) Photographs of lung tissue from mice treated with CBD (10 mg / kg); (G) Photographs of lung tissue from mice treated with hydroxychloroquine (25 mg / kg); and (G) Photographs of lung tissue from mice treated with CBD (10 mg / kg) and hydroxychloroquine (25 mg / kg). All images are shown at 100x magnification and stained with hematoxylin and eosin (H&E). The arrows indicate inflammatory cell infiltration. [Figure 4-2]

[0021] Figure 4 shows that CBD and hydroxychloroquine are effective in treating mice with pneumonia. (A) Photograph of normal lung tissue from a simulated-treated control mouse; (B) Photograph of lung tissue from a vehicle control mouse; (C) Photograph of lung tissue from a mouse treated with CBD (1 mg / kg); (D) Photograph of lung tissue from a mouse treated with hydroxychloroquine (2.5 mg / kg); (E) Photograph of lung tissue from a mouse treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg); (F) Photograph of lung tissue from a mouse treated with CBD (10 mg / kg); (G) Photograph of lung tissue from a mouse treated with hydroxychloroquine (25 mg / kg); and (G) Photograph of lung tissue from a mouse treated with CBD (10 mg / kg) and hydroxychloroquine (25 mg / kg). All images are shown at 100x magnification and stained with hematoxylin and eosin (H&E). Arrows indicate inflammatory cell infiltration. [Figure 5-1]

[0022] Figure 5 shows that CBD and hydroxychloroquine are effective in treating rats with collagen-induced arthritis. (A) Photographs of normal hind leg ankle tissue from a simulated-treated control rat; (B) Photographs of hind leg ankle tissue from a vehicle control rat; (C) Photographs of hind leg ankle tissue from a rat treated with CBD (1 mg / kg); (D) Photographs of hind leg ankle tissue from a rat treated with hydroxychloroquine (2.5 mg / kg); (E) Photographs of hind leg ankle tissue from a rat treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg). All images are shown at 50x magnification and stained with hematoxylin and eosin (H&E). [Figure 5-2]

[0022] Figure 5 shows that CBD and hydroxychloroquine are effective in treating rats with collagen-induced arthritis. (A) Photograph of normal hind leg ankle tissue from a simulated-treated control rat; (B) Photograph of hind leg ankle tissue from a vehicle control rat; (C) Photograph of hind leg ankle tissue from a rat treated with CBD (1 mg / kg); (D) Photograph of hind leg ankle tissue from a rat treated with hydroxychloroquine (2.5 mg / kg); (E) Photograph of hind leg ankle tissue from a rat treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg). All images are shown at 50x magnification and stained with hematoxylin and eosin (H&E). [Figure 5-3]

[0022] Figure 5 shows that CBD and hydroxychloroquine are effective in treating rats with collagen-induced arthritis. (A) Photograph of normal hind leg ankle tissue from a simulated-treated control rat; (B) Photograph of hind leg ankle tissue from a vehicle control rat; (C) Photograph of hind leg ankle tissue from a rat treated with CBD (1 mg / kg); (D) Photograph of hind leg ankle tissue from a rat treated with hydroxychloroquine (2.5 mg / kg); (E) Photograph of hind leg ankle tissue from a rat treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg). All images are shown at 50x magnification and stained with hematoxylin and eosin (H&E). [Modes for carrying out the invention]

[0018]

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this disclosure belongs. Any materials and methods similar or equivalent to those described herein may also be used to carry out the present invention.

[0019]

[0024] Throughout this specification, unless the context requires otherwise, it will be understood that the word “comprise,” or variations such as “comprises,” or “comprising,” indicate the inclusion of the element or integer or group of elements or integers described, but not the exclusion of any other element or integer or group of elements or integers.

[0020]

[0025] The phrase "consists of" means that it includes and is limited to any of the elements that follow it. Therefore, the phrase "consists of" indicates that the listed elements are necessary or mandatory, and that no other elements can exist. The phrase "essentially consists of" means that it includes any of the elements listed after the phrase, and is limited to other elements that do not interfere with or contribute to the activity or action of the listed elements as specified in this disclosure. Therefore, the phrase "essentially consists of" indicates that the listed elements are necessary or mandatory, but the other elements are optional and may or may not exist depending on whether or not they affect the activity or action of the listed elements.

[0021]

[0026] As used herein, the singular forms "a," "an," and "the" include multiple aspects unless the context explicitly indicates otherwise. Thus, for example, a reference to "compound" includes a single compound as well as two or more compounds, a reference to "drug" includes one drug as well as two or more drugs, and so on.

[0022]

[0027] The term "approximately" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. In cases where the term is not obvious to those skilled in the art, judging from the context in which it is used, "approximately" means up to ±10% of a particular post-term.

[0023]

[0028] This disclosure is based at least in part on the inventors' remarkable discovery that administration of cannabidiol (CBD) and hydroxychloroquine can, in a synergistic manner, provide potent anti-inflammatory activity useful in 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). For example, the synergistic effect between CBD and hydroxychloroquine allows for both a reduction in neutrophil infiltration into lung tissue, a decrease in the proliferative phase of ARDS, and improved alveolar fluid clearance. Furthermore, the combination of CBD and hydroxychloroquine can reduce the formation and / or severity of colitis lesions and improve symptoms of inflammatory bowel disease, including a decrease in myeloperoxidase (MPO) levels, stool viscosity scores, and macroscopic damage in the colon, thereby enabling the therapeutic use of this combination in patients with inflammatory bowel disease. Furthermore, the combination of CBD and hydroxychloroquine has been shown to exhibit a synergistic effect to some extent, allowing for a reduction in the dose of hydroxychloroquine to a level that minimizes the adverse effects associated with long-term use, while still eliciting therapeutic effects.

[0024]

[0029] Therefore, in one embodiment disclosed herein, a method is provided for the treatment or prevention of an inflammatory condition, comprising the step of administering to a subject in need of such treatment or prevention an effective amount of CBD or a pharmaceutically acceptable salt thereof, and an effective amount of hydroxychloroquine or a pharmaceutically acceptable salt thereof.

[0025] Inflammatory state

[0030] As used herein, the term “inflammatory state” typically refers to a condition characterized by inflammation, or a complex biological response to a harmful stimulus such as injury, autoimmunity, or infection by a microbial pathogen and / or virus. The clinical features of an inflammatory state may depend on one or more harmful stimuli, but are typically characterized by fever, pain, redness, and swelling of the affected organ or tissue. Inflammatory states can be acute or chronic.

[0026]

[0031] In one embodiment, the inflammatory state is selected from the group consisting of inflammatory respiratory conditions, inflammatory bowel disease, and arthritis.

[0032] In one embodiment, the inflammatory state is an inflammatory respiratory state.

[0027]

[0033] Inflammatory respiratory conditions are known to those skilled in the art, and examples include ARDS, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, sarcoidosis, and cystic fibrosis (CF).

[0028]

[0034] In one embodiment, 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).

[0029]

[0035] In one embodiment, the inflammatory respiratory condition is ARDS. In another embodiment, the inflammatory respiratory condition is sepsis-related ARDS.

[0036] In one embodiment, the inflammatory state is inflammatory bowel disease.

[0030]

[0037] The term "inflammatory bowel disease" refers to a disease or disorder involving chronic inflammation of the gastrointestinal tract. Such diseases or disorders are known to those skilled in the art, and examples include ulcerative colitis and Crohn's disease.

[0031]

[0038] In one embodiment, the inflammatory state is arthritis.

[0039] The term "arthritis" typically refers to a disease characterized by inflammation of the joints, which may also involve cartilage loss. Such diseases are known to those skilled in the art, and examples include rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and ankylosing spondylitis.

[0032]

[0040] In one embodiment, the arthritis is rheumatoid arthritis.

[0041] In one embodiment, the inflammatory state is associated with an increase or upregulation of inflammatory cytokines selected from the group consisting of IL-1β, IL-6, TNF-α, IL-1α, IL-12(p70), IFN-γ, CXCL-1, MCP-1, and MIP-1α, or a combination thereof.

[0033]

[0042] In one embodiment, the inflammatory state is associated with an increase or upregulation of inflammatory cytokines selected from the group consisting of IL-1β, IL-6, and TNF-α, or a combination thereof.

[0034]

[0043] Inflammatory conditions associated with increased or upregulation levels of IL-1β, IL-6, TNF-α, IL-1α, IL-12(p70), IFN-γ, CXCL-1, MCP-1, and / or MIP-1α are known to those skilled in the art, and examples include arthritis (e.g., Feldman et al., 1996, Annual Review of Immunology, 14:397-440; McInnes 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 al., 2011, Nature Reviews). Rheumatology (described in 7:33-42), inflammatory bowel disease (e.g., Neurath, 2014, Nature Reviews Immunology, 14:329-342; Papadakis and Targan, 2000, The Annual Review of Medicine, 51:289-298), pain (e.g., Zhang, 2007, International Anesthesiology Clinics, 45:27-37), gout (e.g., Busso, 2010, Arthritis Research & Therapy, 12:206), fibromyalgia (e.g., Rodriguez-Pinto et al., 2014, Immunology Letters, 161:200-203), endometriosis (e.g., Wu and Ho, 2003, American Journal of Reproductive Immunology, 49: pp. 285-296), chronic obstructive pulmonary disease (e.g., Chung, 2001, European Respiratory Journal, 18: 50s-59s), asthma (e.g., Rincon and Irvin, 2012, International Journal of Biological Sciences, 8: pp. 1281-1290;Thomas, 2001, Immunology & Cell Biology, 79: pp. 132-140; alcoholic liver disease (e.g., McClain et al., 1999, Seminars in Liver Diseases, pp. 205-220; Kawaratani et al., 2013, Mediators of Inflammation, 2013: 495-156); psoriasis / dermatitis (e.g., Jensen, 2010, Current Opinions in Investigative Drug Discovery, 11: pp. 1211-1220; Baliwag et al., 2015, Cytokine, 31: pp. 781-789; Toshitani et al., 1993, Journal of Investigative Dermatology, 100: pp. 299-304); and lupus (e.g., Davis et al., 2011, Journal of Interferon & Cytokine). (Includes the information described in Research, 31:781-789).

[0035] Acute respiratory distress syndrome (ARDS)

[0044] The terms “Acute Respiratory Distress Syndrome,” “Adult Respiratory Distress Syndrome,” or “ARDS” can be used interchangeably herein to refer to an inflammatory condition typically characterized by disruption of the alveolar-capillary barrier, influx of high-protein edema fluid into the alveolar space, and cellular recruitment due to immune system stimulation. ARDS may develop after direct lung injury, such as pneumonia, aspiration, inhalation injury, drowning, pulmonary contusion, reperfusion pulmonary edema, and fat embolism. ARDS may also occur during indirect lung injury, such as sepsis, severe trauma, acute pancreatitis, cardiopulmonary bypass, massive blood transfusion, and drug overdose.

[0036]

[0045] "Sepsis-associated acute respiratory distress syndrome" or "sepsis-associated ARDS" typically refers to ARDS induced after an infection of the lungs or a site other than the lungs. An abnormal host response to infection leads to disruption of the alveolar-capillary barrier in the lungs, resulting in lung injury characterized by hypoxemia, inflammation, and non-cardiogenic pulmonary edema.

[0037]

[0046] In one embodiment, ARDS is sepsis-related ARDS.

[0047] The types of pathogens that can cause sepsis-associated ARDS are known to those skilled in the art, and examples include bacteria, e.g., Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii; fungi, e.g., Pneumocystis jirovecii, Candida albicans, Candida tropicalis, Candida glabrata; and viruses, e.g., cytomegalovirus, influenza, herpes simplex virus-1, respiratory syncytial virus, parainfluenza, human metapneumovirus, enterovirus, and coronavirus.

[0038]

[0048] In one embodiment, sepsis-associated ARDS is caused by a bacterial, fungal, or viral infection. In one embodiment, the bacterial infection is selected from the group consisting of infections with Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii. In one embodiment, the viral infection is selected from the group consisting of infections with cytomegalovirus, influenza, herpes simplex virus-1, respiratory syncytial virus, parainfluenza, human metapneumovirus, enterovirus, and coronavirus. In one embodiment, the fungal infection is selected from the group consisting of infections with Pneumocystis jirovecii, Candida albicans, Candida tropicalis, and Candida glabrata.

[0039]

[0049] ARDS can be classified using, for example, the Berlin criteria described in The ARDS Definition Task Force (2012, American Medical Association, 307(23):2526-2234), which is based on the ratio of arterial oxygen partial pressure to inspired oxygen concentration when measured at the lowest level of positive end-expiratory pressure (PEEP) at 5 cm H2O. According to the Berlin criteria, the severity of ARDS can be classified as mild, moderate, or severe (Table 1).

[0040] [Table 1]

[0041]

[0050] Classification of ARDS based on the Berlin criteria can also be made considering risk factors and the duration of exposure to risk factors (i.e., a maximum period of 7 days between exposure to a risk factor and the onset of ARDS). Risk factors for ARDS include direct risk factors, namely pneumonia, aspiration of gastric contents, inhalation injury, pulmonary contusion, pulmonary vasculitis, and drowning, as well as indirect risk factors, namely non-pulmonary sepsis, multiple trauma, pancreatitis, non-cardiogenic shock, drug overdose, and transfusion-related acute lung injury (TRALI).

[0042]

[0051] Imaging of lung pathobiological features in ARDS patients, as well as measurement of inflammatory markers or other biomarkers for ARDS, can also be used in the classification of ARDS.

[0052] Suitable imaging techniques are known to those skilled in the art, and examples include computed tomography (CT), as described, for example, by Puybasset et al. (1998, American Journal of Respiratory and Critical Care Medicine, 158(5): pp. 1644-1655). Similarly, suitable inflammatory markers and other biomarkers for ARDS are known to those skilled in the art, and examples include biomarkers reviewed, for example, by Blondennet et al. (2016, Disease Markers, 2016: 35101373).

[0043]

[0053] The inventors have surprisingly found that CBD and hydroxychloroquine act synergistically to inhibit the production of inflammatory cytokines in response to harmful stimuli. The inventors have also surprisingly found that administration of CBD and hydroxychloroquine can treat lung inflammation-related conditions, including COPD, asthma, CF, and ARDS, by reducing or alleviating the symptoms or severity of ARDS, particularly by reducing the acute lung inflammatory response, reversing edema, and limiting damage to the lungs.

[0044] Cannabidiol (CBD)

[0054] Cannabidiol, or CBD, is a cannabinoid produced by plants of the genus Cannabis. CBD has antagonist activity at both CB1 and CB2 receptors and acts as an inverse agonist of CB1 and CB2 receptors.

[0045]

[0055] CBD is synthesized in Hemp plants as cannabidiolic acid (CBDA), which is decarboxylated into CBD (Table 2). While some decarboxylation can occur within the plant, decarboxylation typically occurs after harvest and is amplified by exposure of the plant material to heat (Sanchez and Verpoote, 2008, Plant Cell Physiology, 49(12):1767-82). Decarboxylation is usually achieved by drying and / or heating the plant material. Those skilled in the art are familiar with methods by which the decarboxylation of CBDA can be accelerated, examples of which include air drying, combustion, vaporization, curing, heating, and calcination. Decarboxylated CBD typically binds directly or indirectly to and / or stimulates cannabinoid receptors, including CB1 and / or CB2.

[0046] [Table 2]

[0047]

[0056] CBD can be extracted from any suitable plant part, including leaves, flowers, or stems, and can be produced by any suitable means known to those skilled in the art. For example, CBD extracts can be produced by extraction in supercritical or subcritical CO2, or by volatilization of plant material in a heated gas. Examples of methods used for plant-derived CBD and other cannabinoids include those described in U.S. Patent No. 10189762 and WO2004 / 016277.

[0048]

[0057] In one embodiment, the CBD disclosed herein is a synthetic compound.

[0058] Synthesized CBD is particularly useful for pharmaceutical development that is significantly free of contaminants. Several methods for synthesizing CBD are known in the art, including the method for synthesizing CBD described in U.S. Patent No. 10,059,682.

[0049]

[0059] This disclosure further intends to describe the use of pharmaceutically acceptable salts of CBD. Suitable pharmaceutically acceptable salts of CBD are known to those skilled in the art, and examples thereof include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, which are known to those skilled in the art.

[0050] Hydroxychloroquine

[0060] Hydroxychloroquine is a chemical derivative of chloroquine, characterized by a hydroxyethyl group instead of an ethyl group. Hydroxychloroquine, usually referred to by the trademark name Plaquenil®, is known to be effective in treating malaria and has shown efficacy in treating systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome. Functionally, hydroxychloroquine has been shown to increase lysosomal pH in antigen-presenting cells and inhibit or block the activation of Toll-like receptors in plasmacytoid dendritic cells.

[0051]

[0061] As used herein, the term “hydroxychloroquine” includes either racemic hydroxychloroquine, which is 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol disclosed in U.S. Patent No. 2,546,658, or the single enantiomer “(S)-(+)hydroxychloroquine” or “(R)-(-)hydroxychloroquine” disclosed in U.S. Patent No. 5,314,894. The term may refer to the free form of hydroxychloroquine or any pharmaceutically acceptable salt thereof, such as hydroxychloroquine sulfate.

[0052]

[0062] This disclosure further intends to describe the use of pharmaceutically acceptable salts of hydroxychloroquine. Suitable pharmaceutically acceptable salts are known to those skilled in the art, and examples thereof include salts or esters prepared from pharmaceutically acceptable nontoxic bases or acids, including inorganic bases or acids and organic bases or acids, which are well known to those skilled in the art.

[0053]

[0063] In one embodiment, the pharmaceutically acceptable salt is hydroxychloroquine sulfate. Methods for treating or preventing inflammatory conditions

[0064] The terms “to treat,” “treating,” and “treatment” are used interchangeably herein to mean relieving, reducing, alleviating, improving, or suppressing the severity of one or more symptoms of the inflammatory condition in question. It should be understood that when the terms “to treat,” “treating,” and “treatment” are used herein, they do not indicate that the subject is treated until the inflammatory condition disappears or is no longer apparent. Such treatment may also reduce the severity of one or more symptoms of the inflammatory condition.

[0054]

[0065] The terms “prevent,” “preventing,” and “prevention” are used interchangeably herein to mean preventing the establishment of a disease state, or in any case preventing, interfering with, delaying, eliminating, or reversing the onset or progression of a state, disease, or other undesirable symptom.

[0055]

[0066] The term “subject” as used herein means any mammal, including livestock and other farm animals (e.g., cattle, goats, sheep, horses, pigs, and chickens), performing animals (e.g., racehorses), companion animals (e.g., cats and dogs), laboratory test animals, and humans. In one embodiment, the subject is a human.

