EP4188398A1 - Unterdrückung der zytokinfreisetzung und des zytokinsturms - Google Patents

Unterdrückung der zytokinfreisetzung und des zytokinsturms

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Publication number
EP4188398A1
EP4188398A1 EP21850964.4A EP21850964A EP4188398A1 EP 4188398 A1 EP4188398 A1 EP 4188398A1 EP 21850964 A EP21850964 A EP 21850964A EP 4188398 A1 EP4188398 A1 EP 4188398A1
Authority
EP
European Patent Office
Prior art keywords
curcumin
cytokines
disease
cytokine
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21850964.4A
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English (en)
French (fr)
Inventor
Peter P. SORDILLO
Lawrence Helson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Signpath Pharma Inc
Original Assignee
Signpath Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/945,195 external-priority patent/US20200360300A1/en
Application filed by Signpath Pharma Inc filed Critical Signpath Pharma Inc
Publication of EP4188398A1 publication Critical patent/EP4188398A1/de
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates in general to the field of infectious diseases and disease conditions that trigger a cytokine cascade, and more particularly, to the use of compositions that reduce the cytokine cascade.
  • the inventors argue that, in contrast to current allogeneic cell therapy protocols where T-cells in the graft mediate the beneficial graft vs. tumor (GVT) and detrimental graft vs. host (GVH) effects, the allogeneic cells of the invention stimulate host T-cells to mediate the "mirror" of these effects.
  • the highly activated allogeneic cells of the invention are said to stimulate host immunity in a complete HLA mis-matched setting in patients that have not had a prior bone marrow transplant or received chemotherapy and/or radiation conditioning regimens.
  • compositions and methods for inhibiting vascular permeability relate to compounds, compositions and methods for inhibiting vascular permeability and pathologic angiogenesis.
  • These inventors teach methods for producing and screening compounds and compositions capable of inhibiting vascular permeability and pathologic angiogenesis. It is said that the compositions described are useful in, methods of inhibiting vascular permeability and pathologic angiogenesis, including methods of inhibiting vascular permeability and pathologic angiogenesis induced by specific angiogenic, permeability and inflammatory factors, such as, for example VEGF, FGF and thrombin.
  • United States Patent No. 7,479,498, issued to Keller, is entitled “Treatments for viral infections” and relates to improved methods and compositions for treating viral infections and other diseases and conditions that induce a cytokine storm. It is further said that the invention relates to novel compositions comprising quercetin, and an anti-convulsant, such as phenytoin, in combination with multivitamins as an anti-viral composition and methods of use thereof.
  • United States Patent Application No. 20100075329 filed by O'Toole, et al., is entitled “Methods For Predicting Production Of Activating Signals By Cross-Linked Binding Proteins” and relates to human binding proteins and antigen-binding fragments thereof that specifically bind to the human interleukin-21 receptor (IL21R), and uses therefore.
  • the invention is said to include methods to predict whether the binding proteins of the invention may take on agonistic activities in vivo and produce a cytokine storm.
  • the invention is said to provide methods for determining whether an anti-IL21R binding protein is a neutralizing anti-IL21R binding protein, based on the identification of several IL21 -responsive genes.
  • the binding proteins can act as antagonists of IL21R activity, thereby modulating immune responses in general, and those mediated by IL21R in particular.
  • the present invention includes a method of ameliorating symptoms or treating one or more adverse reactions triggered by a widespread release of cytokines in a subject comprising the steps of: identifying the subject in need of amelioration of symptoms or treatment of one or more infectious diseases or disease conditions that trigger a widespread release of cytokines; and administering one or more pharmaceutical compositions comprising a therapeutically effective amount of a lipid dissolved or dispersed in a suitable aqueous or non- aqueous medium sufficient to reduce the level of cytokines in the subject.
  • the widespread release of cytokines is caused by one or more infectious diseases selected from at least one of viral, bacterial, fungal, helminthic, protozoan, or hemorrhagic infectious agents.
  • the one or more infectious diseases is selected from at least one of infection with a Rhinovirus, Coronavirus, Paramyxoviridae, Orthomyxoviridae, Adenovirus, Parainfluenza Virus, Metapneumovirus, Respiratory Syncytial Virus, Influenza virus, Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae, Rhabdoviridae virus, Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Lassa fever viruses.
  • a Rhinovirus Coronavirus
  • Paramyxoviridae Orthomyxoviridae
  • Adenovirus Parainfluenza Virus
  • Metapneumovirus Metapneum
  • the one or more disease conditions is selected from at least one of cachexia, septic shock syndrome, a chronic inflammatory response, septic shock syndrome, traumatic brain injury, cerebral cytokine storm, graft versus host disease (GVHD), autoimmune diseases, multiple sclerosis, acute pancreatitis, or hepatitis.
  • the one or more disease conditions is an adverse reaction caused by the treatment with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells or antitumor cell therapy, activated dendritic cells, activated macrophages, or activated B cells.
  • CAR Chimeric Antigen Receptor
  • the composition further comprises a curcumin extract, curcumin, curcuminoids disposed in a lipid, wherein the curcuminoids are selected from at least one of Ar-tumerone, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione (curcuminl), l,7-bis(piperonyl)-l,6-heptadiene-3,5-dione (piperonyl curcumin) l,7-bis(2- hydroxy naphthyl)-l,6-heptadiene-2,5-dione (2-hydroxyl naphthyl curcumin) and 1,1- bis(phenyl
  • the lipid or the phospholipid is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosohatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), phosphatidylcholine, lysolecithin, lysophosphatidylethanolamine, lysoDMPC, lysoDMPG, lysoDSPG, lysoDPPC, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol,
  • the therapeutically effective amount comprises 50 nM/kg, 10 to 100 nM/kg, 25 to 75 nM/kg, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM/kg of body weight of the subject.
  • the composition comprises an active agent, and has a ratio of lipid phospholipids to active agent of 3:1, 1:1, 0.3:1, and 0.1:1.
  • the diseases is rheumatoid arthritis, psoriasis, multiple sclerosis, relapsing multiple sclerosis, or inflammatory bowel disease.
