KR20230026468A - Inhibition of cytokine release and cytokine storm - Google Patents

Abstract

The present invention provides methods and compositions for treating one or more side effects or ameliorating the symptoms caused by an infectious disease or disease condition that results in widespread release of cytokines in a subject, wherein the infectious disease or disease condition that causes widespread release of cytokines. identifying a subject in need of treatment or improvement of symptoms; One or more agents comprising a therapeutically effective amount of curcumin extract, curcuminoids or synthetic curcumin (S-curcumin) and its derivatives and lipids dissolved or dispersed in a suitable aqueous or non-aqueous medium sufficient to reduce the level of cytokines in the host. methods and compositions comprising administering a medical composition.

Description

Inhibition of cytokine release and cytokine storm

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a PCT International Application, which is a divisional application of US Patent Application Serial No. 16/945,195 filed on July 31, 2020, and US Provisional Application Serial No. 62/098,898 filed on December 31, 2014, filed on May 22, 2015 Priority is claimed to U.S. Provisional Application No. 62/165,567, filed on , and U.S. Provisional Application No. 62/211,450, filed on August 28, 2015, which are incorporated herein by reference in their entirety.

The present invention relates generally to the field of infectious diseases and disease conditions that trigger a cytokine cascade, and in particular to the use of compositions that reduce the cytokine cascade.

US Federal Funded Research Statement

This invention was made with US Government support by USAMRIID under Project No. 1323839. The US Government has certain rights in this invention.

Without limiting the scope of the invention, the background of the invention is described, for example, with respect to infectious diseases and disease conditions that cause the anaphylactic cytokine cascade.

U.S. Patent No. 8,354,276 to Har-Noy entitled "T-Cell Compositions Inducing a Type I Cytokine Response" relates to methods of engineering allogeneic cells for use in allogeneic cell therapy procedures. The present method is a composition of highly activated allogeneic T cells that is infused into an immunocompetent cancer patient to induce a novel anti-tumor immune mechanism termed the "Mirror Effect". provides Unlike current allogeneic cell therapy procedures in which T-cells within the graft mediate beneficial graft-versus-tumour (GVT) and detrimental graft-versus-host (GVH) effects, the present allogeneic cells of the present invention are host T By stimulating cells, it is claimed to mediate a "mirror" of these effects. The highly activated allogeneic cells of the present invention are said to stimulate host immunity in a complete HLA mismatch setting in patients who have not previously undergone bone marrow transplantation or have not received chemotherapy and/or radiation conditioning therapy.

US Patent No. 8,309,519 to Li et al. entitled "Compositions and Methods for Inhibiting Vascular Permeability" relates to compounds, compositions and methods for inhibiting vascular permeability and pathological angiogenesis. These inventors teach methods for producing and screening compounds and compositions capable of inhibiting vascular permeability and pathological angiogenesis. The disclosed compositions are suitable for use in methods of inhibiting vascular permeability and pathological angiogenesis, including methods of inhibiting vascular permeability and pathological angiogenesis induced by certain angiogenic, permeability and inflammatory factors such as, for example, VEGF, βFGF and thrombin. mentioned as useful.

U.S. Patent No. 7,479,498 to Keller entitled "Treatment of Viral Infections" relates to improved methods and compositions for treating viral infections and other diseases and conditions that cause a cytokine storm. It is also further mentioned that the present invention relates to a novel composition comprising an anticonvulsant such as phenytoin and quercetin in combination with a multivitamin as an antiviral composition and a method of use thereof.

U.S. Patent Application No. 20100075329 filed by O'Toole et al. entitled "Method for Predicting Generation of Activation Signal by Cross-Linked Binding Protein," which specifically binds to human interleukin-21 receptor (IL21R) binding proteins and antigen-binding fragments thereof and uses thereof. It is stated that the present invention includes methods for predicting whether a binding protein of the present invention can assume agonist activity in vivo and generate a cytokine storm. It is also stated that the present invention provides a method for determining whether an anti-IL21R binding protein is a neutralizing anti-IL21R binding protein based on the identification of a plurality of IL21 response genes. Finally, it is mentioned that the binding protein can act as an antagonist of IL21R activity and thereby modulate the immune response in general and the immune response mediated by IL21R in particular.

), 구아나리토(Guanarito), 가리사(Garissa), 일레샤(Ilesha), 또는 라사열 바이러스(Lassa fever virus)에 의한 적어도 하나의 감염으로부터 선택된다. 또 다른 양상에서, 하나 이상의 질병 병태는 악액질(cachexia), 패혈성 쇼크 증후군(septic shock syndrome), 만성 염증 반응(chronic inflammatory response), 패혈성 쇼크 증후군, 외상성 뇌 손상(traumatic brain injury), 뇌 사이토카인 폭풍(cerebral cytokine storm), 이식편대숙주병(graft versus host disease) (GVHD), 자가면역 질병(autoimmune disease), 다발 경화증(multiple sclerosis), 급성 췌장염(acute pancreatitis), 또는 간염(hepatitis) 중 적어도 하나로부터 선택된다. 또 다른 양상에서, 하나 이상의 질병 병태는 항-CD19 키메라 항원 수용체 (CAR) T 세포 또는 항-종양 세포 요법, 활성화된 수지상 세포, 활성화된 대식세포, 또는 활성화된 B 세포에 의한 치료에 의해 유발되는 부작용이다. 또 다른 양상에서, 본 조성물이 지질에 배치된, 커큐민(curcumin) 추출물, 커큐민, 커큐미노이드(curcuminoid)를 추가로 포함하고, 커큐미노이드는 Ar-투메론, 메틸커큐민, 데메톡시 커큐민, 비스데메톡시커큐민, 소듐 커큐미네이트, 디벤조일메탄, 아세틸커큐민, 페룰로일 메탄, 테트라하이드로커큐민, 1,7-비스(4-하이드록시-3-메톡시페닐)-1,6-헵타디엔-3,5-디온 (커큐민1), 1,7-비스(피페로닐)-1,6-헵타디엔-3,5-디온 (피페로닐 커큐민) 1,7-비스(2-하이드록시 나프틸)-1,6-헵타디엔-2,5-디온 (2-하이드록실 나프틸 커큐민) 및 1,1-비스(페닐)-1,3,8,10 운데카테트라엔-5,7-디온 중 적어도 하나로부터 선택된다. 또 다른 양상에서, 지질 또는 인지질은 디미리스토일포스파티딜콜린 (DMPC), 디미리스토일포스파티딜글리세롤 (DMPG), 디팔미토일포스파티딜콜린 (DPPC), 디스테로일포스파티딜글리세롤 (DSPG), 디팔미토일포스파티딜글리세롤 (DMPG), 포스파티딜콜린, 리소레시틴, 리소포스파티딜에탄올아민, 리소DMPC, 리소DMPG, 리소DSPG, 리소DPPC, 포스파티딜세린, 포스파티딜이노시톨, 스핑고마이엘린, 포스파티딜에탄올아민, 카디올리핀, 포스파티드산, 세레브로시드, 디세틸포스페이트, 포스파티딜콜린, 및 디팔미토일-포스파티딜글리세롤, 스테아릴아민, 도데실아민, 헥사데실-아민, 아세틸 팔미테이트, 글리세롤 리시놀레에이트, 헥사데실 스테아레이트, 이소프로필 미리스테이트, 양쪽성 아크릴 중합체, 지방산, 지방산 아미드(fatty acid amides), 콜레스테롤, 콜레스테롤 에스테르, 디아실글리세롤, 및 디아실글리세롤숙시네이트로 이루어진 군으로부터 선택된다. 또 다른 양상에서, 치료학적 유효량은 50 nM/kg 대상체 체중, 10 내지 100 nM/kg 대상체 체중, 25 내지 75 nM/kg 대상체 체중, 10, 20, 30, 40, 50, 60, 70, 80, 90, 또는 100 nM/kg 대상체 체중을 포함한다. 또 다른 양상에서, 본 조성물은 활성제(active agent)를 포함하며, 3:1, 1:1, 0.3:1, 및 0.1:1의 지질 인지질 대 활성제의 비율을 갖는다. 또 다른 양상에서, 질병은 류마티스 관절염(rheumatoid arthritis), 건선(psoriasis), 다발 경화증, 재발성 다발 경화증, 또는 염증성 장 질병이다.In one embodiment, the invention provides a method of treating one or more side effects or ameliorating symptoms caused by the widespread release of cytokines in a subject, wherein the treatment or identifying a subject in need of symptom improvement; and administering one or more pharmaceutical compositions comprising a therapeutically effective amount of the lipid dissolved or dispersed in a suitable aqueous or non-aqueous medium sufficient to reduce the level of the cytokine in the subject. In one aspect, the widespread release of cytokines is caused by one or more infectious diseases selected from at least one of a virus, bacteria, fungus, helminthic, protozoan, or hemorrhagic infectious agent. In another aspect, the one or more infectious diseases are 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 fever, yellow fever (yellow fever), Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia (

), Guanarito, Garissa, Ilesha, or at least one infection by Lassa fever virus. In another aspect, the one or more disease conditions are cachexia, septic shock syndrome, chronic inflammatory response, septic shock syndrome, traumatic brain injury, brain cytotoxicity. During cerebral cytokine storm, graft versus host disease (GVHD), autoimmune disease, multiple sclerosis, acute pancreatitis, or hepatitis selected from at least one In another aspect, the one or more disease conditions are caused by treatment with anti-CD19 chimeric antigen receptor (CAR) T cells or anti-tumor cell therapy, activated dendritic cells, activated macrophages, or activated B cells. It is a side effect. In another aspect, the composition further comprises a curcumin extract, curcumin, a curcuminoid disposed in a lipid, wherein the curcuminoid is Ar-turmeron, methylcurcumin, demethoxy curcumin, bis Demethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene- 3,5-dione (curcumin 1), 1,7-bis(piperonyl)-1,6-heptadiene-3,5-dione (piperonyl curcumin) 1,7-bis(2-hydroxy naphtha) Tyl)-1,6-heptadiene-2,5-dione (2-hydroxyl naphthyl curcumin) and 1,1-bis(phenyl)-1,3,8,10 undecatetraene-5,7- is selected from at least one of diones. In another aspect, the lipid or phospholipid is dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), phosphatidylcholine, lysolecithin, lysophosphatidylethanolamine, lysoDMPC, lysoDMPG, lysoDSPG, lysoDPPC, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cereb Roside, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, both It is selected from the group consisting of acrylic polymers, fatty acids, fatty acid amides, cholesterol, cholesterol esters, diacylglycerols, and diacylglycerolsuccinates. In another aspect, a therapeutically effective amount is 50 nM/kg of subject body weight, 10 to 100 nM/kg of subject body weight, 25 to 75 nM/kg of subject body weight, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM/kg subject body weight. In another aspect, the composition includes an active agent and has a ratio of lipid phospholipid to active agent of 3:1, 1:1, 0.3:1, and 0.1:1. In another aspect, the disease is rheumatoid arthritis, psoriasis, multiple sclerosis, relapsing multiple sclerosis, or inflammatory bowel disease.

