WO2022016150A1

WO2022016150A1 - Methods for the treatment of cytokine release syndromes

Info

Publication number: WO2022016150A1
Application number: PCT/US2021/042211
Authority: WO
Inventors: Peter M. Ross
Original assignee: Ross Peter M
Priority date: 2020-07-17
Filing date: 2021-07-19
Publication date: 2022-01-20

Abstract

The present disclosure describes methods for treating cytokine release syndromes, and more particularly to methods using soft corticosteroids to treat the effects of said syndromes in the lungs.

Description

METHODS FOR THE TREATMENT OF CYTOKINE RELEASE

SYNDROMES

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to United States Provisional Application No. 63/053,284, filed July 17, 2020, the disclosure of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

This disclosure relates to methods for treating cytokine release syndromes, and more particularly to methods using soft corticosteroids to prevent or diminish such syndromes in the lungs and inhibit their spread throughout the body.

BACKGROUND

Corticosteroids are steroid hormones and derivative drugs used mainly for their anti inflammatory, vasoconstrictive, and immunomodulatory effects. During the 2003 Severe Acute Respiratory Syndrome (SARS) epidemic, corticosteroids were the mainstay of immunomodulatory therapy. Timely administration of corticosteroids often led to early improvement in terms of reduced fever, resolution of radiographic lung infiltrates, and better oxygenation. However, some studies showed no net benefit, while others demonstrated adverse outcomes to corticosteroid therapy of SARS coronavirus (SARS-CoV) in humans. For example, early corticosteroid treatment of SARS patients enhanced plasma viral load in non-ICU patients, thus leading to exacerbated disease. Overall, the timing, dosage, and duration of corticosteroid therapy are critical for such therapy to be beneficial in human coronavirus respiratory infections. In general, although corticosteroid therapy is controversial for the treatment of such infections (see Semin Immunopathol. 2017, 39(5):529-529), it has become a first line treatment for severe COVID-19, despite adverse systemic effect.

Animal immune systems and immune cells help to neutralize and to eliminate pathogens, for example bacteria, viruses, and fungi, and eliminate other foreign matter introduced within the body. Early in life, mammalian immune systems identify and desensitize themselves to autogenous antigens. Novel antigens can trigger clonal expansion of immune cells recognizing those antigens, permitting elicitation of a cellular or humoral response. This referred to as “acquired immunity” despite the progenitor immune cells preexisting and being selected for clonal expansion in response to the antigen. In acquired immunity, The presence of recognized antigens induces a selected, defensive reaction by clonally expanded immune cells that may attack, neutralize, and/or clear the foreign agent. This physiological mechanism is also thought to explain the rejection of autogenous tumor cells in immune surveillance.

Generally, the immune response involves a polymorphous, yet concerted production of cytokines, small peptides with autocrine, paracrine and endocrine signaling abilities which serve as immunomodulating agents. There are both pro-inflammatory and anti-inflammatory aspects of cytokine action. While not in themselves a part of the humoral or cellular immune recognition system, cytokines and other response modulators influence the intensity and the specificity of both humoral and cellular adaptive responses. The activity of cytokines must be well regulated to maintain homeostatic balance within the body.

Excessive production of inflammatory cytokines is part of the clinical condition known as “cytokine release syndrome”, and, in some specific instances, a cytokine storm. Such reactions can cause significant, collateral damage to body tissues and organs.

In some respiratory infections, for example viral infection by influenza and some coronaviruses, and also following systemic administration of some therapeutic agents or toxic exposures, dysregulated production of cytokines may lead to significant damage to the lungs and other organs. In fact, the worst outcomes of some infections, including influenza and SARS-2 for example, result not only from the direct cytotoxicity of the virus, but also from the damage caused directly or indirectly by the host reaction in the form of immunity and cytokine storm. Cytokine storm in the lungs can kill the alveolar epithelium, leading to fluid leakage into the alveoli, respiratory distress from blockage of the body’s airways, and even death of the patient.

In some respiratory infections, for example SARS-2, type 1 pneumocytes, the structural cells of the alveoli, are killed even though they may not be infected by the vims. Although type 2 pneumocytes support and serve as stem cells for type 1 pneumocytes, it is thought that active tissue destruction by cells or molecules released by type 2 pneumocytes and alveolar macrophages during cytokine release syndrome are the immediate cause of destruction of type 1 pneumocytes and the resulting interstitial pneumonia that, at the time of this writing, kills about half of SARS-2 patients that are intubated. Moreover, inflammatory cells activated in the alveoli can migrate, and cytokines or other activators released during pulmonary cytokine storm reactions to a viral infection, particularly of the alveoli, can cause injury to distant tissue and organ systems throughout the body, including, for example, the heart, vasculature, and kidneys. It is increasingly evident that the long term effects of this damage will be a major residual public health problem for the SARS-2 pandemic.

