Methods for treating cancers associated with ETBR activation

Abstract

Methods for treating cancer using combination therapies comprising CAR-expressing immune cells (e.g., CAR-T cells) and ETBR antagonists are disclosed herein. Methods for treating cancer using combination therapies comprising CAR-expressing immune cells (e.g., CAR-T cells), immune checkpoint inhibitors (e.g., anti-PD1 antibodies), and ETBR antagonists are also disclosed herein.

Description

Technical Field

[0001] Summary of the Invention In certain embodiments, a method of treating cancer that expresses a target in a subject in need of treatment is disclosed herein, the method comprising administering to the subject a combination comprising (a) chimeric antigen receptor (CAR)-expressing immune cells, wherein the CAR specifically binds to the target, and (B) an effective amount of an ETBR antagonist.

[0002] In various embodiments of a method of treating cancer that expresses a target in a subject in need of treatment with chimeric antigen receptor (CAR)-expressing immune cells, wherein the CAR specifically binds to the target, improvements are disclosed herein that include co-administration of an effective amount of an ETBR antagonist to the subject.

[0003] In certain embodiments, a method of treating cancer that expresses a target in a subject in need of treatment is disclosed herein, the method comprising administering to the subject a combination comprising (a) chimeric antigen receptor (CAR)-expressing immune cells, wherein the CAR specifically binds to the target, (b) an immune checkpoint inhibitor (ICPI), and (c) an effective amount of an ETBR antagonist.

[0004] In various embodiments, a method of treating cancer that expresses a target in a subject in need of treatment with chimeric antigen receptor (CAR)-expressing immune cells, wherein the CAR specifically binds to the target, and an immune checkpoint inhibitor (ICPI) is disclosed herein, and improvements are provided that include co-administration of an effective amount of an ETBR antagonist to the subject.

[0005] In some embodiments, the target is a tumor-associated antigen. In some embodiments, the tumor-associated antigen is HER2.

[0006] In certain embodiments, a method for treating a target HER2-expressing cancer requiring treatment is disclosed herein, the method comprising administering to a target a combination comprising (a) chimeric antigen receptor (CAR) expressing immune cells in which the CAR specifically binds to HER2, and (b) an effective amount of an ETBR antagonist.

[0007] In various embodiments of a method for treating HER2-expressing cancers of a target requiring treatment using chimeric antigen receptor (CAR)-expressing immune cells in which the CAR specifically binds to HER2, improvements including the co-administration of an effective amount of ETBR antagonist to the target are disclosed herein.

[0008] In some embodiments, ICPI is an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, or a variant or functional fragment thereof. In some embodiments, ICPI is an anti-PD1 antibody.

[0009] In some embodiments, the ETBR antagonist is a deuterated ETBR antagonist.

[0010] In some embodiments, the deuterated ETBR antagonist is given by formula (1):

[0011] [ka] A compound or stereoisomer thereof, in which, n is an integer from 0 to 4. m is an integer between 0 and 3. X is a positively charged counterion. R1 and R3 are independently -H, -D, -CH3, -CH2D, -CHD2, or -CD3. R 2a , R 2b R4, R5, and R6 are independently -CH3, -CH2D, -CHD2, or -CD3, and R1, R 2a , R 2b, or at least one of R3 is a compound or its stereoisomer containing deuterium.

[0012] In some embodiments, the compound is of formula (1a):

[0013] [ka] It is a compound of or a stereoisomer of .

[0014] In some embodiments, the compound is of formula (2):

[0015] [ka] It is a compound of or a stereoisomer of .

[0016] In some embodiments, the compound is of formula (2a):

[0017] [ka] It is a compound of or a stereoisomer of .

[0018] In some embodiments, the compound is of formula (3):

[0019] [ka] It is a compound of or a stereoisomer of .

[0020] In some embodiments, the compound is of formula (3a):

[0021] [ka] It is a compound of or a stereoisomer of .

[0022] In some embodiments, the compound is of formula (4):

[0023] [ka] It is a compound of or a stereoisomer of .

[0024] In some embodiments, the compound is of formula (4a):

[0025] [ka] It is a compound of or a stereoisomer of .

[0026] In some embodiments, the compound is of formula (5):

[0027] [ka] It is a compound of or a stereoisomer of .

[0028] In some embodiments, the compound is of formula (5a):

[0029] [ka] It is a compound of or a stereoisomer of .

[0030] In some embodiments, the compound is of formula (6):

[0031] [ka] It is a compound of or a stereoisomer of .

[0032] In some embodiments, the compound is of formula (6a):

[0033] [ka] It is a compound of or a stereoisomer of .

[0034] In some embodiments, n is 1, R1 is -D, and R2a and R 2b are each -CH3.

[0035] In some embodiments, R 2a is -CH3, and R 2b is -CH2D.

[0036] In some embodiments, R 2a and R 2b are each -CH2D.

[0037] In some embodiments, n is 1, R1 is -D, and R 2a and R 2b are each -CH2D.

[0038] In some embodiments, the deuterated ETBR antagonist is BQ-788-B

[0039]

Chem.

[0040]

Chem.

[0041]

Chem.

[0042] In some embodiments, the ETBR antagonist is BQ-788-B

[0043]

Chem.

[0044] In some embodiments, the ETBR antagonist is contained in a pharmaceutically acceptable excipient, which includes dimethyl sulfoxide (DMSO).

[0045] In some embodiments, the CAR-expressing immune cells are CAR-T cells or CAR-NK cells. In some embodiments, the CAR-expressing immune cells are CAR-T cells. In some embodiments, the cancer is selected from the group consisting of breast cancer, gastric cancer, esophageal cancer, ovarian cancer, endometrial cancer, bladder cancer, lung cancer, cervical cancer, colon cancer, and head and neck cancer.

[0046] In some embodiments, the cancer is ETBR-related cancer.

[0047] In some embodiments, ETBR-related cancers are selected from the group consisting of breast cancer, gastric cancer, esophageal cancer, ovarian cancer, endometrial cancer, bladder cancer, lung cancer, cervical cancer, colon cancer, and head and neck cancer.

[0048] In some embodiments, the cancer is a HER2-expressing cancer.

[0049] In some embodiments, HER2-expressing cancer is HER2+ cancer.

[0050] In some embodiments, HER2-expressing cancer is HER2-low-expressing cancer.

[0051] In some embodiments, HER2-expressing cancers are selected from the group consisting of breast cancer, gastric cancer, esophageal cancer, ovarian cancer, endometrial cancer, bladder cancer, lung cancer, cervical cancer, colon cancer, and head and neck cancer. [Brief explanation of the drawing]

[0052] The accompanying drawings incorporated herein and forming part of this specification illustrate several embodiments of the invention and, together with the description, serve to illustrate the principles of the invention. The drawings are for illustrative purposes only and should not be construed as limiting the invention. Further objects, features, and advantages of the invention will become apparent from the following detailed description in conjunction with the accompanying drawings illustrating exemplary embodiments of the invention.