[0056]

[0067] It should be understood that CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered in a therapeutically effective dose to the subject requiring it. As used herein, the terms “therapeutic effective dose” or “effective dose” typically refer to an amount of CBD and hydroxychloroquine sufficient to influence one or more beneficial or desirable therapeutic outcomes (e.g., reduction of inflammatory mediators, reduction of leukocyte count and / or neutrophil infiltration, reduction of acute pulmonary inflammatory response, reversal of edema, and limitation of lung damage). The aforementioned beneficial or desirable therapeutic outcomes can be quantified by measuring clinical parameters, examples of which include the oxygenation index (OI[F]). IO2 (× Mean airway pressure × 100) / Pa O2 ]) or oxygenation saturation index (OSI[F) as described by Des Prez et al. (2017, Chest, 152(6):1151-1158). IO2 (× Mean airway pressure × 100) / Oxygen saturation (S) measured by pulse oxygen meter pO2This includes measuring ( )), determining the ratio of arterial oxygen partial pressure to inspired oxygen concentration (PaO2:FiO2) as described by The ARDS Definition Task Force (2012, cited above), detecting bilateral lung opacity using chest X-ray, detecting changes in immunological biomarker levels as described by Blondennet et al. (2016, cited above), and endoscopic and histological evaluation of colonic mucosa and stool analysis (including fecal occult blood score and stool viscosity). The subjective measurement of beneficial or desirable treatment outcomes can also be performed using clinical devices known in the art, examples of which 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), disease severity scores (e.g., Acute Physiological Function and Chronic Health Assessment II (APACHE II) and Simplified Index Score II), and the Berlin Criteria (The ARDS Definition Task). This includes Force, 2012 (cited above), Crohn's Disease Activity Index (CDAI; Best et al., 1976, Gastroenterology, 70:439-444), and the Mayo score for ulcerative colitis (UC; Lewis et al., 2008, Inflammatory Bowel Disease, 14:1660-1666).

[0057]

[0068] Changes in the symptoms or severity of an inflammatory state, as measured by any quantitative method or clinical instrument described elsewhere herein, can be expressed using any appropriate statistical measurement to indicate the magnitude of the reduction in the symptoms or severity of the inflammatory state. In one embodiment, the method disclosed herein reduces the symptoms or severity of an inflammatory state 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%, compared to a subject having the same inflammatory state but not administered CBD and hydroxychloroquine.

[0058]

[0069] An effective dose may be provided in one or more doses. The exact amount required may vary depending on factors such as the nature and severity of the inflammatory condition being treated, the subject's age and overall health, and the form in which the activator is administered.

[0059]

[0070] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 1000 mg (for example, 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) , 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66m g, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91m g, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113m g, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 131mg, 134 mg, 135mg, 136mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 1 55mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg,176mg、177mg、178mg、179mg、180mg、181mg、182mg、183mg、184mg、185mg、186mg、187mg、188mg、189mg、190mg、191mg、192mg、193mg、194mg、195mg、196mg、197mg、198mg、199mg、200mg、201mg、202mg、203mg、204mg、205mg、206mg、207mg、208mg、209mg、210mg、211mg、212mg、213mg、214mg、215mg、216mg、217mg、218mg、219mg、220mg、221mg、222mg、223mg、224mg、225mg、226mg、227mg、228mg、229mg、230mg、231mg、232mg、233mg、234mg、235mg、236mg、237mg、238mg、239mg、240mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、249mg、250mg、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、280mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290mg、291mg、292mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg、300mg、301mg、302mg、303mg、304mg、305mg、306mg、307mg、308mg、309mg、310mg、311mg、312mg、313mg、314mg、315mg、316mg、317mg、318mg、319mg、320mg、321mg、322mg、323mg、324mg、325mg、326mg、327mg、328mg、329mg、330mg、331mg、332mg、333mg、334mg、335mg、336mg、337mg、338mg、339mg、340mg、341mg、342mg、343mg、344mg、345mg、346mg、347mg、348mg、349mg、350mg、351mg、352mg、353mg、354mg、355mg、356mg、357mg、358mg、359mg、360mg、361mg、362mg、363mg、364mg、365mg、366mg、367mg、368mg、369mg、370mg、371mg、372mg、373mg、374mg、375mg、376mg、377mg、378mg、379mg、380mg、381mg、382mg、383mg、384mg、385mg、386mg、387mg、388mg、389mg、390mg、391mg、392mg、393mg、394mg、395mg、396mg、397mg、398mg、399mg、400mg、401mg、402mg、403mg、404mg、405mg、406mg、407mg、408mg、409mg、410mg、411mg、412mg、413mg、414mg、415mg、416mg、417mg、418mg、419mg、420mg、421mg、422mg、423mg、424mg、425mg、426mg、427mg、428mg、429mg、430mg、431mg、432mg、433mg、434mg、435mg、436mg、437mg、438mg、439mg、440mg、441mg、442mg、443mg、444mg、445mg、446mg、447mg、448mg、449mg、450mg、451mg、452mg、453mg、454mg、455mg、456mg、457mg、458mg、459mg、460mg、461mg、462mg、463mg、464mg、465mg、466mg、467mg、468mg、469mg、470mg、471mg、472mg、473mg、474mg、475mg、476mg、477mg、478mg、479mg、480mg、481mg、482mg、483mg、484mg、485mg、486mg、487mg、488mg、489mg、490mg、491mg、492mg、493mg、494mg、495mg、496mg、497mg、498mg、499mg、500mg、501mg、502mg、503mg、504mg、505mg、506mg、507mg、508mg、509mg、510mg、511mg、512mg、513mg、514mg、515mg、516mg、517mg、518mg、519mg、520mg、521mg、522mg、523mg、524mg、525mg、526mg、527mg、528mg、529mg、530mg、531mg、532mg、533mg、534mg、535mg、536mg、537mg、538mg、539mg、540mg、541mg、542mg、543mg、544mg、545mg、546mg、547mg、548mg、549mg、550mg、551mg、552mg、553mg、554mg、555mg、556mg、557mg、558mg、559mg、560mg、561mg、562mg、563mg、564mg、565mg、566mg、567mg、568mg、569mg、570mg、571mg、572mg、573mg、574mg、575mg、576mg、577mg、578mg、579mg、580mg、581mg、582mg、583mg、584mg、585mg、586mg、587mg、588mg、589mg、590mg、591mg、592mg、593mg、594mg、595mg、596mg、597mg、598mg、599mg、600mg、601mg、602mg、603mg、604mg、605mg、606mg、607mg、608mg、609mg、610mg、611mg、612mg、613mg、614mg、615mg、616mg、617mg、618mg、619mg、620mg、621mg、622mg、623mg、624mg、625mg、626mg、627mg、628mg、629mg、630mg、631mg、632mg、633mg、634mg、635mg、636mg、637mg、638mg、639mg、640mg、641mg、642mg、643mg、644mg、645mg、646mg、647mg、648mg、649mg、650mg、651mg、652mg、653mg、654mg、655mg、656mg、657mg、658mg、659mg、660mg、661mg、662mg、663mg、664mg、665mg、666mg、667mg、668mg、669mg、670mg、671mg、672mg、673mg、674mg、675mg、676mg、677mg、678mg、679mg、680mg、681mg、682mg、683mg、68 4mg、685mg、686mg、687mg、688mg、689mg、690mg、691mg、692mg、693mg、694m g、695mg、696mg、697mg、698mg、699mg、700mg、701mg、702mg、703mg、704mg、 705mg、706mg、707mg、708mg、709mg、710mg、711mg、712mg、713mg、714mg、715mg mg、716mg、717mg、718mg、719mg、720mg、721mg、722mg、723mg、724mg、725mg 、726mg、727mg、728mg、729mg、730mg、731mg、732mg、733mg、734mg、735mg、7 36mg, 737mg, 738mg, 739mg, 740mg, 741mg, 742mg, 743mg, 744mg, 745mg, 746mg, 747mg, 748mg, 749mg, 750mg, 751mg, 752mg, 753mg, 754mg, 755mg, 756mg 757mg, 758mg, 759mg, 760mg, 761mg, 762mg, 763mg, 764mg, 765mg, 766mg, 767mg, 768mg, 769mg, 770mg, 771mg, 772mg, 773mg, 774mg, 775mg, 776mg, 777mg g, 778mg, 779mg, 780mg, 781mg, 782mg, 783mg, 784mg, 785mg, 786mg, 787mg, 788mg, 789mg, 790mg, 791mg, 792mg, 793mg, 794mg, 795mg, 796mg, 797mg, 798 mg、799mg、800mg、801mg、802mg、803mg、804mg、805mg、806mg、807mg、808mg 、809mg、810mg、811mg、812mg、813mg、814mg、815mg、816mg、817mg、818mg、8 19mg、820mg、821mg、822mg、823mg、824mg、825mg、826mg、827mg、828mg、829 mg、830mg、831mg、832mg、833mg、834mg、835mg、836mg、837mg、838mg、839mg、840mg, 841mg, 842mg, 843mg, 844mg, 845mg, 846mg, 847mg, 848mg, 849mg, 850mg, 851mg, 852mg, 853mg, 854mg, 855mg, 856mg, 857mg, 858mg, 859mg, 860mg, 861mg, 862mg, , 863mg, 864mg, 865mg, 866mg, 867mg, 868mg, 869mg, 870mg, 871mg, 872mg, 873mg, 874mg, 875mg, 876mg, 877mg, 878mg, 879mg, 88 0mg, 881mg, 882mg, 883mg, 884mg, 885mg, 886mg, 887mg, 888mg, 889mg, 890mg, 891mg, 892mg, 893mg, 894mg, 895mg, 896mg, 897mg , 898mg, 899mg, 900mg, 901mg, 902mg, 903mg, 904mg, 905mg, 906mg, 907mg, 908mg, 909mg, 910mg, 911mg, 912mg, 913mg, 914mg, 91 5mg, 916mg, 917mg, 918mg, 919mg, 920mg, 921mg, 922mg, 923mg, 924mg, 925mg, 926mg, 927mg, 928mg, 929mg, 930mg, 931mg, 932mg, 933mg, 934mg, 935mg, 936mg, 937mg, 938mg, 939mg, 940mg, 941mg, 942mg, 943mg, 944mg, 945mg, 946mg, 947mg, 948mg, 949mg, 950 mg, 951mg, 952mg, 953mg, 954mg, 955mg, 956mg, 957mg, 958mg, 959mg, 960mg, 961mg, 962mg, 963mg, 964mg, 965mg, 966mg, 967mg, 9 It is administered in doses of 68 mg, 969 mg, 970 mg, 971 mg, 972 mg, 973 mg, 974 mg, 975 mg, 976 mg, 977 mg, 978 mg, 979 mg, 980 mg, 981 mg, 982 mg, 983 mg, 984 mg, 985 mg, 986 mg, 987 mg, 988 mg, 989 mg, 990 mg, 991 mg, 992 mg, 993 mg, 994 mg, 995 mg, 996 mg, 997 mg, 998 mg, 999 mg, or 1000 mg.

[0060]