Many therapeutics have been investigated for the treatment of cytokine release syndromes with limited success. In respiratory infections, corticosteroids have been explored for their anti-inflammatory and immune-modulating properties but have generally been found to be ineffective as a treatment for cytokine storms. This may be due to the activities of many corticosteroids unrelated to their regulatory effect in modulating cytokine storm. For example, typical corticosteroid 21-alcohols inhibit the body’s own internal corticosteroid signaling, thereby impairing healing or processes that stop the damage due to dysregulated cytokine expression. In addition, systemic circulation of corticosteroids may cause other adverse side effects. Although corticosteroids were often among the first drugs tested in in the prevention or treatment of cytokine storm, any benefits have always been limited by adverse effects.

There is a clear need for the development of new methods for treating the effects of cytokine release syndrome in the body, particularly in the lungs.

SUMMARY

The present disclosure provides methods for treating the effects of cytokine release syndromes, such as cytokine storms, in the lungs of subjects by administering soft corticosteroids directly to the lungs. The soft corticosteroids as used herein may have the same local activity compared to more standard corticosteroids but are deactivated at or near the site of application, diminishing systemic effects that may countervail the local effects. The soft corticosteroids described herein are directly applied to the lungs of the subject where they may be taken up by cells in the superficial cells of the lung, notably cells involved in the development of infusion reaction/cytokine storm type responses. Once inside the body, these “soft” corticosteroids are inactivated by nonspecific or specific esterases, transferases, hydrolases or other enzymes in plasma and interstitial fluid that convert the soft corticosteroid to an inactivated form, typically a polar or charged form, that does not bind to the steroid receptor in cells and is thus biologically and pharmaceutically inactive. This property limits the activity of soft corticosteroids to the site of application, which is shown herein to be beneficial in the treatment of both local and systemic aspects of cytokine release syndromes resulting from respiratory infections, for example, as the most detrimental, even life-threatening, effects of these self-destructive immune responses to infection may occur or be aggravated throughout the body in response to primary reaction in the pulmonary alveolar epithelium.

Thus, methods are provided for treating or preventing a cytokine release syndrome in the lungs of the subject comprising administering a therapeutically effective amount of a soft corticosteroid as described herein to the lungs of the subject.

In some embodiments, the cytokine release syndrome is the result of a respiratory infection. In some embodiments, the respiratory infection comprises an infection with an influenza virus, for example an H1N1, H2N2, H3N2, or H5N1 influenza serotype. In some embodiments, the respiratory infection comprises an infection with a coronavirus, for example SARS coronavirus or SARS coronavirus 2. Cytokine release syndrome or related phenomena caused by other viruses are also appropriate for treatment by the methods described herein.

In some embodiments, the cytokine release syndrome may comprise a cytokine storm, an infusion reaction, or macrophage activation syndrome.

In some embodiments, the cytokine release syndrome is instigated by a drug, a bacterium, or a fungus.

In some embodiments, the soft corticosteroid is delivered as a formulation suitable for inhalation, such as a powder composition, a spray composition, or an aerosol delivery from a pressurized pack.

The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims.

DETAILED DESCRIPTION

Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compounds, compositions and methods pertain having the benefit of the teaching presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of the disclosure and to be encompassed by the claims herein.

Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from and combined with the features of any of the other several embodiments without departing from the scope and spirit of the present disclosure.

Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or description that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuations, or the number or type of aspects described in the specification.

All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for the disclosure prior to the filing date of the present application. The dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limited. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compounds, compositions, and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

Definitions

As used herein, “comprising” is to be interpreted as specifying the presence of the stated feature, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising”, “comprises”, “comprised of’, “including”, “includes”, “included”, “involving”, “involves”, “involved”, and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of’. Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of’.

As used in the specification and the appended claims, the singular forms “a”, “an” and

“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound”, “a pharmaceutical compositions”, or “a medical disorder” includes, but is not limited to, two or more such compounds, pharmaceutical compositions, or medical disorders, and the like.

As used herein “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medicinal, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore substantially normal physiological function.

As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion, catabolism or inactivation of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desired to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration, including continuous dosing for an appropriate period of time. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgement. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon or require a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

A response to a therapeutically effective dose of a disclosed compound or pharmaceutical composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, by changing the disclosed compound and/or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary and can be administered in one or more dose administrations daily for one, several, or more days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. Because soft corticosteroids do not normally affect systemic corticosteroid levels nor do they directly cause systemic corticosteroid type physiological response, there is accordingly less concern over adverse side effects such as adrenal suppression and damage to bone hypophyses. Of course, the degree of systemic activity will vary with the individual drug and the genetic (e.g., cytochrome P450) makeup of the patient. These will be addressed on a case by case basis against therapeutic effectiveness at stopping dysfunctional immune states of the type this invention is intended to treat/prevent.