[0053] [Figure 1] This diagram illustrates the endothelin B receptor (ETBR) cell signaling pathway. ETBR is a seven-transmembrane G protein-binding receptor (GPCR). Endothelin-1 (ET-1) is the ligand for ETBR. When ET-1 binds to the receptor, it activates numerous downstream kinases, including PTK, RAF, MEK, and MAPK / ERK. [Figure 2] This graph shows the tumor volume over time in mice treated with the combination therapy described and implanted with 4T1. [Figure 3A] Figure 3A shows the growth morphology of 4T1 tumors 11 to 17 days after engraftment in mice treated with the combination therapy described. [Figure 3B] Figure 3B depicts the growth morphology of 4T1 tumors 11 to 17 days after engraftment in mice treated with the combination therapies shown. Figure 3B shows the tumor volume 17 days after engraftment. The difference between group 8 and groups 1 and 2 is P<0.01. The difference between group 8 and groups 3 and 4 is P<0.05. [Figure 4] The tumor volume at 29 days post-graft 4T1 tumor engraftment in mice treated with the indicated combination therapy is shown. The difference between group 1 and 2 is P<0.05. The difference between group 1 and 4 is P<0.01. The difference between group 4 and 6 is P<0.01. The difference between group 1 and groups 5, 6, 7, and 8 is P<0.001. The difference between group 2 and groups 5, 6, 7, and 8 is P<0.001. The difference between group 3 and groups 5, 6, 7, and 8 is P<0.001. The difference between group 4 and groups 5, 7, and 8 is P<0.001. [Figure 5A] This figure depicts tumor growth at the experimental endpoint (30 days after 4T1 tumor engraftment) in mice treated with the combination therapy shown. Figure 5A shows images of the collected tumors. [Figure 5B] The figures show tumor growth at the experimental endpoint (30 days after 4T1 tumor engraftment) in mice treated with the indicated combination therapy. Figure 5B shows tumor weight at 30 days after engraftment. The difference between group 1 and 4 is P<0.05. The difference between group 4 and groups 5, 6, and 7 is P<0.05. The difference between group 4 and 8 is P<0.01. The difference between group 3 and groups 6 and 7 is P<0.01. The difference between group 1 and groups 5, 6, 7, and 8 is P<0.001. The difference between group 2 and groups 5, 6, 7, and 8 is P<0.001. The difference between group 3 and groups 5 and 8 is P<0.001. [Modes for carrying out the invention]

[0054] Disclosed herein are combination therapies and methods for treating cancer, comprising a single or separate dosage form containing an ETBR antagonist and CAR-expressing immune cells (e.g., CAR-T cells), administered simultaneously or separately. In some embodiments, the therapeutic combination further comprises an immune checkpoint inhibitor (ICPI), such as an anti-PD1 antibody or an anti-PD-L1 antibody. In some embodiments, the ETBR antagonist is a specifically deuterated ETBR antagonist as described herein. In some embodiments, the specifically deuterated ETBR antagonist is deuterated BQ-788, BQ-788-A, BQ-788-B, or BQ-788-C, or a combination thereof.

[0055] In some embodiments, combination therapies as described herein demonstrate synergistic effects in that the pharmaceutical composition achieves a greater therapeutic effect (i.e., more effective) than the additional therapeutic effect obtained by administering the components alone, a greater therapeutic effect than achieved by administering the components alone at high doses, an equivalent or better therapeutic effect (i.e., improved therapeutic concentration range) with reduced adverse events and side effects compared to those observed by administering the components alone, or an increased duration of effect, an equivalent or better therapeutic effect at low doses of one or both of the components, or at least one of these combinations.

[0056] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the present invention pertains. Terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0057] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it should be understood that each intermediate value between the upper and lower limits of that range, and any other stated or intermediate values ​​within that stated range, are included within the invention up to one-tenth of the lower limit unit (for example, in the case of a group containing a certain number of carbon atoms, each carbon atom number is within the above range), and any other stated or intermediate values ​​within that stated range. The upper and lower limits of these smaller ranges may be independently included within the smaller range, but are also included within the invention, subject to any specifically excluded limits within the stated range. Where a stated range includes one or both of the limit values, ranges excluding one or both of the included limit values ​​are also included in this disclosure.

[0058] As used herein and in the appended claims, the articles “a” and “an” are used herein to refer to one or more (i.e., at least one) objects of the article unless the context explicitly indicates otherwise. For example, “an element” means one or more elements.

[0059] As used herein and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements thus combined, i.e., elements that exist sometimes congruently and other times separately. Multiple elements enumerated by “and / or” should be interpreted in the same manner, i.e., “one or more” of the elements thus combined. Other elements other than those specifically identified by the phrase “and / or” may be present at their discretion, whether related to or unrelated to those specifically identified elements. Thus, as a non-restrictive example, when used in conjunction with open-ended terms such as “comprising,” a reference to “A and / or B” may, in one embodiment, refer to A only (including elements other than B at their discretion), in another embodiment, refer to B only (including elements other than A at their discretion), and in yet another embodiment, refer to both A and B (including other elements at their discretion).

[0060] As used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, i.e., including at least one of the number of elements or the list, but more than one, and optionally, additional unlisted items. Only terms that are explicitly indicated, such as “one of” or “exactly one of” or, as used in the claims, “consisting of,” refer to the inclusion of exactly one element of the number of elements or the list. In general, as used herein, the term “or” should be interpreted only as indicating an exclusive choice (i.e., “either one or the other, but not both”) such as “either,” “one,” “only one,” or “exactly one.”

[0061] In the claims and the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood as open-ended, meaning unrestricted but including. Only the transitional phrases “consisting of” and “consisting essentially of” are closed or semi-closed transitional phrases, respectively, as described in Section 2111.03 of the Patent Office Manual of Patent Examining Procedures.

[0062] When used herein and in the claims, the phrase “at least one” should be understood to mean, with respect to a list of one or more elements, at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each element specifically enumerated in the list of elements, nor excluding any combination of elements in the list of elements. This definition also allows for the existence of elements other than those specifically identified in the list of elements to which the phrase “at least one” refers, whether related to or unrelated to the specifically identified elements, at the discretion of the definition. Therefore, as a non-restrictive example, “at least one of A and B” (or similarly “at least one of A or B” or equivalently “at least one of A and / or B”) could mean, in one embodiment, at least one which includes, at its discretion, more than one A, and in another embodiment, at least one which includes, at its discretion, more than one B, and in yet another embodiment, at least one which includes, at its discretion, more than one A, and at its discretion, more than one B (and at its discretion, other elements), and so on.

[0063] In certain methods described herein that involve multiple steps or actions, it should be understood that the order of the steps or actions of the Method is not necessarily limited to the order in which the steps or actions are listed, unless the context indicates otherwise.

[0064] The term "combination therapy" refers to both simultaneous administration (simultaneous administration of two or more therapeutic agents) and time-variable administration (administration of one or more therapeutic agents at different times than the administration of additional therapeutic agents). In some embodiments, the therapeutic agents are present simultaneously in the patient to some extent, for example, in effective amounts. In some embodiments, one or more of the compounds described herein are administered in combination with additional bioactive agents, particularly anticancer agents. In some embodiments, combination therapy of compounds results in synergistic activity, including anticancer activity.