[0071] Therefore, in one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is in an amount of 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 The amount is approximately 19 mg, preferably approximately 20 mg, preferably approximately 21 mg, preferably approximately 22 mg, preferably approximately 23 mg, preferably approximately 24 mg, preferably approximately 25 mg, preferably approximately 26 mg, preferably approximately 27 mg, preferably approximately 28 mg, preferably approximately 29 mg, preferably approximately 30 mg, preferably approximately 31 mg, preferably approximately 32 mg, preferably approximately 33 mg, preferably approximately 34 mg, preferably approximately 35 mg, preferably approximately 36 mg, preferably approximately 37 mg, preferably approximately 38 mg, preferably approximately 39 mg, preferably approximately 40 mg, preferably approximately 41 mg. Preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably Approximately 64 mg, preferably approximately 65 mg, preferably approximately 66 mg, preferably approximately 67 mg, preferably approximately 68 mg, preferably approximately 69 mg, preferably approximately 70 mg, preferably approximately 71 mg, preferably approximately 72 mg, preferably approximately 73 mg, preferably approximately 74 mg, preferably approximately 75 mg, preferably approximately 76 mg, preferably approximately 77 mg, preferably approximately 78 mg, preferably approximately 79 mg, preferably approximately 80 mg, preferably approximately 81 mg, preferably approximately 82 mg, preferably approximately 83 mg, preferably approximately 84 mg, preferably approximately 85 mg, preferably approximately 86 mg,Preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 101 mg, preferably about 102 mg, preferably about 103 mg, preferably about 104 mg, preferably about 105 mg, preferably about 106 mg, preferably about 107 mg, preferably about 108 mg, preferably about 109 mg, preferably about 110 mg, preferably about 111 mg, preferably about 112 mg, preferably about 113 mg, preferably about 114 mg, preferably about 115 mg, preferably about 116 mg, preferably about 117 mg, preferably about 118 mg, preferably about 119 mg, preferably about 120 mg, preferably about 121 mg, preferably about 122 mg, preferably about 123 mg, preferably about 124 mg, preferably about 125 mg, preferably about 126 mg, preferably about 127 mg, preferably about 128 mg, preferably about 129 mg, preferably about 130 mg, preferably about 131 mg, preferably about 132 mg, preferably about 131 mg, preferably about 134 mg, preferably about 135 mg, preferably about 136 mg, preferably about 137 mg, preferably about 138 mg, preferably about 139 mg, preferably about 140 mg, preferably about 141 mg, preferably about 142 mg, preferably about 143 mg, preferably about 144 mg, preferably about 145 mg, preferably about 146 mg, preferably about 147 mg, preferably about 148 mg, preferably about 149 mg, preferred The amount is approximately 150 mg, preferably approximately 151 mg, preferably approximately 152 mg, preferably approximately 153 mg, preferably approximately 154 mg, preferably approximately 155 mg, preferably approximately 156 mg, preferably approximately 157 mg, preferably approximately 158 mg, preferably approximately 159 mg, preferably approximately 160 mg, preferably approximately 161 mg, preferably approximately 162 mg, preferably approximately 163 mg, preferably approximately 164 mg, preferably approximately 165 mg, preferably approximately 166 mg, preferably approximately 167 mg, preferably approximately 168 mg, preferably approximately 169 mg, preferably approximately 170 mg.Preferably about 171 mg, preferably about 172 mg, preferably about 173 mg, preferably about 174 mg, preferably about 175 mg, preferably about 176 mg, preferably about 177 mg, preferably about 178 mg, preferably about 179 mg, preferably about 180 mg, preferably about 181 mg, preferably about 182 mg, preferably about 183 mg, preferably about 184 mg, preferably about 185 mg, preferably about 186 mg, preferably about 187 mg, preferably about 188 mg, preferably about 189 mg, preferably about 190 mg, preferably about 191 mg, preferably about 192 mg, preferably about 193 mg, preferably about 194 mg, preferably about 195 mg, preferably about 196 mg, preferably about 197 mg, preferably about 198 mg, preferably about 199 mg, preferably about 200 mg, preferably about 201 mg, preferably about 202 mg, preferably about 203 mg, preferably about 204 mg, preferably about 205 mg, preferably about 206 mg, preferably about 207 mg, preferably about 208 mg, preferably about 209 mg, preferably about 210 mg, preferably about 211 mg, preferably about 212 mg, preferably about 213 mg, preferably about 214 mg, preferably about 215 mg, preferably about 216 mg, preferably about 217 mg, preferably about 218 mg, preferably about 219 mg, preferably about 220 mg, preferably about 221 mg, preferably about 222 mg, preferably about 223 mg, preferably about 224 mg, preferably about 225 mg, preferably about 226 mg, preferably about 227 mg, preferably about 228 mg, preferably about 229 mg, preferably about 230 mg, preferably about 231 mg, preferably about 232 mg, preferred The amount is approximately 233 mg, preferably approximately 234 mg, preferably approximately 235 mg, preferably approximately 236 mg, preferably approximately 237 mg, preferably approximately 238 mg, preferably approximately 239 mg, preferably approximately 240 mg, preferably approximately 241 mg, preferably approximately 242 mg, preferably approximately 243 mg, preferably approximately 244 mg, preferably approximately 245 mg, preferably approximately 246 mg, preferably approximately 247 mg, preferably approximately 248 mg, preferably approximately 249 mg, preferably approximately 250 mg, preferably approximately 251 mg, preferably approximately 252 mg, preferably approximately 253 mg.Preferably about 254 mg, preferably about 255 mg, preferably about 256 mg, preferably about 257 mg, preferably about 258 mg, preferably about 259 mg, preferably about 260 mg, preferably about 261 mg, preferably about 262 mg, preferably about 263 mg, preferably about 264 mg, preferably about 265 mg, preferably about 266 mg, preferably about 267 mg, preferably about 268 mg, preferably about 269 mg, preferably about 270 mg, preferably about 271 mg, preferably about 272 mg, preferably about 273 mg, preferably about 274 mg, preferably about 275 mg, preferably about 276 mg, preferably about 277 mg, preferably about 278 mg, preferably about 279 mg, preferably about 280 mg, preferably about 281 mg, preferably about 282 mg, preferably about 283 mg, preferably about 284 mg, preferably about 285 mg, preferably about 286 mg, preferably about 287 mg, preferably about 288 mg, preferably about 289 mg, preferably about 290 mg, preferably about 291 mg, preferably about 292 mg, preferably about 293 mg, preferably about 294 mg, preferably about 295 mg, preferably about 296 mg, preferably about 297 mg, preferably about 298 mg, preferably about 299 mg, preferably about 300 mg, preferably about 301 mg, preferably about 302 mg, preferably about 303 mg, preferably about 304 mg, preferably about 305 mg, preferably about 306 mg, preferably about 307 mg, preferably about 308 mg, preferably about 309 mg, preferably about 310 mg, preferably about 311 mg, preferably about 312 mg, preferably about 313 mg, preferably about 314 mg, preferably about 315 mg, preferred The amount is approximately 316 mg, preferably approximately 317 mg, preferably approximately 318 mg, preferably approximately 319 mg, preferably approximately 320 mg, preferably approximately 321 mg, preferably approximately 322 mg, preferably approximately 323 mg, preferably approximately 324 mg, preferably approximately 325 mg, preferably approximately 326 mg, preferably approximately 327 mg, preferably approximately 328 mg, preferably approximately 329 mg, preferably approximately 330 mg, preferably approximately 331 mg, preferably approximately 332 mg, preferably approximately 333 mg, preferably approximately 334 mg, preferably approximately 335 mg, preferably approximately 336 mg.Preferably about 337 mg, preferably about 338 mg, preferably about 339 mg, preferably about 340 mg, preferably about 341 mg, preferably about 342 mg, preferably about 343 mg, preferably about 344 mg, preferably about 345 mg, preferably about 346 mg, preferably about 347 mg, preferably about 348 mg, preferably about 349 mg, preferably about 350 mg, preferably about 351 mg, preferably about 352 mg, preferably about 353 mg, preferably about 354 mg, preferably about 355 mg, preferably about 356 mg, preferably about 357 mg, preferably about 358 mg, preferably about 359 mg, preferably about 360 mg, preferably about 361 mg, preferably about 362 mg, preferably about 363 mg, preferably about 364 mg, preferably about 365 mg, preferably about 366 mg, preferably about 367 mg, preferably about 368 mg, preferably about 369 mg, preferably about 370 mg, preferably about 371 mg, preferably about 372 mg, preferably about 373 mg, preferably about 374 mg, preferably about 375 mg, preferably about 376 mg, preferably about 377 mg, preferably about 378 mg, preferably about 379 mg, preferably about 380 mg, preferably about 381 mg, preferably about 382 mg, preferably about 383 mg, preferably about 384 mg, preferably about 385 mg, preferably about 386 mg, preferably about 387 mg, preferably about 388 mg, preferably about 389 mg, preferably about 390 mg, preferably about 391 mg, preferably about 392 mg, preferably about 393 mg, preferably about 394 mg, preferably about 395 mg, preferably about 396 mg, preferably about 397 mg, preferably about 398 mg, preferred The amount is approximately 399 mg, preferably approximately 400 mg, preferably approximately 401 mg, preferably approximately 402 mg, preferably approximately 403 mg, preferably approximately 404 mg, preferably approximately 405 mg, preferably approximately 406 mg, preferably approximately 407 mg, preferably approximately 408 mg, preferably approximately 409 mg, preferably approximately 410 mg, preferably approximately 411 mg, preferably approximately 412 mg, preferably approximately 413 mg, preferably approximately 414 mg, preferably approximately 415 mg, preferably approximately 416 mg, preferably approximately 417 mg, preferably approximately 418 mg, preferably approximately 419 mg.Preferably about 420 mg, preferably about 421 mg, preferably about 422 mg, preferably about 423 mg, preferably about 424 mg, preferably about 425 mg, preferably about 426 mg, preferably about 427 mg, preferably about 428 mg, preferably about 429 mg, preferably about 430 mg, preferably about 431 mg, Preferably about 432 mg, preferably about 433 mg, preferably about 434 mg, preferably about 435 mg, preferably about 436 mg, preferably about 437 mg, preferably about 438 mg, preferably about 439 mg, preferably about 440 mg, preferably about 441 mg, preferably about 442 mg, preferably about 443 mg, preferably about 444 mg, preferably about 445 mg, preferably about 446 mg, preferably about 447 mg, preferably about 448 mg, preferably about 449 mg, preferably about 450 mg, preferably about 451 mg, preferably about 45 2 mg, preferably about 453 mg, preferably about 454 mg, preferably about 455 mg, preferably about 456 mg, preferably about 457 mg, preferably about 458 mg, preferably about 459 mg, preferably about 460 mg, preferably about 461 mg, preferably about 462 mg, preferably about 463 mg, preferably about 464 mg, preferably about 465 mg, preferably about 466 mg, preferably about 467 mg, preferably about 468 mg, preferably about 469 mg, preferably about 470 mg, preferably about 471 mg, preferably about 472 mg, preferably Approximately 473 mg, preferably approximately 474 mg, preferably approximately 475 mg, preferably approximately 476 mg, preferably approximately 477 mg, preferably approximately 478 mg, preferably approximately 479 mg, preferably approximately 480 mg, preferably approximately 481 mg, preferably approximately 482 mg, preferably approximately 483 mg, preferably approximately 484 mg, preferably approximately 485 mg, preferably approximately 486 mg, preferably approximately 487 mg, preferably approximately 488 mg, preferably approximately 489 mg, preferably approximately 490 mg, preferably approximately 491 mg, preferably approximately 492 mg, preferably approximately 493 mg, preferred Or approximately 494 mg, preferably approximately 495 mg, preferably approximately 496 mg, preferably approximately 497 mg, preferably approximately 498 mg, preferably approximately 499 mg, preferably approximately 500 mg, preferably approximately 501 mg, preferably approximately 502 mg, preferably approximately 503 mg, preferably approximately 504 mg, preferably approximately 505 mg, preferably approximately 506 mg, preferably approximately 507 mg, preferably approximately 508 mg, preferably approximately 509 mg, preferably approximately 510 mg, preferably approximately 511 mg, preferably approximately 512 mg, preferably approximately 513 mg, preferably approximately 514 mg,Preferably about 515 mg, preferably about 516 mg, preferably about 517 mg, preferably about 518 mg, preferably about 519 mg, preferably about 520 mg, preferably about 521 mg, preferably about 522 mg, preferably about 523 mg, preferably about 524 mg, preferably about 525 mg, preferably about 526 mg, preferably about 527 mg, preferably about 528 mg, preferably about 529 mg, preferably about 530 mg, preferably about 531 mg, preferably about 532 mg, preferably about 533 mg, preferably about 534 mg, preferably about 535 mg, preferably about 536 mg, preferably about 537 mg, preferably about 538 mg, preferably about 539 mg, preferably about 540 mg, preferably about 541 mg, preferably about 542 mg, preferably about 543 mg, preferably about 544 mg, preferably about 545 mg, preferably about 546 mg, preferably about 547 mg, preferably about 548 mg, preferably about 549 mg, preferably about 550 mg, preferably about 551 mg, preferably about 552 mg, preferably about 553 mg, preferably about 554 mg, preferably about 555 mg, preferably about 556 mg, preferably about 557 mg, preferably about 558 mg, preferably about 559 mg, preferably about 560 mg, preferably about 561 mg, preferably about 562 mg, preferably about 563 mg, preferably about 564 mg, preferably about 565 mg, preferably about 566 mg, preferably about 567 mg, preferably about 568 mg, preferably about 569 mg, preferably about 570 mg, preferably about 571 mg, preferably about 572 mg, preferably about 573 mg, preferably about 574 mg, preferably about 575 mg, preferably about 576 mg, preferred The amount is approximately 577 mg, preferably approximately 578 mg, preferably approximately 579 mg, preferably approximately 580 mg, preferably approximately 581 mg, preferably approximately 582 mg, preferably approximately 583 mg, preferably approximately 584 mg, preferably approximately 585 mg, preferably approximately 586 mg, preferably approximately 587 mg, preferably approximately 588 mg, preferably approximately 589 mg, preferably approximately 590 mg, preferably approximately 591 mg, preferably approximately 592 mg, preferably approximately 593 mg, preferably approximately 594 mg, preferably approximately 595 mg, preferably approximately 596 mg, preferably approximately 597 mg.Preferably about 598 mg, preferably about 599 mg, preferably about 600 mg, preferably about 601 mg, preferably about 602 mg, preferably about 603 mg, preferably about 604 mg, preferably about 605 mg, preferably about 606 mg, preferably about 607 mg, preferably about 608 mg, preferably about 609 mg, preferably about 610 mg, preferably about 611 mg, preferably about 612 mg, preferably about 613 mg, preferably about 614 mg, preferably about 615 mg, preferably about 616 mg, preferably about 617 mg, preferably about 618 mg, preferably about 619 mg, preferably about 620 mg, preferably about 621 mg, preferably about 622 mg, preferably about 623 mg, preferably about 624 mg, preferably about 625 mg, preferably about 626 mg, preferably about 627 mg, preferably about 628 mg, preferably about 629 mg, preferably about 630 mg, preferably about 631 mg, preferably about 632 mg, preferably about 633 mg, preferably about 634 mg, preferably about 635 mg, preferably about 636 mg, preferably about 637 mg, preferably about 638 mg, preferably about 639 mg, preferably about 640 mg, preferably about 641 mg, preferably about 642 mg, preferably about 643 mg, preferably about 644 mg, preferably about 645 mg, preferably about 646 mg, preferably about 647 mg, preferably about 648 mg, preferably about 649 mg, preferably about 650 mg, preferably about 651 mg, preferably about 652 mg, preferably about 653 mg, preferably about 654 mg, preferably about 655 mg, preferably about 656 mg, preferably about 657 mg, preferably about 658 mg, preferably about 659 mg, preferred The amount is approximately 660 mg, preferably approximately 661 mg, preferably approximately 662 mg, preferably approximately 663 mg, preferably approximately 664 mg, preferably approximately 665 mg, preferably approximately 666 mg, preferably approximately 667 mg, preferably approximately 668 mg, preferably approximately 669 mg, preferably approximately 670 mg, preferably approximately 671 mg, preferably approximately 672 mg, preferably approximately 673 mg, preferably approximately 674 mg, preferably approximately 675 mg, preferably approximately 676 mg, preferably approximately 677 mg, preferably approximately 678 mg, preferably approximately 679 mg, preferably approximately 680 mg.Preferably about 681 mg, preferably about 682 mg, preferably about 683 mg, preferably about 684 mg, preferably about 685 mg, preferably about 686 mg, preferably about 687 mg, preferably about 688 mg, preferably about 689 mg, preferably about 690 mg, preferably about 691 mg, preferably about 692 mg, preferably about 693 mg, preferably about 694 mg, preferably about 695 mg, preferably about 696 mg, preferably about 697 mg, preferably about 698 mg, preferably about 699 mg, preferably about 700 mg, preferably about 701 mg, preferably about 702 mg, preferably about 703 mg, preferably about 704 mg, preferably about 705 mg, preferably about 706 mg, preferably about 707 mg, preferably about 708 mg, preferably about 709 mg, preferably about 710 mg, preferably about 711 mg, preferably about 712 mg, preferably about 713 mg, preferably about 714 mg, preferably about 715 mg, preferably about 716 mg, preferably about 717 mg, preferably about 718 mg, preferably about 719 mg, preferably about 720 mg, preferably about 721 mg, preferably about 722 mg, preferably about 723 mg, preferably about 724 mg, preferably about 725 mg, preferably about 726 mg, preferably about 727 mg, preferably about 728 mg, preferably about 729 mg, preferably about 730 mg, preferably about 731 mg, preferably about 732 mg, preferably about 733 mg, preferably about 734 mg, preferably about 735 mg, preferably about 736 mg, preferably about 737 mg, preferably about 738 mg, preferably about 739 mg, preferably about 740 mg, preferably about 741 mg, preferably about 742 mg, preferred The amount is approximately 743 mg, preferably approximately 744 mg, preferably approximately 745 mg, preferably approximately 746 mg, preferably approximately 747 mg, preferably approximately 748 mg, preferably approximately 749 mg, preferably approximately 750 mg, preferably approximately 751 mg, preferably approximately 752 mg, preferably approximately 753 mg, preferably approximately 754 mg, preferably approximately 755 mg, preferably approximately 756 mg, preferably approximately 757 mg, preferably approximately 758 mg, preferably approximately 759 mg, preferably approximately 760 mg, preferably approximately 761 mg, preferably approximately 762 mg, preferably approximately 763 mg.Preferably about 764 mg, preferably about 765 mg, preferably about 766 mg, preferably about 767 mg, preferably about 768 mg, preferably about 769 mg, preferably about 770 mg, preferably about 771 mg, preferably about 772 mg, preferably about 773 mg, preferably about 774 mg, preferably about 775 mg, preferably about 776 mg, preferably about 777 mg, preferably about 778 mg, preferably about 779 mg, preferably about 780 mg, preferably about 781 mg, preferably about 782 mg, preferably about 783 mg, preferably about 784 mg, preferably about 785 mg, preferably about 786 mg, preferably about 787 mg, preferably about 788 mg, preferably about 789 mg, preferably about 790 mg, preferably about 791 mg, preferably about 792 mg, preferably about 793 mg, preferably about 794 mg, preferably about 795 mg, preferably about 796 mg, preferably about 797 mg, preferably about 798 mg, preferably about 799 mg, preferably about 800 mg, preferably about 801 mg, preferably about 802 mg, preferably about 803 mg, preferably about 804 mg, preferably about 805 mg, preferably about 806 mg, preferably about 807 mg, preferably about 808 mg, preferably about 809 mg, preferably about 810 mg, preferably about 811 mg, preferably about 812 mg, preferably about 813 mg, preferably about 814 mg, preferably about 815 mg, preferably about 816 mg, preferably about 817 mg, preferably about 818 mg, preferably about 819 mg, preferably about 820 mg, preferably about 821 mg, preferably about 822 mg, preferably about 823 mg, preferably about 824 mg, preferably about 825 mg, preferred The amount is approximately 826 mg, preferably approximately 827 mg, preferably approximately 828 mg, preferably approximately 829 mg, preferably approximately 830 mg, preferably approximately 831 mg, preferably approximately 832 mg, preferably approximately 833 mg, preferably approximately 834 mg, preferably approximately 835 mg, preferably approximately 836 mg, preferably approximately 837 mg, preferably approximately 838 mg, preferably approximately 839 mg, preferably approximately 840 mg, preferably approximately 841 mg, preferably approximately 842 mg, preferably approximately 843 mg, preferably approximately 844 mg, preferably approximately 845 mg, preferably approximately 846 mg.Preferably about 847 mg, preferably about 848 mg, preferably about 849 mg, preferably about 850 mg, preferably about 851 mg, preferably about 852 mg, preferably about 853 mg, preferably about 854 mg, preferably about 855 mg, preferably about 856 mg, preferably about 857 mg, preferably about 85, 8 mg, preferably about 859 mg, preferably about 860 mg, preferably about 861 mg, preferably about 862 mg, preferably about 863 mg, preferably about 864 mg, preferably about 865 mg, preferably about 866 mg, preferably about 867 mg, preferably about 868 mg, preferably about 869 mg, preferably about 870 mg, preferably about 871 mg, preferably about 872 mg, preferably about 873 mg, preferably about 874 mg, preferably about 875 mg, preferably about 876 mg, preferably about 877 mg, preferably about 878 mg, preferably about 879 mg, preferably about 880 mg, preferably about 881 mg, preferably about 882 mg, preferably about 883 mg, preferably about 884 mg, preferably about 885 mg, preferably about 886 mg, preferably about 887 mg, preferably about 888 mg, preferably about 889 mg, preferably about 890 mg, preferably about 891 mg, preferably about 892 mg, preferably about 893 mg, preferably about 894 mg, preferably about 895 mg, preferably about 896 mg, preferably about 897 mg, preferably about 898 mg, preferably about 899 mg, preferably The amount is approximately 900 mg, preferably approximately 901 mg, preferably approximately 902 mg, preferably approximately 903 mg, preferably approximately 904 mg, preferably approximately 905 mg, preferably approximately 906 mg, preferably approximately 907 mg, preferably approximately 908 mg, preferably approximately 909 mg, preferably approximately 910 mg, preferably approximately 911 mg, preferably approximately 912 mg, preferably approximately 913 mg, preferably approximately 914 mg, preferably approximately 915 mg, preferably approximately 916 mg, preferably approximately 917 mg, preferably approximately 918 mg, preferably approximately 919 mg, preferably approximately 920 mg, preferred Or approximately 921 mg, preferably approximately 922 mg, preferably approximately 923 mg, preferably approximately 924 mg, preferably approximately 925 mg, preferably approximately 926 mg, preferably approximately 927 mg, preferably approximately 928 mg, preferably approximately 929 mg, preferably approximately 930 mg, preferably approximately 931 mg, preferably approximately 932 mg, preferably approximately 933 mg, preferably approximately 934 mg, preferably approximately 935 mg, preferably approximately 936 mg, preferably approximately 937 mg, preferably approximately 938 mg, preferably approximately 939 mg, preferably approximately 940 mg, preferably approximately 941 mg,Preferably about 942 mg, preferably about 943 mg, preferably about 944 mg, preferably about 945 mg, preferably about 946 mg, preferably about 947 mg, preferably about 948 mg, preferably about 949 mg, preferably about 950 mg, preferably about 951 mg, preferably about 952 mg, preferably about 953 mg, preferably about 954 mg, preferably about 955 mg, preferably about 956 mg, preferably about 957 mg, preferably about 958 mg, preferably about 959 mg, preferably about 960 mg, preferably about 961 mg, preferably about 962 mg, preferably about 963 mg, preferably about 964 mg, preferably about 965 mg, preferably about 966 mg, preferably about 967 mg, preferably about 968 mg, preferably about 969 mg, preferably about 970 mg, preferably about 971 mg, The drug is administered in doses of approximately 972 mg, preferably approximately 973 mg, preferably approximately 974 mg, preferably approximately 975 mg, preferably approximately 976 mg, preferably approximately 977 mg, preferably approximately 978 mg, preferably approximately 979 mg, preferably approximately 980 mg, preferably approximately 981 mg, preferably approximately 982 mg, preferably approximately 983 mg, preferably approximately 984 mg, preferably approximately 985 mg, preferably approximately 986 mg, preferably approximately 987 mg, preferably approximately 988 mg, preferably approximately 989 mg, preferably approximately 990 mg, preferably approximately 991 mg, preferably approximately 992 mg, preferably approximately 993 mg, preferably approximately 994 mg, preferably approximately 995 mg, preferably approximately 996 mg, preferably approximately 997 mg, preferably approximately 998 mg, preferably approximately 999 mg, or more preferably approximately 1000 mg.

[0061]

[0072] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily in the aforementioned doses.

[0073] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of at least about 1 mg.

[0062]

[0074] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily in doses of about 1 mg to about 500 mg.

[0075] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily in doses of about 200 mg to about 400 mg.

[0063]

[0076] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily at a loading dose of at least about 1 mg.

[0077] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily in a loading dose of about 1 mg to about 500 mg.

[0064]

[0078] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily at a loading dose of approximately 400 mg.

[0079] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily at a maintenance dose of at least about 1 mg.

[0065]

[0080] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily at a maintenance dose of about 1 mg to about 500 mg.

[0081] In one embodiment, hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered twice daily at a maintenance dose of approximately 200 mg.