As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

As used interchangeably herein, “subject”, “individual”, or “patient” can refer to a vertebrate organism, such as a mammal (e.g., human). “Subject” can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof. As used herein, the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and/or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a medical disorder. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder or condition. The term “treatment” as used herein can include any treatment of a medical disorder in a subject, such as a human or an animal, and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions. The term “treatment” as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder and/or those in which the disorder is to be prevented. As used herein, the term “treating”, can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

As used herein, “dose”, “unit dose”, or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration·

As used herein, “therapeutic” can refer to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect, or to decreasing the rate of advancement of a disease, disorder, condition, or side effect.

An “immune response” as used herein typically refers to the net response of all branches of the immune system - currently known to include the innate, the humoral, and the cellular - unless otherwise specified herein.

Soft Corticosteroids

The present disclosure provides methods for treating a cytokine release syndrome in lungs of a subject by administering a therapeutically effective amount of a soft corticosteroid to the lungs. A “soft corticosteroid” comprises a corticosteroid compound (or a derivative thereof) that has potent therapeutic activity localized to the site of treatment but that has minimal systemic activity. Compared to soft corticosteroids, which act at the site of application but which are inactivated systemically due to rapid catabolism or inherent instability in the extracellular space and in plasma, standard corticosteroids instead show overall systemic activity, including side effects undesirable in this context, such as vasoconstriction, systemic deactivation of internal steroid signaling by negative feedback to the loop known as the HPA (hypothalamic pituitary adrenal) axis, systemic immune suppression, and other adverse effects. These undesirable side effects due to systemic action of some corticosteroids may directly or indirectly inhibit normal vims clearance with or without cytokine storm or have other undesirable side effects in the pharmacological effort to block cytokine storm.

Representative examples of soft corticosteroids include cortolic or cortolonic acid esters whose glucocorticoid 21-carboxylic acid analogs, including triamcinolonic acid or triamcinolone acetonide 21-carboxylic acids, prednisolonic acid, and weaker analogues such as cortolic acid esters.

In some embodiments, the soft corticosteroid may comprise a compound having the chemical structure:

wherein R is C_\-Ce alkyl (for example, methyl, ethyl, n-propyl, isopropyl, or n-butyl) or phenyl.

wherein R is as defined above. In some embodiments, the soft corticosteroid may comprise a compound having the chemical structure:

wherein R is as defined herein. In some embodiments, the soft corticosteroid may comprise a compound having the chemical structure:

wherein R is as defined above.

wherein R is as defined above.

In some embodiments, the soft corticosteroid may comprise lotoprednol etabonate having the chemical structure:

In some embodiments, the soft corticosteroid may comprise ciclesonide having the chemical structure:

In some embodiments, the soft corticosteroid may comprise beclometasone dipropionate having the chemical structure:

In some embodiments, the soft corticosteroid may comprise rimexolone having the chemical structure:

In some embodiments, the soft corticosteroid may comprise fluorometholone having the chemical structure:

In some embodiments, the soft corticosteroid may comprise butixocort having the chemical structure:

In some embodiments, the soft corticosteroid may comprise tipredane having the chemical structure:

In some embodiments, the soft corticosteroid may comprise hydrocortisone aceponate. In some embodiments, the soft corticosteroid may comprise prednicarbate having the chemical structure:

Further exemplary soft corticosteroids which may be used in the disclosed methods include, but are not limited to: triamcinolone acetonide 21-oic methyl ester; methyl 11b,17a- dihydroxy-3,20-dioxo-l,4-pregnadiene-21-oate; methyl 1 i -hydroxy-3,20-dioxo-l,4- pregnadiene-21-oate; methyl 1 1 b, 17,20a-lrihydroxy-3-oxo- 1 ,4-pregnadiene-21 -oale; methyl 11 b, 17 a,20a-trihydroxy-3-oxo- 1 ,4-pregnadiene-21 -oate; methyl 11 b-hydroxy- 17 a, 20a- isopropylidenedioxy-3-oxo- 1 ,4-pregnadiene-21-oate; methyl 11 b-hydroxy- 17a, 20- isopropylidenedioxy-3-oxo-l,4-pregnadiene-21-oate; l^,17a,2(^-trihydroxy-3-oxo-l,4- pregnadiene-21-N-(n-propyl)-carboxyamide; l^,17,2(^-trihydroxy-3-oxo-l,4-pregnadiene-21- N-(n-propyl)-carboxyamide; methyl 1 1 b, 17a, 21 -lrihydroxy-3,20-dioxo- 1 ,4-pregnadiene- 16- carboxylate; methyl 1 1 b,21 -dihydroxy-3, 20-dioxo- 1 ,4-pregnadiene- 16-carboxylale; and methyl 9a-fluoro- 11 b-hydroxy- 16, 17a-isopropylidenedioxy- 1 ,4-pregnadiene-21 -oate.