In another embodiment, the present invention is a composition for treating or ameliorating the symptoms of one or more side effects caused by a disease condition or infectious disease that causes widespread release of cytokines in a subject, dissolved in a suitable aqueous or non-aqueous medium. A composition comprising a therapeutically effective amount of a lipid or lysophosphatidyl dispersed or dispersed therein. In one aspect, the one or more infectious diseases are selected from at least one of viruses, bacteria, fungi, parasites, protozoa, or hemorrhagic infectious agents. In another aspect, the one or more infectious diseases is rhinovirus, coronavirus, paramyxoviridae, orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus, influenza virus, arenaviridae, filoviridae, Bunyaviridae, Flaviviridae, Rhabdoviridae viruses, Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue fever, yellow fever, Rift valley fever, Omsk hemorrhagic fever virus, Kiasanu forest, Junin, Machupo , at least one infection by a Sabia, Guanarito, Garissa, Ilesha, or Lassa fever virus. In another aspect, the one or more disease conditions include cachexia, septic shock syndrome, chronic inflammatory response, septic shock syndrome, traumatic brain injury, brain cytokine storm, graft-versus-host disease (GVHD), an autoimmune disease, multiple sclerosis, at least one of acute pancreatitis, or hepatitis. In another aspect, the curcumin extract, curcuminoids or synthetic curcumin are disposed in a lipid. In another aspect, or lysophosphatidyl is dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), phosphatidylcholine, lysolecithin, lysophosphatidylethanolamine, lysoDMPC, lysoDMPG, lysoDSPG, lysoDPPC, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cereb Roside, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, both It is selected from the group consisting of acrylic polymers, fatty acids, fatty acid amides, cholesterol, cholesterol esters, diacylglycerols, and diacylglycerolsuccinates. In another aspect, the biodegradable polymer is a polyester, polylactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, polydioxanone, polyacetal, 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. In another aspect, the composition is suitable for intravenous, subcutaneous, intramuscular or intraperitoneal injection in a subject. In another aspect, the composition comprises Ar-turmeron, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, 1,7- Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin 1), 1,7-bis(piperonyl)-1,6-heptadiene-3 ,5-dione (piperonyl curcumin) 1,7-bis(2-hydroxy naphthyl)-1,6-heptadiene-2,5-dione (2-hydroxyl naphthyl curcumin) and 1,1- and curcumin or a curcuminoid selected from at least one of bis(phenyl)-1,3,8,10 undecatetraene-5,7-dione. In another aspect, the composition comprises an active agent and has a ratio of lipid to active agent of 3:1, 1:1, 0.3:1, and 0.1:1.

In another embodiment, the present invention includes a method for determining whether a candidate drug treats or ameliorates symptoms of one or more side effects caused by an infectious disease or disease condition that causes widespread release of cytokines in a subject. and the method comprises: (a) administering to a second subset of patients an amount of a candidate drug in combination with empty liposomes and a placebo, wherein the candidate drug increases the cytokine level in the subject. provided in an amount effective to reduce or inhibit overall levels; (b) measuring the subject's cytokine levels from the first and second sets of patients; and (c) whether the candidate drug in combination with empty liposomes treats or ameliorates symptoms of one or more side effects caused by a disease condition or infectious disease that causes widespread release of cytokines in a subset of patients receiving placebo. comparing to any reduction in the target drug to determine whether it is statistically significant, wherein a statistically significant reduction indicates that the candidate drug reduces or eliminates the overall cytokine level of the subject while being useful in treating the disease condition.

In another embodiment, the present invention provides a method for treating or ameliorating the symptoms of a cytokine storm caused by a therapeutic agent in a subject: identifying a subject in need of treatment or amelioration of symptoms of a cytokine storm caused by a therapeutic agent. ; and at least one pharmaceutical composition comprising a therapeutically effective amount of 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 cytokine levels in a subject. It includes a method comprising the step of administering.

For a more complete understanding of the features and advantages of the present invention, reference is made to the detailed description of the present invention in conjunction with the accompanying drawings:
1A and 1B show the percent inhibition and percent viability achieved with liposomal curcumin in HeLa cells, respectively.
2A and 2B show percent inhibition and percent viability using solid S-curcumin curcumin in HeLa cells, respectively.
3A and 3B show percent inhibition and percent viability comparing liposomal curcumin and solid curcumin in HeLa cells, respectively.
4A is a graph showing the effect of liposomal curcumin on liver function during sepsis, including aspartate aminotransferase (AST) and alanine aminotransferase (AST) levels. Results show the effect of liposomal curcumin compared to standard of care in sepsis and age-matched controls. Liposomal curcumin showed higher efficacy compared to standard treatment for AST and ALT.
4B-4D are graphs showing the effect of liposomal curcumin during sepsis on renal function measuring creatine, neutrophil gelatinase-associated lipocalin (NGAL) and blood urea nitrogen (BUN). Liposomal curcumin showed higher efficacy in maintaining kidney function compared to standard treatment, particularly NGAL, which measures the progression of chronic kidney disease.
4E and 4F are graphs showing the effect of liposomal curcumin during sepsis on cardiac function and percent ejection fraction for c-troponin. Liposomal curcumin was shown to reduce cardiac damage when compared to standard treatment and was equivalent to standard treatment in percent ejection fraction.
4G is a graph showing the effect of liposomal curcumin during sepsis on overall survival. Liposomal curcumin showed a higher survival time compared to standard of care treatment.

Although the manufacture and use of various embodiments of the present invention are discussed in detail below, it should be understood that the present invention provides many applicable inventive concepts that may be implemented in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not limit the scope of the invention.

To facilitate understanding of the present invention, a number of terms are defined below. Terms defined herein have meanings commonly understood by those of ordinary skill in the field related to the present invention. Terms such as "a", "an" and "the" are not intended to refer to single objects only, but include general classes for which specific examples may be used for illustration. Although terminology is used herein to describe specific embodiments of the invention, their use does not limit the invention except as outlined in the claims.

As used herein, the term "cytokine storm" refers to a pro-inflammatory cytokine that causes a disease referred to as "cytokine storm", "cytokine release syndrome" or "inflammatory cascade". refers to dysregulation of A cytokine storm or chain reaction is often referred to as part of a sequence because one cytokine usually produces several other cytokines that can enhance and amplify the immune response. Generally, these pro-inflammatory mediators are divided into two subgroups: early mediators and late mediators. For example, early mediators such as tumor-necrosis factor, interleukin-1, and interleukin-6 are degraded within the time window when a patient travels to the clinic for treatment, so sufficient therapy to re-establish the homeostatic balance. not a target In contrast, so-called "late mediators" have been targeted because it is during the late "inflammatory chain reaction" that patients realize they are ill.

Infectious diseases commonly associated with "cytokine storms" include, but are not limited to, malaria, avian influenza, smallpox, pandemic influenza, and adult respiratory distress syndrome (adult). respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS). Certain specific infectious agents include, but are not limited to: Infectious diseases include Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue fever, yellow fever, Rift valley fever, Omsk hemorrhagic fever virus, Kiasanu is selected from at least one of Forrest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Lassa fever virus. Other viruses may include rhinovirus, coronavirus, paramyxoviridae, orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus or influenza virus.

Disease conditions commonly associated with a “cytokine storm” include, but are not limited to, sepsis, systemic inflammatory response syndrome (SIRS), cachexia, septic shock syndrome, traumatic brain injury (e.g., brain cytokine storm), graft-versus-host disease (GVHD), or as a result of treatment with activated immune cells, such as IL-2 activated T cells, anti-CD19 chimeric antigen receptor (CAR) T cells.

In general, a cytokine storm is a healthy systemic manifestation of an active immune system. The present invention is directed to e.g. rapidly proliferating and highly activated T-cells or It can be used to reduce or eliminate some or most of the exaggerated immune response elicited by natural killer (NK) cells. Pro-inflammatory cytokines (eg, tumor necrosis factor-α, interleukin-1, and intercukin-6) and anti-inflammatory cytokines (eg, interleukin-10 and interleukin-1 receptor antagonists) (IL-1RA)) all eg greatly increase in serum. It is the excessive release of inflammatory mediators that causes a “cytokine storm”.

In the absence of immediate intervention as provided by the present invention, a cytokine storm can cause permanent lung damage and in many cases death. Late symptoms of a 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. Death from an infectious disease such as Ebola virus infection is not caused by the virus itself, but by uncontrollable hemorrhage; severe metabolic dysregulation; low blood pressure; tachycardia; shortness of breath; Fever; ischemia or insufficient tissue perfusion; and by cytokine storms that cause multi-organ organ failure.

As used herein, the term "curcumin (diferuloyl methane; 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)" is a naturally occurring compound and is the main coloring principle found in the rhizome of the Curcuma longa plant (US Pat. No. 5,679,864 to Krackov et al.). In one aspect, the synthetic curcumin is 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96% pure diferuloylmethane. Non-limiting examples of curcumin and curcuminoids include, for example, Ar-turmeron, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin , 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin 1), 1,7-bis(piperonyl)-1,6 -Heptadiene-3,5-dione (piperonyl curcumin) 1,7-bis(2-hydroxy naphthyl)-1,6-heptadiene-2,5-dione (2-hydroxy naphthyl curcumin) and 1,1-bis(phenyl)-1,3,8,10 undecatetraene-5,7-dione.

The term "liposome" refers to a capsule whose walls or membranes are formed of lipids, in particular phospholipids, to which sterols, in particular cholesterol, are optionally added. In certain non-limiting examples, liposomes are empty liposomes and may be formulated from a single type of phospholipid or a combination of phospholipids. Empty liposomes or lipids may further comprise one or more surface modifications such as proteins, carbohydrates, glycolipids or glycoproteins, and nucleic acids such as aptamers, thio-modified nucleic acids, protein nucleic acid mimics, protein mimics, masking agents, and the like. can In one specific, non-limiting example, the composition also includes an active agent in or around the liposome or lipid, the composition comprising a 3:1, 1:1, 0.3:1 and 0.1:1 lipid to active agent. have a ratio

As used herein, the term “lipid” refers to amphiphilic biomolecules that are soluble in non-polar solvents. Lipids are capable of liposome formation, vesicle formation, micelle formation, emulsion formation and are substantially non-toxic when administered at the required concentration as liposomes. The lipid composition of the present invention, for example, dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoyl Phosphatidylglycerol (DMPG), phosphatidylcholine, lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cerebroside, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, amphoteric acrylic polymers, fatty acids, fatty acid amides, cholesterol, cholesterol esters, diacylglycerols, and diacylglycerolsuccinates.