[0065] As used herein, the term “compound” refers to any specific chemical compound disclosed herein unless otherwise indicated, and in context includes tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers (including optical isomers (enantiomers) and other stereoisomers (diastereomers)), as well as, where applicable, pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). Within the scope of its use in context, the term “compound” generally refers to a single compound, but may also include other compounds, e.g., stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically concentrated mixtures of the disclosed compound. The term also, in context, refers to prodrug forms of a compound modified to facilitate the administration and delivery of the compound to the active site. Note that, in the description of the compound, a number of associated substituents and variables will be described, among other things. It will be understood by those skilled in the art that the molecules described herein are stable compounds, as generally described below. When bonds are shown, both double and single bonds are represented within the context of the compound being shown.

[0066] The terms “to treat,” “to treat,” and “treatment” as used herein refer to any action that benefits a patient to whom the Compound may be administered, including the treatment of any disease condition or illness modulated by the protein to which the Compound binds. Disease conditions or illnesses, including cancer, that may be treated using the Compounds of this Disclosure are described above.

[0067] The term “pharmaceutically acceptable salt” is used throughout this specification to describe one or more salt forms of the compounds described herein that are presented to increase the solubility of the compounds in gastric juice of a patient’s gastrointestinal tract, where applicable, in order to facilitate the dissolution and bioavailability of the compounds. Pharmacopoeia acceptable salts include, where applicable, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Preferred salts include those derived from alkali metals such as potassium and sodium, and alkaline earth metals such as calcium, magnesium, and ammonium salts. In some embodiments, sodium and potassium salts are preferred neutralizing salts of phosphates.

[0068] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (ester, amide, or other prodrug group) that directly or indirectly provides the compound or its active metabolites to a patient when administered to a patient.

[0069] The term “effective,” when used in the context of its intended use, is used to describe the amount of a compound, composition, or component that produces the intended result. The term “effective” encompasses all other terms of effective amount or effective concentration, which are described or used differently in this application.

[0070] The term "therapeutic dose" refers to an amount sufficient to produce a treatment, as defined herein, when administered to a mammal requiring such treatment.

[0071] The terms “patient” or “subject” are used throughout this specification to describe animals, such as humans or livestock, to which treatment including prophylactic treatment using the compositions of this disclosure is provided. In relation to the treatment of infections, diseases, or disease conditions specific to certain animals, such as human patients, the term patient refers to certain animals, including livestock such as dogs or cats, or farm animals such as horses, cattle, or sheep. In general, in this disclosure, the term patient refers to human patients unless otherwise stated or implied by the context of its use. Activation of ETBR by endothelin such as ET-1 and ET-3 results in various molecular events that promote melanoma invasion and metastasis. While not bound by any particular theory, it is assumed that the majority of melanomas express ETBR, and that these subsets also express the ETBR activators ET-1 and / or ET-3. Therefore, this subset is most likely to depend on ETBR activation for viability, invasiveness, and metastasis. Thus, this subset of patients is most likely to respond to ETBR blockade. Furthermore, this subset of patients is the least likely to respond to immunotherapy.

[0072] Deuterated ETBR antagonist In some embodiments, the methods and pharmaceutical compositions described herein use or include a deuterated ETBR antagonist, for example, a deuterated form of BQ-788 as described herein. The specific deuterated compounds referred to herein are beneficial because they have an improvement in one or more pharmaceutically acceptable properties (e.g., efficacy, solubility) compared to the same compound that is not deuterated. Specifically deuterated ETBR antagonists, including the deuterated forms of BQ-788 (e.g., BQ-788A, BQ-788B, and BQ-788C) referred to herein, are described in WO2019140324, which is incorporated herein by reference in its entirety. The specifically deuterated ETBR antagonist BQ-788-B is also known as ENB-003.

[0073] The endothelin B receptor (ETBR) pathway (Figure 1) plays a crucial role in the metastatic spread of melanoma and is therefore a target for therapeutic intervention. The endothelin B receptor is a seven-transmembrane G protein-binding receptor (GPCR). In normal melanocytes, it is expressed at very low levels but is upregulated during the development and progression of melanoma. RAF and MEK kinases, current drug targets for melanoma, are activated by deuterated ETBR. In some embodiments, the physiological role of ETBR is to remove excess levels of endothelin-1 (ET-1) from circulation. While not bound by any particular theory, it is hypothesized that administration of an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) impedes ET-1 clearance and increases serum ET-1 levels. Elevated plasma levels of ET-1 are associated with a variety of adverse effects resulting from endothelin A receptor (ETAR) activation, including hypertension, pulmonary hypertension, and renal vasoconstriction.

[0074] In some embodiments, this description provides compositions comprising an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist, e.g., a deuterated form of BQ-788 as described herein) and a pharmaceutically acceptable carrier. In some embodiments, this description provides compositions comprising a therapeutically effective amount of an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist, e.g., a deuterated form of BQ-788 as described herein) and a pharmaceutically acceptable carrier, e.g., pharmaceutical compositions. In some embodiments, pharmaceutical compositions as described herein may be in unit dosage forms configured for administration once or more times, e.g., once or more times per day, once or more times per week, or once or more times per month.

[0075] In some embodiments, the specifically deuterated ETBR antagonist is given by the following formula (1):

[0076] [ka] It is a compound of, During the ceremony, n is an integer from 0 to 5. m is an integer between 0 and 3. X is a positively charged counterion. R1 and R3 are independently -H, -D, -CH3, -CH2D, -CHD2, or -CD3. R 2a , R 2b R4, R5, and R6 are independently -CH3, -CH2D, -CHD2, or -CD3, and at least one of R1, R2, or R3 contains deuterium.

[0077] In some embodiments, the specifically deuterated ETBR antagonist of formula (1) contains 1 to 8 deuterium atoms. In certain embodiments, the specifically deuterated ETBR antagonist of formula (1) contains 1, 2, or 3 deuterium atoms.

[0078] In some embodiments, the compound is given by the following formula (1a):

[0079] [ka] It is a compound of, In the formula, X, R 2a , R 2b R4, R5, and R6 are as described herein.

[0080] In some embodiments, the specifically deuterated ETBR antagonist is given by the following formula (2):

[0081] [ka] It is a compound of, In the formula, X, m, n, R1, R3, R 2a , R 2b R4, R5, and R6 are as described herein.

[0082] In some embodiments, the compound is given by the following formula (2a):

[0083] [ka] It is a compound of, In the formula, X, R 2a , R 2b R4, R5, and R6 are as described herein.

[0084] In some embodiments, the specifically deuterated ETBR antagonist is given by the following formula (3):

[0085] [ka] It is a compound of, In the formula, X, m, n, R1, R3, R 2a , R 2b R4, R5, and R6 are as described herein.

[0086] In some embodiments, the compound is given by the following formula (3a):

[0087] [ka] It is a compound of, In the formula, X, R 2a , R 2b R4, R5, and R6 are as described herein.

[0088] In some embodiments, the specifically deuterated ETBR antagonist is given by the following formula (4):

[0089] [ka] It is a compound of, In the formula, X, m, n, R1, R3, R 2a , R 2b R4, R5, and R6 are as described herein.

[0090] In some embodiments, the compound is given by the following formula (4a):

[0091] [ka] It is a compound of, In the formula, X, R 2a , R 2b R4, R5, and R6 are as described herein.

[0092] In some embodiments, the specifically deuterated ETBR antagonist is given by the following formula (5):

[0093] [ka] It is a compound of, In the formula, X, m, n, R1, R3, R 2a , R 2b R4, R5, and R6 are as described herein.