In some embodiments, the compounds as used in the methods of the present disclosure may be administered in the form of a pharmaceutically acceptable salt where allowed by valence. In some embodiments, the compounds as used herein may be substituted with an appropriate functional group that allows or facilitates formation of a pharmaceutically acceptable salt. A “pharmaceutically acceptable salt” is a derivative of the compound as used herein in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the compounds as used herein can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the presently used compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts which are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts. Example of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2- acetoxy benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)_I-4-COOH, and the like, or using a different acid that produced the same counterion. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, PA., p. 1418 (1985).

The compounds as used in the methods of the present disclosure may form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes use of a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, or d6-DMSO. A solvate can be in a liquid or solid form. In some embodiments, the compounds as used in the methods of the present disclosure may be administered in the form of a prodrug. A “prodrug” as used herein means a compound lacking the desired activity which, when administered to a patient, is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described active compounds herein. Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including to increase the half-life of the drug in vivo. Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug. Non-limiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to, acylating, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides, among others.

In certain embodiments, the prodrug renders the parent compound more lipophilic. In certain embodiments, a prodrug can be provided that has several prodrug moieties in a linear, branched, or cyclic manner. For example, non-limiting embodiments include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compound that has at least two functional groups that can link the parent compound with another prodrug moiety, and is typically biodegradable in vivo. In some embodiments, 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound. Non-limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and a hydroxylated prodrug moiety to form a phosphate ester; a hydroxyl on the parent drug and a phosphonate on the prodrug to form a phosphonate ester; a hydroxyl on the parent drug and a phosphoric acid prodrug moiety to form a phosphate ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-

0-(C_2-24 alkyl) to form an ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-S-(C2-24 alkyl) to form a thioester; a hydroxyl on the parent drug and a prodrug of the structure H0-(CH2)2-0-(C2-24 alkyl) to form an ether; a hydroxyl on the parent drug and a prodrug of the structure H0-(CH2)2-0-(C2-24 alkyl) to form an thioether; and a carboxylic acid, oxime, hydrazide, hydrazine, amine or hydroxyl on the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer including but not limited to polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyanhydride, polyester, polyamide, or a peptide.

In some embodiments, a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug. The amino acid can be used alone or covalently linked (straight, branched or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties. The amino acid can be any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid.

Methods of Treatment

Provided in the present disclosure are methods for treating one or more signs or symptoms of a cytokine release syndrome in lungs of a subject comprising administering a therapeutically effective amount of a soft corticosteroid as described herein to the lungs. This local treatment, possibly in conjunction with other treatments, may have a desired effect of limiting the reaction’s scope, that is, to preventing the reaction from causing damage to the lung or other organics including those now known to be damaged by alveolar cytokine release syndromes.

A “cytokine release syndrome” (CRS) is a pathologic systemic inflammatory response syndrome triggered most often by certain infections or drugs, sometimes against a profile of genetic predisposition. CRS occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS can be elicited by some monoclonal antibody medications and adoptive T-cell therapies. When occurring as a result of a medication, CRS is also known as an “infusion reaction”.

A “cytokine storm”, also called “cytokine storm syndrome” (CS) or “hypercytokinemia”, is a strong, physiological reaction to massive release by the innate immune system of pro- inflammatory cytokines. Cytokines are released during the body’s normal immune response to infection, but sudden release in large quantities can cause CRS or CS, with consequences ranging from tissue damage to multisystem organ failure and death. CS is sometimes differentiated from CRS by its sudden onset. CS etiologies include respiratory infections caused by, for example, H5N1 influenza, SARS-CoV, SARS-CoV-2, Epstein-Barr vims, cytomegalovirus, and group A streptococcus, as well as non-infectious conditions such as graft-versus-host disease.

CS is used interchangeably with CRS but is more precisely a differentiable syndrome that may represent a severe episode of CRS or may be a component of another disease entity, such as macrophage activation syndrome. When occurring as a result of therapy (i.e., an infusion reaction), CRS may be delayed until days or weeks after treatment. Immediate-onset (fulminant) CRS comprises a cytokine storm.