[0066]

[0082] In one embodiment, CBD or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 1500 mg (for example, 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 mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68 mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93 mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 11 5mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 131mg, 134mg, 135mg, 1 36mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg,178mg、179mg、180mg、181mg、182mg、183mg、184mg、185mg、186mg、187mg、188mg、189mg、190mg、191mg、192mg、193mg、194mg、195mg、196mg、197mg、198mg、199mg、200mg、201mg、202mg、203mg、204mg、205mg、206mg、207mg、208mg、209mg、210mg、211mg、212mg、213mg、214mg、215mg、216mg、217mg、218mg、219mg、220mg、221mg、222mg、223mg、224mg、225mg、226mg、227mg、228mg、229mg、230mg、231mg、232mg、233mg、234mg、235mg、236mg、237mg、238mg、239mg、240mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、249mg、250mg、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、280mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290mg、291mg、292mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg、300mg、301mg、302mg、303mg、304mg、305mg、306mg、307mg、308mg、309mg、310mg、311mg、312mg、313mg、314mg、315mg、316mg、317mg、318mg、319mg、320mg、321mg、322mg、323mg、324mg、325mg、326mg、327mg、328mg、329mg、330mg、331mg、332mg、333mg、334mg、335mg、336mg、337mg、338mg、339mg、340mg、341mg、342mg、343mg、344mg、345mg、346mg、347mg、348mg、349mg、350mg、351mg、352mg、353mg、354mg、355mg、356mg、357mg、358mg、359mg、360mg、361mg、362mg、363mg、364mg、365mg、366mg、367mg、368mg、369mg、370mg、371mg、372mg、373mg、374mg、375mg、376mg、377mg、378mg、379mg、380mg、381mg、382mg、383mg、384mg、385mg、386mg、387mg、388mg、389mg、390mg、391mg、392mg、393mg、394mg、395mg、396mg、397mg、398mg、399mg、400mg、401mg、402mg、403mg、404mg、405mg、406mg、407mg、408mg、409mg、410mg、411mg、412mg、413mg、414mg、415mg、416mg、417mg、418mg、419mg、420mg、421mg、422mg、423mg、424mg、425mg、426mg、427mg、428mg、429mg、430mg、431mg、432mg、433mg、434mg、435mg、436mg、437mg、438mg、439mg、440mg、441mg、442mg、443mg、444mg、445mg、446mg、447mg、448mg、449mg、450mg、451mg、452mg、453mg、454mg、455mg、456mg、457mg、458mg、459mg、460mg、461mg、462mg、463mg、464mg、465mg、466mg、467mg、468mg、469mg、470mg、471mg、472mg、473mg、474mg、475mg、476mg、477mg、478mg、479mg、480mg、481mg、482mg、483mg、484mg、485mg、486mg、487mg、488mg、489mg、490mg、491mg、492mg、493mg、494mg、495mg、496mg、497mg、498mg、499mg、500mg、501mg、502mg、503mg、504mg、505mg、506mg、507mg、508mg、509mg、510mg、511mg、512mg、513mg、514mg、515mg、516mg、517mg、518mg、519mg、520mg、521mg、522mg、523mg、524mg、525mg、526mg、527mg、528mg、529mg、530mg、531mg、532mg、533mg、534mg、535mg、536mg、537mg、538mg、539mg、540mg、541mg、542mg、543mg、544mg、545mg、546mg、547mg、548mg、549mg、550mg、551mg、552mg、553mg、554mg、555mg、556mg、557mg、558mg、559mg、560mg、561mg、562mg、563mg、564mg、565mg、566mg、567mg、568mg、569mg、570mg、571mg、572mg、573mg、574mg、575mg、576mg、577mg、578mg、579mg、580mg、581mg、582mg、583mg、584mg、585mg、586mg、587mg、588mg、589mg、590mg、591mg、592mg、593mg、594mg、595mg、596mg、597mg、598mg、599mg、600mg、601mg、602mg、603mg、604mg、605mg、606mg、607mg、608mg、609mg、610mg、611mg、612mg、613mg、614mg、615mg、616mg、617mg、618mg、619mg、620mg、621mg、622mg、623mg、624mg、625mg、626mg、627mg、628mg、629mg、630mg、631mg、632mg、633mg、634mg、635mg、636mg、637mg、638mg、639mg、640mg、641mg、642mg、643mg、644mg、645mg、646mg、647mg、648mg、649mg、650mg、651mg、652mg、653mg、654mg、655mg、656mg、657mg、658mg、659mg、660mg、661mg、662mg、663mg、664mg、665mg、666mg、667mg、668mg、669mg、670mg、671mg、672mg、673mg、674mg、675mg、676mg、677mg、678mg、679mg、680mg、681mg、682mg、683mg、684mg、685mg、68 6mg、687mg、688mg、689mg、690mg、691mg、692mg、693mg、694mg、695mg、696m g、697mg、698mg、699mg、700mg、701mg、702mg、703mg、704mg、705mg、706mg、 707mg、708mg、709mg、710mg、711mg、712mg、713mg、714mg、715mg、716mg、717mg mg, 718mg, 719mg, 720mg, 721mg, 722mg, 723mg, 724mg, 725mg, 726mg, 727mg, 728mg, 729mg, 730mg, 731mg, 732mg, 733mg, 734mg, 735mg, 736mg, 737mg, 7 38mg, 739mg, 740mg, 741mg, 742mg, 743mg, 744mg, 745mg, 746mg, 747mg, 748mg, 749mg, 750mg, 751mg, 752mg, 753mg, 754mg, 755mg, 756mg, 757mg, 758mg 759mg, 760mg, 761mg, 762mg, 763mg, 764mg, 765mg, 766mg, 767mg, 768mg, 769mg, 770mg, 771mg, 772mg, 773mg, 774mg, 775mg, 776mg, 777mg, 778mg, 779mg g, 780mg, 781mg, 782mg, 783mg, 784mg, 785mg, 786mg, 787mg, 788mg, 789mg, 790mg, 791mg, 792mg, 793mg, 794mg, 795mg, 796mg, 797mg, 798mg, 799mg, 800 mg、801mg、802mg、803mg、804mg、805mg、806mg、807mg、808mg、809mg、810mg 、811mg、812mg、813mg、814mg、815mg、816mg、817mg、818mg、819mg、820mg、8 21mg、822mg、823mg、824mg、825mg、826mg、827mg、828mg、829mg、830mg、831 mg、832mg、833mg、834mg、835mg、836mg、837mg、838mg、839mg、840mg、841mg、842mg、843mg、844mg、845mg、846mg、847mg、848mg、849mg、850mg、851mg、852mg、853mg、854mg、855mg、856mg、857mg、858mg、859mg、860mg、861mg、862mg、863mg、 864mg、865mg、866mg、867mg、868mg、869mg、870mg、871mg、872mg、873mg、874mg、875mg、876mg、877mg、878mg、879mg、880mg、881mg、882mg、883mg、884mg、885mg、886mg、887mg、888mg、889mg、890mg、891mg、892mg、893mg、894mg、895mg、896mg、897mg、898mg、899mg、900mg、901mg、902mg、903mg、904mg、905mg、906mg、907mg、908mg、909mg、910mg、911mg、912mg、913mg、914mg、915mg、916mg、917mg、918mg、919mg、920mg、921mg、922mg、923mg、924mg、925mg、926mg、927mg、928mg、929mg、930mg、931mg、932mg、933mg、934mg、935mg、936mg、937mg、938mg、939mg、940mg、941mg、942mg、943mg、944mg、945mg、946mg、947mg、948mg、949mg、950mg、951mg、952mg、953mg、954mg、955mg、956mg、957mg、958mg、959mg、960mg、961mg、962mg、963mg、964mg、965mg、966mg、967mg、968mg、969mg、970mg、971mg、972mg、973mg、974mg、975mg、976mg、977mg、978mg、979mg、980mg、981mg、982mg、983mg、984mg、985mg、986mg、987mg、988mg、989mg、990mg、991mg、992mg、993mg、994mg、995mg、996mg、997mg、998mg、999mg、1000mg、1100mg、1101mg、1102mg、1103mg、1104mg、1105mg、1106mg、1107mg、1108mg、1109mg、1110mg、1111mg、1112mg、1113mg、1114mg、1115mg、1116mg、1117mg、1118mg、1119mg、1120mg、1121mg、1122mg、1123mg、1124mg、1125mg、1126mg、1127mg、1128mg、1129mg、1130mg、1131mg、1132mg、1133mg、1134mg、1135mg、1136mg、1137mg、1138mg、1139mg、1140mg、1141mg、1142mg、1143mg、1144mg、1145mg、1146mg、1147mg、1148mg、1149mg、1150mg、1151mg、1152mg、1153mg、1154mg、1155mg、1156mg、1157mg、1158mg、1159mg、1160mg、1161mg、1162mg、1163mg、1164mg、1165mg、1166mg、1167mg、1168mg、1169mg、1170mg、1171mg、1172mg、1173mg、1174mg、1175mg、1176mg、1177mg、1178mg、1179mg、1180mg、1181mg、1182mg、1183mg、1184mg、1185mg、1186mg、1187mg、1188mg、1189mg、1190mg、1191mg、1192mg、1193mg、1194mg、1195mg、1196mg、1197mg、1198mg、1199mg、1200mg、1201mg、1202mg、1203mg、1204mg、1205mg、1206mg、1207mg、1208mg、1209mg、1210mg、1211mg、1212mg、1213mg、1214mg、1215mg、1216mg、1217mg、1218mg、1219mg、1220mg、1221mg、1222mg、1223mg、1224mg、1225mg、1226mg、1227mg、1228mg、1229mg、1230mg、1231mg、1232mg、1233mg、1234mg、1235mg、1236mg、1237mg、1238mg、239mg、1240mg、1241mg、1242mg、1243mg、1244mg、1245mg、1246mg、1247mg、1248mg、1249mg、1250mg、1251mg、1252mg、1253mg、1254mg、1255mg、1256mg、1257mg、1258mg、1259mg、1260mg、1261mg、1262mg、1263mg、1264mg、1265mg、1266mg、1267mg、1268mg、1269mg、1270mg、1271mg、1272mg、1273mg、1274mg、1275mg、1276mg、1277mg、1278mg、1279mg、1280mg、1281mg、1282mg、1283mg、1284mg、1285mg、1286mg、1287mg、1288mg、1289mg、1290mg、1291mg、1292mg、1293mg、1294mg、1295mg、1296mg、1297mg、1298mg、1299mg、1300mg、1301mg、1302mg、303mg、1304mg、1305mg、1306mg、1307mg、1308mg、1309mg、1310mg、1311mg、1312mg、1313mg、1314mg、1315mg、1316mg、1317mg、1318mg、1319mg、1320mg、1321mg、1322mg、1323mg、1324mg、1325mg、1326mg、1327mg、1328mg、1329mg、1330mg、1331mg、1332mg、1333mg、1334mg、1335mg、1336mg、1337mg、1338mg、1339mg、1340mg、1341mg、1342mg、1343mg、1344mg、1345mg、1346mg、1347mg、1348mg、1349mg、1350mg、1351mg、1352mg、1353mg、1354mg、1355mg、1356mg、1357mg、1358mg、1359mg、1360mg、1361mg、1362mg、1363mg、1364mg、1365mg、1366mg、1367mg、1368mg、1369mg、1370mg、1371mg、1372mg、1373mg、1374mg、1375mg、1376mg、1377mg、1378mg、1379mg、1380mg、1381mg、1382mg、1383mg、1384mg、1385mg、1386mg、1387mg、1388mg、1389mg、1390mg、1391mg、1392mg、1393mg、1394mg、1395mg、1396mg、1397mg、1398mg、1399mg、1400mg、1401mg、1402mg、1403mg、1404mg、1405mg、1406mg、1407mg、1408mg、1409mg、1410mg、1411mg, 1412mg, 1413mg, 1414mg, 1415mg, 1416mg, 1417mg, 1418mg, 1419mg, 1420mg, 1421mg, 142 2mg, 1423mg, 1424mg, 1425mg, 1426mg, 1427mg, 1428mg, 1429mg, 1430mg, 1431mg, 1432mg, 1433mg , 1434mg, 1435mg, 1436mg, 1437mg, 1438mg, 1439mg, 1440mg, 1441mg, 1442mg, 1443mg, 1444mg, 14 45mg, 1446mg, 1447mg, 1448mg, 1449mg, 1450mg, 1451mg, 1452mg, 1453mg, 1454mg, 1455mg, 1456mg , 1457mg, 1458mg, 1459mg, 1460mg, 1461mg, 1462mg, 1463mg, 1464mg, 1465mg, 1466mg, 1467mg, 14 68mg, 1469mg, 1470mg, 1471mg, 1472mg, 1473mg, 1474mg, 1475mg, 1476mg, 1477mg, 1478mg, 1479mg It is administered in doses of 1480mg, 1481mg, 1482mg, 1483mg, 1484mg, 1485mg, 1486mg, 1487mg, 1488mg, 1489mg, 1490mg, 1491mg, 1492mg, 1493mg, 1494mg, 1495mg, 1496mg, 1497mg, 1498mg, 1499mg, or 1500mg.

[0067]