As used herein, the term “ in vivo ” refers to taking place inside the body. As used in this application, the term " in vitro" should be understood to denote operations performed in an inanimate world .

As used herein, the term "treatment" refers to treatment of a condition referred to herein, particularly in a patient exhibiting symptoms of a disease or disorder. As used herein, the term "treatment" refers to any administration of a compound of the present invention and refers to (i) inhibition of disease in an animal experiencing or exhibiting disease pathology or symptoms (i.e., further development of pathology and/or symptoms). deterrence) or (ii) amelioration of disease (ie, reversal of pathology and/or symptoms) in animals experiencing or displaying pathology or symptoms of disease. The term “control” includes preventing, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a subject compound that will elicit a biological or medical response in a tissue, system, animal or human being examined by a researcher, veterinarian, physician or other clinician. In one example, a therapeutically effective amount is 50 nM/kg subject body weight, 10 to 100 nM/kg subject body weight, 25 to 75 nM/kg subject body weight, 10, 20, 30, 40, 50, 60, 70, 80, 90 , or 100 nM/kg subject body weight.

As used herein, the term "administration of" or "administration of" a compound refers to oral dosage forms such as, but not limited to, tablets, capsules, syrups, suspensions, and the like; injectable dosage forms such as intravenous (IV), intramuscular (IM) or intraperitoneal (IP); enteral or parenteral, transdermal dosage forms including creams, jellies, powders or patches; buccal dosage form; inhalation powders, sprays, suspensions, etc.; and providing a compound of the present invention to a subject in need of treatment in a therapeutically useful form, including rectal suppository, and in a form that can be introduced into the subject's body in a therapeutically useful amount.

As used herein, the term “intravenous administration” includes injection and other intravenous modes of administration.

As used herein to describe a carrier, diluent or excipient, the term "pharmaceutically acceptable" must be compatible with the other ingredients of the formulation and not injurious to the recipient.

The curcumin formulations of the present invention may contain one or more optional pharmaceutical excipients, diluents, extended or controlled release agents, lubricants, preservatives or any combination thereof, and when dissolved may be added to or administered to an injectable antidiabetic drug, or , can be administered on a schedule according to the release kinetics of the curcumin formulation. A number of biodegradable polymers can be used in the formulations of the present invention. Non-limiting examples of polymers include polyesters, polylactides, polyglycolides, polycaprolactone polyanhydrides, polyamides, polyurethanes, polyesteramides, polydiaxanone, polyacetals, polyketals, polycarbonates, Polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxyvalerates, polyhydroxyvalerates, polyalkelene oxalates, polyalkylene succinates, poly(mal) acids, poly(amino acids) ) acids, copolymers, terpolymers, and combinations or mixtures thereof. Specific polymers that may be used include acrylic acid, vinylpyrrolidinome, N-isopropylacrylamide or combinations and variations thereof. Synthetic curcumin that may be used includes curcumin, curcumin analogues, curcumin derivatives and any variations thereof.

treatment of infectious diseases. The late stages of Ebola and other viral diseases are often the onset of a cytokine storm in which cytokines are produced in large quantities by the body's immune system. The present invention includes the treatment of infectious agents that induce cytokine storms, such as Ebola virus, through the action of curcumin to inhibit cytokine release and cytokine storms.

Curcumin has been shown to block cytokine release, most importantly the major pro-inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis factor-α. Curcumin's inhibition of cytokine release has been associated with clinical improvement in experimental models of disease conditions in which cytokine storms play an important role in mortality. Thus, curcumin can be used to treat the cytokine storm in Ebola patients. In certain instances, intravenous formulations enable the achievement of therapeutic blood levels.

The high mortality of patients infected with Ebola virus is considered to be due in part to the initiation of a cytokine storm at an advanced stage of infection ^1-2. Cytokine storms can occur after a variety of infectious and non-infectious stimuli. In the cytokine storm, numerous pro-inflammatory (IL-1, IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines are released, leading to hypotension, hemorrhage, and ultimately multi-organ failure. The term "cytokine storm" is most associated with the 1918 H1N1 influenza pandemic and more recent cases of avian influenza H5N1 infection ^3-5. In this case, young individuals with healthy immune systems died disproportionately from the disease, and abnormal activity of the immune system is considered to be the cause. This syndrome is also known to occur in advanced or late-stage cases of SARS ⁶ , Epstein-Barr virus-associated erythrocytopenic lymphohistiocytosis ⁷ , Gram-negative sepsis ⁸ , malaria ⁹ and numerous other infectious diseases. Cytokine storms can occur from non-infectious causes, such as acute pancreatitis ¹⁰ , severe burns or trauma ¹¹ , and acute respiratory distress syndrome following drug use or inhalation of toxins ¹² . In a recent phase 1 trial, injection of TGN1412, a monoclonal antibody that binds to the CD28 receptor on T cells, resulted in severe cytokine storms and multi-organ failure in six human volunteers who received the agent. This was despite the fact that prescribed doses of this drug were 500 times lower than those found to be safe in animals ^13. Other viruses include rhinovirus, coronavirus, paramyxoviridae, orthomyxoviridae, adenovirus, paramyxovirus Influenza virus, metapneumovirus, respiratory syncytial virus or influenza virus.

Inhibition of the cytokine curcumin

Curcumin has been shown to inhibit the release of numerous cytokines. Abe et al. reported that curcumin is inhibited by IL-1β, IL-8, TNF-α, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) from monocytes and macrophages. ) was shown to inhibit release. Jain et al showed that curcumin significantly reduced the release of IL-6, IL-8, TNF-α and MCP-1 from monocytes cultured in a hyperglycemic environment ¹⁵ . These same investigators studied rats with streptozotocin-induced elevations in plasma glucose levels and significant elevations in IL-6, TNF-α and MCP-1 levels; These levels were significantly reduced by curcumin ^{15 .} Curcumin significantly reduced IL-6 in rheumatoid synovial fibroblasts ¹⁶ , IL-8 in human esophageal epithelial cells ¹⁷ and alveolar epithelial cells ¹⁸ , bone marrow stromal cells ¹⁹ , colon epithelial cells ²⁰ and human It has been reported to block the release of IL-1 from articular chondrocytes ²¹ . Curcumin also prevents the release of IL-2 ²² , IL-12 ^22-23 , Interferon-γ ^22-23 and many other key cytokines ^24-26 (Tables 1 and 2).

Example 1: Curcumin cytokine inhibition is associated with clinical improvement in conditions associated with cytokine storms.

Curcumin has a positive effect on numerous disease conditions in patients and animal systems. Avasarala et al reported the effects of curcumin on cytokine expression and disease progression in a mouse model of virus-induced acute respiratory distress syndrome. Curcumin reduced the expression of the major cytokines IL-6, IL-10, interferon γ, and MCP-1, which were associated with significant reductions in inflammation and reductions in fibrosis ^27. Yu et al. showed that it was associated with reduced pancreatic damage in a mouse model of acute pancreatitis ^28. Cheppudira et al. reported that curcumin's inhibition of IL-8 and GRO-α, and ultimately NF-κB, was associated with reduced thermal injury in a rat model. ^29. Curcumin's cytokine inhibition is also associated with clinical improvement in severe viral infection models. Song et al showed that curcumin administration reduced the expression of IL-1β, IL-6 and TNF-α, and ultimately NF-κB, and protected against coxsackie virus-induced severe myocardial damage in infected mice. ^30. Curcumin has been shown to be active against numerous viruses, including coronavirus, HIV-1, HIV-2, HSV, HPV, HTLV-1, HBV, HCV and Japanese encephalitis virus ^. Paramyxoviridae, orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus or influenza virus. Additionally, curcumin has been shown to have specific activity against H1N1 virus in culture ^32-33 , but cytokine levels were not measured in these two studies. Most importantly, curcumin has been shown to stimulate the SOCS protein ^{34 .} This protein has been shown to play an important role in protecting against severe cytokine storms in mice infected with influenza virus ³⁵ .

Curcumin's activity to inhibit several cytokines and its activity in experimental models of diseases and conditions associated with cytokine storms suggest that curcumin may be useful in the treatment of patients with Ebola and cytokine storms. Curcumin is poorly absorbed from the intestine; The intravenous formulation makes it possible to achieve therapeutic curcumin blood levels in patients diagnosed with a cytokine storm. Clinical status and levels of important cytokines such as IL-1β, IL-6 and TNF-α should be carefully monitored when patients are being treated with curcumin.

Curcumin effect on interleukins biomolecule main function ↓IL-1 Key pro-inflammatory cytokines, hematopoiesis, CNS development ↓IL-2 T cell lymphocyte differentiation ↓↑IL-4 B cell proliferation ↓IL-5 Immunoglobulin secretion, eosinophil function, allergy ↓IL-6 Key pro-inflammatory cytokines, B cell differentiation, neuronal differentiation ↓IL-8 Neutrophil chemotaxis, angiogenesis ↑IL-10 Anti-inflammatory cytokine, also has T cell stimulating effect ↓IL-11 Induction of acute phase proteins, antigen-antibody response, and bone remodeling ↓IL-12 Defense against intracellular pathogens ↓IL-13 Matrix metalloproteinase induction, IgE induction ↓IL-17 pro-inflammatory cytokines

Curcumin inhibition of other key cytokines biomolecules main function ↓TNF-α Induction of secretion of key pro-inflammatory cytokines, insulin resistance, and corticotropin-releasing hormone ↓Interferonγ Macrophage activation, T and B cell activation and differentiation ↓MCP-1 (CCL2) Neuroinflammation, monocyte and basophil chemotaxis ↓M1P-1α (CCL3) Activation of granulocytes, induction of pro-inflammatory cytokine synthesis ↓GROα(CXCL1) Neutrophil chemoattractant, angiogenesis, wound healing ↓GROβ(CXCL2) Neutrophil and monocyte chemoattractants ↓IP-10 (CXCL10) Monocyte and macrophage chemoattractants, NK cell chemoattractants, angiogenesis ↓SDF-1 (CXCL12) Lymphocyte chemoattractant, angiogenesis, inhibition of osteoclastogenesis

Test result. first study.

Liposomes and liposome-curcumin were prepared as 6 mg/ml solutions. Curcumin (solid) was dissolved in DMSO at 6mg/ml. All three compounds were tested in an EBOV infection assay using two cell lines Hela and HFF-1. There were two sets of studies performed with different dilution strategies.