Signs and symptoms of CRS/CS include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion, delirium, hallucinations, tremor, and loss of coordination. Lab tests and clinical monitoring show low blood oxygen, widened pulse pressure, increased cardiac output (early), potentially diminished cardiac output (late), azotemia, elevated D-dimer, elevated transaminases, factor I deficiency, excessive bleeding, and elevated bilirubin.

CRS occurs when large numbers of white blood cells, including B cells, T cells, natural killer cells, macrophages, dendritic cells, and monocytes are activated and release inflammatory cytokines, which in turn activate more white blood cells in a positive feedback loop of pathogenic inflammation· The reaction may self-perpetuate by positive feedback because the offending agent is not removed. Immune cells activated by stressed or infected cells recruit more effector immune cells such as T-cells and inflammatory monocytes (which differentiate into macrophages) to the site of inflammation or infection. In the case of respiratory infection, this can lead directly or indirectly to attack on other organs, such as the heart. The direct attack is mediated by aseptic attack by effector cells migrating from the lungs to a second target tissue. Indirect attack occurs when failure to remove the pathogen from the pulmonary epithelium, aggravated by excessive cytokine release, permits pathogen spread to normally privileged sites within the body. . This can progress to life-threatening systemic hyper-inflammation, hypotensive shock, and multi-organ failure.

Adoptive cell transfer of autologous T-cells modified with chimeric antigen receptors (CAR-T cell therapy) also causes CRS. In addition to adoptive T-cell therapies, severe CRS or cytokine reactions can occur in a number of infectious and non-infectious diseases including graft-versus-host disease, coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome, sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sufficiently cleared by the early acute phase anti-viral response in most individuals, some infections progress to a hyperinflammatory condition, often with life-threatening pulmonary involvement. This systemic hyperinflammation results in inflammatory lymphocytic and monocytic infiltration of the lung and the heart, causing ARDS and cardiac failure. Patients with fulminant COVID-19 and ARDS have classical serum biomarkers of CRS including elevated CRP, LDH, IL-6, and ferritin.

Hemophagocytic lymphohistiocytosis and Epstein-Barr virus-related hemophagocytic lymphohistiocytosis are caused by extreme elevations in cytokines and can be regarded as one form of severe cytokine release syndrome.

Cytokine release syndrome may also be induced by certain medications, such as the CD20 antibody rituximab and the CD 19 CAR-T cell tisagenlecleucel. CRS has also arisen with biotherapeutics intended to suppress or activate the immune system through receptors on white blood cells.Muromanab-CD3, alemtuzumab, and rituximab all cause CRS.

“Macrophage- activation syndrome” is a severe, potentially life-threatening, complication of several chronic rheumatic diseases of childhood. It occurs most commonly with systemic- onset juvenile idiopathic arthritis. In addition, macrophage- activation syndrome has been described in association with systemic lupus erythematosus, Kawasaki disease, and adult-onset Still’s disease. It is thought to be closely related and pathophysiologically very similar to reactive (secondary) hemophagocytic lymphohistiocytosis. The hallmark clinical and laboratory features include high fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, liver dysfunction, disseminated intravascular coagulation, hypofibrinogenemia, hyperferritinemia, and hypertriglyceridemia. Despite marked systemic inflammation, the erythrocyte sedimentation rate (ESR) is paradoxically depressed, caused by low fibrinogen levels. The low ESR helps to distinguish the disorder from a flare of the underlying rheumatic disorder, in which case the ESR is usually elevated. A bone marrow biopsy or aspirate usually shows hemophagocytosis. In many cases a trigger is identified, often a viral infection or a medication. There is uncontrolled activation and proliferation of macrophages and T lymphocytes, with a marked increase in circulating cytokines, such as IFN-gamma and GM-CSF. In many cases, a decreased natural killer cell function is found.

In some embodiments, the cytokine release syndrome, for example a cytokine storm, may be the result of a respiratory infection. In some embodiments, the respiratory infection may be the result of a coronavirus, for example but not limited to human coronavirus 229E (HCoV-

229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKUl), human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In some embodiments, the respiratory infection may be the result of an influenza virus, for example Influenzavirus A (including the H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9, and H6N1 serotypes), Influenzavirus B, Influenzavirus C, and Influenzavirus D.