  • the present invention includes a composition for ameliorating symptoms or treating one or more adverse reactions triggered by an infectious disease or a disease condition that trigger a widespread release of cytokines in a subject comprising a therapeutically effective amount of a lipid or a lysophosphatidyl dissolved or dispersed in a suitable aqueous or non- aqueous medium.
  • the one or more infectious diseases are selected from at least one of viral, bacterial, fungal, helminthic, protozoan, or hemorrhagic infectious agents.
  • the one or more infectious diseases is selected from at least one of infection with a Rhinovirus, Coronavirus, Paramyxoviridae, Orthomyxoviridae, Adenovirus, Parainfluenza Virus, Metapneumovirus, Respiratory Syncytial Virus, Influenza Virus, Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae, Rhabdoviridae virus, Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Lassa fever viruses.
  • a Rhinovirus Coronavirus
  • Paramyxoviridae Orthomyxoviridae
  • Adenovirus Parainfluenza Virus
  • Metapneumovirus Respiratory
  • the one or more disease conditions is selected from at least one of cachexia, septic shock syndrome, a chronic inflammatory response, septic shock syndrome, traumatic brain injury, cerebral cytokine storm, graft versus host disease (GVHD), autoimmune diseases, multiple sclerosis, acute pancreatitis, or hepatitis.
  • the curcumin extract, curcuminoids or synthetic curcumin are disposed in a lipid.
  • the or the lysophosphatidyl is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG),
  • Dipalmitoylphosohatidylcholine DPPC
  • disteroylphosphatidylglycerol DSPG
  • dipalmitoylphosphatidylglycerol DMPG
  • phosphatidylcholine lysolecithin
  • lysophosphatidylethanolamine lysoDMPC
  • lysoDMPG lysoDMPG
  • lysoDSPG lysoDPPC
  • phosphatidylserine phosphatidylinositol
  • sphingomyelin phosphatidylethanolamine
  • cardiolipin phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl- phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate
  • the biodegradable polymer is selected from the group consisting of polyesters, polylactides, polyglycolides, polycaprolactones, poly anhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), copolymers, terpolymers, and combinations or mixtures thereof.
  • the composition adapted for intravenous, sub-cutaneous, intramuscular, or intraperitoneal injection in the subject.
  • the composition further comprises a curcumin or curcuminoids are selected from at least one of Ar-tumerone, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5- dione (curcuminl), l,7-bis(piperonyl)-l,6-heptadiene-3,5-dione (piperonyl curcumin) l,7-bis(2- hydroxy naphthyl)-!, 6-heptadiene-2,5-dione (2-hydroxyl naphthyl curcumin)
  • the present invention includes a method of determining if a candidate drug causes an amelioration of symptoms or treats one or more adverse reactions triggered by an infectious disease or a disease condition that trigger a widespread release of cytokines in a subject, the method comprising: (a) administering an amount of the candidate drug in combination with empty liposomes, and a placebo to a second subset of the patients, wherein the candidate drug is provided in an amount effective to reduce or prevent the overall level of cytokines in the subject; (b) measuring the level of cytokines in the subject from the first and second set of patients; and (c) determining if the candidate drug in combination with empty liposomes ameliorates symptoms or treats one or more adverse reactions triggered by infectious diseases or disease conditions that trigger a widespread release of cytokines is statistically significant as compared to any reduction occurring in the subset of patients that took the placebo, wherein a statistically significant reduction indicates that the candidate drug is useful in treating a disease state while also reducing or eliminating the overall level of cytokines in
  • the present invention includes a method of ameliorating symptoms or treating a cytokine storm caused by a therapeutic agent in a subject comprising the steps of: identifying the subject in need of amelioration of symptoms or treatment of the cytokine storm caused by a therapeutic agent; and administering one or more pharmaceutical compositions comprising a therapeutically effective amount of a curcumin extract, curcuminoids or synthetic curcumin and derivatives thereof, or empty liposomes, dissolved or dispersed in a suitable aqueous or non-aqueous medium sufficient to reduce the level of cytokines in the subject.
  • FIGS. 1A and IB show the percent inhibition and percent viability, respectively, achieved with liposomal curcumin in HeFa cells.
  • FIGS. 2A and 2B show the percent inhibition and percent viability, respectively, using solid S-curcumin curcumin in HeFa cells.
  • FIGS. 3A and 3B show the percent inhibition and percent viability, respectively, comparing liposomal curcumin and solid curcumin in HeFa cells.
  • FIG. 4 A is a graph that shows the effect of liposomal curcumin on liver function during sepsis, including asparate aminotransferase (AST) and alanine aminotransferase (AST) levels.
  • AST asparate aminotransferase
  • AST alanine aminotransferase
  • FIGS. 4B to 4D are graphs that show the effect of liposomal curcumin during sepsis on kidney function measuring Creatine, Neutrophil gelatinase-associated lipocalin (NGAL) and Blood Urea Nitrogen (BUN).
  • NGAL Neutrophil gelatinase-associated lipocalin
  • BUN Blood Urea Nitrogen
  • FIGS. 4E and 4F are graphs that show the effect of liposomal curcumin during sepsis on heart function for c-Troponin and the percent ejection fraction. Liposomal curcumin showed a decrease in cardiac damage when compared to the standard of care and equaled the standard of care in percent ejection fraction.
  • FIG. 4G is a graph that shows the effect of liposomal curcumin during sepsis on overall survival. Liposomal curcumin showed a higher survival time versus the standard of care treatment.
  • cytokine storm refers to the dysregulated of pro-inflammatory cytokines leading to disease has been referred to as a "cytokine storm,” “cytokine release syndrome” or "inflammatory cascade”. Often, a cytokine storm or cascade is referred to as being part of a sequence because one cytokine typically leads to the production of multiple other cytokines that can reinforce and amplify the immune response. Generally, these pro- inflammatory mediators have been divided into two subgroups: early mediators and late mediators.