[0094] In some embodiments, the compound is given by the following formula (5a):

[0095] [ka] It is a compound of, In the formula, X, R 2a , R 2b R4, R5, and R6 are as described herein.

[0096] In some embodiments, the specifically deuterated ETBR antagonist is given by the following formula (6):

[0097] [ka] It is a compound of, In the formula, n, R1, R 2a , and R 2b This is as described herein.

[0098] In some embodiments, the compound is given by the following formula (6a):

[0099] [ka] It is a compound of, In the formula, R 2a and R 2b This is as described herein.

[0100] In some embodiments of the specifically deuterated ETBR antagonists of formulas (1) to (6), n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0101] In some embodiments of the specifically deuterated ETBR antagonists of formulas (1) to (5), m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0102] In some embodiments of the specifically deuterated ETBR antagonists of formulas (1) to (6), n is 1 and R1 is -D.

[0103] In some embodiments of the specifically deuterated ETBR antagonists of formulas (1) to (5a), X is Na + and K + Selected from. In some embodiments, X is Na + That is the case.

[0104] In some embodiments of the specifically deuterated ETBR antagonists of formulas (1) to (6a), R 2a and R 2b It is -CH2D.

[0105] In some embodiments of the specifically deuterated ETBR antagonists of formulas (1) to (6a), R 2a and R 2bIt is -CH3.

[0106] In some embodiments of the specifically deuterated ETBR antagonists of formulas (1) to (6a), R 2a or R 2b One of them is CH2D, and the other is -CH3.

[0107] In some embodiments, the specifically deuterated ETBR antagonist is BQ-788-A, BQ-788-B, BQ-788-C, or a combination thereof, including fluorinated analogues, their analogues, derivatives, polymorphs, prodrugs, and salts. For example, the specifically deuterated ETBR antagonist may be a fluorinated analogue of BQ-788-A, BQ-788-B, or BQ-788-C.

[0108] In some embodiments, the specifically deuterated ETBR antagonist is BQ-788-A:

[0109] [ka] or its stereoisomer. In some embodiments, the specifically deuterated ETBR antagonist is BQ-788-A.

[0110] In some embodiments, the specifically deuterated ETBR antagonist is BQ-788-B, as shown below:

[0111] [ka] or its stereoisomer. In some embodiments, the specifically deuterated ETBR antagonist is BQ-788-B (also known as ENB-003).

[0112] In some embodiments, the specifically deuterated ETBR antagonist is BQ-788-C:

[0113] [ka] or its stereoisomer. In some embodiments, the specifically deuterated ETBR antagonist is BQ-788-C.

[0114] Pharmaceutical composition In various embodiments, pharmaceutical compositions comprising an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist, such as the deuterated form of BQ-788 described herein) and a pharmaceutically acceptable carrier are provided herein.

[0115] In some embodiments, the compositions herein are formulated in unit dosage forms comprising any desired carrier or excipient and are configured for administration via any desired route, such as oral, intravenous, subcutaneous, intramuscular, intraperitoneal, parenteral, intranasal, or intracranial.

[0116] In some embodiments, the pharmaceutical composition is delivered intravenously, intramuscularly, subcutaneously, or orally, intranasally, sublingually, transdermally, topically, intraperitoneally, parenterally, intranasally, or intracranially.

[0117] In some embodiments, ETBR antagonists, such as deuterated ETBR antagonists or deuterated BQ-788, are administered in the form of liposomal formulations as described herein.

[0118] In some embodiments, the pharmaceutical composition contains about 1% to about 95% of the active ingredient, the single-dose form of administration contains about 20% to about 90% of the active ingredient, and the non-single-dose form of administration contains about 5% to about 20% of the active ingredient. The form of the unit dose is, for example, coated tablets, tablets, ampoules, vials, suppositories, or capsules. Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersants, etc. An example is a capsule containing about 0.05 g to about 5.0 g of the active ingredient.

[0119] In some embodiments, the active ingredient is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient for the desired indication without causing serious toxic effects in the patient being treated. Exemplary doses of the active compound for all the diseases mentioned herein range from about 10 ng / kg to 300 mg / kg, for example, 0.001 to 100 mg / kg / day, and more generally, from 0.01 to about 0.5 mg per kilogram of recipient / patient body weight per day.

[0120] Typical topical doses range from 0.01 to 5% wt / wt in a suitable carrier. The compounds are not limited to, but the unit dose forms include 0.01 mg to 50 mg, 0.01 mg to 40 mg, 0.01 mg to 30 mg, 0.01 mg to 20 mg, 0.01 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 50 mg, 0.1 mg to 40 mg, 0.1 mg to 30 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, and 1 mg. It is conveniently administered in any suitable unit dose form, including those containing the active ingredient in amounts of g-10mg, 5mg-50mg, 5mg-40mg, 5mg-30mg, 5mg-20mg, 5mg-15mg, 5mg-10mg, 7.5mg-50mg, 7.5mg-40mg, 7.5mg-30mg, 7.5mg-20mg, 7.5mg-15mg, 7.5mg-10mg, 10mg-50mg, 10mg-40mg, 10mg-30mg, or 10mg-20mg. In some embodiments, the composition comprises an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) in doses of about 0.1 mg to about 50 mg (e.g., about 1 mg to about 25 mg), and / or an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) in concentrations of about 0.001 mg / mL to about 10 mg / mL (e.g., about 0.01 mg / mL to about 1 mg / mL).

[0121] In some embodiments, the compositions described herein may be formulated by conventional methods using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, dimethyl sulfoxide (DMSO), soybean oil as a carrier, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, water, salts, or partial glyceride mixtures of electrolytes, e.g., prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0122] In some embodiments, the composition comprises soybean oil, dimethyl sulfoxide (DMSO), hydrogel, or a combination thereof. Any of the embodiments described herein may be a single-component oil-phase formulation as described above, where each active ingredient may be in any of the doses or concentrations described herein. The single-component oil phase may be a non-volatile oil such as soybean oil. For example, the formulation contains about 0.1 mg to about 5.0 mg of each active ingredient in 1 mL of single-component oil (i.e., about 0.5 mg / mL, about 1 mg / mL, or about 1.5 mg / mL of each active ingredient in the single-component oil). A single-component oil-phase formulation may be prepared by adding each active ingredient (e.g., about 1 mg to about 50 mg of each active ingredient) to about 10 mL of single-component oil.

[0123] In some embodiments, the pharmaceutical compositions according to this specification include DMSO in a DMSO solution which is, for example, about 5% to about 100% DMSO (e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 30% to about 95%, about 45% to about 95%, about 75% to about 95%, about 30% to about 90%, about 45% to about 90%, about 75% to about 90%, about 30% to about 85%, about 45% to about 85%, or about 75% to about 85%). For example, a pharmaceutical composition contains approximately 0.01 mg to 5.0 mg of each active ingredient in 1 mL of DMSO (i.e., approximately 0.05 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.5 mg / mL, 1 mg / mL, or 1.5 mg / mL of each active ingredient in DMSO). A DMSO pharmaceutical composition can be prepared by adding each active ingredient (for example, approximately 0.1 mg to 50 mg of each active ingredient) to approximately 10 mL of DMSO solution. For example, DMSO is a DMSO solution containing approximately 5% to 100% DMSO, approximately 25% to 100% DMSO, approximately 50% to 100% DMSO, approximately 75% to 100% DMSO, approximately 5% to 75% DMSO, approximately 25% to 75% DMSO, approximately 50% to 75% DMSO, approximately 5% to 50% DMSO, approximately 25% to 50% DMSO, or approximately 5% to 25% DMSO.