Signs and symptoms in these pro-inflammatory syndromes can be attributed directly or indirectly to the release of pathologically large amounts of pro-inflammatory cytokines, usually by tissue-resident or migratory macrophages in response to an identifiable stimulus. The instigating stimulus may be biological, such as a pathogen, chemical, such as a drug or therapeutic antibody, genetic, or some combination of these factors. Triggering differences account for some or all of the variability between the syndromes. Cytokine release syndromes often occur against specific, genetic predispositions, usually in response to environmental stimulus. CS affects patients suffering from pulmonary viral infections, including notably some strains of flu and the SARS/MERS coronaviruses. Unchecked, in some patients, CS may become generalized with widespread, multi-organ pathology of varying severity, with endpoints up to and including death of the patient. Generally, cytokine release syndromes arise from failure to clear antigen, to signal its clearing, or to recognize the signal that antigen has been cleared. These along with other situations create a positive feedback loop of increasing cytokine release, usually by tissue macrophages. These macrophages may stay put or migrate to other tissues, where they may provoke distal reactivity and attendant pathology at those sites. Therapy of cytokine release syndromes, particularly CS, aims to reduce local inflammation and prevent spread.

The apparent positive feedback loop of unchecked inflammatory cytokine production causes a syndrome whose endpoint may run, depending on the individual and the level and type of inciting agent, from malaise to death by multiple organ failure. As a positive feedback phenomenon, the condition tends to progress but may self-limit by the multiple internal controls that limit cytokine reactions.

CS causes the most serious adverse outcomes, including mortality, of Covid-19 along with other respiratory viruses such as influenza. For Covid-19 in particular, CS is associated with and probably causes long-term sequelae such as heart and kidney inflammatory disease and, possibly, “long covid”, which may be detected at least to some degree in most survivors of even mild covid-19. Glucocorticoid therapy is commonly used to calm or quell inflammatory reactions, so physicians unsurprisingly turned to glucocorticoids to treat severe inflammatory symptoms of CS in covid-19. Published efforts to treat CS using glucocorticoids have employed convention drugs such as dexamethasone and methylprednisolone, which bind the glucocorticoid receptor tightly, are catabolized slowly, and act internally to suppress the HPA axis. These efforts yielded mixed results in the control of covid-19 induced CS. Nonetheless, systemic dexamethasone became the treatment of choice for the grave risk of sequelae including death from system CS in covid-19.

The present invention seeks better treatment or prevention of this kind of reaction as caused in the lungs, especially by viral infections, and to prevent the tendency of pulmonary- based cytokine reactions to the virus to propagate to other tissues, with severe health consequences of more generalized cytokine release syndromes. For this reason, reference to CS should be interpreted in the broadest possible way as representative of etiologically distinct syndromes as described herein which have similar pathological mechanisms and overlapping symptoms.

Methods of Administration

Pharmaceutical compositions for administration to the lungs can be delivery by a wide range of passive breath driven and active power driven single-/multiple-dose inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lung.

Formulations for inhalation include powder compositions, which preferably contain lactose, and spray compositions which may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivery from pressurized packs, with the use of a suitable propellant, e.g., 1,1,1, 2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, carbon dioxide or other suitable gas. A class of propellants, which are believed to have minimal ozone-depleting effects in comparison to convention chlorofluorocarbons comprise hydrofluorocarbons and a number of medicinal aerosol formulations using such propellant systems have been previously described. Due to problems with the stability of pharmaceutical formulations prepared with these propellants, the addition of one or more excipients is typical, such as polar cosolvents or wetting agents (e.g., alcohols such as ethanol), alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids such as oleic acid, poly ethoxy lates, etc.) or bulking agents such as a sugar and vehicles such as cromoglicic acid and/or nedocromil which are contained at concentrations that are not therapeutically and prophylactically active. For suspension aerosols, the active ingredients should be micronized so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the aerosol formulation, thus the active ingredients will have a mean particle size of less than 100 microns, desirably less than 20 microns, and preferably in the range of 0.7 to 10 microns, for example 1 to 5 microns.

In some embodiments, the pharmaceutical composition may comprise a therapeutically effective amount of the active agent, a hydrofluorocarbon propellant (for example, 1, 1,1,2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or mixtures thereof), a cosolvent (for example, ethanol), and optionally a surfactant. In some embodiments, the formulation comprises ethanol in an amount effective to solubilize the active agent. The propellant preferably includes a hydrofluoroalkane, in particular Propellant 134a, Propellant 227 or a mixture thereof. In the case of a mixture, the ratio of Propellant 134a to Propellant 227 is generally in a range from 75:25 w/w to 25:75 w/w. The formulations may contain a surfactant such as oleic acid, but may also be free of surfactant. The formulations are preferably free of other excipients.

The formulations may be manufactured by preparing a drug concentrate of the active ingredients with ethanol and adding this concentrate to the pre-chilled propellant in a batching vessel. The resulting formulation is filled into vials. Alternatively, the formulations may be prepared by adding the required quantity of active ingredient into an aerosol vial, crimping a valve on the vial, and introducing a premixed blend of propellant and ethanol through the valve. The vial may then be placed in an ultrasonic bath to ensure solubilization of the active agent.