The Hela cell line was used in two independent experiments (duplicate replicate 1 and duplicate replicate 2) and HFF-1 was used in one. Two hours prior to infection, liposomes and curcumin-liposomes were diluted with medium from the highest concentration of 600 ug/ml (final in the assay) to generate 10 points for the dose response curve in 2-fold serial dilutions. 5ul of each dose was dispensed into assay wells with cells with a PE Janus 384 tip dispenser. Curcumin (solid) was dispensed directly from a 100% DMSO stock into assay wells with cells by HP D300. DMSO was normalized to a final 1% in all wells. Each dose was tested 4 times in plates n=4.

Test result. second study.

Both cell lines were used in one study (duplicate replicate 1). Two hours prior to infection, Curcumin-Lip and Lip. were diluted in medium from the highest concentration of 60 ug/ml (final in the assay) to generate 10 points for the dose response curve in 2-fold serial dilution. Titration in this case was performed with manual mixing and changing tips for each new dose. Curcumin (solid) was manually titrated in DMSO and then diluted 1/10 in media while mixing equal amounts for each dose. 5ul of each dose was dispensed into assay wells with cells with a PE Janus 384 tip dispenser. Each dose was tested 4 times in plates n=4. In both studies: cells were infected with EBOV (Zaire) at MOI=0.5 for Hela cells and MOI=3 for HFF-1, and infection was stopped after 48 h by fixing cells in formalin solution. Immunostaining was performed using an anti-GP antibody to detect infected cells. Images were taken with a PE Opera confocal platform with a 10x objective lens analyzed using Acapella software.

Signals for GP-staining were converted to % infection. The number of nuclei per well was used to determine the percent viability of cells (n=16 compared to infected but untreated control wells). Data were analyzed using GeneData software and % infection was converted to % inhibition (INH%) using plate controls.

1A and 1B show the percent inhibition and percent viability achieved with liposomal curcumin in HeLa cells, respectively. 2A and 2B show percent inhibition and percent viability using solid S-curcumin curcumin in HeLa cells, respectively. Similar results were obtained in the same study using HFF-1 cells.

3A and 3B show percent inhibition and percent viability comparing liposomal curcumin and solid curcumin in HeLa cells, respectively. Similar results were obtained in the same study using HFF-1 cells.

Anti-EBOV activity was determined in Hela cells and was related to “cytotoxicity”. Briefly, the results are as follows: (1) curcumin-liposome EC ₅₀ =2.5 ± 0.2ug/ml, safety index =2. Liposome EC ₅₀ =3.9±0.2ug/ml, safety index = 4. Curcumin EC ₅₀ =6.5 ±0.5ug/ml, safety index = 1. Therefore, liposomes have an EC ₅₀ =0.6 ± 2ug/ml, which is a very good safety index of about 50. indicates

Role of the pro-inflammatory cytokines: ceramide and sphingosine-1 phosphate pathways in the cause of prolonged QT interval. There is increasing evidence that excessive levels of pro-inflammatory cytokines play an important role in the pathogenesis of the prolonged QT syndrome. Anticancer tests showed QT prolongation as a side effect of interferon γ, a cytokine, and QT prolongation after interleukin-18 treatment. Patients with inflammatory diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease have a higher incidence of QT prolongation and a higher mortality rate from this complication. The degree of QT prolongation was shown to directly correlate with the degree of elevation of the major pro-inflammatory cytokines TNF-α, IL-1β and IL-6. A large study of normal populations has shown that asymptomatic elevations of these cytokines are associated with QT prolongation. Clinical trials of the IL-6 blocker tocilizumab in patients with rheumatoid arthritis previously showed shortening of the prolonged QT interval, and the degree of QT shortening was associated with a decrease in serum inflammatory markers. Studies in animal models and cultured cardiomyocytes have shown that TNF-α inhibits IKr, IK and Ito. This was considered to be due to stimulation of reactive oxygen species (ROS). TNF-α and other cytokines have been shown to increase ROS production. The effects of TNF-α can be blocked by administration of anti-TNF-α antibodies or antioxidants. IL-1β 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 tight association between phospholipidemia and prolonged QT provides another hint to the importance of these cytokines. 77% of agents that can induce phospholipidosis are also hERG channel blockers. Phospholipidosis cells have been shown to secrete large amounts of TNF-α and IL-6 after LPS stimulation. It has also been speculated that the mechanism of damage in drug-induced phospholipidosis is the accumulation of ceramide. Numerous studies have shown that cytokines such as interferon γ, IL-1β and TNF-α increase sphingomyelinase activation and increase the production of ceramide, which is known to inhibit hERG currents. It is also known that sphingolipids mediate ROS signaling. Ceramides are metabolized to sphingosine and fatty acids, and sphingosine is phosphorylated by sphingosine kinase to form sphingosine-1 phosphate. Ceramide and sphingosine-1 phosphate show opposite effects of ceramide, which induces apoptosis, and sphingosine-1 phosphate, which promotes cell survival. Fingolimod, a sphingosine analogue (having both agonist and antagonist effects on the sphingosine-1 phosphate-1 receptor), is used to treat patients with relapsing multiple sclerosis and induces QT prolongation through suppression of hERG currents and causes lethal ventricular cause sexual arrhythmia In addition, a study on a mouse model of influenza-induced cytokine storm showed that sphingosine-1 phosphate-1 signaling is a major pathway for activation of cytokine storm. The cytokine storm was reversed by sphingosine analogues through feedback inhibition of cytokines, resulting in significant reductions in TNF-α, IL-1α, IL-6, MCP-1, interferon α and MIP-1α and clinical improvement. The survival rate of mice in this study was much higher with sphingosine analogues than with antiviral therapy. In addition, agents that have been clinically shown to be inhibitors of QT prolongation, progestins, statins, liposomal curcumin, resveratrol, and antioxidants have also been shown to be potent inhibitors of these inflammatory cytokines. Even β-blockers, the standard treatment for patients with prolonged QT, appear to inhibit cytokines as part of their mechanism of action to treat these patients. All these agents shift the balance from the ceramide pathway towards the sphingosine-1 phosphate pathway. Thus, excessive levels of pro-inflammatory cytokines play an important role in the etiology of the prolonged QT syndrome, presumably through stimulation of the ROS and ceramide pathways.

For purposes of illustration, but not limiting the present invention, a proposed mechanism for modifying the previously prolonged QT interval by liposomal curcumin and EU8120 is described. There is ample evidence from early phase 2 anticancer trials of pro-inflammatory cytokines and from recent studies in patients with rheumatoid arthritis, psoriasis and inflammatory bowel disease that increased pro-inflammatory cytokine levels lead to a prolongation of the QT interval. These patients have a markedly increased incidence of prolonged QT. In addition, anti-IL-6-antibody trials in patients with rheumatoid arthritis showed a shortened QT that was associated with a decrease in cytokines. A correlation between increased cytokine levels and asymptomatic QT prolongation is also found in large studies of normal populations. In animal models and ventricular myocytes, TNF-α administration reduces the fast component of the delayed rectifier potassium current (IKr), the slow component of the delayed rectifier current (IK), and the transient outward current (Ito). These effects are considered to be due to stimulation of reactive oxygen species (ROS) and can be blocked by administration of anti-TNF-α antibodies or antioxidants. Other studies have shown that TNF-α and other pro-inflammatory cytokines stimulate ROS production. IL-1β and IL-6 also show a QT prolonging effect in this model. Research on other diseases is also known to shift the balance from the sphingosine-1-phosphate (S1P) pathway (protection) to the ceramide pathway (destruction) by increasing ceramide production. Several studies in experimental models have shown that ceramide inhibits hERG currents. It has been suggested that statins, which reduce the levels of pro-inflammatory cytokines and cause shortening of the prolonged QT, may have stimulation of this protective S1P pathway as an underlying mechanism. Other agents that shorten prolonged QT, including antioxidants such as vitamin E, reduce levels of pro-inflammatory cytokines and ROS and stimulate S1P. Finally, we have a list of agents that cause cytokine inhibition and shortening of the previously prolonged QT interval, which have been shown to reduce cytokine levels and secondary brain inflammation in animal models, as well as reduce the extent of brain damage. It was found to be strikingly similar to the list of . Thus, the present invention can be used to shift the balance from the sphingosine-1-phosphate (S1P) pathway (protection) to the ceramide pathway (disruption) by targeting diseases that increase ceramide production.

We found that liposomal curcumin and EU8120 reduced IL-1β, IL-6, TNF-α, MCP-1, MIP-1 and Rantes in both in vitro and in vivo models. Liposomes have also been shown to shift the ceramide/S1P balance to S1P by competing with the enzyme sphingomyelinase and lowering ceramide levels in another model.

LPS-induced cytokine storm produces QTc prolongation, which is prevented by anti-inflammatory lipids. There is increasing evidence that excessive levels of pro-inflammatory cytokines play an important role in the pathogenesis of the prolonged QT syndrome. In contrast, blocking agents such as tocilizumab (IL-6) or anti-cytokine antibodies (TNFα) are involved in shortening the previously prolonged QT interval.

In this study, LPS and Kdo2-lipid-A were used to induce cytokine release in guinea pigs and Q-ELISA measurements of cytokine production were performed after concomitant ECG monitoring and blood draw. Guinea pigs were selected because they yield reliable QTc prolongation as a result of arrhythmia induction experiments with T waves consistently appearing on ECG. Adult male guinea pigs were given 300 μg/kg LPS at time 0, and ECGs were analyzed after 1, 2, and 4 hours of LPS, and bled simultaneously. Animals given LPS showed only an 8-msec increase in QTc 1 hour after LPS when TNFα levels were maximal at 5.5 times the pre-LPS value. A 29-msec QTc prolongation after 2 h of LPS was associated with a 7- and 9-fold increase in IL-1β and IL-6, respectively. QTc prolongation was maintained even after 4 h of LPS when animals were euthanized (27 msec). When 9 mg/kg of EU8120 (a lipid mixture shown to prevent IKr channel blockade by various hERG blockers) was administered 1 hour before LPS induction, QTc prolongation was limited to 5 ms after 2 hours and completely prevented after 1 and 4 hours of LPS. Plasma levels of TNFα, IL1β and IL-6 were significantly lower in EU8120 administered animals. This example shows that EU8120 inhibits QTc prolongation through an anti-inflammatory cytokine effect and not through interaction with an active agent (LPS).

synthetic curcumin.

The present invention may use compositions to treat cytokine storm disorders using synthetic curcumin (S-curcumin).

Curcumin is the active ingredient of the turmeric plant synthesized in near purity (99.2%). It can be formulated as liposomes, polymers or PLGM and administered intravenously over 1 to 72 hours as a bolus or continuous infusion along with other active agents. Curcumin has antioxidant and anti-inflammatory activity and can block autonomous intracellular signaling pathways that are aberrantly responsive to extracellular growth factors, uncontrolled cell proliferation and fibrosis-related and tissue-degenerative conditions. In particular, curcumin reacts negatively with components of key signaling pathways that command proliferation, metabolism, survival and death.