[0124] In some embodiments, this description provides a controlled-release subcutaneous or intramuscular dosage formulation comprising a homogeneous dispersion of an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist, e.g., BQ-788, its deuterated or fluorinated analogues, or a combination thereof).

[0125] In some embodiments, pharmaceutical compositions as described herein are formulated into controlled-release delivery systems containing biocompatible polymers. In some embodiments, the active compound is prepared using a carrier that protects the compound from rapid elimination from the body, such as controlled-release formulations including implants, hydrogels, thermosensitive hydrogels, and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, acrylates, polycarboxylic acids, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. In some embodiments, the biocompatible polymer is poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), polycaprolactone, polycarbonate, polyesteramide, polyanhydride, poly(amino acid), polyorthoester, polycyanoacrylate, poly(p-dioxanone), poly(alkylene oxalate), biodegradable polyurethane, blends, or copolymers thereof.

[0126] In some embodiments, the pharmaceutically acceptable carrier comprises or is a liposome. For example, the pharmaceutical composition or formulation may comprise a liposome having an internal volume containing an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist). In some embodiments, the liposome is configured to achieve controlled release of the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist), such as immediate release, extended release, or a combination thereof.

[0127] In some embodiments, liposomes are configured to achieve controlled release of a pharmaceutical composition. In some embodiments, liposomes are configured to achieve immediate release of a pharmaceutical composition. In some embodiments, liposomes are configured or formulated to achieve extended release of a pharmaceutical composition. In some embodiments, liposomes are configured to provide both immediate and extended release of a pharmaceutical composition.

[0128] In some embodiments, the liposome suspension is a pharmaceutically acceptable carrier. For example, a liposome formulation can be prepared by dissolving a suitable lipid(s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, evaporating it, and leaving a dry lipid film on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The liposome suspension is then formed by rotating the container by hand to dislodge the lipid material from the sides of the container and disperse the lipid aggregates. In some embodiments, the liposomes include neutral lipids, basic (net positively charged) lipids, acidic (net negatively charged) lipids, cholesterol, or a combination thereof. In some embodiments, the liposomes further include polymer components. In some embodiments, the internal volume of the liposome is at least partially aqueous and contains an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist).

[0129] In some embodiments, this description provides pharmaceutical compositions as described herein, which are liposome delivery systems, for example, phosphatidylethanolamine (PE) such as dipalmitoyl PE (DPPE), and partially unsaturated phosphatidylcholine (PC) such as egg PC (EPC) or SPC, fully unsaturated PC such as HSPC, PG, phosphatidylserine (PS), phosphatidylinositol (PI), or combinations thereof. In some embodiments, the phospholipid is partially unsaturated PG, dipalmitoylphosphatidylglycerol (DPPG), cholesterol, DSPE-PEG2000, polysorbate 80, or combinations thereof. In some embodiments, the liposome delivery system is a controlled release system, for example, at least one of immediate release, extended release, immediate and extended release, delayed release, sustained release, sustained release, and combinations thereof.

[0130] In some embodiments, the pharmaceutical compositions herein are pharmaceutically acceptable salts, particularly acid-added or base-added salts of compounds as described herein. In accordance with this embodiment, the acids used to prepare pharmaceutically acceptable acid-added salts of the aforementioned useful base compounds are acids that form non-toxic acid-added salts, i.e., salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, tartrate, phosphate, acidic phosphate, acetate, lactate, citrate, acidic citrate, tartrate, tartrate, succinate, maleate, fumarate, gluconate, saccharinate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoethate)]. Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives relating to this disclosure. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable basic salts of the compounds which are inherently acidic are bases that, in combination with such compounds, form non-toxic basic salts. Such non-toxic basic salts include, but are not limited to, those derived from pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium, or water-soluble amine addition salts such as N-methylglucamine-(meglumine), as well as lower alkanolammonium and other pharmaceutically acceptable inorganic amine basic salts.

[0131] In some embodiments, the oral composition includes an inert diluent or an edible carrier. These may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative may be incorporated into an excipient and used in the form of tablets, lozenges, or capsules. A pharmaceutically acceptable binder and / or adjuvant may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain the following components: a binder such as microcrystalline cellulose, tragacanth gum, or gelatin; an excipient such as starch or lactose; a dispersant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a flow enhancer such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavor, or a compound having similar properties. When the unit form of the dosage is a capsule, in addition to the above materials, a liquid carrier such as fatty oil may be included. In addition, the dosage unit form may include a coating of various other materials that alter the physical form of the dosage unit, such as sugar, shellac, or enteric-coated material.

[0132] In some embodiments, the active compound or a pharmaceutically acceptable salt thereof is administered as an ingredient in elixirs, suspensions, syrups, wafers, chewing gum, etc. In addition to the active compound, the syrup may contain sucrose as a sweetener, as well as certain preservatives, pigments, colorants, and flavorings.

[0133] In some embodiments, solutions or suspensions used for parenteral, intradermal, subcutaneous, intravenous, intramuscular, or topical application include the following components: sterile diluents such as water for injection, physiological saline, non-volatile oils (e.g., soybean oil), polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and agents for adjusting osmotic pressure such as sodium chloride or dextrose. Parenteral preparations may be placed in glass or plastic ampoules, disposable syringes, or vials for multiple doses. In some embodiments, the carrier for intravenous administration is physiological saline or phosphate-buffered saline (PBS).