  • infectious diseases commonly associated with a “cytokine storm” include but at not limited to, malaria, avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS).
  • Certain specific infectious agents include but are not limited to: infectious diseases is selected from at least one of Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Fassa fever viruses.
  • Other viruses can include rhinovirus, coronavirus, paramyxoviridae, Orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus or influenza virus.
  • cytokine storm Disease conditions commonly associated with a “cytokine storm” include but at not limited to: sepsis, systemic inflammatory response syndrome (SIRS), cachexia, septic shock syndrome, traumatic brain injury (e.g., cerebral cytokine storm), graft versus host disease (GVHD), or the result of treatment with activated immune cells, e.g., IF-2 activated T cells, T cells activated with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells.
  • SIRS systemic inflammatory response syndrome
  • cachexia e.g., cerebral cytokine storm
  • GVHD graft versus host disease
  • activated immune cells e.g., IF-2 activated T cells, T cells activated with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells.
  • CAR Chimeric Antigen Receptor
  • a cytokine storm is a healthy systemic expression of a vigorous immune system.
  • the present invention can be used to reduce or eliminate some or most of an exaggerated immune response caused by, e.g., rapidly proliferating and highly activated T-cells or natural killer (NK) cells that results in the release of the “cytokine storm” that can include more than 150 inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors).
  • cytokine storm can include more than 150 inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors).
  • pro-inflammatory cytokines such as Tumor Necrosis Factor-a, Interleukin- 1, and Interkeukin-6
  • anti-inflammatory cytokines such as Interleukin- 10, and Interleukin- 1 receptor antagonist (IF- 1RA)
  • IF- 1RA Interleukin- 1 receptor antagonist
  • a cytokine storm can result in permanent lung damage and, in many cases, death.
  • the end stage symptoms of the cytokine storm include but are not limited to: hypotension; tachycardia; dyspnea; fever; ischemia or insufficient tissue perfusion; uncontrollable hemorrhage; severe metabolism dysregulation; and multisystem organ failure.
  • Deaths from infectious diseases such as Ebola virus infection are not caused by the virus itself, but rather, the cytokine storm that causes uncontrollable hemorrhaging; severe metabolism dysregulation; hypotension; tachycardia; dyspnea; fever; ischemia or insufficient tissue perfusion; and multisystem organ failure.
  • the term “Curcumin (diferuloyl methane; l,7-bis(4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione)” is a naturally occurring compound which is the main coloring principle found in the rhizomes of the plant Curcuma longa (U.S. Pat. No. 5,679,864 (Krackov et al.)).
  • the synthetic curcumin is 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96% pine diferuloylmethane.
  • curcumin and curcuminoids include, e.g., Ar-tumerone, methylcurcumin, demethoxy curcumin, bisdemethoxy curcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione (curcuminl), l,7-bis(piperonyl)- l,6-heptadiene-3,5-dione (piperonyl curcumin) l,7-bis(2-hydroxy naphthyl)-l,6-heptadiene-2,5- dione (2-hydroxyl naphthyl curcumin) and l,l-bis(phenyl)-l,3,8,10 undecatetraene-5,7-dione.
  • liposome refers to a capsule wherein the wall or membrane thereof is formed of lipids, especially phospholipid, with the optional addition therewith of a sterol, especially cholesterol.
  • the liposomes are empty liposomes and can be formulated from a single type of phospholipid or combinations of phospholipids.
  • the empty liposomes or lipid can further include one or more surface modifications, such as proteins, carbohydrates, glycolipids or glycoproteins, and even nucleic acids such as aptamers, thio- modified nucleic acids, protein nucleic acid mimics, protein mimics, stealthing agents, etc.
  • the composition also comprises an active agent in or about the liposome or lipid and the composition has a ratio of lipids to active agent of 3:1, 1:1, 0.3:1, and 0.1:1.
  • lipid refers to amphiphilic biomolecules that are soluble in nonpolar solvents. Lipids are capable of liposome formation, vesicle formation, micelle formation, emulsion formation, and are substantially non-toxic when administrated at the necessary concentrations as liposomes.
  • the lipid composition of the present invention can include, e.g., dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosohatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), phosphatidylcholine, lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl
  • the term “in vivo ” refers to being inside the body.
  • the term “in vitro” as used in the present application is to be understood as indicating an operation carried out in a non living system.
  • the term “treatment” refers to the treatment of the conditions mentioned herein, particularly in a patient who demonstrates symptoms of the disease or disorder.
  • treating refers to any administration of a compound of the present invention and includes (i) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology) or (ii) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
  • controlling includes preventing treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.
  • the terms “effective amount” or “therapeutically effective amount” described herein means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the therapeutically effective amount comprises 50 nM/kg, 10 to 100 nM/kg, 25 to 75 nM/kg, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM/kg of body weight of the subject.
  • administering should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP), and the like; enteral or parenteral, transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • oral dosage forms such as tablets, capsules, syrups, suspensions, and the like
  • injectable dosage forms such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP), and the like
  • enteral or parenteral, transdermal dosage forms including creams, jellies, powders, or patches
  • buccal dosage forms inhalation powder
  • intravenous administration includes injection and other modes of intravenous administration.
  • the curcumin formulation of the present invention may comprise one or more optional pharmaceutical excipients, diluents, extended or controlled release agents, lubricants, preservatives or any combination thereof, and once solubilized may be added to injectable anti diabetic medications or administered in a schedule depending upon the release kinetics of the curcumin formulation.
  • a large number of biodegradable polymers may be used in the formulation of the present invention.
  • Non-limiting examples of these polymers include polysesters, polylactides, polyglycolides, polycaprolactones polyanhydrides, polyamides, polyurethanes, polyesteramides, polydiaxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybuterates, polyhydroxyvalerates, polyalkelene oxalates, polyalkylene succinates, poly(malic)acid, poly(amino)acids, copolymers, terpolymers, and combinations or mixtures thereof.
  • Specific polymers that may be used include an acrylic acid, a vinylpyrolidinome, a N- isopropylacrylamide or combinations and modifications thereof.