[0083] Therefore, in one embodiment, the amount of CBD or a pharmaceutically acceptable salt thereof is 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 The amount is approximately 20 mg, preferably approximately 21 mg, preferably approximately 22 mg, preferably approximately 23 mg, preferably approximately 24 mg, preferably approximately 25 mg, preferably approximately 26 mg, preferably approximately 27 mg, preferably approximately 28 mg, preferably approximately 29 mg, preferably approximately 30 mg, preferably approximately 31 mg, preferably approximately 32 mg, preferably approximately 33 mg, preferably approximately 34 mg, preferably approximately 35 mg, preferably approximately 36 mg, preferably approximately 37 mg, preferably approximately 38 mg, preferably approximately 39 mg, preferably approximately 40 mg, preferably approximately 41 mg, preferably approximately 42 mg mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably about 64 mg, preferably Approximately 65 mg, preferably approximately 66 mg, preferably approximately 67 mg, preferably approximately 68 mg, preferably approximately 69 mg, preferably approximately 70 mg, preferably approximately 71 mg, preferably approximately 72 mg, preferably approximately 73 mg, preferably approximately 74 mg, preferably approximately 75 mg, preferably approximately 76 mg, preferably approximately 77 mg, preferably approximately 78 mg, preferably approximately 79 mg, preferably approximately 80 mg, preferably approximately 81 mg, preferably approximately 82 mg, preferably approximately 83 mg, preferably approximately 84 mg, preferably approximately 85 mg, preferably approximately 86 mg, preferably approximately 87 mg,Preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 101 mg, preferably about 102 mg, preferably about 103 mg, preferably about 104 mg, preferably about 105 mg, preferably about 106 mg, preferably about 107 mg, preferably about 108 mg, preferably about 109 mg, preferably about 110 mg, preferably about 111 mg, preferably about 112 mg, preferably about 113 mg, preferably about 114 mg, preferably about 115 mg, preferably about 116 mg, preferably about 117 mg, preferably about 118 mg, preferably about 119 mg, preferably about 120 mg, preferably about 121 mg, preferably about 122 mg, preferably about 123 mg, preferably about 124 mg, preferably about 125 mg, preferably about 126 mg, preferably about 127 mg, preferably about 128 mg, preferably about 129 mg, preferably about 130 mg, preferably about 131 mg, preferably about 132 mg, preferably about 131 mg, preferably about 134 mg, preferably about 135 mg, preferably about 136 mg, preferably about 137 mg, preferably about 138 mg, preferably about 139 mg, preferably about 140 mg, preferably about 141 mg, preferably about 142 mg, preferably about 143 mg, preferably about 144 mg, preferably about 145 mg, preferably about 146 mg, preferably about 147 mg, preferably about 148 mg, preferably about 149 mg, preferably about 150 mg, preferred The amount is approximately 151 mg, preferably approximately 152 mg, preferably approximately 153 mg, preferably approximately 154 mg, preferably approximately 155 mg, preferably approximately 156 mg, preferably approximately 157 mg, preferably approximately 158 mg, preferably approximately 159 mg, preferably approximately 160 mg, preferably approximately 161 mg, preferably approximately 162 mg, preferably approximately 163 mg, preferably approximately 164 mg, preferably approximately 165 mg, preferably approximately 166 mg, preferably approximately 167 mg, preferably approximately 168 mg, preferably approximately 169 mg, preferably approximately 170 mg, preferably approximately 171 mg.Preferably about 172 mg, preferably about 173 mg, preferably about 174 mg, preferably about 175 mg, preferably about 176 mg, preferably about 177 mg, preferably about 178 mg, preferably about 179 mg, preferably about 180 mg, preferably about 181 mg, preferably about 182 mg, preferably about 183 mg, preferably about 184 mg, preferably about 185 mg, preferably about 186 mg, preferably about 187 mg, preferably about 188 mg, preferably about 189 mg, preferably about 190 mg, preferably about 191 mg, preferably about 192 mg mg, preferably about 193 mg, preferably about 194 mg, preferably about 195 mg, preferably about 196 mg, preferably about 197 mg, preferably about 198 mg, preferably about 199 mg, preferably about 200 mg, preferably about 201 mg, preferably about 202 mg, preferably about 203 mg, preferably about 204 mg, preferably about 205 mg, preferably about 206 mg, preferably about 207 mg, preferably about 208 mg, preferably about 209 mg, preferably about 210 mg, preferably about 211 mg, preferably about 212 mg, preferably about 213 mg, preferably about 214 mg, preferably about 215 mg, preferably about 216 mg, preferably about 217 mg, preferably about 218 mg, preferably about 219 mg, preferably about 220 mg, preferably about 221 mg, preferably about 222 mg, preferably about 223 mg, preferably about 224 mg, preferably about 225 mg, preferably about 226 mg, preferably about 227 mg, preferably about 228 mg, preferably about 229 mg, preferably about 230 mg, preferably about 231 mg, preferably about 232 mg, preferably about 233 mg, preferred The amount is approximately 234 mg, preferably approximately 235 mg, preferably approximately 236 mg, preferably approximately 237 mg, preferably approximately 238 mg, preferably approximately 239 mg, preferably approximately 240 mg, preferably approximately 241 mg, preferably approximately 242 mg, preferably approximately 243 mg, preferably approximately 244 mg, preferably approximately 245 mg, preferably approximately 246 mg, preferably approximately 247 mg, preferably approximately 248 mg, preferably approximately 249 mg, preferably approximately 250 mg, preferably approximately 251 mg, preferably approximately 252 mg, preferably approximately 253 mg, preferably approximately 254 mg,Preferably about 255 mg, preferably about 256 mg, preferably about 257 mg, preferably about 258 mg, preferably about 259 mg, preferably about 260 mg, preferably about 261 mg, preferably about 262 mg, preferably about 263 mg, preferably about 264 mg, preferably about 265 mg, preferably about 266 mg, preferably about 267 mg, preferably about 268 mg, preferably about 269 mg, preferably about 270 mg, preferably about 271 mg, preferably about 272 mg, preferably about 273 mg, preferably about 274 mg, preferably about 275 mg, preferably about 276 mg, preferably about 277 mg, preferably about 278 mg, preferably about 279 mg, preferably about 280 mg, preferably about 281 mg, preferably about 282 mg, preferably about 283 mg, preferably about 284 mg, preferably about 285 mg, preferably about 286 mg, preferably about 287 mg, preferably about 288 mg, preferably about 289 mg, preferably about 290 mg, preferably about 291 mg, preferably about 292 mg, preferably about 293 mg, preferably about 294 mg, preferably about 295 mg, preferably about 296 mg, preferably about 297 mg, preferably about 298 mg, preferably about 299 mg, preferably about 300 mg, preferably about 301 mg, preferably about 302 mg, preferably about 303 mg, preferably about 304 mg, preferably about 305 mg, preferably about 306 mg, preferably about 307 mg, preferably about 308 mg, preferably about 309 mg, preferably about 310 mg, preferably about 311 mg, preferably about 312 mg, preferably about 313 mg, preferably about 314 mg, preferably about 315 mg, preferably about 316 mg, preferred The amount is approximately 317 mg, preferably approximately 318 mg, preferably approximately 319 mg, preferably approximately 320 mg, preferably approximately 321 mg, preferably approximately 322 mg, preferably approximately 323 mg, preferably approximately 324 mg, preferably approximately 325 mg, preferably approximately 326 mg, preferably approximately 327 mg, preferably approximately 328 mg, preferably approximately 329 mg, preferably approximately 330 mg, preferably approximately 331 mg, preferably approximately 332 mg, preferably approximately 333 mg, preferably approximately 334 mg, preferably approximately 335 mg, preferably approximately 336 mg, preferably approximately 337 mg.Preferably about 338 mg, preferably about 339 mg, preferably about 340 mg, preferably about 341 mg, preferably about 342 mg, preferably about 343 mg, preferably about 344 mg, preferably about 345 mg, preferably about 346 mg, preferably about 347 mg, preferably about 348 mg, preferably about 349 mg, preferably about 350 mg, preferably about 351 mg, preferably about 352 mg, preferably about 353 mg, preferably about 354 mg, preferably about 355 mg, preferably about 356 mg, preferably about 357 mg, preferably about 358 mg, preferably about 359 mg, preferably about 360 mg, preferably about 361 mg, preferably about 362 mg, preferably about 363 mg, preferably about 364 mg, preferably about 365 mg, preferably about 366 mg, preferably about 367 mg, preferably about 368 mg, preferably about 369 mg, preferably about 370 mg, preferably about 371 mg, preferably about 372 mg, preferably about 373 mg, preferably about 374 mg, preferably about 375 mg, preferably about 376 mg, preferably about 377 mg, preferably about 378 mg, preferably about 379 mg, preferably about 380 mg, preferably about 381 mg, preferably about 382 mg, preferably about 383 mg, preferably about 384 mg, preferably about 385 mg, preferably about 386 mg, preferably about 387 mg, preferably about 388 mg, preferably about 389 mg, preferably about 390 mg, preferably about 391 mg, preferably about 392 mg, preferably about 393 mg, preferably about 394 mg, preferably about 395 mg, preferably about 396 mg, preferably about 397 mg, preferably about 398 mg, preferably about 399 mg, preferred The amount is approximately 400 mg, preferably approximately 401 mg, preferably approximately 402 mg, preferably approximately 403 mg, preferably approximately 404 mg, preferably approximately 405 mg, preferably approximately 406 mg, preferably approximately 407 mg, preferably approximately 408 mg, preferably approximately 409 mg, preferably approximately 410 mg, preferably approximately 411 mg, preferably approximately 412 mg, preferably approximately 413 mg, preferably approximately 414 mg, preferably approximately 415 mg, preferably approximately 416 mg, preferably approximately 417 mg, preferably approximately 418 mg, preferably approximately 419 mg, preferably approximately 420 mg.Preferably about 421 mg, preferably about 422 mg, preferably about 423 mg, preferably about 424 mg, preferably about 425 mg, preferably about 426 mg, preferably about 427 mg, preferably about 428 mg, preferably about 429 mg, preferably about 430 mg, preferably about 431 mg, preferably about, 432 mg, preferably about 433 mg, preferably about 434 mg, preferably about 435 mg, preferably about 436 mg, preferably about 437 mg, preferably about 438 mg, preferably about 439 mg, preferably about 440 mg, preferably about 441 mg, preferably about 442 mg, preferably about 443 mg, preferably about 444 mg, preferably about 445 mg, preferably about 446 mg, preferably about 447 mg, preferably about 448 mg, preferably about 449 mg, preferably about 450 mg, preferably about 451 mg, preferably about 452 mg, preferred The amount is approximately 453 mg, preferably approximately 454 mg, preferably approximately 455 mg, preferably approximately 456 mg, preferably approximately 457 mg, preferably approximately 458 mg, preferably approximately 459 mg, preferably approximately 460 mg, preferably approximately 461 mg, preferably approximately 462 mg, preferably approximately 463 mg, preferably approximately 464 mg, preferably approximately 465 mg, preferably approximately 466 mg, preferably approximately 467 mg, preferably approximately 468 mg, preferably approximately 469 mg, preferably approximately 470 mg, preferably approximately 471 mg, preferably approximately 472 mg, preferably approximately 473 mg mg, preferably about 474 mg, preferably about 475 mg, preferably about 476 mg, preferably about 477 mg, preferably about 478 mg, preferably about 479 mg, preferably about 480 mg, preferably about 481 mg, preferably about 482 mg, preferably about 483 mg, preferably about 484 mg, preferably about 485 mg, preferably about 486 mg, preferably about 487 mg, preferably about 488 mg, preferably about 489 mg, preferably about 490 mg, preferably about 491 mg, preferably about 492 mg, preferably about 493 mg, preferably Approximately 494 mg, preferably approximately 495 mg, preferably approximately 496 mg, preferably approximately 497 mg, preferably approximately 498 mg, preferably approximately 499 mg, preferably approximately 500 mg, preferably approximately 501 mg, preferably approximately 502 mg, preferably approximately 503 mg, preferably approximately 504 mg, preferably approximately 505 mg, preferably approximately 506 mg, preferably approximately 507 mg, preferably approximately 508 mg, preferably approximately 509 mg, preferably approximately 510 mg, preferably approximately 511 mg, preferably approximately 512 mg, preferably approximately 513 mg, preferably approximately 514 mg,Preferably about 515 mg, preferably about 516 mg, preferably about 517 mg, preferably about 518 mg, preferably about 519 mg, preferably about 520 mg, preferably about 521 mg, preferably about 522 mg, preferably about 523 mg, preferably about 524 mg, preferably about 525 mg, preferably about 526 mg, preferably about 527 mg, preferably about 528 mg, preferably about 529 mg, preferably about 530 mg, preferably about 531 mg, preferably about 532 mg, preferably about 533 mg, preferably about 534 mg, preferably about 535 mg, preferably about 536 mg, preferably about 537 mg, preferably about 538 mg, preferably about 539 mg, preferably about 540 mg, preferably about 541 mg, preferably about 542 mg, preferably about 543 mg, preferably about 544 mg, preferably about 545 mg, preferably about 546 mg, preferably about 547 mg, preferably about 548 mg, preferably about 549 mg, preferably about 550 mg, preferably about 551 mg, preferably about 552 mg, preferably about 553 mg, preferably about 554 mg, preferably about 555 mg, preferably about 556 mg, preferably about 557 mg, preferably about 558 mg, preferably about 559 mg, preferably about 560 mg, preferably about 561 mg, preferably about 562 mg, preferably about 563 mg, preferably about 564 mg, preferably about 565 mg, preferably about 566 mg, preferably about 567 mg, preferably about 568 mg, preferably about 569 mg, preferably about 570 mg, preferably about 571 mg, preferably about 572 mg, preferably about 573 mg, preferably about 574 mg, preferably about 575 mg, preferably about 576 mg, preferred The amount is approximately 577 mg, preferably approximately 578 mg, preferably approximately 579 mg, preferably approximately 580 mg, preferably approximately 581 mg, preferably approximately 582 mg, preferably approximately 583 mg, preferably approximately 584 mg, preferably approximately 585 mg, preferably approximately 586 mg, preferably approximately 587 mg, preferably approximately 588 mg, preferably approximately 589 mg, preferably approximately 590 mg, preferably approximately 591 mg, preferably approximately 592 mg, preferably approximately 593 mg, preferably approximately 594 mg, preferably approximately 595 mg, preferably approximately 596 mg, preferably approximately 597 mg.Preferably about 598 mg, preferably about 599 mg, preferably about 600 mg, preferably about 601 mg, preferably about 602 mg, preferably about 603 mg, preferably about 604 mg, preferably about 605 mg, preferably about 606 mg, preferably about 607 mg, preferably about 608 mg, preferably about 609 mg, preferably about 610 mg, preferably about 611 mg, preferably about 612 mg, preferably about 613 mg, preferably about 614 mg, preferably about 615 mg, preferably about 616 mg, preferably about 617 mg, preferably about 618 mg, preferably about 619 mg, preferably about 620 mg, preferably about 621 mg, preferably about 622 mg, preferably about 623 mg, preferably about 624 mg, preferably about 625 mg, preferably about 626 mg, preferably about 627 mg, preferably about 628 mg, preferably about 629 mg, preferably about 630 mg, preferably about 631 mg, preferably about 632 mg, preferably about 633 mg, preferably about 634 mg, preferably about 635 mg, preferably about 636 mg, preferably about 637 mg, preferably about 638 mg, preferably about 639 mg, preferably about 640 mg, preferably about 641 mg, preferably about 642 mg, preferably about 643 mg, preferably about 644 mg, preferably about 645 mg, preferably about 646 mg, preferably about 647 mg, preferably about 648 mg, preferably about 649 mg, preferably about 650 mg, preferably about 651 mg, preferably about 652 mg, preferably about 653 mg, preferably about 654 mg, preferably about 655 mg, preferably about 656 mg, preferably about 657 mg, preferably about 658 mg, preferably about 659 mg, preferred The amount is approximately 660 mg, preferably approximately 661 mg, preferably approximately 662 mg, preferably approximately 663 mg, preferably approximately 664 mg, preferably approximately 665 mg, preferably approximately 666 mg, preferably approximately 667 mg, preferably approximately 668 mg, preferably approximately 669 mg, preferably approximately 670 mg, preferably approximately 671 mg, preferably approximately 672 mg, preferably approximately 673 mg, preferably approximately 674 mg, preferably approximately 675 mg, preferably approximately 676 mg, preferably approximately 677 mg, preferably approximately 678 mg, preferably approximately 679 mg, preferably approximately 680 mg.Preferably about 681 mg, preferably about 682 mg, preferably about 683 mg, preferably about 684 mg, preferably about 685 mg, preferably about 686 mg, preferably about 687 mg, preferably about 688 mg, preferably about 689 mg, preferably about 690 mg, preferably about 691 mg, preferably about 692 mg, preferably about 693 mg, preferably about 694 mg, preferably about 695 mg, preferably about 696 mg, preferably about 697 mg, preferably about 698 mg, preferably about 699 mg, preferably about 700 mg, preferably about 701 mg, preferably about 702 mg, preferably about 703 mg, preferably about 704 mg, preferably about 705 mg, preferably about 706 mg, preferably about 707 mg, preferably about 708 mg, preferably about 709 mg, preferably about 710 mg, preferably about 711 mg, preferably about 712 mg, preferably about 713 mg, preferably about 714 mg, preferably about 715 mg, preferably about 716 mg, preferably about 717 mg, preferably about 718 mg, preferably about 719 mg, preferably about 720 mg, preferably about 721 mg, preferably about 722 mg, preferably about 723 mg, preferably about 724 mg, preferably about 725 mg, preferably about 726 mg, preferably about 727 mg, preferably about 728 mg, preferably about 729 mg, preferably about 730 mg, preferably about 731 mg, preferably about 732 mg, preferably about 733 mg, preferably about 734 mg, preferably about 735 mg, preferably about 736 mg, preferably about 737 mg, preferably about 738 mg, preferably about 739 mg, preferably about 740 mg, preferably about 741 mg, preferably about 742 mg, preferred The amount is approximately 743 mg, preferably approximately 744 mg, preferably approximately 745 mg, preferably approximately 746 mg, preferably approximately 747 mg, preferably approximately 748 mg, preferably approximately 749 mg, preferably approximately 750 mg, preferably approximately 751 mg, preferably approximately 752 mg, preferably approximately 753 mg, preferably approximately 754 mg, preferably approximately 755 mg, preferably approximately 756 mg, preferably approximately 757 mg, preferably approximately 758 mg, preferably approximately 759 mg, preferably approximately 760 mg, preferably approximately 761 mg, preferably approximately 762 mg, preferably approximately 763 mg.Preferably about 764 mg, preferably about 765 mg, preferably about 766 mg, preferably about 767 mg, preferably about 768 mg, preferably about 769 mg, preferably about 770 mg, preferably about 771 mg, preferably about 772 mg, preferably about 773 mg, preferably about 774 mg, preferably about 775 mg, preferably about 776 mg, preferably about 777 mg, preferably about 778 mg, preferably about 779 mg, preferably about 780 mg, preferably about 781 mg, preferably about 782 mg, preferably about 783 mg, preferably about 784 mg, preferably about 785 mg, preferably about 786 mg, preferably about 787 mg, preferably about 788 mg, preferably about 789 mg, preferably about 790 mg, preferably about 791 mg, preferably about 792 mg, preferably about 793 mg, preferably about 794 mg, preferably about 795 mg, preferably about 796 mg, preferably about 797 mg, preferably about 798 mg, preferably about 799 mg, preferably about 800 mg, preferably about 801 mg, preferably about 802 mg, preferably about 803 mg, preferably about 804 mg, preferably about 805 mg, preferably about 806 mg, preferably about 807 mg, preferably about 808 mg, preferably about 809 mg, preferably about 810 mg, preferably about 811 mg, preferably about 812 mg, preferably about 813 mg, preferably about 814 mg, preferably about 815 mg, preferably about 816 mg, preferably about 817 mg, preferably about 818 mg, preferably about 819 mg, preferably about 820 mg, preferably about 821 mg, preferably about 822 mg, preferably about 823 mg, preferably about 824 mg, preferably about 825 mg, preferred The amount is approximately 826 mg, preferably approximately 827 mg, preferably approximately 828 mg, preferably approximately 829 mg, preferably approximately 830 mg, preferably approximately 831 mg, preferably approximately 832 mg, preferably approximately 833 mg, preferably approximately 834 mg, preferably approximately 835 mg, preferably approximately 836 mg, preferably approximately 837 mg, preferably approximately 838 mg, preferably approximately 839 mg, preferably approximately 840 mg, preferably approximately 841 mg, preferably approximately 842 mg, preferably approximately 843 mg, preferably approximately 844 mg, preferably approximately 845 mg, preferably approximately 846 mg.Preferably about 847 mg, preferably about 848 mg, preferably about 849 mg, preferably about 850 mg, preferably about 851 mg, preferably about 852 mg, preferably about 853 mg, preferably about 854 mg, preferably about 855 mg, preferably about 856 mg, preferably about 857 mg, preferably about 858 mg, preferred, The amount is approximately 859 mg, preferably approximately 860 mg, preferably approximately 861 mg, preferably approximately 862 mg, preferably approximately 863 mg, preferably approximately 864 mg, preferably approximately 865 mg, preferably approximately 866 mg, preferably approximately 867 mg, preferably approximately 868 mg, preferably approximately 869 mg, preferably approximately 870 mg, preferably approximately 871 mg, preferably approximately 872 mg, preferably approximately 873 mg, preferably approximately 874 mg, preferably approximately 875 mg, preferably approximately 876 mg, preferably approximately 877 mg, preferably approximately 878 mg, preferably approximately 879 mg. Preferably about 880 mg, preferably about 881 mg, preferably about 882 mg, preferably about 883 mg, preferably about 884 mg, preferably about 885 mg, preferably about 886 mg, preferably about 887 mg, preferably about 888 mg, preferably about 889 mg, preferably about 890 mg, preferably about 891 mg, preferably about 892 mg, preferably about 893 mg, preferably about 894 mg, preferably about 895 mg, preferably about 896 mg, preferably about 897 mg, preferably about 898 mg, preferably about 899 mg, preferably about 9 00 mg, preferably about 901 mg, preferably about 902 mg, preferably about 903 mg, preferably about 904 mg, preferably about 905 mg, preferably about 906 mg, preferably about 907 mg, preferably about 908 mg, preferably about 909 mg, preferably about 910 mg, preferably about 911 mg, preferably about 912 mg, preferably about 913 mg, preferably about 914 mg, preferably about 915 mg, preferably about 916 mg, preferably about 917 mg, preferably about 918 mg, preferably about 919 mg, preferably about 920 mg, preferred The amount is approximately 921 mg, preferably approximately 922 mg, preferably approximately 923 mg, preferably approximately 924 mg, preferably approximately 925 mg, preferably approximately 926 mg, preferably approximately 927 mg, preferably approximately 928 mg, preferably approximately 929 mg, preferably approximately 930 mg, preferably approximately 931 mg, preferably approximately 932 mg, preferably approximately 933 mg, preferably approximately 934 mg, preferably approximately 935 mg, preferably approximately 936 mg, preferably approximately 937 mg, preferably approximately 938 mg, preferably approximately 939 mg, preferably approximately 940 mg, preferably approximately 941 mg.Preferably about 942 mg, preferably about 943 mg, preferably about 944 mg, preferably about 945 mg, preferably about 946 mg, preferably about 947 mg, preferably about 948 mg, preferably about 949 mg, preferably about 950 mg, preferably about 951 mg, preferably about 952 mg, preferably about 953 mg, preferably about 954 mg, preferably about 955 mg, preferably about 956 mg, preferably about 957 mg, preferably about 958 mg, preferably about 959 mg, preferably about 960 mg, preferably about 961 mg, preferably about 96 2 mg, preferably about 963 mg, preferably about 964 mg, preferably about 965 mg, preferably about 966 mg, preferably about 967 mg, preferably about 968 mg, preferably about 969 mg, preferably about 970 mg, preferably about 971 mg, preferably about 972 mg, preferably about 973 mg, preferably about 974 mg, preferably about 975 mg, preferably about 976 mg, preferably about 977 mg, preferably about 978 mg, preferably about 979 mg, preferably about 980 mg, preferably about 981 mg, preferably about 982 mg, preferably Approximately 983 mg, preferably approximately 984 mg, preferably approximately 985 mg, preferably approximately 986 mg, preferably approximately 987 mg, preferably approximately 988 mg, preferably approximately 989 mg, preferably approximately 990 mg, preferably approximately 991 mg, preferably approximately 992 mg, preferably approximately 993 mg, preferably approximately 994 mg, preferably approximately 995 mg, preferably approximately 996 mg, preferably approximately 997 mg, preferably approximately 998 mg, preferably approximately 999 mg, preferably approximately 1000 mg, preferably approximately 1100 mg, preferably approximately 1101 mg, preferably approximately 1102 mg g, preferably about 1103 mg, preferably about 1104 mg, preferably about 1105 mg, preferably about 1106 mg, preferably about 1107 mg, preferably about 1108 mg, preferably about 1109 mg, preferably about 1110 mg, preferably about 1111 mg, preferably about 1112 mg, preferably about 1113 mg, preferably about 1114 mg, preferably about 1115 mg, preferably about 1116 mg, preferably about 1117 mg, preferably about 1118 mg, preferably about 1119 mg, preferably about 1120 mg, preferably about 1121 mg,Preferably about 1122 mg, preferably about 1123 mg, preferably about 1124 mg, preferably about 1125 mg, preferably about 1126 mg, preferably about 1127 mg, preferably about 1128 mg, preferably about 1129 mg, preferably about 1130 mg, preferably about 1131 mg, preferably about 1132 mg, preferably about 1133 mg, preferably about 1134 mg, preferably about 1135 mg, preferably about 1136 mg, preferably about 1137 mg, preferably about 1138 mg, preferably about 1139 mg, preferably about 1140 mg, preferred The amount is approximately 1141 mg, preferably approximately 1142 mg, preferably approximately 1143 mg, preferably approximately 1144 mg, preferably approximately 1145 mg, preferably approximately 1146 mg, preferably approximately 1147 mg, preferably approximately 1148 mg, preferably approximately 1149 mg, preferably approximately 1150 mg, preferably approximately 1151 mg, preferably approximately 1152 mg, preferably approximately 1153 mg, preferably approximately 1154 mg, preferably approximately 1155 mg, preferably approximately 1156 mg, preferably approximately 1157 mg, preferably approximately 1158 mg, preferably approximately 1159 mg, preferably approximately 1160 mg, preferably about 1161 mg, preferably about 1162 mg, preferably about 1163 mg, preferably about 1164 mg, preferably about 1165 mg, preferably about 1166 mg, preferably about 1167 mg, preferably about 1168 mg, preferably about 1169 mg, preferably about 1170 mg, preferably about 1171 mg, preferably about 1172 mg, preferably about 1173 mg, preferably about 1174 mg, preferably about 1175 mg, preferably about 1176 mg, preferably about 1177 mg, preferably about 1178 mg, preferably about 117 9 mg, preferably about 1180 mg, preferably about 1181 mg, preferably about 1182 mg, preferably about 1183 mg, preferably about 1184 mg, preferably about 1185 mg, preferably about 1186 mg, preferably about 1187 mg, preferably about 1188 mg, preferably about 1189 mg, preferably about 1190 mg, preferably about 1191 mg, preferably about 1192 mg, preferably about 1193 mg, preferably about 1194 mg, preferably about 1195 mg, preferably about 1196 mg, preferably about 1197 mg, preferably about 1198 mg,Preferably about 1199 mg, preferably about 1200 mg, preferably about 1201 mg, preferably about 1202 mg, preferably about 1203 mg, preferably about 1204 mg, preferably about 1205 mg, preferably about 1206 mg, preferably about 1207 mg, preferably about 1208 mg, preferably about 1209 mg, preferably about 1210 mg, preferably about 1211 mg, preferably about 1212 mg, preferably about 1213 mg, preferably about 1214 mg, preferably about 1215 mg, preferably about 1216 mg, preferably about 1217 mg, preferred The amount is approximately 1218 mg, preferably approximately 1219 mg, preferably approximately 1220 mg, preferably approximately 1221 mg, preferably approximately 1222 mg, preferably approximately 1223 mg, preferably approximately 1224 mg, preferably approximately 1225 mg, preferably approximately 1226 mg, preferably approximately 1227 mg, preferably approximately 1228 mg, preferably approximately 1229 mg, preferably approximately 1230 mg, preferably approximately 1231 mg, preferably approximately 1232 mg, preferably approximately 1233 mg, preferably approximately 1234 mg, preferably approximately 1235 mg, preferably approximately 1236 mg, preferably approximately 1237 mg, preferably about 1238 mg, preferably about 239 mg, preferably about 1240 mg, preferably about 1241 mg, preferably about 1242 mg, preferably about 1243 mg, preferably about 1244 mg, preferably about 1245 mg, preferably about 1246 mg, preferably about 1247 mg, preferably about 1248 mg, preferably about 1249 mg, preferably about 1250 mg, preferably about 1251 mg, preferably about 1252 mg, preferably about 1253 mg, preferably about 1254 mg, preferably about 1255 mg, preferably about 1256 mg, preferably about 1257 mg, preferably about 1258 mg, preferably about 1259 mg, preferably about 1260 mg, preferably about 1261 mg, preferably about 1262 mg, preferably about 1263 mg, preferably about 1264 mg, preferably about 1265 mg, preferably about 1266 mg, preferably about 1267 mg, preferably about 1268 mg, preferably about 1269 mg, preferably about 1270 mg, preferably about 1271 mg, preferably about 1272 mg, preferably about 1273 mg, preferably about 1274 mg, preferably about 1275 mg,Preferably about 1276 mg, preferably about 1277 mg, preferably about 1278 mg, preferably about 1279 mg, preferably about 1280 mg, preferably about 1281 mg, preferably about 1282 mg, preferably about 1283 mg, preferably about 1284 mg, preferably about 1285 mg, preferably about 1286 mg, preferably about 1287 mg, preferably about 1288 mg, preferably about 1289 mg, preferably about 1290 mg, preferably about 1291 mg, preferably about 1292 mg, preferably about 1293 mg, preferably about 1294 mg, preferred The amount is approximately 1295 mg, preferably approximately 1296 mg, preferably approximately 1297 mg, preferably approximately 1298 mg, preferably approximately 1299 mg, preferably approximately 1300 mg, preferably approximately 1301 mg, preferably approximately 1302 mg, preferably approximately 303 mg, preferably approximately 1304 mg, preferably approximately 1305 mg, preferably approximately 1306 mg, preferably approximately 1307 mg, preferably approximately 1308 mg, preferably approximately 1309 mg, preferably approximately 1310 mg, preferably approximately 1311 mg, preferably approximately 1312 mg, preferably approximately 1313 mg, preferably approximately 1 314 mg, preferably about 1315 mg, preferably about 1316 mg, preferably about 1317 mg, preferably about 1318 mg, preferably about 1319 mg, preferably about 1320 mg, preferably about 1321 mg, preferably about 1322 mg, preferably about 1323 mg, preferably about 1324 mg, preferably about 1325 mg, preferably about 1326 mg, preferably about 1327 mg, preferably about 1328 mg, preferably about 1329 mg, preferably about 1330 mg, preferably about 1331 mg, preferably about 1332 mg, preferably about 1333 mg, preferably about 1334 mg, preferably about 1335 mg, preferably about 1336 mg, preferably about 1337 mg, preferably about 1338 mg, preferably about 1339 mg, preferably about 1340 mg, preferably about 1341 mg, preferably about 1342 mg, preferably about 1343 mg, preferably about 1344 mg, preferably about 1345 mg, preferably about 1346 mg, preferably about 1347 mg, preferably about 1348 mg, preferably about 1349 mg, preferably about 1350 mg, preferably about 1351 mg, preferably about 1352 mg,Preferably about 1353 mg, preferably about 1354 mg, preferably about 1355 mg, preferably about 1356 mg, preferably about 1357 mg, preferably about 1358 mg, preferably about 1359 mg, preferably about 1360 mg, preferably about 1361 mg, preferably about 1362 mg, preferred, Or approximately 1363 mg, preferably approximately 1364 mg, preferably approximately 1365 mg, preferably approximately 1366 mg, preferably approximately 1367 mg, preferably approximately 1368 mg, preferably approximately 1369 mg, preferably approximately 1370 mg, preferably approximately 1371 mg, preferably approximately 1372 mg, preferably approximately 1373 mg, preferably approximately 1374 mg, preferably approximately 1375 mg, preferably approximately 1376 mg, preferably approximately 1377 mg, preferably approximately 1378 mg, preferably approximately 1379 mg, preferably approximately 1380 mg, preferably approximately 1381 mg, preferably The amount is approximately 1382 mg, preferably approximately 1383 mg, preferably approximately 1384 mg, preferably approximately 1385 mg, preferably approximately 1386 mg, preferably approximately 1387 mg, preferably approximately 1388 mg, preferably approximately 1389 mg, preferably approximately 1390 mg, preferably approximately 1391 mg, preferably approximately 1392 mg, preferably approximately 1393 mg, preferably approximately 1394 mg, preferably approximately 1395 mg, preferably approximately 1396 mg, preferably approximately 1397 mg, preferably approximately 1398 mg, preferably approximately 1399 mg, preferably approximately 1400 mg, preferably approximately 1 401 mg, preferably about 1402 mg, preferably about 1403 mg, preferably about 1404 mg, preferably about 1405 mg, preferably about 1406 mg, preferably about 1407 mg, preferably about 1408 mg, preferably about 1409 mg, preferably about 1410 mg, preferably about 1411 mg, preferably about 1412 mg, preferably about 1413 mg, preferably about 1414 mg, preferably about 1415 mg, preferably about 1416 mg, preferably about 1417 mg, preferably about 1418 mg, preferably about 1419 mg, preferably about 1420 mg mg, preferably about 1421 mg, preferably about 1422 mg, preferably about 1423 mg, preferably about 1424 mg, preferably about 1425 mg, preferably about 1426 mg, preferably about 1427 mg, preferably about 1428 mg, preferably about 1429 mg, preferably about 1430 mg, preferably about 1431 mg, preferably about 1432 mg, preferably about 1433 mg, preferably about 1434 mg, preferably about 1435 mg, preferably about 1436 mg, preferably about 1437 mg, preferably about 1438 mg, preferably about 1439 mg,Preferably about 1440 mg, preferably about 1441 mg, preferably about 1442 mg, preferably about 1443 mg, preferably about 1444 mg, preferably about 1445 mg, preferably about 1446 mg, preferably about 1447 mg, preferably about 1448 mg, preferably about 1449 mg, preferably about 1450 mg, preferably about 1451 mg, preferably about 1452 mg, preferably about 1453 mg, preferably about 1454 mg, preferably about 1455 mg, preferably about 1456 mg, preferably about 1457 mg, preferably about 1458 mg, preferably about 1459 mg, preferably about 1460 mg, preferably about 1461 mg, preferably about 1462 mg, preferably about 1463 mg, preferably about 1464 mg, preferably about 1465 mg, preferably about 1466 mg, preferably about 1467 mg, preferably about 1468 mg, preferably about 1469 mg, preferably about 1470 mg, Preferably about 1471 mg, preferably about 1472 mg, preferably about 1473 mg, preferably about 1474 mg, preferably about 1475 mg, preferably about 1476 mg, preferably about 1477 mg, preferably about 1478 mg, preferably about 1479 mg, preferably about 1480 mg, preferably about 1481 mg, preferably about 1482 mg, preferably about 1483 mg, preferably about 1484 mg, preferably about 1485 mg, preferably about 1 It is administered in doses of 486 mg, preferably about 1487 mg, preferably about 1488 mg, preferably about 1489 mg, preferably about 1490 mg, preferably about 1491 mg, preferably about 1492 mg, preferably about 1493 mg, preferably about 1494 mg, preferably about 1495 mg, preferably about 1496 mg, preferably about 1497 mg, preferably about 1498 mg, preferably about 1499 mg, or more preferably about 1500 mg.