[0134] In some embodiments, each of the active ingredients of the pharmaceutical composition of this disclosure is approximately 50 μg to approximately 100,000 μg, approximately 50 μg to approximately 90,000 μg, approximately 50 μg to approximately 80,000 μg, approximately 50 μg to approximately 70,000 μg, approximately 50 μg to approximately 60,000 μg, approximately 50 μg to approximately 50,000 μg, approximately 50 μg to approximately 40,000 μg, approximately 50 μg to approximately 30,000 μg, approximately 50 μg to approximately 25,000 μg, approximately 50 μg to approximately 20,000 μg, approximately 50 μg to approximately 15,000 μg, approximately 50 μg to approximately 10,000 μg, approximately 50 μg to approximately 9,000 μg, approximately 50 μg to approximately 8,000 μg, and approximately 50 μg to approximately 700 μg. 0μg, about 50μg to about 6000μg, about 50μg to about 5000μg, about 50μg to about 4000μg, about 50μg to about 3000μg, about 5 0 μg to approx. 2500 μg, approx. 50 μg to approx. 2000 μg, approx. 50 μg to approx. 1500 μg, approx. 50 μg to approx. 1000 μg, approx. 50 μg to approx. 75 0μg, about 50μg to about 500μg, about 50μg to about 400μg, about 50μg to about 300μg, about 50μg to about 200μg, about 50μg to about Approximately 100μg, approximately 100μg~approximately 100000μg, approximately 100μg~approximately 90000μg, approximately 100μg~approximately 80000μg, approximately 100μg~ Approximately 70000μg, approximately 100μg to approximately 60000μg, approximately 100μg to approximately 50000μg, approximately 100μg to approximately 40000μg, approximately 100μg g ~ approx. 30000μg, approx. 100μg ~ approx. 25000μg, approx. 100μg ~ approx. 20000μg, approx. 100μg ~ approx. 15000μg, approx. 100 μg ~ approx. 10000 μg, approx. 100 μg ~ approx. 9000 μg, approx. 100 μg ~ approx. 8000 μg, approx. 100 μg ~ approx. 7000 μg, approx. 100 μg g~about 6000μg, about 100μg~about 5000μg, about 100μg~about 4000μg, about 100μg~about 3000μg, about 100μg~about 2500μg, about 100μg to about 2000μg, about 100μg to about 1500μg, about 100μg to about 1000μg, about 100μg to about 75 0μg, about 100μg to about 500μg, about 100μg to about 400μg, about 100μg to about 300μg, about 100μg to about 200μg, about 20 0μg~about 100000μg, about 200μg~about 90000μg, about 200μg~about 80000μg, about 200μg~about 70000μg, about 200μg~about 60000μg, about 200μg~about 50000μg, about 200μg~about 40000μg, about 200μg~about 30000μg,Approximately 200 μg to approximately 25000 μg, approximately 200 μg to approximately 20000 μg, approximately 200 μg to approximately 15000 μg, approximately 200 μg to approximately 10000 μg, approximately 200 μg to approximately 9000 μg, approximately 200 μg to approximately 8000 μg, approximately 200 μg to approximately 7000 μg, approximately 200 μg to approximately 6000 μg. Approximately 200 μg to approximately 5000 μg, approximately 200 μg to approximately 4000 μg, approximately 200 μg to approximately 3000 μg, approximately 200 μg to approximately 2500 μg, approximately 200 μg to approximately 2000 μg, approximately 200 μg to approximately 1500 μg, approximately 200 μg to approximately 1000 μg, approximately 200 μg to approximately 750 μg, approximately 200 μg ~Approximately 500μg, approximately 200μg~approximately 400μg, approximately 200μg~approximately 300μg, approximately 300μg~approximately 100,000μg, approximately 300μg~approximately 90,000μg, approximately 300μg~approximately 80,000μg, approximately 300μg~approximately 70,000μg, approximately 300μg~approximately 60,000μg, approximately 300μg~approximately 50,000 μg, approximately 300 μg to approximately 40,000 μg, approximately 300 μg to approximately 30,000 μg, approximately 300 μg to approximately 25,000 μg, approximately 300 μg to approximately 20,000 μg, approximately 300 μg to approximately 15,000 μg, approximately 300 μg to approximately 10,000 μg, approximately 300 μg to approximately 9,000 μg, approximately 300 μg ~Approx. 8000μg, Approx. 300μg~Approx. 7000μg, Approx. 300μg~Approx. 6000μg, Approx. 300μg~Approx. 5000μg, Approx. 300μg~Approx. 4000μg, Approx. 300μg~Approx. 300μg~Approx. 2500μg, Approx. 300μg~Approx. 2000μg, Approx. 300μg~Approx. 15 0.00μg, approximately 300μg to approximately 1000μg, approximately 300μg to approximately 750μg, approximately 300μg to approximately 500μg, approximately 300μg to approximately 400μg, approximately 400μg to approximately 100000μg, approximately 400μg to approximately 90000μg, approximately 400μg to approximately 80000μg, approximately 400μg to approximately 70000μg g, approximately 400μg~approx. 60000μg, approximately 400μg~approx. 50000μg, approximately 400μg~approx. 40000μg, approximately 400μg~approx. 30000μg, approximately 400μg~approx. 25000μg, approximately 400μg~approx. 20000μg, approximately 400μg~approx. 15000μg, approximately 400μg~approx. 100 00μg, approximately 400μg to approximately 9000μg, approximately 400μg to approximately 8000μg, approximately 400μg to approximately 7000μg, approximately 400μg to approximately 6000μg, approximately 400μg to approximately 5000μg, approximately 400μg to approximately 4000μg, approximately 400μg to approximately 3000μg, approximately 400μg to approximately 2500μg,Approximately 400 μg to approximately 2000 μg, approximately 400 μg to approximately 1500 μg, approximately 400 μg to approximately 1000 μg, approximately 400 μg to approximately 750 μg, approximately 400 μg to approximately 500 μg, approximately 500 μg to approximately 100000 μg, approximately 500 μg to approximately 90000 μg, approximately 500 μg to approximately 80000 μg, approximately 500μg~approx. 70000μg, approx. 500μg~approx. 60000μg, approx. 500μg~approx. 50000μg, approx. 500μg~approx. 40000μg, approx. 500μg~approx. 30000μg, approx. 500μg~approx. 25000μg, approx. 500μg~approx. 20000μg, approx. 500μg~approx. 15000μg μg, approximately 500μg to approximately 10000μg, approximately 500μg to approximately 9000μg, approximately 500μg to approximately 8000μg, approximately 500μg to approximately 7000μg, approximately 500μg to approximately 6000μg, approximately 500μg to approximately 5000μg, approximately 500μg to approximately 4000μg, approximately 500μg to approximately 3000μg, Approximately 500 μg to approximately 2500 μg, approximately 500 μg to approximately 2000 μg, approximately 500 μg to approximately 1500 μg, approximately 500 μg to approximately 1000 μg, approximately 500 μg to approximately 750 μg, approximately 750 μg to approximately 100000 μg, approximately 750 μg to approximately 90000 μg, approximately 750 μg to approximately 80000 μg, approximately 750μg~approx. 70000μg, approx. 750μg~approx. 60000μg, approx. 750μg~approx. 50000μg, approx. 750μg~approx. 40000μg, approx. 750μg~approx. 30000μg, approx. 750μg~approx. 25000μg, approx. 750μg~approx. 20000μg, approx. 750μg~approx. 15000μg μg, approximately 750μg~approx. 10000μg, approximately 750μg~approx. 9000μg, approximately 750μg~approx. 8000μg, approximately 750μg~approx. 7000μg, approximately 750μg~approx. 6000μg, approximately 750μg~approx. 5000μg, approximately 750μg~approx. 4000μg, approximately 750μg~approx. 3000μg Approximately 750 μg to approximately 2500 μg, approximately 750 μg to approximately 2000 μg, approximately 750 μg to approximately 1500 μg, approximately 750 μg to approximately 1000 μg, approximately 1000 μg to approximately 100000 μg, approximately 1000 μg to approximately 90000 μg, approximately 1000 μg to approximately 80000 μg, approximately 1000 μg to approximately 700 μg 0.00 μg, approximately 1000 μg to approximately 60000 μg, approximately 1000 μg to approximately 50000 μg, approximately 1000 μg to approximately 40000 μg, approximately 1000 μg to approximately 30000 μg, approximately 1000 μg to approximately 25000 μg, approximately 1000 μg to approximately 20000 μg, approximately 1000 μg to approximately 15000 μg,Approximately 1000μg~approximately 10000μg, approximately 1000μg~approximately 9000μg, approximately 1000μg~approximately 8000μg, approximately 1000μg~approximately 7000μg, approximately 1000μg~approximately 6000μg, approximately 1000μg~approximately 5000μg, approximately 1000μg~approximately 4000μg, approximately 1000μg~approximately 30 00μg, approximately 1000μg~approx. 2500μg, approximately 1000μg~approx. 2000μg, approximately 1000μg~approx. 1500μg, approximately 1500μg~approx. 100000μg, approximately 1500μg~approx. 90000μg, approximately 1500μg~approx. 80000μg, approximately 1500μg~approx. 70000μg, approximately 15 00μg~approx. 60000μg, approx. 1500μg~approx. 50000μg, approx. 1500μg~approx. 40000μg, approx. 1500μg~approx. 30000μg, approx. 1500μg~approx. 