Oral and topical administration of turmeric plant extracts has been used in traditional medicine for over 2000 years. Oral administration has no systemic toxicity but no systemic therapeutic activity. This is due to blood insolubility, barrier and hepatic inactivation, ie very little bioavailability for systemic diseases via the oral route. To overcome these limitations, parenteral intravenous curcumin formulations including liposomes, polymers (n-isopropylacrylamide, N-vinylpyrrolidione and acrylic acid) and polylactic acid glycolic acid copolymers have been introduced into preclinical drug development. ⁴

Curcumin, an extract of turmeric root, is available to researchers as a mixture of three curcuminoids and, according to the FDA, to the public as a food supplement or spice. The extract is 79.2% curcumin (diferuloylmethane), 18.27% demethoxycurcumin and 2.53% bisdemethoxycurcumin.

The synthesized curcumin is 99.2% pure diferuloylmethane of GMP grade produced for non-human experimental studies and future phase I clinical trials. There are clear differences between the C3 tri-component extract and the mono-component synthetic S-curcumin, extending to identifiable analytical, physicochemical and biological properties. In certain aspects, 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 activity of S-curcumin to liposomal curcumin, NANOCURC ^® and PLGA-curcumin (hereafter referred to as C3-complex).

Liposomal Curcumin: Initial studies of liposomal curcumin were conducted using material purchased as a complex. Studies with ^6-7 S-curcumin are Mach CM, et al (2009) ⁸ and Mach CM et al (2010) ⁹ .

^Nanocurc® : Initial studies of Nanocurc® were conducted using product purchased from Savita Bisht et al (2007) ¹⁰ using a non-sabinsa source. Since then, research on S-Curcumin is used in the rest of Nanocurc® publications. ^11-13

PLGA-Curcumin: Initial studies of PLGA-Curcumin were conducted using products made with C3-complex. ^14-18 Studies included PLGA-curcumin C3 complex and PLGA-S-curcumin pharmacokinetic studies in the rat brain.

A comparison of PLGA C3-complex-curcumin versus PLGA S-curcumin revealed the following differences. Solubility of 99.2% S-Curcumin in all four solvents. Ethanol, ethyl acetate, acetone and acetonitrile were significantly different from the C3 complex containing 76% curcumin. When normalized to the same concentration, the pure substance exhibits greater solubility. This confers improved manufacturing capabilities and attributes to various pharmacokinetics and pharmacodynamics in an in vivo environment (Table 3).

Solubility of S-curcumin and C3-complex curcumin in different organic solvents. menstruum Weight of Curcumin
(mg) amount of solvent
(μL) density
(mg/mL) physical state of solubility Solvent in which 1 g of solvent is dissolved (mL) Batch-C100609, Curcumin=99.2% ethyl acetate 20.8
2000 10.4 part 96.2 ethanol 17.5 4600 3.804 part 263 acetone 46.5 1100 42.3 entire 23.6 acetonitrile 17.4 3200 5.44 part 184 Batch-C3 Complex Curcumin=76% ethyl acetate 21.5
1800 11.9 entire 83.7 ethanol 28.4 6500 4.37 entire 229 acetone 39.8 700 56.9 entire 17.6 acetonitrile 18.2 2900 6.28 entire 159

* Weigh the sample and transfer it to a scintillation vial. Add a small amount of solvent and stir well repeatedly with each addition until dissolved.

Comparison of differences between S-curcumin and C3-complex curcumin. C3-curcumin S-Curcumin Residue on Ignition 0.03% 0.4% loss on drying 0.98% 0.24% melting range 172-175 C 179.8-181.9C tapped bulk density 0.61 g/ml 0.26 g/ml loose bulk density 0.37 g/ml 0.18 g/ml sieve test -40 mesh 100% 64.71% -80 mesh 98.27% 64.0% HPLC content curcumin 79.2% 99.2% total curcuminoids 96.21% 99.2% Bisdemethoxycurcumin 2.53% 0 Demethoxy Curcumin 18.27 0 heavy metal lead 0.91 ppm (ug/g) <0.2ppm arsenic 0.54 ppm (ug/g) <0.2ppm cadmium <0.2 ppm (ug/g) - Mercury <0.02 ppm (ug/g) - residual solvent according to table according to table Total number of microplates <100cfg 10 cfu/g yeast and mold count <10 cfu/g 15 cfu/g Escherichia coli neg/10g neg/10g Salmonella neg/10g neg/10g Staph. aureus neg/10g neg/10g Pseudomonas aeruginosa neg/10g neg/10g

4A is a graph showing the effect of liposomal curcumin on liver function during sepsis including aspartate aminotransferase (AST) and alanine aminotransferase (AST) levels in a mouse model system. Results show the effect of liposomal curcumin compared to standard of care for sepsis on age-matched controls. Liposomal curcumin showed higher efficacy compared to standard treatment for AST and ALT.

4B-4D show creatine, neutrophil gelatinase-associated lipocalin (NGAL), which measures the progression of chronic kidney disease, and blood urea, which measures the ability of the kidneys to remove urea from the blood, respectively. A graph showing the effect of liposomal curcumin during sepsis on renal function on glomerular filtration rate (GFR) by measuring nitrogen (Blood Urea Nitrogen). Liposomal curcumin showed higher efficacy in maintaining kidney function compared to standard treatment, particularly NGAL, which measures the progression of chronic kidney disease.

4E and 4F show liposomal curcumin during sepsis for cardiac function for c-troponin, which measures cardiac tissue damage, and for percent ejection fraction, which measures the efficiency of the left ventricle (or right ventricle) to pump blood with each heartbeat. It is a graph showing the effect of Liposomal curcumin was shown to reduce cardiac damage compared to standard treatment and equal to standard treatment in ejection fraction ratio.

4G is a graph showing the effect of liposomal curcumin during sepsis on overall survival. Liposomal curcumin showed a higher survival time compared to standard of care treatment.

Yang, et al., Protective effect of curcumin against cardiac dysfunction in sepsis rats, Pharmaceutical Biology, 2013; 51(4): 482-487], the present invention showed a significant improvement in results without the cardiotoxicity associated with curcumin.

14:0 lysophosphatidylglycerol (lyso PG)

myristoyl monoglyceride

Myristic acid, a free fatty acid

Example 2

Brain damage after traumatic brain injury (TBI) is a two-step process: the damage caused by the initial injury leads to an inflammatory phase in which significant further damage can occur. This inflammation begins within minutes of the initial injury, may persist for months or years, and includes a series of marked increases in cytokines, particularly pro-inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α. is the result of complex metabolic processes. Levels of these cytokines can increase thousands of fold above the corresponding levels in serum. Strategies for regulating the levels of these pro-inflammatory cytokines and reducing cytokine-induced brain damage are discussed. There is extensive evidence from animal model experiments that cytokine inhibition is effective in ameliorating neurological damage after TBI. However, the efficacy of this approach must be demonstrated in patient trials.

It is increasingly recognized that abnormal immune systems and massive overproduction of pro-inflammatory cytokines, 'cytokine storms', are major factors in disease progression and mortality from a number of diseases. After infection with malaria [1], SARS [2], dengue fever [3], leptospirosis [4], Lassa fever [5], Gram-negative sepsis [6], as well as numerous other infectious diseases [7-10], 'cytokine A cytokine storm, also called 'release syndrome', can occur. Cytokine storms are the leading cause of death in Ebola patients [11-13]. Cytokine storm patients may experience increased vascular permeability, severe hemorrhage, and multi-organ failure, which may ultimately cause fatal outcomes [8, 13, 14]. Significant increases in systemic cytokine levels of both pro-inflammatory and anti-inflammatory cytokines are seen. This excessive production of cytokines by a healthy immune system is thought to explain why people in their 20s and 40s were more likely to die than older people during the 1918 H1N1 pandemic [15, 16]. Cytokine storms can also occur after severe burns or trauma [17], acute pancreatitis [18], or ARDS following toxin inhalation. Severe acute graft-versus-host disease can be considered a cytokine storm [20, 21]. The cytokine storm is caused by the commonly used anti-tumor drug rituximab [22] and the monoclonal antibodies tositumomab, alemtuzumab, muromonab and blinatumomab. ) [23] is known to be a complication of treatment. Elevated levels of cytokines are associated with Alzheimer's disease [24], Parkinson's disease [25], autism [26] and multiple sclerosis [27], as well as in acute phase Gillian. - It is considered an important cause of pathology in many neurological conditions including Guillian-Barre syndrome [28, 29]. Elevated cytokine levels are associated with worsening of psychiatric disorders [30, 31] and lupus encephalopathy [32, 33].

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 sequelae are particularly common after severe injury [35]. Brain injury after traumatic brain injury is due to a cascade of processes involving the initial stage of damage caused by an external mechanical force and cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. It is now understood that damage occurs in two phases of secondary inflammatory stages where it can occur [36]. Increased levels of cytokines in the brain can increase dramatically, especially after a severe TBI. IL-6 is generally not detectable in CSF or can be detected only at very low concentrations (1 to 23 pg/ml) [37, 38]. In one study, CSF levels of IL-6 as high as 35,500 pg/ml were found after severe TBI [38, 39]. These IL-6 levels were 40 to 100 times higher 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 at 24, 72, and 168 hours of admission after severe TBI in 22 patients. In the 9 deceased, mean IL-6 values in CSF were 15 241, 97 384, 548 225 and 336 500 pg/ml compared to 102, 176, 873 and 3 059 pg/ml in blood, a 'storm' of cytokines. was mostly located in the brain. For the 13 survivors, mean IL-6 CSF values were lower but still significantly higher than in peripheral blood, with 5 376, 3 565, 328 and 764 pg/ml compared to 181, 105, 37 and 26 pg/ml in blood. [41]. A similar difference was seen in IL-8. Although IL-8 levels in CSF are generally very low (5 to 72 pg/ml) [37], Kushi et al reported that CSF IL-8 levels were consistently elevated thousands of times above normal or comparable levels in peripheral blood. [41]. These investigators also noted that significantly elevated IL-6 and IL-8 blood levels even after 72 hours were associated with poorer prognosis and higher mortality. Helmy et al. reported IL-1α, IL-1β, IL-6, IL-8, IL-10, monocyte chemotactic protein (MCP-1) and macrophage inflammatory protein-1α in brain extracellular fluid after severe TBI in 12 patients. We found significant elevations of several cytokines including (MIP-1α). These levels were significantly increased compared to corresponding blood levels [42]. Other researchers reported similar results and indicated that very high cytokine levels were associated with poor prognosis [43, 44]. For example, Arand et al noted that IL-6 levels were 8-fold higher in deceased patients compared to living patients. In addition, elevated levels of another pro-inflammatory cytokine, IL-12, were found only in deceased patients [43]. These data support the hypothesis that a cytokine storm is responsible for increased neurological damage after TBI. Many studies suggest that some of these same cytokines can have both beneficial and detrimental effects on the brain [45-47]. However, numerous studies have shown that blockade of these cytokines can reduce brain damage after TBI, at least in animal models. A list of the major cytokines increased in the brain and CSF after TBI is shown in Table 5.