In another embodiment, the pharmaceutical compositions contain the active agent in particulate form, and 1,1,1, 2-tetrafluoroethane, 1,1,1,2,3,3,3-hepafluoropropane, or mixtures thereof as propellant. Such formulations generally comprise from 0.01 to 5% (w/w relative to the total weight of the formulation) of polar cosolvent, in particular ethanol. In a preferred embodiment, no less than 3% w/w of polar cosolvent, in particular ethanol, is contained. Especially preferred compositions for aerosol delivery consist of particular active ingredient, and 1,1,1, 2-tetrafluoroethane, 1,1,1,2,3,3,3,-heptafluoropropane, or mixtures thereof as propellant and optionally a surfactant (preferably oleic acid). In the case of a mixture, the ratio of Propellant 134a to Propellant 227 is generally in a range from 75:25 w/w to 25:75 w/w.

The formulations may be prepared by adding the required quantity of active agent into an aerosol vial, crimpling a valve on the vial, and introducing propellant or optionally a pre-mixed blend of propellant and optionally the cosolvent and surfactant through the valve. Canisters generally comprise a container capable of withstanding the vapor pressure of the propellant, such as a plastic or plastic-coated glass bottle or a metal can, for example an aluminum can which may be optionally anodized, lacquer-coated and/or plastic-coated, which contain is closed with a metering valve. Canisters may be coated with a fluorocarbon polymer, for example, a copolymer of polyethersulfone (PES) and polytetrafluoroethylene (PTFE). Another polymer for coating that may be contemplated is fluorinated ethylene propylene (FEP).

The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadiene- acrylonitrile rubbers, butyl rubber and neoprene. Thermoplastic elastomer valves and valves containing EPDM rubber may be suitable. Suitable valves are commercially available from manufacturers well known in the aerosol industry.

Valve seals, especially the gasket seal and also the seals around the metering chamber, can be manufactured of a material which is inert to and resists extraction into the contents of the formulation, especially when the contents include a cosolvent such as ethanol.

Valve materials, especially the material of manufacture of the metering chamber, can be manufactured of a material which is inert to and resists distorting by contents of the formulation, especially when the contents include a cosolvent such as ethanol. Particularly suitable materials for use in manufacture of the metering chamber include polyesters e.g. polybutyleneterephthalate and acetals.

Materials of manufacture of the metering chamber and/or the valve stem may desirably be fluorinated, partially fluorinated, or impregnated with fluorine containing substances in order to resists drug deposition.

Valves, which are entirely or substantially composed of metal components are especially preferred.

Intranasal sprays or nasal drops may be formulated with aqueous or non-aqueous vehicles with or without the addition of agents such as thickening agents, buffer salts or acid or base to adjust the pH, isotonicity adjusting agents, preservatives, or anti-oxidants.

In some embodiments, the pharmaceutical formulation comprises the activate agent as a dry powder, i.e. the active agent is present in a dry powder comprising the finely divided agent optionally together with a finely divided pharmaceutically acceptable carrier, which is preferably present and may be one or more materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides, and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol. An especially preferred carrier is lactose, particularly in the form of the monohydrate. The dry powder may be in capsules of gelatin or plastic, or in blisters, for use in a dry powder inhalation device. Alternatively, the dry powder may be contained in a reservoir of a multi-dose dry powder inhalation device. Capsules and cartridges of for example gelatin, or blisters of for example laminated aluminum foil, for use in an inhaler or insulator may be formulated containing a powder mix of the active ingredients and a suitable powder base such as lactose or starch. In this aspect, the active ingredient is suitably micronized so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the dry powder formulation, thus the active ingredient will have a particle size of less than 100 microns, desirably less than 20 microns, a preferably in the range of 1 to 10 microns. The solid carrier, wherein present, generally has a maximum particle diameter of 300 microns, preferably 200 microns, and conveniently has a mean particle diameter of 40 to 100 microns, preferably 50 to 75 microns. The particle size of the active ingredient and that of a solid carrier where present in dry powder compositions can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation, spray drying, lyophilization or recrystallization from supercritical media.

Where the inhalable form of the composition is a finely divided particular form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing dosage unit of the dry powder. Such dry powder inhalation devices are known in the art.

Formulations for inhalation by nebulization may be formulated with an aqueous vehicle with the addition of agents such as acid or base, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilized by filtration or heating in an autoclave. Suitable technologies for this type of administration are known in the art.

In some embodiments, the formulation may comprise a pulmonary surfactant. Pulmonary surfactants are synthesized by type 2 pneumocytes and form a thin film at the air water interface of alveoli. Pulmonary surfactants consist mostly of phospholipids with small amounts of cholesterol and proteins. Pulmonary surfactants are known in the art, as they are used medically in inhalation preparations to protect the lungs of at-risk neonates.