[0068]

[0084] In one embodiment, CBD or a pharmaceutically acceptable salt thereof is administered twice daily in the aforementioned doses.

[0085] In one embodiment, CBD or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of at least about 1 mg.

[0069]

[0086] In one embodiment, CBD or a pharmaceutically acceptable salt thereof is administered twice daily in doses of approximately 1 mg to approximately 500 mg.

[0087] In one embodiment, CBD or a pharmaceutically acceptable salt thereof is administered twice daily in doses of approximately 500 mg to approximately 1000 mg.

[0070]

[0088] 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 inhalation, topically to the eye, or to the ear. 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 in dosage forms, as well as formulations containing conventional non-toxic and pharmaceutically acceptable carriers, adjuvants, and vehicles. Formulations include liposomes, nanoparticles, microparticles, polymer systems, dispersions, suspensions, coatings to devices, powders, microspheres, carrier-mediated, implants, and encapsulants. In one embodiment, a composition comprising CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered orally. In another embodiment, a composition comprising CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof is administered parenterally.

[0071]

[0089] The term “parenteral” as used herein includes subcutaneous injection, aerosols for administration into the lungs or nasal cavity, and intravenous, intramuscular, intrasacral, and intracranial injection or infusion techniques. This disclosure also provides topical, oral, and parenteral pharmaceutical formulations suitable for use in novel methods of the treatments described herein.

[0072]

[0090] In preferred embodiments, compositions comprising CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered intraperitoneally.

[0073]

[0091] In preferred embodiments, compositions comprising CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof are formulated for oral administration.

[0074]

[0092] Dosage forms suitable for oral administration are known to those skilled in the art, and examples include tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, liquids, syrups, or elixirs.

[0075]

[0093] In one embodiment, compositions comprising CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof are in the form of liquids, oils, tablets, or capsules.

[0076]

[0094] It is further intended herein that compositions comprising CBD or a pharmaceutically acceptable salt thereof, hydroxychloroquine or a pharmaceutically acceptable salt thereof, and 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 improving symptoms associated with inflammatory conditions such as sepsis-associated ARDS, examples of which include antibiotics, antivirals, and antifungals.

[0077]

[0095] In one embodiment disclosed herein, a composition is provided comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof.

[0078]

[0096] In one embodiment, the composition contains about 1 mg to about 1000 mg of hydroxychloroquine or a pharmaceutically acceptable salt thereof per dose. In another embodiment, the composition contains about 200 mg to about 400 mg of hydroxychloroquine or a pharmaceutically acceptable salt thereof per dose.

[0079]

[0097] In one embodiment, the composition contains about 1 mg to about 1500 mg of CBD or a pharmaceutically acceptable salt thereof per dose. In another embodiment, the composition contains about 500 mg to about 1000 mg of CBD or a pharmaceutically acceptable salt thereof per dose.

[0080]

[0098] In another embodiment, the composition is formulated for oral administration.

[0099] In another embodiment, the composition is formulated for intraperitoneal administration.

[0100] Compositions containing CBD and hydroxychloroquine for oral administration may contain one or more agents selected from the group of sweeteners, flavorings, colorings, and preservatives to produce a pharmaceutically refined and flavorful preparation. Suitable sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid, or agar. Suitable flavorings include peppermint oil, wintergreen oil, cherry blossom, orange, or raspberry flavorings. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methylparaben, propylparaben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Suitable time delayers include glyceryl monostearate or glyceryl distearate.

[0081]

[0101] In one embodiment, the composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0102] Suitable pharmaceutically acceptable carriers, diluents, or excipients are known to those skilled in the art, and examples include inert diluents (e.g., calcium carbonate, lactose, calcium phosphate, or sodium phosphate), granulators and disintegrants (e.g., corn starch or alginic acid), binders (e.g., starch, gelatin, or acacia), lubricants (e.g., magnesium stearate, stearic acid, or talc), and materials that delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a long period (e.g., glyceryl monostearate or glyceryl distearate). Coatings can also be carried out using the techniques described in U.S. Patents 4,256,108, 4,160,452, and 4,265,874 to form controlled-release penetrating therapeutic tablets.

[0082]

[0103] The compositions disclosed herein can be prepared according to conventional methods well known in the pharmaceutical and nutritional supplement industries, such as those described in Remington's Pharmaceutical Handbook (Mack Publishing Co., NY, USA), using suitable excipients, diluents, and fillers.

[0083]

[0104] Compositions suitable for oral administration may be provided as separate units (i.e., dosage forms), each containing a predetermined amount of each component of the composition as a liquid or suspension in an aqueous or non-aqueous liquid, or as an emulsion, in the form of a powder, tablet, capsule, or granule.

[0084]

[0105] As described elsewhere in this specification, the compositions may be formulated for administration as separate unit dosage forms. The unit dosage forms may be capsules, tablets, oil-based solutions, or liquid solutions.

[0085]

[0106] Oral administration of CBD has been shown to be an effective route of administration (review by Millar et al., 2018, Frontiers in Pharmacology, 9:1365). Similarly, oral administration of hydroxychloroquine has also been shown to be effective for absorption of its high bioavailability (Tett et al., 1989, British Journal of Clinical Pharmacology, 27:771-779).

[0086]

[0107] In one embodiment, the composition is intended for use in the treatment or prevention of inflammatory conditions.

[0108] In one embodiment, the composition is intended for use in the treatment or prevention of inflammatory respiratory conditions.

[0087]

[0109] In one embodiment, the composition is for use in the treatment or prevention of inflammatory respiratory conditions selected from the group consisting of ARDS, COPD, asthma, bronchitis, and CF.

[0088]

[0110] In one embodiment, the composition is intended for use in the treatment or prevention of ARDS.

[0111] In one embodiment, the composition is intended for use in the treatment or prevention of sepsis-related ARDS.

[0089]

[0112] In one embodiment, the composition is intended for use in the treatment or prevention of sepsis-associated ARDS caused by bacterial, fungal, or viral infections, as described elsewhere herein.

[0090]

[0113] In one embodiment, the composition is intended for use in the treatment or prevention of inflammatory bowel disease.

[0114] In one embodiment, 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.

[0091]

[0115] In one embodiment disclosed herein, the use of 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 is provided.

[0092]

[0116] In one embodiment, the inflammatory state is an inflammatory respiratory state.

[0117] In one embodiment, the inflammatory respiratory condition is selected from the group consisting of ARDS, COPD, asthma, bronchitis, and CF.

[0093]

[0118] In one embodiment, the inflammatory state is ARDS. In another embodiment, the ARDS is sepsis-associated ARDS.

[0119] In another embodiment, the inflammatory state is inflammatory bowel disease.

[0094]

[0120] In another embodiment, the inflammatory condition is arthritis. In another embodiment, the arthritis is rheumatoid arthritis.

[0121] According to the methods disclosed herein, CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof may be administered as a single composition or as separate compositions.

[0095]

[0122] In one embodiment, CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered sequentially.

[0123] "Sequential" administration means that there is an interval between the administration of CBD and hydroxychloroquine. The interval for sequential administration can be a few seconds, a few minutes, a few hours, or a few days. In a preferred embodiment, the interval between sequential administration of CBD and hydroxychloroquine is less than one hour, preferably less than 30 minutes, and most preferably less than one minute. Sequential administration can be in any order (i.e., administration of CBD before administration of hydroxychloroquine, or administration of hydroxychloroquine before administration of CBD).

[0096]

[0124] In another embodiment, CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0125] "Simultaneous" administration means that CBD and hydroxychloroquine are administered at the same time. According to the methods disclosed herein, CBD and hydroxychloroquine may be administered simultaneously in a single composition or dosage form. Alternatively, CBD and hydroxychloroquine may be administered simultaneously as two separate compositions or dosage forms.

[0097]

[0126] In some embodiments, periodic re-administration (sequentially or co-administration) of the activator may be necessary to achieve the desired therapeutic effect. The precise amount and rate of administration of CBD and hydroxychloroquine depend on several factors, such as the subject's age, weight, overall health, sex, and dietary requirements (examples of which are described elsewhere herein), as well as any drugs or medications used in combination with or in conjunction with the administration of the composition. Where multiple doses are required, these may be administered hourly, daily, weekly, monthly, or at other suitable time intervals, or the dose may be reduced proportionally according to the urgency of the situation.

[0098]

[0127] In one embodiment, a composition comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0099]

[0128] In one embodiment, a composition comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof, is administered for at least one week.

[0100]

[0129] In one embodiment, a composition comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof, is administered to a subject for 1 to 10 weeks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks).

[0101]

[0130] Therefore, in one embodiment, a composition comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof, is administered to a subject for 1 to 10 weeks, preferably 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 about 10 weeks.

[0102]

[0131] In one embodiment, a composition comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, or CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof, is administered to a subject for 3 to 4 weeks.

[0103]

[0132] In one embodiment, 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 daily thereafter, with the loading dose being approximately 1 mg to approximately 1000 mg twice daily and the maintenance dose being approximately 1 mg to approximately 1000 mg twice daily. In another embodiment, 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 daily thereafter, with the loading dose being approximately 1 mg to approximately 500 mg twice daily and the maintenance dose being approximately 1 mg to approximately 500 mg twice daily. In yet another embodiment, 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 daily thereafter, with the loading dose being approximately 1 mg twice daily and the maintenance dose being approximately 1 mg twice daily.

[0104]

[0133] In one embodiment, the subject is administered approximately 1 mg to approximately 1500 mg of CBD or a pharmaceutically acceptable salt thereof twice daily with a loading dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof. In another embodiment, the subject is administered approximately 1 mg to approximately 1000 mg of CBD or a pharmaceutically acceptable salt thereof twice daily with a loading dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is administered approximately 1 mg to approximately 1500 mg of CBD or a pharmaceutically acceptable salt thereof twice daily with a maintenance dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof. In another embodiment, the subject is administered approximately 500 mg to approximately 1000 mg of CBD or a pharmaceutically acceptable salt thereof twice daily with a maintenance dose of hydroxychloroquine or a pharmaceutically acceptable salt thereof.

[0105]

[0134] The term "loading dose," as used herein, refers to the first higher dose of a drug administered at the start of treatment before being reduced to a lower maintenance dose.

[0135] The term "maintenance dose," as used herein, refers to the maintenance rate (mg / h) of the drug following administration, which is equal to the elimination rate at steady state.