25000μg, approx. 1500μg~approx. 20000μg, approx. 1500μg~approx. 15000μg, approx. 1500μg~ Approximately 10,000 μg, approximately 1,500 μg to approximately 9,000 μg, approximately 1,500 μg to approximately 8,000 μg, approximately 1,500 μg to approximately 7,000 μg, approximately 1,500 μg to approximately 6,000 μg, approximately 1,500 μg to approximately 5,000 μg, approximately 1,500 μg to approximately 4,000 μg, approximately 1,500 μg to approximately 3,000 μg, approximately 150 μg 0 μg ~ approx. 2500 μg, approx. 1500 μg ~ approx. 2000 μg, approx. 2000 μg ~ approx. 100000 μg, approx. 2000 μg ~ approx. 90000 μg, approx. 2000 μg ~ approx. 80000 μg, approx. 2000 μg ~ approx. 70000 μg, approx. 2000 μg ~ approx. 60000 μg, approx. 2000 μg ~ approx. 5 0000μg, approximately 2000μg to approximately 40000μg, approximately 2000μg to approximately 30000μg, approximately 2000μg to approximately 25000μg, approximately 2000μg to approximately 20000μg, approximately 2000μg to approximately 15000μg, approximately 2000μg to approximately 10000μg, approximately 2000μg to approximately 9000μg Approximately 2000μg~8000μg, approximately 2000μg~7000μg, approximately 2000μg~6000μg, approximately 2000μg~5000μg, approximately 2000μg~4000μg, approximately 2000μg~3000μg, approximately 2000μg~2500μg, approximately 2500μg~100 000μg, approximately 2500μg to approximately 90000μg, approximately 2500μg to approximately 80000μg, approximately 2500μg to approximately 70000μg, approximately 2500μg to approximately 60000μg, approximately 2500μg to approximately 50000μg, approximately 2500μg to approximately 40000μg, approximately 2500μg to approximately 30000μg,Approximately 2500 μg to approximately 25000 μg, approximately 2500 μg to approximately 20000 μg, approximately 2500 μg to approximately 15000 μg, approximately 2500 μg to approximately 10000 μg, approximately 2500 μg to approximately 9000 μg, approximately 2500 μg to approximately 8000 μg, approximately 2500 μg to approximately 7000 μg, approximately 2500 μg ~approx. 6000μg, approx. 2500μg~approx. 5000μg, approx. 2500μg~approx. 4000μg, approx. 2500μg~approx. 3000μg, approx. 3000μg~approx. 100000μg, approx. 3000μg~approx. 90000μg, approx. 3000μg~approx. 80000μg, approx. 3000μg~approx. 70000μg, approx. 3000μg~approx. 60000μg, approx. 3000μg~approx. 50000μg, approx. 3000μg~approx. 40000μg, approx. 3000μg~approx. 30000μg, approx. 3000μg~approx. 25000μg, approx. 3000μg~approx. 20000μg, approx. 3000μg~approx. 15000μg, approx. 3000μg~approx. 10000μg, approx. 3000μg~approx. 9000μg, approx. 3000μg~approx. 8000μg, approx. 3000μg~approx. 7000μg, approx. 3000μg~approx. 6000μg, approx. 3000μg~approx. 5000μg, approx. 3000μg~approx. 4000μg, approx. 4000μg~approx. 100 000μg, approximately 4000μg~approx. 90000μg, approximately 4000μg~approx. 80000μg, approximately 4000μg~approx. 70000μg, approximately 4000μg~approx. 60000μg, approximately 4000μg~approx. 50000μg, approximately 4000μg~approx. 40000μg, approximately 4000μg~approx. 30000μg g, approximately 4000μg~approx. 25000μg, approximately 4000μg~approx. 20000μg, approximately 4000μg~approx. 15000μg, approximately 4000μg~approx. 10000μg, approximately 4000μg~approx. 9000μg, approximately 4000μg~approx. 8000μg, approximately 4000μg~approx. 7000μg, approximately 4000μg g ~ approximately 6000 μg, approximately 4000 μg ~ approximately 5000 μg, approximately 5000 μg ~ approximately 100000 μg, approximately 5000 μg ~ approximately 90000 μg, approximately 5000 μg ~ approximately 80000 μg, approximately 5000 μg ~ approximately 70000 μg, approximately 5000 μg ~ approximately 60000 μg, approximately 5000 μg ~ approximately 50 000μg, approximately 5000μg to approximately 40000μg, approximately 5000μg to approximately 30000μg, approximately 5000μg to approximately 25000μg, approximately 5000μg to approximately 20000μg, approximately 5000μg to approximately 15000μg, approximately 5000μg to approximately 10000μg, approximately 5000μg to approximately 9000μgApproximately 5000μg~8000μg, approximately 5000μg~7000μg, approximately 5000μg~6000μg, approximately 6000μg~100000μg, approximately 6000μg~90000μg, approximately 6000μg~80000μg, approximately 6000μg~70000μg, approximately 6000μg~60000μg, approximately 6000μg~5000μg 0 μg, approximately 6000 μg to approximately 40000 μg, approximately 6000 μg to approximately 30000 μg, approximately 6000 μg to approximately 25000 μg, approximately 6000 μg to approximately 20000 μg, approximately 6000 μg to approximately 15000 μg, approximately 6000 μg to approximately 10000 μg, approximately 6000 μg to approximately 9000 μg, approximately 6 000μg~approx. 8000μg, approx. 6000μg~approx. 7000μg, approx. 7000μg~approx. 100000μg, approx. 7000μg~approx. 90000μg, approx. 7000μg~approx. 80000μg, approx. 7000μg~approx. 70000μg, approx. 7000μg~approx. 60000μg, approx. 7000μg~approx. 50,000 μg, approximately 7,000 μg to approximately 40,000 μg, approximately 7,000 μg to approximately 30,000 μg, approximately 7,000 μg to approximately 25,000 μg, approximately 7,000 μg to approximately 20,000 μg, approximately 7,000 μg to approximately 15,000 μg, approximately 7,000 μg to approximately 10,000 μg, approximately 7,000 μg to approximately 9,000 μg Approximately 7000μg~8000μg, approximately 8000μg~100000μg, approximately 8000μg~90000μg, approximately 8000μg~80000μg, approximately 8000μg~70000μg, approximately 8000μg~60000μg, approximately 8000μg~50000μg, approximately 8000μg μg ~ approximately 40,000 μg, approximately 8,000 μg ~ approximately 30,000 μg, approximately 8,000 μg ~ approximately 25,000 μg, approximately 8,000 μg ~ approximately 20,000 μg, approximately 8,000 μg ~ approximately 15,000 μg, approximately 8,000 μg ~ approximately 10,000 μg, approximately 8,000 μg ~ approximately 9,000 μg, approximately 9,000 μg ~ approximately 10 0000μg, approximately 9000μg to approximately 90000μg, approximately 9000μg to approximately 80000μg, approximately 9000μg to approximately 70000μg, approximately 9000μg to approximately 60000μg, approximately 9000μg to approximately 50000μg, approximately 9000μg to approximately 40000μg, approximately 9000μg to approximately 30000μg Approximately 9000μg to approximately 25000μg, approximately 9000μg to approximately 20000μg, approximately 9000μg to approximately 15000μg, approximately 9000μg to approximately 10000μg, approximately 10000μg to approximately 100000μg, approximately 10000μg to approximately 90000μg, approximately 10000μg to approximately 80000μg, approximately 10,000 μg ~ approximately 70,000 μg, approximately 10,000 μg ~ approximately 60,000 μg, approximately 10,000 μg ~ approximately 50,000 μg, approximately 10,000 μg ~ approximately 40,000 μg, approximately 10,000 μg ~ approximately 30,000 μg, approximately 10,000 μg ~ approximately 25,000 μg, approximately 10,000 μg ~ approximately 20,000 μgApproximately 10,000μg to approximately 15,000μg, approximately 15,000μg to approximately 100,000μg, approximately 15,000μg to approximately 90,000μg, approximately 15,000μg to approximately 80,000μg, approximately 15,000μg to approximately 70,000μg, approximately 15,000μg to approximately 60,000μg, approximately 1,500 0μg to about 50000μg, about 15000μg to about 40000μg, about 15000μg to about 30000μg, about 15000μg to about 25000μg, about 15000μg to about 20000μg, about 20000μg to about 100000μg, about 20000μg to about 9 0000μg, about 20000μg to about 80000μg, about 20000μg to about 70000μg, about 20000μg to about 60000μg, about 20000μg to about 50000μg, about 20000μg to about 40000μg, about 20000μg to about 30000μg , about 20000μg to about 25000μg, about 30000μg to about 100000μg, about 30000μg to about 90000μg, about 30000μg to about 80000μg, about 30000μg to about 70000μg, about 30000μg to about 60000μg, about 3000 0μg to about 50000μg, about 30000μg to about 40000μg, about 40000μg to about 100000μg, about 40000μg to about 90000μg, about 40000μg to about 80000μg, about 40000μg to about 70000μg, about 40000μg to about 60000μg, about 40000μg to about 50000μg, about 50000μg to about 100000μg, about 50000μg to about 90000μg, about 50000μg to about 80000μg, about 50000μg to about 70000μg, about 50000μg to about 60000μg It may be present in any of the following dosage formulations (e.g., initial burst, sustained-release dose, etc.) in amounts of approximately 60,000 μg to 100,000 μg, approximately 60,000 μg to 90,000 μg, approximately 60,000 μg to 80,000 μg, approximately 60,000 μg to 70,000 μg, approximately 70,000 μg to 100,000 μg, approximately 70,000 μg to 90,000 μg, approximately 70,000 μg to 80,000 μg, approximately 80,000 μg to 100,000 μg, or approximately 90,000 μg to 100,000 μg.