  • the synthesized curcumin that is used includes curcumin, curcumin analogues, curcumin derivatives and any modifications thereof.
  • the terminal stage of Ebola and other viral diseases is often the onset of cytokine storm, the massive overproduction of cytokines by the body’s immune system.
  • the present invention includes the treatment of infectious agents that trigger a cytokine storm, such as Ebola virus, with curcumin actions to suppress cytokine release and cytokine storm.
  • curcumin blocks cytokine release, most importantly the key pro- inflammatory cytokines, interleukin- 1, interleukin-6 and tumor necrosis factor-a. Curcumin’ s suppression of cytokine release correlates with clinical improvement in experimental models of disease conditions where cytokine storm plays a significant role in mortality. Thus, curcumin can be used to treat the cytokine storm of patients with Ebola. In certain examples, intravenous formulations allow achievement of therapeutic blood levels.
  • Cytokine storm can occur after a wide variety of infectious and non-infectious stimuli.
  • cytokine storm numerous cytokines, both pro-inflammatory (IL-1, IL-6, TNF-a) and anti-inflammatory (IL-10), are released, resulting in hypotension, hemorrhage, and, ultimately, multi-organ failure.
  • IL-1, IL-6, TNF-a pro-inflammatory
  • IL-10 anti-inflammatory
  • the term “cytokine storm” is most associated with the 1918 H1N1 influenza pandemic and the more recent cases of bird flu H5N1 infection 3 5 .
  • viruses can include rhinovirus, coronavirus, paramyxoviridae, Orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus or influenza virus.
  • Curcumin has been shown to inhibit the release of numerous cytokines. Abe et al showed that curcumin suppresses IL-Ib, IL-8, TNF-a, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-la (MIP-la) release from monocytes and macrophages 14 . Jain et al., showed that curcumin markedly reduced the release of IL-6, IL-8, TNF-a and MCP-1 from monocytes that had been cultured in a high glucose environment 15 .
  • Curcumin 15 has been reported to block the release of IL-6 in rheumatoid synovial fibroblasts 16 , of IL-8 in human esophageal epithelial cells 17 and alveolar epithelial cells 18 , and of IL-1 in bone marrow stromal cells 19 , colonic epithelial cells 20 and human articular chondrocytes 21 . Curcumin also prevents release of IL-2 , IL-12 , Interferon-g and many other key cytokines (Tables 1 and 2).
  • EXAMPLE 1 Curcumin Cytokine Suppression Correlates with Clinical Improvement in Conditions Associated with Cytokine Storm.
  • Curcumin has positive effects on numerous disease conditions in patients and in animal systems.
  • Avasarala et al reported on curcumin’s effects on cytokine expression and disease progression in a mouse model of viral-induced acute respiratory distress syndrome.
  • Curcumin reduced the expression of key cytokines IL-6, IL-10, interferon g and MCP-1, and this correlated with a marked decrease in inflammation and reduction in fibrosis 27 .
  • Yu et al showed curcumin’s suppression of TNF-a levels was associated with decreased pancreatic injury in an acute pancreatitis mouse model 28 .
  • Curcumin has been shown to have activity against numerous viruses, including, Coronavirus, HIV-1, HIV-2, HSV, HPV, HTLV-1, HBV, HCV, and Japanese encephalitis virus 31 .
  • the virus can include rhinovirus, coronavirus, paramyxoviridae, Orthomyxoviridae, adenovirus, parainfluenza virus, metapneumo virus, respiratory syncytial virus or influenza virus.
  • curcumin has been shown to have specific activity against the H1N1 virus in culture 32 33 , although cytokine levels were not measured in these two studies. Most importantly, curcumin has been shown to stimulate the SOCS proteins 34 . These proteins have been shown to be crucial in protecting against severe cytokine storm in mice infected with influenza virus 35 .
  • Curcumin s activity in suppressing multiple cytokines, and its activity in experimental models of diseases and conditions associated with cytokine storm, suggest it may be useful in the treatment of patients with Ebola and cytokine storm. Curcumin is poorly absorbed from the intestinal tract; however intravenous formulations may allow therapeutic curcumin blood levels to be achieved in patients diagnosed with cytokine storm. Clinical status and levels of important cytokines, such as IL-Ib, IL-6 and TNF-a, should be monitored carefully when patients are treated with curcumin. [0042] Table 1: Curcumin Effect on Interleukins
  • Liposomes and Liposomal-Curcumin were prepared as a 6 mg/ml solutions. Curcumin (solid) was solubilized in DMSO at 6mg/ml. All three compounds were tested in EBOV infection assay with two cell lines Hela and HFF-1. There were two sets for studies done with different dilution strategy.
  • FIGS. 1A and IB show the percent inhibition and percent viability, respectively, achieved with liposomal curcumin in HeLa cells.
  • FIGS. 2A and 2B shows the percent inhibition and percent viability, respectively, using solid S-curcumin curcumin in HeLa cells. Similar results were obtained with the same study using HFF-1 cells.
  • FIGS. 3A and 3B show the percent inhibition and percent viability, respectively, comparing liposomal curcumin and solid curcumin in HeLa cells. Similar results were obtained with the same study using HFF-1 cells.
  • Pro-Inflammatory Cytokines in the Causation of The Prolonged QT Interval Role of the Ceramide and Sphingosine-1 Phosphate Pathways.
  • QT prolongation was noted as a side effect of the cytokine, interferon g, and QT prolongation has been seen after treatment with interleukin- 18.
  • Patients with inflammatory diseases, such as rheumatoid arthritis, psoriasis and inflammatory bowel disease have a high incidence of QT prolongation, and die more frequently secondary to this complication.
  • TNF-a and other cytokines have been shown to cause increased production of ROS.
  • the effects of TNF-a could be blocked by administration of an anti-TNF-a antibody or by an anti-oxidant.
  • IL-Ib and IL-6 have been shown to increase the L-type Ca(2 + ) current (ICaL), and this effect can be blocked by aspirin or indomethacin.