[0106]

[0136] In other embodiments disclosed herein, 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 forms may be in the form of an oral liquid, capsule, or tablet. Those skilled in the art will understand that the unit dosage forms containing CBD or a pharmaceutically acceptable salt thereof and / or hydroxychloroquine or a pharmaceutically acceptable salt thereof do not need to be of the same type. Thus, the methods of this disclosure intend, for example, the administration of CBD in liquid form and hydroxychloroquine as capsules or tablets.

[0107] kit

[0137] In one embodiment disclosed herein, a kit is provided comprising CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of inflammatory conditions.

[0108]

[0138] In one embodiment, the kit comprises CBD or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof in separate unit dosage forms for loading dose and maintenance dose, as described elsewhere herein.

[0109] Methods for modulating immune responses

[0139] In another embodiment disclosed herein, a method is provided for modulating an immune response, comprising the step of administering cannabidiol (CBD) or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0110]

[0140] Those skilled in the art will understand that modulation of the immune response by the methods disclosed herein can be determined by various methods known in the art, examples of which include, for example, measuring changes in cytokine production (e.g., levels, concentrations, ratios) in a subject before, during, or after treatment. It should be understood that, as used herein, the term “modulation” means an increase or decrease in the immune response determined by, for example, an increase or decrease in the levels, concentrations, and / or ratios of inflammatory mediators such as cytokines.

[0111]

[0141] The terms “level” and “quantity” are used interchangeably herein to refer to quantitative quantities (e.g., moles or number), semi-quantitative quantities, relative quantities (e.g., weight percent, or mole percent within a class, or ratio), concentrations, etc. Thus, these terms encompass absolute or relative quantities or concentrations of inflammatory mediators in a sample.

[0112]

[0142] Inflammatory mediators such as cytokines can be quantified or detected using any suitable technique, including, but not limited to, nucleic acid and protein-based assays. In exemplary nucleic acid-based assays, nucleic acids are isolated from cells contained in a biological sample according to standard methods (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual; and Ausubel et al., 1994, Current Protocols in Molecular Biology).

[0113]

[0143] In other exemplary embodiments, protein levels of inflammatory mediators can be measured using protein-based assays known in the art. For example, antibody-based techniques can be used to determine the level of autoantibodies in a sample, examples of which include immunoassays, such as enzyme-linked immunosorbent assays (ELISA), immunohistochemical tests (IHC), and radioimmunoassays (RIA).

[0114]

[0144] In one embodiment, protein expression is measured using a multiplexed protein expression analysis method. In another embodiment, the multiplexed protein expression analysis method is a protein microarray or a Luminex bead array.

[0115]

[0145] Protein capture arrays that enable the simultaneous detection and / or quantification of multiple proteins are also available. For example, low-density protein arrays on filter membranes, such as general-purpose protein array systems, allow imaging of arranged antigens using standard ELISA techniques and scanning charge-coupled device (CCD) detectors. Exemplary protein capture arrays include protein function arrays containing spatially arranged protein-binding molecules (i.e., antigens), which can facilitate extensive parallel analysis of autoantibodies specific to antigens containing the protein function array. The core of this type of analysis is the retention of confirmation of precisely folded proteins of the arranged antigens. Protein function arrays have been shown to possess the necessary properties of specificity and acceptable background and are commercially available (e.g., Sengenics). Various methods for constructing protein function arrays have been reported (see, e.g., Gnjatic et al., 2009, Journal of Immunological Methods, 341(50): pp. 1-2; PCT / GB01 / 00395, PCT / GB02 / 05499, PCT / GB03 / 00362). Individually spatially distinct functional proteins are typically bound to a support surface, which is generally planar or contoured. Common physical supports include glass slides, silicon, microwells, nitrocellulose or PVDF membranes, as well as magnetic and other macrobeads.

[0116]

[0146] The particles in suspension can also be used as the basis for an array if they are coded for identification; this includes color coding for microbeads (e.g., available from Luminex, Bio-Rad, and Nanomics Biosystems) and semiconductor nanocrystals (e.g., QDots®, available from Quantum Dots), as well as barcoding for beads (UltraPlex®, available from Smartbeads) and multi-metal microrods (Nanobarcodes® particles, available from Surromed). The beads can also be assembled into planar arrays on semiconductor chips (e.g., available from LEAPS technology and BioArray Solutions). When particles are used, individual protein capture agents (e.g., antibodies against inflammatory mediators or fragments thereof that bind to inflammatory mediators) typically bind to individual particles to result in spatial definition or separation of the array. The particles can then be assayed separately but in parallel, in a partitioned manner, for example, in wells of a microtiter plate or in separate test tubes.

[0117]

[0147] In one embodiment, 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 nonspecifically bound components of the sample from the array. The array is then incubated with a fluorescently labeled antibody to detect interactions between array antigens and inflammatory mediators present in the sample. The presence or amount of proteins or peptides bound to each feature of the array is detected using a suitable fluorescence detection system. The amount of protein bound to the array feature is proportional to the fluorescence intensity. In a particular embodiment, local background fluorescence obtained from the control feature of the array is automatically subtracted, and relative fluorescence units (RFU) for each feature of the array are recorded.

[0118]

[0148] In some embodiments, the protein function array is a Luminex-based multiplex assay, a bead-based multiplex assay, where the beads are first stained with a fluorescent dye to generate specific spectral addresses. Biomolecules (e.g., oligos or antibodies) can be conjugated to the surface of the beads to capture the analyte of interest, i.e., inflammatory markers, such as cytokines. Flow cytometry or other suitable imaging techniques known to those skilled in the art can then be used to characterize the beads and detect the presence of the analyte. The Luminex technology enables the detection of a large number of proteins, genes, or other gene expression products (e.g., 100 or more, 200 or more, 300 or more, 400 or more) using very small sample volumes (e.g., in 96 or 384-well plates).

[0119]

[0149] In some embodiments, levels of inflammatory mediators can be normalized to housekeeping biomarkers. The term “housekeeping biomarkers” refers to a biomarker or group of biomarkers (e.g., polynucleotides and / or polypeptides) that are typically found at a constant level in the cell type or tissue being analyzed, across the conditions being evaluated.

[0120]

[0150] In other embodiments, levels of inflammatory mediators measured using protein arrays can be normalized by both intra-array and inter-array data normalization. For example, the entire median of all median relative fluorescence units (rfu) for each protein in the protein function array (excluding data from control proteins) is calculated, and intra-array normalization is achieved by dividing the median of the quadruple spot for each protein on the array by the entire median of all proteins on the array in each sample. Inter-array normalization can be achieved using bioinformatics software packages known in the art. For example, inter-array normalization can be achieved using the quantile normalization package in R (Bolstad et al., 2003, Bioinformatics, 19(2):185-193).

[0121]

[0151] As described elsewhere in this specification, it will be understood by those skilled in the art that methods for analyzing the levels of inflammatory mediators in a sample may be quantitative, semi-quantitative, or qualitative. For example, quantitative analysis typically provides the concentration or number of inflammatory mediator nucleic acid molecules or proteins in a sample within a suitable margin of error (e.g., mean ± standard deviation). In contrast, semi-quantitative or qualitative analysis typically provides an indicator of the relative amount of inflammatory mediators in a sample. This may involve comparing the amount of inflammatory mediators in a first sample with the amount of inflammatory mediators in a second sample, and making a determination regarding the relative amount of inflammatory mediators between the first and second samples.

[0122]

[0152] Those skilled in the art will understand that, when comparisons are made against a reference value, the manner in which a sample is evaluated against the levels of one or more inflammatory mediators should be substantially identical to the manner in which the reference value is derived, in order to ensure that appropriate comparisons can be made for the purpose of determining whether the immune response has been regulated in the subject following administration of CBD and hydroxychloroquine.

[0123]

[0153] In one embodiment, a method for modulating an immune response includes the step of reducing the level of an inflammatory mediator relative to a reference level.

[0154] In one embodiment, the inflammatory mediator is a cytokine.

[0124]

[0155] As used herein, the term "cytokine" refers to factors that exert various effects on cells, including, for example, growth or proliferation, and examples include IL-1β, IL-2, IL-10, IL-12(p70), IFN-γ, TNF-α, IL-1α, IL-3, IL-4, IL-5, IL-6, IL-9, IL-12(p40), IL-13, IL-17A, eotaxin, G-CSF, GM-CSF, IFN-γ, KC, MCP-1(MCAF), MIP-1α, MIP-1β, RANTES, and CXCL-1.

[0125]

[0156] In one embodiment, a method for modulating an immune response includes reducing the level of an inflammatory cytokine selected from the group consisting of IL-1β, IL-6, TNF-α, IL-1α, IL-12(p70), IFN-γ, CXCL-1, MCP-1, and MIP-1α relative to a reference level.

[0126]

[0157] In one embodiment, a method for modulating an immune response includes the step of reducing the level of an inflammatory cytokine selected from the group consisting of IL-1β, IL-6, and TNF-α relative to a reference level.

[0127]

[0158] Those skilled in the art will understand that the inventions described herein are subject to modifications and alterations other than those specifically described. It will be understood that the inventions include all such modifications and alterations that fall within the spirit and scope of the inventions. The inventions also include all of the processes, features, compositions, and compounds that are referred to or shown herein individually or collectively, as well as any combination of any two or more of the aforementioned processes or features.

[0128]

[0159] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention belongs.

[0160] All patents, patent applications, and publications described herein are incorporated herein by reference in their entirety.

[0129]

[0161] Various embodiments made possible herein are further described by the following non-limiting examples. [Examples]

[0130] material Activating agent

[0162] Cannabidiol (CBD) and hydroxychloroquine (HCQ) were purchased by Pharmacology Discovery Services Taiwan, Ltd. The formulations are summarized in Table 3.

[0131] [Table 3]

[0132] animal

[0163] Male C57BL / 6 or BALB / c mice and female Lewis rats weighing 19±1g were provided by BioLasco Taiwan. The animals were acclimatized for three days prior to use to ensure good health. All animals were maintained in a hygienic environment with controlled temperature (20–24°C) and humidity (30%–70%) in a 12-hour light / dark cycle. They were provided with free access to sterile standard laboratory diets (MFG, Oriental Yeast Co., Ltd., Japan) and autoclaved tap water. All aspects of this operation, including animal containment, experimentation, and disposal, were carried out in accordance with the Guide for the Care and Use of Laboratory Animals: 8th Edition (National Academy Press, Washington, DC, 2011) at the inventors' AAALAC-accredited laboratory animal facility. The animal care and use protocols were reviewed and approved by IACUC at Pharmacology Discovery Services Taiwan, Ltd.

[0133] chemicals

[0164] 0.9% NaCl (Sintong Chemical Industry Co., Ltd., Taiwan), Bio-Plex mouse cytokine Th1-7plex panel (Bio-Rad, USA), Bio-Plex mouse cytokine group I 23-plex panel (Bio-Rad, USA), lipopolysaccharide (Escherichia coli O55:B5, Sigma L-2880, USA), mouse D-dimer (D2D) ELISA kit (MyBioSource, USA), phosphate-buffered saline (Sigma, USA), and water for injection (WFI) (Tai-Yu, Taiwan).

[0134] method Lipopolysaccharide (LPS)-induced sepsis

[0165] Male C57BL / 6 mice weighing 10–20 g were used. The vehicle and activator (i.e., CBD and hydroxychloroquine) were administered intraperitoneally (IP) (Table 4) or orally (Table 5) one hour prior to intravenous (IV) injection of LPS (100 μg / 100 μL / mouse). Two hours after LPS injection, blood was collected from all mice by cardiac puncture, serum was processed, and assays were performed against biomarkers using either Th17-plex for IL-1β, IL-2, IL-10, IL-12(p70), IFN-γ, and TNF-α by Luminex, and IL-6 and D-dimer by ELISA, or 23-plex for IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-17A, eotaxin, G-CSF, GM-CSF, IFN-γ, KC, MCP-1(MCAF), MIP-1α, MIP-1β, RANTES, and TNF-α, and IL-6 by ELISA. A one-way ANOVA followed by Dunnett's test was applied to the comparison between the vehicle and the treatment group. A p<0.05 is considered statistically significant.

[0135]

[0166] For synergistic analysis, the data were baselines, subtracted using cytokine levels from sham-treated mice (i.e., not injected with LPS) before normalizing the values ​​for each cytokine against the maximum value across the groups. The normalized values ​​were used to calculate relative inhibition, where a value of 1 represents complete inhibition and a value of 0 represents no inhibition. Synergistic effects were calculated using the statistical methods described elsewhere in this specification.

[0136] LPS-induced pneumonia

[0167] Male C57BL / B6 mice weighing 10–20 g were used. The vehicle and activators (i.e., CBD and hydroxychloroquine), either alone or in combination, were administered intraperitoneally (IP) one hour before intratracheal administration of LPS (approximately 80 mg / kg). Twenty-four hours after LPS injection, the mice were anesthetized with pentoparbital, and 0.5 mL of PBS was administered twice via tracheal cannula, followed by approximately 0.6 mL of bronchoalveolar lavage fluid (BALF). The BALF was assayed for IL-1β, TNF-α, MCP-1 (MCAF), and CXCL-1 using Luminex. One-way ANOVA followed by Dunnett's test was applied to compare the vehicle and treatment groups. p<0.05 was considered significant.

[0137]

[0168] In separate test groups of animals with induced pneumonia as detailed above, lungs were collected at the end of the study (five lobes per lung) and fixed in 10% neutral buffered formalin for histopathology. Samples were divided into 4-6 μm sections and stained with hematoxylin and eosin (H&E) for examination of inflammatory lesions as described by Shackleford et al. (2002, Toxicologic Pathology, 30(1):93-96). Briefly, a score of 0 corresponds to no lesions, and a score of 5 indicates severe / numerous lesions. Scores were averaged per lobe for each animal, and then averaged for each treatment group.

[0138]

[0169] For synergistic analysis, the data were baselines, subtracted using cytokine levels from sham-treated mice (i.e., not injected with LPS) before normalizing the values ​​for each cytokine against the maximum value across the groups. The normalized values ​​were used to calculate relative inhibition, where a value of 1 represents complete inhibition and a value of 0 represents no inhibition. Synergistic effects were calculated using the statistical methods described elsewhere in this specification.

[0139] 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis

[0170] Male BALB / c dogs were used as an in vivo model of colitis induced by intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in 50% ethanol, as previously described by Antoniou et al. (2016, Annals of Medicine and Surgery, 11: pp. 9-15). In short, ethanol disrupts the intestinal barrier, allowing TNBS to interact with colonic proteins. The interaction of TNBS with high molecular weight proteins makes them immunogenic, leading to Th1-mediated inflammation, which causes symptoms including mismatched stool formation and blood in the feces.

[0140]

[0171] The vehicle and activators (i.e., CBD and hydroxychloroquine) were administered intraperitoneally (IP) once daily for four consecutive days, starting on day 1 (i.e., 24 hours before TNBS) and continuing until day 4 (days 1-4). On the day of the TNBS attack (i.e., day 2), the test items and vehicle were administered 2 hours before the TNBS.

[0141]

[0172] Colon tissue was collected from all animals at the end of the study. Colon samples were taken from 0.5, 2, and 3.5 cm from the anus, fixed with formalin, and then encased in paraffin blocks. 4-micrometer tissue sections were excised and stained with H&E for histological analysis according to the method of Dieleman et al. (1998, Clinical Experimental Immunology, 114:385-391). Histological criteria included abnormalities in mucosal structure, degree of inflammation, erosion or ulceration, epithelial regeneration, and percentage involvement by the disease process. Scoring was based on observer findings by examining three sections from each colon per animal. A total score for colitis (pancolitis index) was added, resulting in a combined histological score ranging from 0 to 60.

[0142]

[0173] Other endpoint measurements were also evaluated, including fecal viscosity score (i.e., 0 - normal stool, 1 - loose but still formed stool, 2 - very loose stool, 3 - diarrhea), fecal occult blood score (i.e., 0 - Hemocult negative, 1 - Hemocult positive, 2 - visible blood in stool, 3 - rectal bleeding), colon weight, colonic gross injury score (complex of adhesions, strictures, ulcers / inflammation, and wall thickening), and myeloperoxidase levels in colonic tissue. Data from each of these endpoints were subtracted from baseline using equivalent measurements and the reduction in any measurement calculated as a relative reduction from sham-treated mice (i.e., without TNBS). Synergistic effects were calculated using statistical methods described elsewhere herein.

[0143] Collagen-induced arthritis

[0174] Female Lewis rats were attacked on day 1 with porcine type II collagen containing Freund's adjuvant (0.2 mg / 0.2 mL / rat) via subcutaneous injection at the base of the tail to induce arthritis. A booster injection of 0.1 mg / 0.1 mL / rat was administered on day 7. On day 16, the rats were assigned to six groups based on hind leg volume, but the animals were assigned to groups to produce a similar distribution of hind leg volume.

[0144]

[0175] The vehicle and activators (i.e., CBD and hydroxychloroquine) were administered intraperitoneally (IP) once daily, either alone or in combination, starting on day 17 and continuing until day 30, for a total of 14 consecutive days.

[0145]

[0176] The disease was assessed by measuring hind paw volume using a paw volume measurement device on days 1, 7, 10, 14, 16, 18, 20, 22, 24, 26, 28, and 30, using a qualitative severity scoring system outlined in Table 32.

[0146]

[0177] After the end of day 30, blood was collected from all rats and analyzed by ELISA for levels of inflammatory cytokines IL-1β, IL-6, and TNF-α. Both hind paws were collected, weighed, and fixed in formalin for histopathology. The tissue was evaluated to assess cartilage and bone destruction by pannus formation and mononuclear cell infiltration in the synovial tissue according to the scoring matrix described in Tables 33 and 34. The total histological score, which is the sum of the scores for pannus formation and mononuclear cell infiltration, was also calculated.

[0147]

[0178] For synergistic analysis, the data were baselines subtracted using sham-treated mice (i.e., not injected with collagen) before normalizing the values ​​against vehicle controls. Synergistic effects were calculated using the statistical methods described elsewhere in this specification.

[0148] In vitro analysis of the anti-inflammatory activity of the combination of CBD and hydroxychloroquine.

[0179] The anti-inflammatory activity of the combination of CBD and hydroxychloroquine was evaluated by determining cytokine release from human peripheral blood mononuclear cells (PBMC) stimulated with bacterial lipopolysaccharide (LPS) using a Luminex-based assay. Checkerboard assays based on 96-well microtiter plates at seven concentrations of CBD and hydroxychloroquine (including those without drug controls) were evaluated in combination and used to determine drug-drug interactions. Briefly, frozen PBMC derived from two independent donors were thawed, diluted in culture medium, seeded into 96-well microtiter plates, and incubated at 37°C under 5% CO2 for 1 hour before adding the test compounds. After addition of the test compounds, the cells were returned to the incubator for 1 hour, after which LPS was added to the wells. Plates were incubated at 37°C under 5% CO2 for 24 hours. After 24 hours, cell culture supernatants were removed and analyzed for cytokine levels using the Luminex method according to the manufacturer's instructions. All values have vehicle background subtracted before further analysis. Three plates were set up in parallel using PBMC from the same donor. Inhibition of cytokine release was determined relative to untreated controls (i.e., those stimulated with LPS) and averaged over three replicates. Cytotoxicity assays using AlmarBlue with the same plate setup were performed in parallel.