In some embodiments, the soft corticosteroids as used herein may be formulated in a time-release delivery vehicle, liposomes, microspheres, microdroplets, or any other time release delivery system which encapsulates the soft corticosteroids. Such vehicles may also facilitate the release of the soft corticosteroids at particular depths of lung tissue as needed for the desired therapeutic effect.

In some embodiments, the soft corticosteroids used herein may be formulated with one or more additional therapeutic agents, for example but not limited to antiviral agents and esterase inhibitors.

The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art.

The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.

A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating or preventing a cytokine release syndrome in lungs of a subject, the method comprising administering a therapeutically effective amount of a soft corticosteroid to the lungs of the subject.

2. The method of claim 1, wherein the subject is a human.

3. The method of any one of claims 1 or 2, wherein the cytokine release syndrome is the result of a respiratory infection.

4. The method of claim 3, wherein the respiratory infection comprises an infection with an influenza vims.

5. The method of claim 4, wherein the influenza virus comprises an H1N1, H2N2, H3N2, or H5N 1 influenza serotype.

6. The method of claim 3, wherein the respiratory infection comprises an infection with a coronavirus.

7. The method of claim 6, wherein the coronavirus comprises SARS coronavirus or SARS coronavirus 2 or MERS coronavirus.

8. The method of any one of claims 1-7, wherein the cytokine release syndrome comprises a cytokine storm.

9. The method of any one of claims 1-7, wherein the cytokine release syndrome comprises an infusion reaction.

10. The method of any one of claims 1-7, wherein the cytokine release syndrome comprises macrophage activation syndrome.

11. The method of any one of claims 1-10, wherein the soft corticosteroid is selected from a compound having the chemical structure:

wherein R is C1-C6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, or n-butyl) or phenyl.

12. The method of any one of claims 1-10, wherein the soft corticosteroid is selected from lotoprednol etabonate, ciclesonide, beclomethasone dipropionate, rimexolone, fluorometholone, butixocort, tipredane, or hydrocortisone aceponate.

13. The method of any one of claims 1-10, wherein the soft corticosteroid is selected from the group consisting of: triamcinolone acetonide 21-oic methyl ester; methyl 1 1 b, 17a-di hydroxy- 3, 20-dioxo- 1 ,4-pregnadiene-21 -oate; methyl 1 i -hydroxy-3,20-dioxo-l,4-pregnadiene-21-oate; methyl 1 1 b, 17,20a-trihydroxy-3-oxo- 1 ,4-pregnadiene-21 -oate; methyl 1 1b, 17a,20a-trihydroxy- 3-oxo-l,4-pregnadiene-21-oate; methyl 1 i -hydroxy-17a,20a-isopropylidenedioxy-3-oxo-l,4- pregnadiene-21 -oate; methyl 11 b-hydroxy- 17a,20-isopropylidenedioxy-3-oxo- 1 ,4-pregnadiene- 21-oate; 1 1 b, 17a,2(^-trihydroxy-3-oxo- 1 ,4-pregnadiene-21 -N-(n-propyl)-carboxyamide; llb,17,20b-trihydroxy-3-oxo-l,4-pregnadiene-21-N-(n-propyl)-carboxyamide; methyl

1 1 b, 17a, 21 -trihydroxy-3, 20-dioxo- 1 ,4-pregnadiene- 16-carhoxylate; methyl 1 1 b,21 -di hydroxy- 3, 20-dioxo- 1 ,4-pregnadiene- 16-carhoxylate; and methyl 9a-lluoro- 1 1 b-hydroxy- 16, 17 a- isopropylidenedioxy-l,4-pregnadiene-21-oate.

14. The method of any one of claims 1-13, wherein the soft corticosteroid is delivered as a formulation suitable for inhalation.

15. The method of claim 14, wherein the formulation comprises a powder composition.

16. The method of claim 14, wherein the formulation comprises a spray composition.

17. The method of claim 14, wherein the formulation comprises an aerosol delivery from a pressurized pack and/or in conjunction with or in oxygen or other therapeutic inhalant delivered separately in a mixture by intubation.

18. The method of any one of claims 1-17, wherein administration of the soft corticosteroid does not result in systemic effects that interfere or counteract with the local effect of the corticosteroid.

19. The method of claim 1, wherein the cytokine release syndrome is the result of exposure to a drug or other chemical.

20. The method of claim 1 , wherein the cytokine release syndrome is the result of exposure to or infection by bacteria, fungi, archaebacteria, or other biological agent(s).