  • the close link between phospholipidosis and prolonged QT provides another hint of the importance of these cytokines. 77% of the agents that can cause phospholipidosis also are hERG channel blockers.
  • Phospholipidotic cells have been shown to secrete large amounts of TNF-a and IL-6 after LPS stimulation. It has also been speculated that the mechanism of damage from drug-induced phospholipidosis is accumulation of ceramides. Numerous studies have shown that cytokines such as interferon g, IL-Ib and TNF-a increase sphingomyelinase activation, and increase production of ceramides, which are known to suppress hERG current. It is also known that sphingolipids mediate ROS signaling. Ceramides are metabolized to sphingosine and fatty acids, and sphingosine is phosphorylated by sphingosine kinases to form sphingosine-1 phosphate.
  • cytokines such as interferon g, IL-Ib and TNF-a increase sphingomyelinase activation, and increase production of ceramides, which are known to suppress hERG current. It is also known that
  • Ceramides and sphingosine-1 phosphate have opposite effects, ceramides causing apoptosis and sphingosine-1 phosphate promoting cell survival.
  • Fingolimod a sphingosine analogue (which has both agonist and antagonist effects on the sphingosine-1 phosphate- 1 receptor), is used to treat patients with relapsing multiple sclerosis, causes QT prolongation through inhibition of the hERG current, as well as fatal ventricular arrhythmias.
  • studies in the mouse model of influenza-induced cytokine storm have shown sphingosine-1 phosphate- 1 signaling to be the primary pathway for activation of the cytokine storm.
  • the cytokine storm was reversed by a sphingosine analogue through feedback inhibition of cytokines, with marked reductions in TNF- a, IL-la, IL-6, MCP-1, interferon a and MIP-la, and clinical improvement seen.
  • the survival of the mice in the study was much higher with the sphingosine analogue than with anti-viral therapy.
  • agents found clinically to be suppressors of QT prolongation progestins, statins, liposomal curcumin, resveratrol, anti-oxidants, are also strong suppressors of these inflammatory cytokines.
  • TNF-a administration causes a decrease in the rapid component of the delayed rectifier potassium current (IKr), in the slow component of the delayed rectifier current (IKs) and in the transient outward current (Ito).
  • IKr delayed rectifier potassium current
  • IKs slow component of the delayed rectifier current
  • Ito transient outward current
  • ROS reactive oxygen species
  • the present inventors have recognized that the list of agents which cause both cytokine suppression and shortening of the previously prolonged QT interval is strikingly similar to the list of agents that have been shown in animal models to reduce cytokine levels and secondary brain inflammation and also reduce the degree of brain damage.
  • the present invention can be used to target those diseases that increase ceramide production, thus shifting the balance from the sphingosine-1 -phosphate (SIP) pathway (protective), to the ceramide pathway (destructive).
  • SIP sphingosine-1 -phosphate
  • the present inventors have shown, in both in vitro and in vivo models, that Liposomal Curcumin and EU8120 reduce IL-Ib, IL-6, TNF-a, MCP-1, MIP-1 and Rantes. Liposomes have also been shown, in other models, to compete for the enzyme sphingomyelinase and to reduce levels of ceramides, thus also shifting the ceramide/SlP balance toward SIP.
  • LPS-induced cytokine storm produces QTc prolongation, which is prevented by an anti inflammatory lipid.
  • QTc prolongation There is increasing evidence that excess levels of pro-inflammatory cytokines play a major role in the pathogenesis of the prolonged QT syndrome.
  • blockers such as tocilizumab (IL-6), or anti-cytokine antibodies (TNFa) contribute to a shortening of the previously -prolonged QT interval.
  • EU8120 a lipid blend shown to prevent IKr- channel block by a variety of hERG blockers
  • QTc prolongation was limited to 5 ms after 2 hours, and completely prevented at 1 and 4 hours post- LPS.
  • Plasma levels of TNFa, IL1 b, and IL-6 were significantly lower in EU8120-administered animals.
  • This example demonstrates that EU8120 suppresses QTc prolongation via an anti inflammatory cytokine -effect and not by any interaction with the active agent (LPS).
  • LPS active agent
  • the present invention can use the compositions to treat the cytokine storm disorders using synthetic curcumin (S-curcumin).
  • S-curcumin synthetic curcumin
  • Curcumin is the active principle of the turmeric plant, which has been synthesized to near purity (99.2%). It is formulated with liposomes, polymers, or PLGM to render it capable of being administered intravenously as a bolus or as a continuous infusion over 1-72 hours in combination with other active agents. Curcumin has antioxidant and anti-inflammatory activity, and can block autonomous intracellular signaling pathways abnormally responsive to extracellular growth factors, uncontrolled proliferation of cells and fibrosis-associated and tissue degenerative conditions. Specifically, Curcumin reacts negatively with components of key signaling pathways commanding proliferation, metabolism, survival and death.
  • Curcumin as an extract of turmeric root is available to researchers as a mixture of three curcuminoids and to the public as a food supplement or spice according to the FDA.
  • the extract is 79.2% curcumin (diferuloylmethane), 18.27% demethoxycurcumin, and 2.53 % bisdemethoxycurcumin.
  • Synthesized curcumin is GMP grade 99.2% pure diferuloylmethane produced for non human experimental study and future Phase I clinical trials. There are obvious differences between the C3 three component extract and the single component synthesized S-curcumin that extend to discernable analytic, physicochemical, and biological characteristics.
  • the diferuloylmethane is 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96% pure diferuloylmethane.
  • the present invention relates to synthetic curcumin (S-curcumin) and compares the properties and the activity of S-curcumin with liposomal curcumin, NANOCURC ® , and PLGA- curcumin (hereinafter C3 -complex).
  • Liposomal curcumin The initial studies of liposomal curcumin were done using material bought as the complex. 6 7 Studies with S-curcumin are Mach CM, et al (2009) 8 and Mach CM et al (20 lO) 9 [0066] NANOCURC ® : The initial study of Nanocurc® was done using product bought as the complex Savita Bisht et al (2007) 10 used a non-sabinsa source. Since then studies with S-curcumin are used in the remainder of Nanocurc® publications. 11 13
  • PLGA-curcumin The initial studies of PLGA-curcumin were done using product manufactured as the C3 -complex. 14-18 Studies included PLGA -curcumin C3 complex and PLGA- S-curcumin pharmacokinetic studies in rat brains.