[0149] Statistical Analysis

[0180] Drug synergy was determined using the Bliss independence method, where the expected effect of a drug combination is given by the formula: E pred A+B =(E A +E B )-(E A E B ) calculated using the above formula.

[0150]

[0181] The synergistic effect values ​​for each combination of drug concentrations were calculated using the Bliss excess method (difference between observed inhibition and predicted inhibition), as described, for example, by Liu et al. (2018, Statistics in Biopharmaceutical Research, 10: pp. 112-122). Values ​​greater than 0 indicate a synergistic effect, and higher values ​​indicate a stronger synergistic effect.

[0151] Dose conversion

[0182] The doses of CBD and hydroxychloroquine used in the in vivo models of inflammatory conditions illustrated herein can be modified (i.e., theoretically extrapolated) to appropriate human starting doses using methods known in the art, including the U.S. Department of Health and Human Services and Food and Drug Administration (FDA) guidelines to 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 doses can be tested for safety and efficacy using conventional methods such as first-in-human clinical trials for novel therapies in healthy adult volunteers.

[0152] Example 1 Exemplary compositions for the treatment of sepsis-related ARDS

[0183] The exemplary loading dose compositions described herein include the following components:

[0153] [Table 4]

[0154]

[0184] The exemplary maintenance dose compositions described herein include the following components:

[0155] [Table 5]

[0156]

[0185] Both the loading dose and maintenance dose compositions described herein are formulated for oral administration according to a twice-daily dose regimen. Example 2 Exemplary methods for in vitro treatment of sepsis-associated ARDS

[0186] The in vitro treatment of ARDS described herein is evaluated using a classic rodent model system for sepsis-associated ARDS (e.g., reviewed by Matute-Bello et al., 2008, American Journal of Physiology-Lung Cellular and Molecular Physiology, 295:L379~L399) to assess the pharmacodynamics of CBD and hydroxychloroquine, or compositions containing CBD and / or hydroxychloroquine. Plasma concentrations of the activator, reduction of markers of acute inflammation, and elevation of lung function are key experimental endpoints for these methods.

[0157] Example 3 Exemplary methods for the treatment of sepsis-associated ARDS

[0187] Exemplary methods for treating sepsis-related ARDS as described herein are as follows: Composition of Example 1: Loading dose - Oral administration or co-administration of the activator to the subject twice daily on day 1 of treatment.

[0158] Maintenance dose - Oral administration or co-administration of the activator to the subject twice daily, starting from the second day of treatment.

[0188] The treatment is urgent and is expected to last 3-4 weeks.

[0159]

[0189] The subjects were randomly divided into four groups to evaluate the efficacy and safety of CBD and hydroxychloroquine, or compositions containing CBD and / or hydroxychloroquine, for the treatment of sepsis-related ARDS, as follows: Group 1: Loading dose: 500mg-1000mg of CBD + 400mg of hydroxychloroquine, twice daily.

[0160] Maintenance dose: 500mg-1000mg of CBD + 200mg of hydroxychloroquine, twice daily. Group 2: Loading dose: 500mg-1000mg of CBD + placebo, twice daily.

[0161] Maintenance dose: 500mg-1000mg of CBD + placebo, twice daily. Group 3: Loading dose: Placebo + 400 mg of hydroxychloroquine, twice daily. Maintenance dose: Placebo + 200 mg of hydroxychloroquine, twice daily.

[0162] Group 4: Placebo + Placebo.

[0190] The efficacy of each treatment group will be evaluated based on the efficacy of the target against clinical significance (i.e., reduction in acute inflammation markers / reduction in LIS > 20%).

[0163]

[0191] ARDS is an inflammatory disorder associated with the release of pro-inflammatory cytokines, along with the accumulation of immune cells in lung tissue. The production of pro-inflammatory transcription factors (e.g., NF-κβ) by such immune cells is a key factor in disease development. Administration of CBD and hydroxychloroquine is expected to promote regulatory pathways of the immune system that can simultaneously reduce inflammation, reverse lung tissue damage in ARDS patients, effectively treat ARDS, and improve associated symptoms. Without being bound by any particular mode of theory or application, the anti-inflammatory activity of CBD may show a synergistic effect with the anti-inflammatory activity and promotion of inflammation resolution mediated by hydroxychloroquine, reducing the response of acute pneumonia to treat ARDS.

[0164] Example 4 Intraperitoneal administration of CBD or hydroxychloroquine modulates the immune response to LPS-induced sepsis in vivo.

[0192] 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.

[0165]

[0193] Administration of CBD at doses of 1, 5, 10, 25, 50, and 100 mg / kg showed dose-dependent increases in LPS-induced D-dimer, IL-1β, and IL-10 levels compared to the vehicle control. Furthermore, compared to the vehicle group, CBD in 100 mg / kg IP showed a significant increase (p<0.05) in IL-1β and IL-10 levels in the study (Table 8).

[0166]

[0194] Moderate decreases in IL-1β, IL-2, IL-12 (p70), IFN-γ, and TNF-α levels were observed with a 10 mg / kg dose of CBD compared to the vehicle group (Table 7). Moderate decreases in IFN-γ and TNF-α, or IFN-γ alone, were also observed with CBD doses of 25 and 5 mg / kg, respectively (Figure 1, Table 7). The decrease in cytokine levels at intermediate but not low or high doses shows a bell-shaped dose-response curve for CBD in relation to the decrease in LPS-induced cytokine levels.

[0167]

[0195] Administration of hydroxychloroquine at 1, 5, 10, 25, 50, and 100 mg / kg also showed dose-dependent increases in D-dimer levels and significant (p<0.05) increases in IL-10 levels compared to vehicle controls. Furthermore, compared to the vehicle group, hydroxychloroquine administered at 50 and 100 mg / kg resulted in significant (p<0.05) decreases in IL-1β and IL-2 levels, as well as moderate decreases in IL-12 (p70), TNF-α, and IFN-γ levels in an in vivo model of LPS-induced sepsis (Figure 1, Table 9).

[0168]

[0196] As expected, dexamethasone at 10 mg / kg, compared to the positive control group in the study, significantly reduced levels of IL-1β, IL-2, IL-12 (p70), and TNF-α (p<0.05) (Figure 1, Table 10).

[0169]

[0197] In summary, these data suggest that the anti-inflammatory dose-response curves for CBD and hydroxychloroquine may act through different mechanisms. Drugs with different mechanisms of action are optimal candidates for designing synergistic combination drugs that better perform these components as a whole.

[0170] Example 5 Oral administration of a combination of CBD and hydroxychloroquine modulates the immune response to LPS-induced sepsis in vivo.

[0198] CBD and hydroxychloroquine were evaluated, both individually and in combination, for their ability to modulate the immune response to LPS-induced sepsis in mice at two different dose levels following oral administration.

[0171]

[0199] CBD administered at 10 mg / kg or hydroxychloroquine administered at 20 mg / kg via oral gastric tube feeding (PO) alone showed moderate suppression of LPS-induced IL-1α, IL-1β, 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 administered via PO alone had little to no effect on biomarker levels (Figure 2; Tables 13 and 14).

[0172]

[0200] CBD administered at 1 mg / kg in combination with hydroxychloroquine administered at 2 mg / kg via PO resulted in significant (p<0.05) reductions in IL-1α, IL-2, IL-4, and GM-CSF levels, as well as moderate effects on IL-1β, IL-5, IL-9, IL-13, and IFN-γ compared to the vehicle group (Figure 2; Tables 15 and 17).

[0173]

[0201] CBD administered at 10 mg / kg in combination with hydroxychloroquine administered at 2 mg / kg via PO showed a significant (p<0.05) effect at IL-1α levels and moderate effects at IL-4, IL-5, IL-9, and IL-13 levels compared to the vehicle group (Tables 16 and 18). Furthermore, compared to the vehicle group, CBD administered at 10 mg / kg in combination with hydroxychloroquine administered at PO at 20 mg / kg resulted in a significant (p<0.05) effect at IL-4 levels and moderate effects at IL-1α, IL-1β, IL-5, IL-9, IL-13, and IFN-γ in an LPS-induced sepsis model (Figure 2; Tables 16 and 18).

[0174]

[0202] As expected, dexamethasone at 10 mg / kg, compared to the positive control group in the study, significantly reduced (p<0.05) levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p40), IL-12 (p70), IL-17A, eotaxin, GM-CSF, MCP-1, MIP-1α, MIP-1β, RANTES, and TNF-α (Figure 2, Tables 11 and 12).

[0175] Example 6 The combination of CBD and hydroxychloroquine shows a synergistic effect in regulating inflammatory responses in vitro.

[0203] CBD and hydroxychloroquine act synergistically to inhibit LPS-induced production of inflammatory cytokines, IL-1β, IL-6, TNF-α, IL-1α, and MIP-1α, at a wide range of drug concentrations. PBMCs from Donor 1 were treated with 5 μg / mL CBD in combination with 0.63, 1.25, 2.5, 5, and 10 μg / mL hydroxychloroquine, and the results are shown in Table 19. PBMCs from Donor 2 were treated with 5 μg / mL CBD in combination with 0.63, 1.25, 2.5, 5, 10, and 20 μg / mL hydroxychloroquine, and the results are shown in Table 20.

[0176]

[0204] The values ​​expressed herein are expressed as inhibition relative to the untreated control; i.e., a value of 0 represents no inhibition, and a value of 1 represents complete inhibition of the release of the relevant cytokines. Cell viability exceeded 84% for all treatments listed in Tables 19 and 20.

[0177] Example 7 The combination of CBD and hydroxychloroquine shows a synergistic effect in regulating the inflammatory response in vivo.

[0205] CBD and hydroxychloroquine act synergistically to inhibit LPS-induced production of inflammatory cytokines, IL-1β, IL-6, IL-12 (p70), IFN-γ, and / or TNF-α, at a wide range of drug concentrations (Tables 21-24).

[0178] Example 8 The combination of CBD and hydroxychloroquine shows a synergistic effect in modulating the inflammatory response in an in vivo model of pneumonia.

[0206] Mice were attacked intratracheally with LPS, inducing pneumonia in a manner that mirrored the clinical aspects of pneumonia observed in inflammatory respiratory conditions such as COPD (see, for example, Hakannsson et al., 2012, Pulmonary Pharmacology & Therapeutics, 25:399-406).

[0179]

[0207] CBD and hydroxychloroquine act synergistically to inhibit the production of inflammatory cytokines, IL-1β, IL-6, TNF-α, CXCL-1, and MCP-1, at numerous drug concentrations, as measured from BALF in mice with LPS-induced pneumonia (Tables 25-26).

[0180]

[0208] BALF collected from mice was also analyzed for white blood cell (WBC) count using an automated blood analyzer. Cell counts were normalized using sham-treated mice and analyzed against the highest value across groups (Table 27). These data indicate that the combination of CBD and hydroxychloroquine reduced total WBC count and neutrophil levels to a greater extent than either CBD or hydroxychloroquine alone.

[0181]

[0209] The combination of CBD and hydroxychloroquine was also superior to either CBD or hydroxychloroquine alone at equivalent doses in reducing inflammatory lesions in the lungs of mice with LPS-induced pneumonia (Tables 30 and 31; Figure 4).

[0182] Example 9 The combination of CBD and hydroxychloroquine shows a synergistic effect in treating inflammatory bowel disease in vivo.

[0183]

[0210] CBD and hydroxychloroquine work synergistically to reduce myeloperoxidase (MPO) levels, stool viscosity scores, and macroscopic injury scores in colonic tissue (Table 27).

[0184]

[0211] The combination of CBD and hydroxychloroquine was evaluated by histological analysis of the progression to colitis in the distal colon of mice with TNBS-induced colitis, showing superiority over each drug alone in reducing the pancolitis index (Table 28). Representative stained sections are shown in Figure 3. The combination of CBD and hydroxychloroquine also improved the ratio of colon weight to body weight compared to administration of either drug alone (Table 28).

[0185] Example 10 The combination of CBD and hydroxychloroquine shows a synergistic effect in treating arthritis in vivo.

[0212] CBD and hydroxychloroquine, at doses of 1 mg / kg and 2.5 mg / kg, act synergistically to reduce clinical score and foot volume at day 24, along with pannus formation and overall histological score at the endpoint (i.e., day 30). The Bliss excess scores for clinical score, foot volume, pannus formation, and overall histological score were 0.05, 0.26, 0.30, and 0.03, respectively (Table 35).

[0186]

[0213] The combination of 1 mg / kg CBD and 2.5 mg / kg hydroxychloroquine demonstrated superiority over each drug alone in reducing serum levels of inflammatory cytokines, IL-1β and IL-6 (Table 36; Figure 5).

[0187]

[0214] Hydroxychloroquine is used in the treatment of rheumatoid arthritis in the form of hydroxychloroquine sulfate. However, long-term use of hydroxychloroquine is associated with ocular toxicity and cardiac effects (e.g., cardiomyopathy and QT prolongation). Clinically, the most important predictor of ocular toxicity and cardiac effects in patients with rheumatoid arthritis is the cumulative dose of hydroxychloroquine. To understand the ability of CBD to enable a reduction in hydroxychloroquine dose, results obtained using 1 mg / kg CBD in combination with 2.5 mg / kg hydroxychloroquine (i.e., low-dose HCQ) were compared with 25 mg / kg hydroxychloroquine alone (i.e., high-dose HCQ) while maintaining therapeutic efficacy. The combination of 1 mg / kg CBD and low-dose HCQ was more or equally effective in reducing arthritis across all assessments, except for mononuclear cell infiltration (Table 37). These data suggest that the combination of CBD with hydroxychloroquine may enable a 10-fold reduction in hydroxychloroquine dose without sacrificing therapeutic efficacy.

[0188] overview

[0215] Collectively, these data demonstrate that the combination of CBD and hydroxychloroquine exhibits synergistic effects in significantly modulating inflammatory responses in vitro and in vivo. The methods described herein are employed to modulate inflammatory responses, to treat inflammatory conditions such as septicemic ARDS, COPD, pneumonia characterized by inflammatory respiratory conditions like asthma and CF, inflammatory bowel disease, and arthritis. In this regard, the combination of CBD and hydroxychloroquine can be used to modulate inflammatory mediators in septicemic ARDS and pneumonia, including a reduction in IL-1β, which is known to be elevated in both bronchoalveolar lavage fluid and circulating plasma in ARDS patients (see, e.g., Meduri et al., 2009, Chest, 136: pp. 1631-1643). Furthermore, the combination of CBD and hydroxychloroquine demonstrates synergistic effects to the extent that it is possible to reduce the dose of hydroxychloroquine to a level that minimizes the adverse effects associated with long-term use while still eliciting therapeutic effects.

[0189] [Table 6]

[0190] [Table 7]

[0191] [Table 8-1]

[0192] [Table 8-2]

[0193] [Table 9-1]

[0194] [Table 9-2]

[0195] Table 10-1

[0196] Table 10-2

[0197] Table 11-1

[0198] Table 11-2

[0199] Table 12

[0200] Table 13-1

[0201] Table 13-2

[0202] Table 13-3

[0203] Table 14-1

[0204] Table 14-2

[0205] Table 14-3

[0206] Table 15-1

[0207] Table 15-2

[0208] Table 15-3

[0209] Table 16-1

[0210] Table 16-2

[0211] Table 16-3

[0212] Table 17-1

[0213] Table 17-2

[0214] Table 17-3

[0215] Table 18-1

[0216] Table 18-2

[0217] Table 18-3

[0218] Table 19-1

[0219] Table 19-2

[0220] Table 19-3

[0221] Table 20-1

[0222] Table 20-2

[0223] Table 20-3

[0224] Table 21

[0225] Table 22

[0226] Table 23

[0227] Table 24

[0228] Table 25

[0229] Table 26

[0230] Table 27

[0231] Table 28

[0232] Table 29

[0233] Table 30

[0234] Table 31

[0235] Table 32

[0236] Table 33

[0237] Table 34

[0238] Table 35

[0239] Table 36

[0240] Table 37

[0241] Table 38

[0242] Table 39

Claims

1. A composition for use in the treatment or prevention of inflammatory conditions, comprising cannabidiol (CBD) or a pharmaceutically acceptable salt thereof and hydroxychloroquine or a pharmaceutically acceptable salt thereof, a. Approximately 1 mg to approximately 1000 mg of hydroxychloroquine per dose, b. Approximately 1 mg to 1500 mg of CBD per dose. The composition comprising either or both of the following.

2. The composition according to claim 1, further comprising one or more pharmaceutically acceptable carriers, diluents, and excipients.

3. The composition according to claim 1 or 2, wherein the inflammatory state is selected from the group consisting of inflammatory respiratory state, inflammatory bowel disease, and arthritis.

4. The composition according to claim 3, wherein the inflammatory respiratory condition is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), and acute respiratory distress syndrome (ARDS).

5. The composition according to claim 4, wherein the inflammatory respiratory condition is ARDS.

6. The composition according to claim 5, wherein the ARDS is a sepsis-related ARDS.

7. The composition according to claim 6, wherein sepsis-associated ARDS are caused by a bacterial, fungal, or viral infection.

8. A composition according to any one of claims 1 to 7, administered twice a day.

9. A composition according to any one of claims 1 to 8, which is administered orally.

10. A composition according to any one of claims 1 to 9, administered for at least one week.

11. A composition according to any one of claims 1 to 10, administered for 1 to 10 weeks.

12. A composition comprising CBD or a pharmaceutically acceptable salt thereof, for use in conjunction with a composition comprising hydroxychloroquine or a pharmaceutically acceptable salt thereof, Herein, the composition is intended for use in the treatment or prevention of inflammatory conditions, a. One dose of hydroxychloroquine contains approximately 1 mg to approximately 1000 mg of hydroxychloroquine. b. One dose of CBD contains approximately 1 mg to approximately 1500 mg of CBD. The aforementioned composition.

13. A composition comprising hydroxychloroquine or a pharmaceutically acceptable salt thereof, for use in conjunction with CBD or a pharmaceutically acceptable salt thereof, Herein, the composition is intended for use in the treatment or prevention of inflammatory conditions, a. One dose of hydroxychloroquine contains approximately 1 mg to approximately 1000 mg of hydroxychloroquine. b. One dose of CBD contains approximately 1 mg to approximately 1500 mg of CBD. The aforementioned composition.

14. The composition according to claim 12 or 13, wherein a composition comprising CBD or a pharmaceutically acceptable salt thereof and a composition comprising hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered sequentially.

15. The composition according to claim 12 or 13, wherein a composition comprising CBD or a pharmaceutically acceptable salt thereof and a composition comprising hydroxychloroquine or a pharmaceutically acceptable salt thereof are administered simultaneously.

16. A kit 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. One dose of hydroxychloroquine contains approximately 1 mg to approximately 1000 mg of hydroxychloroquine. b. One dose of CBD contains approximately 1 mg to approximately 1500 mg of CBD. The aforementioned kit.

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