Key cytokines show marked increases in brain and CSF after TBI cytokines function TNF-α May also have major pro-inflammatory cytokine, insulin resistance, promote apoptosis, and neuroprotective function IL-1α Pro-inflammatory cytokine, stimulates TNF-α release from endothelial cells IL-1β Regulation of production of key pro-inflammatory cytokines, IL-2, IL-6, IL-8 and interferon-γ, stimulation of phagocytosis and programmed cell death, early CNS development IL-2 Pro-inflammatory cytokines, T cell lymphocyte differentiation IL-4 Anti-inflammatory cytokine, also promotes B cell proliferation IL-6 Major pro-inflammatory cytokines, B cell differentiation, neurogenesis, and myokine anti-inflammatory functions (inhibition of IL-1 and TNF-α) IL-8 (CXCL8) Key pro-inflammatory cytokines (chemokines), neutrophil chemotaxis IL-10 Key anti-inflammatory cytokine, also has T cell stimulatory function IL-12 Pro-inflammatory cytokines, T cell differentiation interferon-γ Pro-inflammatory cytokines, T and B cell lymphocyte and macrophage activation MCP-1 (CCL2) Pro-inflammatory cytokines, monocyte and basophil chemotaxis MIP-1α (CCL3) Pro-inflammatory cytokine, induction of pro-inflammatory cytokine synthesis, neutrophil activation TGF-β Anti-inflammatory cytokines, also pro-inflammatory functions, may have long-term detrimental effects

Interleukin-1. The IL-1 family is a group of 11 cytokines that are closely involved in the body's response to injury or infection [48, 49] and play important roles in tumor angiogenesis [50] and stimulation of cancer stem cells [51]. The most important cytokines in the IL-1 group are IL-1β, IL-1α and the IL-1 receptor antagonist IL-1RA, but the IL-1 group includes the pro-inflammatory cytokines IL-18, IL-33, IL-36, A number of poorly studied cytokines are also included. The major cytokine IL-1β is a protein produced by activated macrophages. Among these, the most important functions are neutrophil activation, regulation of production of other cytokines (IL-2, IL-6, IL-8, interferon-γ), regulation of mitosis, stimulation of phagocytosis, thermogenesis, angiogenesis and programmed cell death [ 48, 49]. Elevated levels of IL-1β have been found in the CSF of TBI patients and can be detected within minutes after acute injury [38, 52, 53]. Very high CSF levels in patients with TBI are associated with poor prognosis [54, 55].

Similar results were obtained in studies on animal models [56-60]. Kamm et al showed that IL-1β levels appeared in the brain of rats within the first hour after TBI and peaked at 8 hours, and no changes in IL-1β levels were detected in the blood or liver [56]. In addition, intraventricular administration of IL-1β in animal models has been shown to significantly aggravate brain damage [61]. Most importantly, administration of an IL-1β antagonist prevents this cytokine-induced damage in experimental models. Administration of IL-1RA to rodents has been shown to reduce brain damage after TBI. For example, Yang et al previously showed that brain damage due to middle cerebral artery occlusion in mice was reduced in animals transfected with an adenoviral vector to induce IL-1RA overexpression [62]. Jones et al showed that administration of a single intraventricular dose of IL-1RA to mice during the development of TBI reduced lesion volume, improved function, and significantly reduced nitric oxide synthase-2 positive cells in the lesion [63- Jones]. Sanderson et al studied the effects of systemically administered IL-1RA on Sprague Dawley rats after TBI. No effect was observed at low doses. After high-dose administration, the researchers observed a decrease in the animals' neurological loss and an increase in memory and cognitive function. However, motor function was not improved [64]. Hasturk et al showed that IL-1RA reduced tissue IL-1β levels and increased levels of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in rats after TBI. [65]. Other groups reported similar results [66, 67]. Basu et al also reported that mice lacking the IL-1 receptor experienced less brain damage after traumatic injury [68]. Researchers found decreased basal levels of IL-1, IL-6 and COX-2 and reduced amoebic microglia/macrophages, suggesting that a cycle of brain inflammation was prevented at this critical stage. In addition, Tehranian et al. reported that transgenic mice overexpressing human IL-1RA in astrocytes showed reduced levels of IL-1β, IL-6, and TNF-α and better neurological outcomes after head injury compared to wild-type mice. showed recovery [69].

These data suggest that the use of IL-1RA may be an effective strategy in TBI patients. Human recombinant IL-1RA has been a standard drug for patients with rheumatoid arthritis for many years, and its use has been found in diabetes [70], heart failure [71], multiple myeloma [72] and sepsis. ) [73] have been studied in a number of diseases involving increased cytokines in destructive processes. In a randomized phase 2 trial for patients with acute stroke, patients treated with IL-1RA had less cognitive loss compared to the control group [74]. Helmy et al conducted a phase 2 controlled trial of this agent in 20 patients with severe TBI and were able to conclude that IL-1RA passed the blood-brain barrier and was safe in this population [75]. They could not conclude that IL-1RA administration produced a therapeutic effect in these patients [75]. However, while many of these results are promising, the efficacy of IL-1RA may be limited as it directly blocks only one of the important cytokines involved in inflammation (IL-1RA can indirectly block other cytokines, while IL-1 may increase the expression of other cytokines), which may be part of the explanation for why this agent has not had greater than limited success for rheumatoid arthritis. In addition, combined use of TNF-α blockers and IL-1RA is contraindicated as serious side effects may occur from such combined use [76].

Tumor necrosis factor-α. The second major pro-inflammatory cytokine is TNF-α. This cytokine plays an important role in the body's response to infection and cancer. Since the report on TNF-α by Helson et al. in 1975 [77], it has been found to be abnormal in numerous diseases, including various conditions such as diabetes [78], cardiovascular disease [79], inflammatory bowel disease [80] and Alzheimer's disease [81]. TNF-α function has been reported. TNF blockers such as infliximab, etanercept, and adalimumab are standard of care for patients with rheumatoid arthritis, ankylosing spondylitis, and psoriasis. As mentioned, TNF-α is considered to have both beneficial and detrimental effects in patients with TBI [46]. However, results from experimental models suggest that these effects are mostly detrimental, especially when excessive levels of this cytokine are produced. Knoblach et al reported a correlation between the level of TNF in rats and the extent of brain damage and nerve damage after experimental TBI, and in rats with the most severe brain damage, TNF levels were highest 1 to 4 hours after injury [82]. In addition, studies using the TNF-blocker etanercept showed a sustained reduction in brain damage in these animals after administration of this agent. Chio et al. reported that administration of etanercept to rats after TBI reduced ischemia, increased glutamate levels, decreased neuronal and glial cell apoptosis and microglia activation, and increased levels of TNF-α [83]. In a later report, researchers concluded that etanercept alleviates brain damage by reducing the early expression of TNF-α by microglia [84]. Ekici et al showed that a combination of etanercept and lithium chloride administered 1 hour after TBI reduced cerebral edema, tissue damage and TNF levels [85]. Cheong et al. found that etanercept administered to rats immediately after TBI increased 5-bromodeoxyuridine and doublecortin markers in the damaged brain, suggesting that the increased TNF-α level in the brain is toxic to neural stem cells and inhibits neurogenesis. It was shown that it can interfere [86]. Wang et al reported that early use of this agent after injury promotes the survival of transplanted neural stem cells and promotes nerve regeneration [87]. Other groups have reported similar results using etanercept or other TNF blockers [88-91].

Although TNF blockers have been extensively studied in animal models, little work has been done to evaluate 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 patients with TBI treated with etanercept. Significant improvements in neurological function were also observed in patients treated more than 10 years after the initial injury. The researchers concluded that this supports the view that long-term inflammation, which lasts predictably for many years, is a major cause of nerve damage in these patients [93]. However, the data in this report are difficult to interpret as it is not clear whether TNF blockade is responsible for the observed improvements due to the small number of patients in the TBI group and the absence of controls. Randomized trials are needed to demonstrate benefit in patients with TBI, and TNF blockers can have significant toxicity. In addition, the use of these blockers in the treatment of these patients may not be the most effective strategy because TNF blockers only target a single cytokine and the use of these agents in combination with IL-1 antagonists is inconsistent.

Interleukin-6. A third major pro-inflammatory cytokine is IL-6. Like TNF-α, elevated IL-6 has been considered to be responsible for numerous diseases, and like TNF-α, IL-6 is considered to have beneficial as well as deleterious effects after TBI [94]. Indeed, IL-6 appears to have both beneficial and detrimental roles in many neurological conditions [95]. IL-6 plays an important role in the induction of nerve growth factor by astrocytes to repair damaged brain [39]. Ley et al reported that IL-6 knockout mice showed reduced neurological function after TBI compared to normal mice, again suggesting that IL-6 is required for neuronal recovery. However, IL-6 knockout mice showed significantly elevated levels of IL-1β [96]. A neuroprotective role of IL-6 was also suggested in a study of parenchymal IL-6 levels in the frontal lobe of patients after severe TBI. Significantly increased IL-6 levels were found in survivors compared to those who died, but IL-1β levels were not different [97]. However, the number of these studies was small.

On the other hand, numerous studies have suggested that IL-6 has deleterious effects after TBI. Conroy et al showed that IL-6 is toxic to rodent cerebellar granule neurons in culture [98]. Another study showed that intranasal administration of IL-6 to rats increased seizure intensity and increased mortality [99]. Similar results were obtained in transgenic mice displaying astrocyte IL-6 production from the glial fibrillary acidic protein promoter [100]. Yang et al showed that motor coordination deficits in mice after mild TBI could be corrected by IL-6 blockade [101]. Similar results have been reported in experimental spinal cord injury. Okada et al showed that an anti-IL-6 receptor mouse monoclonal antibody could increase functional spinal cord recovery in mice after injury [102]. Nakamura et al reported that antibodies against IL-6R reduced glial scar formation and increased recovery after spinal injury [103]. Crack et al reported that an anti-lysophosphatidic acid antibody significantly reduced brain damage in mice after experimental TBI. Researchers attributed this to a significant reduction in IL-6-induced secondary inflammation. The antibody did not affect the levels of IL-1β or TNF-α [104]. Suzuki et al suggested that the diverse results seen in these studies could be explained because the inflammatory effects of IL-6 predominate in the acute phase after TBI, and effects on neurogenesis may be important later [105]. Little work has been done to investigate IL-6 blockers in patients with TBI. Tocilizumab, an anti-IL-6 antibody, is available and used to treat rheumatoid arthritis patients [106] but this agent has not been studied in this population.