  • FIG. 4A is a graph that shows the effect of liposomal curcumin on liver function during sepsis, including aspartate aminotransferase (AST) and alanine aminotransferase (AST) levels in a mouse model system. The results show the effectiveness of liposomal curcumin compared to the standard of care in sepsis for age matched controls. Liposomal curcumin showed a higher effectiveness when compared to the standard of care for AST and ALT.
  • FIGS. 4B to 4D are graphs that show the effect of liposomal curcumin during sepsis on kidney function for glomerular filtration rate (GFR) by measuring Creatine, Neutrophil gelatinase-associated lipocalin (NGAL) which measures the progression of chronic kidney disease, and Blood Urea Nitrogen which measures the kidney’s ability to remove urea from blood, respectively.
  • Liposomal curcumin showed a higher effectiveness is preserving kidney function when compared to the standard of care, in particular, and importantly with NGAL which measures the progression of chronic kidney disease.
  • FIGS. 4E and 4F are graphs that show the effect of liposomal curcumin during sepsis on heart function for c-Troponin, which measures cardia tissue damage and the percent ejection fraction, which measures the efficacy with which the left ventricle (or right ventricle) pumps blood with each heartbeat.
  • Liposomal curcumin showed a decrease in cardiac damage when compared to the standard of care and equaled the standard of care in percent ejection fraction.
  • FIG. 4G is a graph that shows the effect of liposomal curcumin during sepsis on overall survival. Liposomal curcumin showed a higher survival time versus the standard of care treatment.
  • Brain damage after traumatic brain injury is a two-stage process: the injury caused by the initial insult is followed by a stage of inflammation where a great deal of additional damage may occur.
  • This inflammation begins within minutes of the initial insult and can continue for months or years, and results from a complex series of metabolic processes involving marked increases in cytokines, particularly the pro-inflammatory cytokines, interleukin- 1b, interleukin-6 and tumor necrosis factor-a. Levels of these cytokines may increase thousands of times more than the corresponding levels in serum. Strategies to control the levels of these pro- inflammatory cytokines and to reduce the cytokine-induced brain damage are discussed. There is extensive evidence from experiments in animal models that suppression of cytokines is effective in ameliorating neurologic damage after TBI. However, the efficacy of this approach remains to be proven in patient trials.
  • Cytokine storm also known as 'cytokine release syndrome,' can occur after infection with malaria [1], SARS [2], dengue [3], leptospirosis [4], Lassa fever [5], gram-negative sepsis [6] as well as with numerous other infectious diseases (7-10] Cytokine storm is a major cause of death in patients with Ebola [11-13] Patients with cytokine storm may experience increased vascular permeability, severe hemorrhage and multi organ failure, which may ultimately be the cause of a fatal outcome [8, 13, 14] Marked increases in systemic cytokine levels, of both pro -inflammatory and anti-inflammatory cytokines, are seen.
  • Cytokine storm is also a recognized complication of treatment with the commonly-used antineoplastic agent rituximab [22], as well as of treatment with the monoclonal antibodies, tositumomab, alemtuzumab, muromonab and blinatumomab [23] Elevated levels of cytokines are found and are thought to be an important cause of the pathology in many neurological conditions, including Alzheimer’s disease [24], Parkinson’s disease [25], autism [26], and multiple sclerosis [27], as well as in the acute phase of Guillian-Barre syndrome [28, 29] .
  • TBI represents a major health problem in the United States, with 1.7 million cases, 275 000 hospitalizations and 52 000 deaths each year [34], and neuropsychiatric sequalae are common, especially after severe injury [35]
  • ILj-Ib interleukin
  • IL-6 tumour necrosis factor
  • TNF tumour necrosis factor
  • IL-6 is not usually detectable in CSF, or is detectable in only very low concentrations (1-23 pg/ml) [37, 38]
  • CSF levels of IL-6 as high as 35 500 pg/ml were seen after severe TBI [38, 39]
  • These IL-6 levels were 40-100x greater than the corresponding levels in the serum of these patients [40]
  • Kushi et al reported very large increases in both IL-6 and IL-8, measured on admission, at 24 hours, at 72 hours and at 168 hours after severe TBI in 22 patients.
  • IL-6 values at these times in the CSF were 15 241, 97384, 548 225 and 336 500 pg/ml compared to 102, 176, 873, 3 059 pg/ml in the blood, a 'storm' of cytokines mostly localized to the brain.
  • average IL-6 CSF values were lower, but still much greater than in the peripheral blood: 5 376, 3 565, 328 and 764 pg/ml compared to 181, 105, 37 and 26 pg/ml in the blood [41] Similar differences were seen for IL-8.
  • IL-8 levels in the CSF are normally very low (5-72 pg/ml) [37]
  • Kushi et al reported CSF IL-8 levels that were consistently elevated thousands of times more than normal levels or comparable levels in the peripheral blood [41]
  • IL-6 and IL-8 blood levels that remained markedly elevated after 72 hours correlated with a worse prognosis and high fatality rate.
  • Helmy et al found marked elevations of multiple cytokines, including IL-la, IL-Ib, IL-6, IL-8, IL-10, monocyte chemotactic protein (MCP-1) and macrophage inflammatory protein-la (MIP-la), in brain extracellular fluid after severe TBI in 12 patients.
  • MCP-1 monocyte chemotactic protein
  • MIP-la macrophage inflammatory protein-la
  • Interleukin- 1 The IL-1 family is a group of 11 cytokines which are intimately involved in the body’s response to injury or infection [48, 49], and which also play a key role in tumour angiogenesis [50] and stimulation of cancer stem cells [51]
  • the most important cytokines of the IL-1 group are IL-Ib, IL-1 a and the IL-1 receptor antagonist, IL-1RA, but the IL-1 group also includes the pro-inflammatory cytokines IL-18, IL-33 and IL-36, as well as several less well- studied cytokines.
  • the key cytokine IL-Ib is a protein produced by activated macrophages.
  • IL-1RA IL-1RA
  • Yang et al showed that the cerebral damage caused by middle cerebral artery occlusion in mice was reduced in those animals that were previously transfected with an adenoviral vector to induce IL-1RA overexpression
  • Jones et al showed that a single intracerebroventricular dose of IL-1RA administered to mice at the time of TBI reduced lesion volume, resulted in functional improvement and caused a major decrease in nitric oxide synthase-2 -positive cells in the lesion [63-Jones].
  • Sanderson et al studied the effect of systemically-administered IL-1RA to Sprague Dawley rats after TBI.
  • Hasturk et al showed IL-1RA reduced tissue IL-Ib levels and increased levels of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in rats after TBI [65] .
  • Other groups have reported similar results [66, 67] .
  • IL-1RA Human recombinant IL-IRA has been a standard medication for patients with rheumatoid arthritis for several years, and its use has been investigated in a number of diseases where increased cytokines play a role in the destructive process, including diabetes [70], heart failure [71], multiple myeloma [72] and sepsis [73]
  • IL-IRA In a randomized phase II trial of patients with acute stroke, there was less loss of cognitive function in patients treated with IL-IRA compared to the control group
  • Helmy et al conducted a phase II controlled trial of this agent in 20 patients with severe TBI, and were able to conclude that IL-IRA does cross the blood-brain barrier and is safe in this population [75] They were unable to conclude that IL-IRA administration resulted in therapeutic benefit in these patients [75] While many of these results seem promising, however, the efficacy of IL-IRA may be limited, as it directly blocks only
  • TNF-a Tumor necrosis factor-a.
  • This cytokine plays an important role in the body’s response to infections and to cancer. Since the report on TNF-a by Helson et al in 1975 [77], aberrant TNF-a function has been reported in numerous diseases, including conditions as diverse as diabetes [78], cardiovascular disease [79], inflammatory bowel disease [80] and Alzheimer’s disease [81] TNF blockers, such as infliximab, etanercept, and adalimumab, are standard therapies for patients with rheumatoid arthritis, ankylosing spondylitis and psoriasis.
  • TNF-a is thought to have both beneficial and detrimental effects in patients with TBI [46] .
  • results in experimental models suggest that these effects are mostly detrimental, especially when excessive levels of this cytokine are produced.
  • Knoblach et al reported the correlation of TNF levels and the degree of brain injury and neurological impairment in rats after experimental TBI, with the highest levels of TNF at 1-4 hours after injury in rats with the most severe brain injury [82] .
  • studies with the TNF-blocker, etanercept have consistently shown reduction of brain damage in these animals after administration of this agent.
  • TNF blockers have been studied extensively in animal models, little work has been done to assess the potential efficacy of these agents in patients with TBI [92] Tobinick et al reviewed the medical records of 617 patients with stroke and 12 with TBI who had been treated with etanercept. Marked improvement in neurological function was observed, even for patients treated more than 10 years after the initial insult. The investigators concluded that this supported the view that long-term inflammation, perhaps lasting many years, was a major cause of neurological impairment in these patients [93] However, the small number of patients in the TBI group and the lack of a control group make the data in this report difficult to interpret, as it is not clear that TNF blockade was responsible for the observed improvement.
  • TNF blockers may have substantial toxicity.
  • TNF blockers target only a single cytokine, and since the use of these agents is contradicted in combination with IL-1 antagonists, the use of these blockers may not be the most effective strategy in treatment of these patients.
  • Interleukin-6 A third major pro-inflammatory cytokine is IL-6.
  • IL-6 A third major pro-inflammatory cytokine is IL-6.
  • TNF-a elevated levels of IL-6 have been thought to have a role in the causation of numerous diseases, and like TNF-a, IL-6 is thought to have beneficial as well as harmful effects after TBI [94] Indeed, IL-6 appears to have both a beneficial and a deleterious role in a number of neurological conditions [95]
  • IL-6 plays a key role in induction of nerve growth factor by astrocytes, and thus in the repair of the injured brain [39]
  • Ley et al reported that IL-6 knockout mice demonstrated reduced neurological function after TBI compared to normal mice, again suggesting IL-6 is necessary for neuronal recovery.
  • the IL-6 knockout mice did, however, show significantly elevated levels of IL-Ib [96]
  • the neuroprotective role of IL-6 was also suggested in a study of frontal lobe parenchymal IL-6 levels in patients after severe TBI. Markedly elevated IL-6 levels were found in survivors compared to those who died, while levels of IL-Ib were not different
  • Anti-inflammatory cytokines such as IL-4, IL-10, IL-11 IL-13 and transforming growth factor (TGF)-[L can also be markedly elevated in inflammatory conditions.
  • TGF transforming growth factor
  • One of the major functions of these cytokines is to inhibit synthesis of pro- inflammatory cytokines
  • IL-10 is the most important anti-inflammatory cytokine, and IL- 10 levels are markedly elevated in the brain and CSF after TBI [54, 108]
  • IL-10 is known to also have pro-inflammatory functions [107], its main effect after TBI appears to be primarily protective against inflammatory damage.
  • Kumar et al studied cytokine levels in 87 patients with severe TBI over a twelve-month period and found that patients with an elevated IL- 6/IL-10 ratio at six months had a poor prognosis [109]
  • BBis et al showed IL-10 blocks caspase- 3 and reduces neuronal death after exposure of rat cerebellar granule cells in culture to toxic doses of glutamate [110]
  • Knoblach et al showed that either intravenous or subcutaneous administration of IL-10 after experimental TBI in rats could reduce synthesis of IL-1 and enhance neurological recovery in the animals. Intracerebroventricular administration was not effective, however [111].
  • mice deficient in IL-10 failed to respond to the beneficial effects of hyperbaric oxygen treatment after TBI (112- X. Chen 2013).