Anti-inflammatory cytokines. Anti-inflammatory cytokines such as IL-4, IL-10, IL-11, IL-13 and transforming growth factor (TGF)-β may also be significantly increased in inflammatory conditions. One of the major functions of these cytokines is to inhibit the synthesis of pro-inflammatory cytokines [107]. IL-10 is the most important anti-inflammatory cytokine, and IL-10 levels are markedly elevated in brain and CSF after TBI [54, 108]. Although IL-10 is also known to have a pro-inflammatory function [107], its main effect after TBI appears to be mainly to prevent inflammatory damage. Kumar et al studied cytokine levels in 87 patients with severe TBI for 12 months and found that patients with an elevated IL-6/IL-10 ratio at 6 months had a poor prognosis [109]. Studies in cell culture and animal models appear to confirm the protective effects of IL-10. Bachis et al showed that IL-10 blocks caspase-3 and reduces neuronal apoptosis after exposure of cultured rat cerebellar granule cells to toxic doses of glutamate [110]. Knoblach et al showed that intravenous or subcutaneous administration of IL-10 after experimental TBI in rats could reduce IL-1 synthesis and enhance neuronal recovery in animals. However, intraventricular administration was not effective [111]. Chen et al showed that mice lacking IL-10 failed to respond to the beneficial effects of hyperbaric oxygen treatment after TBI ([112]-literature [X. Chen 2013]). Bethea et al. showed that IL-10 reduced TNF-α production and improved motor function after spinal cord injury in rats [113]. Similar neuroprotective effects of IL-10 have been shown in other studies of experimental spinal cord injury [114, 115]. This suggests that another approach to treating patients with TBI may be to administer anti-inflammatory cytokines such as IL-10. Recombinant human IL-10 (ilodecakin) has been tested in a number of diseases. However, the results so far have been disappointing [116].

Targeting multiple cytokines

Progestin. It is well known in animal system studies that progestins can reduce nerve damage after TBI [117-121]. A major mechanism of neuroprotection seen in progestins is the ability of these agents to inhibit pro-inflammatory cytokines. Cutler et al showed that progesterone administered to aged male rats after TBI reduced brain levels of IL-6 at 24, 48 and 72 hours. NF-κB and COX-2 levels were also reduced, and rats improved motor performance, reduced cerebral edema, and reduced mortality ([122]-Cutler). He et al reported that intraperitoneal administration of progesterone could reduce IL-1β and TNF-α at 3 hours after injury. Similar results were obtained after administration of another progestin, allopregnanolone [123]. Chen et al reported that progesterone administered to rats after TBI reduced the levels of IL-1β, IL-6, and TNF-α in the brain as well as reduced apoptosis in brain tissue [124]. Pan et al showed that intraperitoneal administration of progesterone reduced brain levels of TNF-α and NF-κB in rats after experimental TBI. Treated rats also showed better results in the neurological severity score test [125]. Unfortunately, these results have not been confirmed in patient trials. Xiao et al reported positive results in a randomized trial of progesterone given within 8 hours of TBI [126]. However, this was not confirmed in a large multicenter trial. A large-scale phase 3 trial of progesterone in patients with TBI conducted by the Neurological Emergency Treatment Trial Network was prematurely discontinued due to lack of efficacy [127]. The second major clinical trial, SYNAPSE, was a multinational, placebo-controlled clinical trial of progesterone in 1,195 patients with severe TBI and showed no effect. On the Glasgow outcome scale, only 50.4% of the progesterone group had a positive outcome compared to 50.5% of patients receiving placebo [128, 129].

Statin. It is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used to inhibit cholesterol production in the liver. These drugs are widely used clinically in patients with hypercholesterolemia. Statins are also known to have significant anti-inflammatory effects. Chen et al. showed that pre-administration of lovastatin to rats subjected to experimental TBI induced significant reductions in IL-1β and TNF-α at brain injury sites at 6 and 96 hours after injury. Rats receiving the treatment significantly reduced FJB-positive degenerative neurons and exhibited better functional recovery [130]. Simvastatin has been shown to reduce brain levels of IL-1β and reduce microglia and astrocyte activation in rats after TBI with functional improvement in NCS scores. However, no changes in IL-6 or TNF-α levels were observed [131]. Atorvastatin was found to lower both IL-6 and TNF-α in mice after TBI. Hippocampal degeneration and functional neurological deficits were reduced in treated animals compared to controls [132]. There is also evidence that discontinuation of these statins in patients can lead to an increase in pro-inflammatory cytokines, including IL-6 [133-135], and discontinuation of these drugs after TBI appears to worsen prognosis [136]. . Additionally, a retrospective study suggests that statin use before injury is associated with better outcomes [137]. This led to the suggestion that these agents should be studied in patients with TBI. Only a few small clinical trials have been reported. Tapia-Perez et al investigated the effects of rosuvastatin in patients with severe TBI and reported that the amnesia time was reduced in the treated patients [138]. However, there was no difference in disability at 3 months. In addition, only 8 patients with rosuvastatin and 13 controls were included in this trial, and 21 of 43 patients with TBI evaluated were considered ineligible. In another small study in 19 patients and 17 controls who received rosuvastatin for 10 days, Sanchez-Aquilar et al found that patients with rosuvastatin had a dramatic decrease in plasma TNF-α levels and a disability score compared with placebo. reported improvement. No effect was seen on IL-1β, 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; There was no difference between the treatment group and the control group [140].

Tetracycline. Tetracycline has been shown to inhibit inflammation and to have better outcomes in several neurological conditions in animal models. Bye et al showed that minocycline could reduce IL-1β and IL-6 expression and microglia and macrophage activation in mice after TBI. Neurological function was better on day 1 in treated mice, but there was no difference at day 4 between treated and control mice [141]. However, a follow-up study of this same group showed comparative improvement in the minocycline group by week 6 [142]. Shanchez Mejia et al reported that minocycline administered to mice after TBI inhibited caspase-1 activation and decreased IL-1β, resulting in improved neurological function and reduced lesion volume in treated animals [143]. Lee et al. showed that minocycline administered to rats after spinal cord injury decreased TNF-α, increased IL-10, decreased neuronal cell death, and improved motor function [144]. Yrjanheikki reported that doxycycline or minocycline could reduce the mRNA induction of IL-1β converting enzyme and prevent neuronal cell death after ischemic stroke [145]. Other researchers have also reported positive results with tetracyclines in animal models of TBI [146-148]. However, Turtzo et al. were able to demonstrate no benefit in rats treated with minocycline after TBI [149]. Additionally, in another study, minocycline was found to increase ischemic brain damage in neonatal mice [150, 151].

Other anti-inflammatory drugs. A number of different agents have shown anti-inflammatory activity in animal models of TBI. Melatonin has been reported to reduce TNF-α and IL-1β and increase the number of surviving neurons in mice after TBI. Researchers considered this effect to be due to dephosphorylation of the m-TOR pathway [152]. Other researchers have also reported positive results for melatonin in animal models [153-156].

Zhu et al. reported that intraperitoneal administration of curcumin to mice 15 min after TBI significantly reduced the levels of IL-1β, IL-6, and MCP-1, and decreased the number of TLR4-positive microglia/macrophages, resulting in neuronal apoptosis. reported to decrease [157]. Other researchers have also reported the neuroprotective effects of curcumin in animal models of TBI [158-161].

Cyclosporine is a powerful immunosuppressive drug. Due to its wide range of effects on cytokines [162-165] and activity in animal models [166], it was studied in clinical trials in patients with TBI. However, no activity was found in a randomized, placebo-controlled trial of this drug in patients with TBI [167]. Formulations of cyclosporine (Neurostat) continue to be investigated in patients with TBI and other neurological conditions, but a recent report showed that Neurostat has no neuroprotective activity in acute ischemic stroke [168].

Many other agents that inhibit pro-inflammatory cytokines have also been studied in animal models. Carprofen, a COX-2 inhibitor currently used for the treatment of arthritis in dogs and other animals, has been shown to significantly reduce IL-1β and IL-6 and improve neurological function in mice after TBI [169]. Triptolide, a diterpenoid epoxide with anticancer activity in animal models, inhibits IL-1β, IL-6, and TNF-α and increases IL-10 levels in Sprague-Dawley rats after experimental TBI. It has been shown to reduce neuronal cell apoptosis [170]. TSG-6 (TNF-α stimulating gene/protein 6) inhibits IL-1β, IL-6 and other pro-inflammatory cytokines (MIP-1α, MCP-1) and inhibits anti-inflammatory cytokines such as IL-4 It is an anti-inflammatory agent that can stimulate production [171]. Watanabe et al. showed that administration of this agent to mice after TBI reduced lesion size and improved neurological recovery [172]. Another agent known to inhibit IL-1β and TNF-α but not to affect anti-inflammatory cytokines such as IL-10, the CNS penetrating small molecule MW151, was tested in mice after TBI. This formulation restored abnormal cytokine levels to normal, reduced glial activation, and improved neurological function in treated animals [173]. However, none of these formulations have been tested in patient trials.

Brain damage after TBI can be markedly exacerbated during subsequent stages of brain inflammation. At this stage, levels of key cytokines, especially IL-1β, IL-6 and TNF-α, are greatly increased, and these levels are a 'brain cytokine storm' that can increase thousands of folds compared to the corresponding levels in serum. . Although some of these cytokines, such as IL-6 and TNF-α, may have beneficial effects, evidence suggests that excessive use of these cytokines in animal models has shown that blocking these cytokines can reduce brain damage. Levels can be harmful. Thus, inhibition of pro-inflammatory cytokines may limit secondary damage due to neuroinflammation after TBI.

It is contemplated that any embodiment discussed herein may be implemented in connection with any method, kit, reagent or composition of the present invention and vice versa. In addition, the composition of the present invention can be used to achieve the method of the present invention.

It is to be understood that the specific embodiments described herein are shown by way of example and not as limitations of the invention. The main features of this invention can be used in various embodiments without departing from the scope of this invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.

All publications and patent applications mentioned herein are indicative of the level of skill in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

The use of the singular word ("a" or "an") when used in conjunction with the term "comprising" in the claims and/or specification may mean "one," but "one or more," "at least It also coincides with the meaning of "one" and "more than one". Although the use of the term "or" in the claims is used to mean "and/or" unless explicitly referring to only alternatives or the alternatives are mutually exclusive, this disclosure refers only to the alternatives and "and/or". support the definition of Throughout this application, the term "about" is used to denote a value that includes the error variability inherent in a device, the method used to determine the value, or the variability that exists among study subjects.