  • Bethea et al showed that IL-10 reduced TNF-a production and improved motor function after spinal cord injury in rats [113]
  • Similar neuroprotective effects of IL-10 were also seen in other studies of experimental spinal cord injury [114, 115] This suggests another approach to the treatment of TBI in patients might be administration of an anti-inflammatory cytokine like IL-10.
  • Trials of recombinant human IL- 10 (ilodecakin) have been done in a number of diseases. However, results have so far been disappointing [116]
  • progestins It is well known, from studies in animal systems, that progestins can reduce neuronal damage after TBI [117-121] A major mechanism for the neuroprotection seen with progestins is the ability of these agents to suppress pro-inflammatory cytokines. Cutler et al showed that progesterone given to aged male rats after TBI reduced brain levels of IL-6 at 24, 48 and 72 hours. Decreased levels of NF-KB and COX-2 were also seen, and the rats demonstrated improved motor skills, decreased cerebral edema and decreased mortality (122 -Cutler). He et al reported that intraperitoneal administration of progesterone could reduce IL-Ib and TNF-a at 3 hours after injury.
  • Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are used to inhibit cholesterol production in the liver. These drugs are widely utilized clinically in patients with hypercholesterolemia. Statins are also known to have marked anti-inflammatory effects. Chen et al showed that lovastatin pre-administered to rats with experimental TBI caused marked decreases in IL-Ib and TNF-a in the areas of brain injury at 6 hours and at 96 hours post injury.
  • this trial included only 8 rosuvastatin patients and 13 controls, while 21 of the 43 assessed TBI patients were deemed ineligible.
  • Sanchez-Aquilar et al reported that the rosuvastatin patients had a dramatic decrease in plasma levels of TNF-a compared to placebo and an improvement in disability scores. No effect was seen on IL-Ib, IL-6 or IL-10 [139]
  • Rasras et al investigated the effects of a similar agent, simuvastatin, in a randomized trial of 66 patients with severe TBI; however, no difference was found between the treated and the control groups [140] [0095] Tetracyclines.
  • Tetracyclines have been shown, in animal models, to suppress inflammation and better outcomes in several neurological conditions.
  • minocycline could reduce IL-Ib and IL-6 expression and microglial and macrophage activation in mice after TBI. Neurological functioning was better at day 1 in treated mice, although there was no difference between treated mice and controls at day 4 [141] Later studies by this same group did show, however, comparative improvement in the minocycline group by 6 weeks [142]
  • Shanchez Mejia et al reported that minocycline given to mice after TBI reduced IL-Ib by inhibiting caspase-1 activation, resulting in improved neurological function and decreased lesion volume in the treated animals [143]
  • Lee et al showed that minocycline given to rats after spinal cord injury reduced TNF-a, increased IL-10, reduced neuronal cell death and improved motor function
  • Yrjanheikki reported that either doxycycline or minocycline could reduce mRNA induction of IL-Ib converting enzyme and protect
  • Cyclosporine is a potent, immunosuppressant drug. Because of its wide-ranging effects on cytokines [162-165], and activity in animal models [166], it has been studied in trials of patients with TBI. However, a randomized, placebo-controlled, trial of this agent in patients with TBI showed no activity [167] A formulation of cyclosporine (neurostat) continues to be investigated in patients with TBI and other neurological conditions, although a recent report showed neurostat had no neuroprotective activity in acute ischemic stroke [168]
  • TBI pro-inflammatory cytokines
  • Carprofen a COX-2 inhibitor, which is currently used to treat arthritis in dogs and other animals, was found to markedly reduce IL-Ib and IL-6, and to improve neurological functioning in mice after TBI
  • Triptolide a diterpenoid epoxide, which has anti-cancer activity in animal models, was found to suppress IL-Ib, IL-6 and TNF-a, to increase IL-10 levels and to reduce neuronal apoptosis in Sprague-Dawley rats after experimental TBI
  • TSG-6 TNF-a stimulated gene/protein 6
  • MIP-la pro-inflammatory cytokines
  • Watanabe et al showed that administration of this agent to mice after TBI
  • the brain damage after TBI may be markedly worsened during a succeeding phase of brain inflammation.
  • Dining this phase massive increases occur in the levels of key cytokines, particularly IL-Ib, IL-6 and TNF-a, a 'cerebral cytokine storm' where levels may increase thousands of times compared to their corresponding levels in serum.
  • cytokines particularly IL-6 and TNF-a
  • IL-6 and TNF-a may have beneficial actions, evidence suggests excessive levels are harmful, since numerous studies in animal models have shown blockade of these cytokines can reduce brain injury.
  • suppression of pro-inflammatory cytokines can limit the secondary damage caused by neuro-inflammation after TBI.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • “comprising” may be replaced with “consisting essentially of’ or “consisting of’.
  • the phrase “consisting essentially of’ requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention.
  • the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), propertie(s), method/process steps or limitation(s)) only.
  • words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
  • the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
  • a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ⁇ 1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
  • Clark IA Alieva LM
  • Budd AC Budd AC
  • Cowden WB Understanding the role of inflammatory cytokines in malaria and related diseases. Travel Med Infect Dis 2008, 6:67-81.
  • IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 2003;100:2645-2650.
  • Antagonism of the interleukin- 1 receptor following traumatic brain injury in the mouse reduces the number of nitric oxide synthase-2-positive cells and improves anatomical and functional outcomes. Eur J Neurosci 2005;22:72-78.
  • Genovese MC Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2014;50:1412- 1419.
  • Opal SM DePalo VA. Anti-inflammatory cytokines. Chest 2000;117:1162-1172.
  • CE Agoston DV.
  • Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury.
  • Senol N Vietnameseroglu M. Melatonin reduces traumatic brain injury-induced oxidative stress in the cerebral cortex and blood of rats. Neural Regen Res 2014;9: 1112-1116.
  • HY Cyclosporine differentially regulates interleukin- 10, interleukin- 15, and tumor necrosis factor a production by rheumatoid synoviocytes. Arthritis Rheum 2002;46:42-51.

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