As used in this specification and claim(s), the words “comprising” (and any form of including, such as “comprises” and “comprises”), “comprising” has" (and any form of having, such as "has" and "has") and "comprises" (and includes "comprises" and "comprises" Any form of inclusive) or "comprising" (and any form of containing, such as "contains" and "contains") is inclusive or open-ended and is not further, recited. Do not exclude elements or method steps that are not included. In any of the compositions and method embodiments provided herein, “comprising of” may be replaced with “consisting essentially of” or “consisting of”. As used herein, the phrase “consisting essentially of” requires specified integer(s) or steps as well as integer(s) or steps that do not materially affect the characteristics or functions of the claimed invention. . As used herein, the term “consisting of” refers to a recited integer (e.g., a feature, element, property, attribute, method/process step, or limitation) or group of integers (e.g., function(s)). , element(s), characteristic(s), property(s), method/process steps, or limitation(s) only.

As used herein, the term “or combinations thereof” refers to all permutations and combinations of the items listed before the term. For example, "A, B, C, or a combination thereof" could be A, B, C, AB, AC, BC, or ABC, or if order is important in certain circumstances, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations containing repetitions of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. One skilled in the art will understand that there is generally no limit to the number of items or terms in any combination unless the context clearly dictates otherwise.

As used herein, words of approximation such as, without limitation, "about", "substantially" or "substantially", when so modified, are not necessarily absolute or complete, but are intended to designate the skilled person that the condition exists. conditions that are considered close enough to warrant The degree to which the description may be varied will depend on how many changes can be made and whether a person skilled in the art will still be able to recognize the modified feature as still having the desired features and functionality of the unmodified feature. In general, however, in accordance with the foregoing discussion, a numerical value herein modified by an approximation word such as "about" is at least ±1, 2, 3, 4, 5, 6, 7, 10, 12 or more from the stated value. It can vary by as much as 15%.

Additionally, section headings herein are provided for consistency with the proposal under 37 CFR 1.77 or to provide organizational clues. These headings do not limit or characterize the invention(s) set forth in any claims that may arise from this disclosure. Specifically, for example, although a title may refer to a "field of invention," such claims should not be limited by the language under this heading to describe a so-called technical field. Further, a description of a technology in the “Background of the Invention” section is not to be construed as an admission that the technology is prior art to any invention(s) in this disclosure. Neither "Summary" is to be considered a characterization of the invention(s) set forth in the claimed claims. Moreover, any reference in this disclosure to “invention” in the singular should not be used to assert that there is a single novelty in this disclosure. A number of inventions may be presented from this disclosure subject to the limitations of a number of claimed claims, which claims define the invention(s) thus protected and equivalents thereof. In all cases, these claims are to be considered on their own merits in light of this disclosure, but not limited by the headings presented herein.

Any compositions and/or methods disclosed and claimed herein can be made and practiced without undue experimentation in light of the present disclosure. Although the compositions and methods of this invention have been described in terms of preferred embodiments, variations may be applied to the compositions and/or methods described herein and to the steps or sequence of steps of the methods without departing from the concept, spirit and scope of the invention. It will be clear to those skilled in the art. All such similar alternatives and modifications obvious to those skilled in the art are considered to be within the spirit, scope and concept of the invention as defined by the appended claims.

Reference Example 1

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Claims (22)

A method of treating or ameliorating symptoms of one or more side effects caused by extensive release of cytokines in a subject, comprising:
identifying a subject in need of treatment or amelioration of symptoms of one or more infectious diseases or disease conditions that result in widespread release of cytokines; and
Administering one or more pharmaceutical compositions comprising a therapeutically effective amount of the lipid dissolved or dispersed in a suitable aqueous or non-aqueous medium sufficient to reduce the level of the cytokine in the subject.
How to include. The method of claim 1 , wherein the widespread release of cytokines is caused by one or more infectious diseases selected from at least one of viruses, bacteria, fungi, helminthic, protozoan, or hemorrhagic infectious agents. how to be The method of claim 1, wherein the one or more infectious diseases are 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 fever, Yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia (

), Guanarito, Garissa, Ilesha, or infection by Lassa fever virus. The method of claim 1 , wherein the one or more disease conditions are cachexia, septic shock syndrome, chronic inflammatory response, septic shock syndrome, traumatic brain injury, brain cytokine storm, graft versus host disease (GVHD), autoimmune disease, multiple sclerosis, acute pancreatitis, or hepatitis selected from at least one of the methods. The method of claim 1 , wherein the one or more disease conditions are caused by treatment with anti-CD19 chimeric antigen receptor (CAR) T cells or anti-tumor cell therapy, activated dendritic cells, activated macrophages, or activated B cells. A side effect that becomes, how. 2. The method of claim 1, wherein the composition further comprises a curcumin extract, curcumin, curcuminoid disposed in a lipid, wherein the curcuminoid is Ar-turmeron, methylcurcumin, demethoxy curcumin, bis Demethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene- 3,5-dione (curcumin 1), 1,7-bis(piperonyl)-1,6-heptadiene-3,5-dione (piperonyl curcumin) 1,7-bis(2-hydroxy naphtha) Tyl)-1,6-heptadiene-2,5-dione (2-hydroxyl naphthyl curcumin) and 1,1-bis(phenyl)-1,3,8,10 undecatetraene-5,7- selected from at least one of diones. The method of claim 6, wherein the lipid or phospholipid is dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidyl Glycerol (DMPG), Phosphatidylcholine, Lysolecithin, Lysophosphatidylethanolamine, LysoDMPC, LysoDMPG, LysoDSPG, LysoDPPC, Phosphatidylserine, Phosphatidylinositol, Sphingomyelin, Phosphatidylethanolamine, Cardiolipin, Phosphatidic Acid, Cerebroside, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, Amphoteric acrylic polymers, fatty acids, fatty acid amides, cholesterol, cholesterol esters, diacylglycerols, and diacylglycerolsuccinates. The method of claim 1, wherein the therapeutically effective amount is 50 nM/kg of subject body weight, 10 to 100 nM/kg of subject body weight, 25 to 75 nM/kg of subject body weight, 10, 20, 30, 40, 50, 60, 70, 80 , 90, or 100 nM/kg subject body weight. The method of claim 1 , wherein the composition comprises an active agent and has a ratio of lipid phospholipid to active agent of 3:1, 1:1, 0.3:1, and 0.1:1. The method of claim 1 , wherein the disease is rheumatoid arthritis, psoriasis, multiple sclerosis, relapsing multiple sclerosis, or inflammatory bowel disease. Treatment of lipids or lysophosphatidyl, dissolved or dispersed in a suitable aqueous or non-aqueous medium, as a composition for treating one or more side effects or ameliorating the symptoms caused by an infectious disease or disease condition that causes widespread release of cytokines in a subject. A composition comprising a scientifically effective amount. 12. The composition of claim 11, wherein the one or more infectious diseases are selected from at least one of viruses, bacteria, fungi, parasites, protozoa, or hemorrhagic infectious agents. 12. The method of claim 11, wherein the one or more infectious diseases are rhinovirus, coronavirus, paramyxoviridae, orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus, influenza virus, arenaviridae, filoviridae , Bunyaviridae, Flaviviridae, Rhabdoviridae viruses, Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue fever, yellow fever, Rift valley fever, Omsk hemorrhagic fever virus, Kiasanu forest, Junin, Machu Po, Sabia, Guanarito, Garissa, Ilesha, or infection by at least one of Lassa fever virus, the composition. 12. The method of claim 11, wherein the one or more disease conditions are cachexia, septic shock syndrome, chronic inflammatory response, septic shock syndrome, traumatic brain injury, brain cytokine storm, graft versus host disease (GVHD), autoimmune disease, multiple sclerosis , acute pancreatitis, or hepatitis. 12. The composition of claim 11, wherein the curcumin extract, curcuminoids or synthetic curcumin are disposed in the lipid. 12. The method of claim 11, wherein the lipid or lysophosphatidyl is dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoyl Phosphatidylglycerol (DMPG), Phosphatidylcholine, Lysolecithin, Lysophosphatidylethanolamine, LysoDMPC, LysoDMPG, LysoDSPG, LysoDPPC, Phosphatidylserine, Phosphatidylinositol, Sphingomyelin, Phosphatidylethanolamine, Cardiolipin, Phosphatidic Acid , cerebroside, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate A composition selected from the group consisting of amphoteric acrylic polymers, fatty acids, fatty acid amides, cholesterol, cholesterol esters, diacylglycerols, and diacylglycerolsuccinates. 12. The method of claim 11, wherein the biodegradable polymer is polyester, polylactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, polydioxanone, polyacetal, 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. 12. The composition of claim 11, wherein the composition is suitable for intravenous, subcutaneous, intramuscular or intraperitoneal injection in a subject. 12. The method of claim 11, wherein the composition further comprises curcumin, or the curcuminoids are Ar-turmeron, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, ferulo yl methane, tetrahydrocurcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin 1), 1,7-bis(pipero Nyl)-1,6-heptadiene-3,5-dione (piperonyl curcumin) 1,7-bis(2-hydroxy naphthyl)-1,6-heptadiene-2,5-dione (2- hydroxyl naphthyl curcumin) and 1,1-bis(phenyl)-1,3,8,10 undecatetraene-5,7-dione. 12. The composition of claim 11, wherein the composition comprises the active agent and has a ratio of lipid to active agent of 3:1, 1:1, 0.3:1, and 0.1:1. A method of determining whether a candidate drug treats or ameliorates symptoms of one or more side effects caused by an infectious disease or disease condition that causes widespread release of cytokines in a subject, the method comprising:
(a) administering to a second subset of patients an amount of a candidate drug in combination with empty liposomes and a placebo, wherein the candidate drug reduces overall levels of cytokines in the subject. provided in an amount effective to inhibit or inhibit;
(b) measuring the subject's total level of cytokines from the first and second sets of patients; and
(c) whether the candidate drug in combination with empty liposomes treats or ameliorates the symptoms of one or more side effects caused by an infectious disease or disease condition that causes widespread release of cytokines, occurring in a subset of patients receiving placebo. comparing any reduction to determine whether it is statistically significant, wherein the statistically significant reduction indicates that the candidate drug reduces or eliminates the overall cytokine level of the subject while being useful in treating the disease condition.
Including, method. A method of treating or ameliorating symptoms of a cytokine storm induced by a therapeutic agent in a subject, comprising:
identifying a subject in need of treatment or amelioration of symptoms of a cytokine storm induced by a therapeutic agent; and
One or more pharmaceutical compositions comprising a therapeutically effective amount of 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 a subject. Including the step of administering, a method.

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