[0135] In some embodiments, each of the active ingredients of the pharmaceutical compositions of this disclosure may be present in any of the following dosage formulations (e.g., initial burst dose, sustained-release dose, etc.) in amounts of about 50 μg to about 500 μg, about 500 μg to about 2000 μg, about 20000 μg to about 10000 μg, about 10000 μg to about 20000 μg, about 20000 μg to about 50000 μg, or about 50000 μg to about 100000 μg.

[0136] In some embodiments, each active ingredient of the pharmaceutical composition of this disclosure is approximately 0.1 mg / mL to approximately 50 mg / mL, approximately 0.1 mg / mL to approximately 25 mg / mL, approximately 0.1 mg / mL to approximately 10 mg / mL, approximately 1 mg / mL to approximately 50 mg / mL, approximately 1 mg / mL to approximately 25 mg / mL, approximately 1 mg / mL to approximately 10 mg / mL, approximately 0.1 mg / mL to approximately 5.0 mg / mL (for example, approximately 0.1 mg / mL to approximately 4.5 mg / mL, approximately 0.1 mg / mL to approximately 4.0 mg / mL, approximately 0.1 mg / mL to approximately 3.5 mg / mL, approximately 0.1 mg / mL to approximately 3.0 mg / mL relative to the pharmaceutical composition). mL, approximately 0.1 mg / mL to approximately 2.5 mg / mL, approximately 0.1 mg / mL to approximately 2.0 mg / mL, approximately 0.1 mg / mL to approximately 1.5 mg / mL, approximately 0.1 mg / mL to approximately 1.0 mg / mL, approximately 0.1 mg / mL to approximately 0.5 mg / mL, approximately 0.5 mg / mL to approximately 4.5 mg / mL, approximately 0.5mg / mL to about 4.0mg / mL, about 0.5mg / mL to about 3.5mg / mL, about 0.5mg / mL to about 3.0mg / mL, about 0.5mg / mL to about 2.5mg / mL, about 0.5mg / mL to about 2.0mg / mL, about 0.5mg / mL to about 1.5mg / mL, about 0.5mg / mL~about 1.0mg / mL, about 1.0mg / mL~about 4.5mg / mL, about 1.0mg / mL~about 4.0mg / mL, about 1.0mg / mL~about 3.5mg / mL, about 1.0mg / mL~about 3.0mg / mL, about 1.0mg / mL~about 2.5mg / mL, about 1.0mg / mL~ Approximately 2.0 mg / mL, approximately 1.0 mg / mL to approximately 1.5 mg / mL, approximately 1.5 mg / mL to approximately 4.5 mg / mL, approximately 1.5 mg / mL to approximately 4.0 mg / mL, approximately 1.5 mg / mL to approximately 3.5 mg / mL, approximately 1.5 mg / mL to approximately 3.0 mg / mL, approximately 1.5 mg / mL to approximately 2.5 mg / mL, approximately 1.5 mg / mL to approximately 2.0 mg / mL, approximately 2.0 mg / mL to approximately 4.5 mg / mL, approximately 2.0 mg / mL to approximately 4.0 mg / mL, approximately 2.0 mg / mL to approximately 3.5 mg / mL, approximately 2.0 mg / mL to approximately 3.0 mg / mL, approximately 2.0 mg / mL to approximately 2.5 mg / m L, about 2.5 mg / mL to about 4.5 mg / mL, about 2.5 mg / mL to about 4.0 mg / mL, about 2.5 mg / mL to about 3.5 mg / mL, about 2.5 mg / mL to about 3.0 mg / mL, about 3.0 mg / mL to about 4.5 mg / mL, about 3.0 mg / mL to about 4.0 mg / mL, about 3.It exists in concentrations ranging from 0 mg / mL to approximately 3.5 mg / mL, approximately 3.5 mg / mL to approximately 4.5 mg / mL, approximately 3.5 mg / mL to approximately 4.0 mg / mL, or approximately 3.5 mg / mL to approximately 4.5 mg / mL.

[0137] In some embodiments, each active ingredient of the pharmaceutical composition of this disclosure is approximately 0.1 μg / mL to approximately 50 μg / mL, approximately 0.1 μg / mL to approximately 25 μg / mL, approximately 0.1 μg / mL to approximately 10 μg / mL, approximately 1 μg / mL to approximately 50 μg / mL, approximately 1 μg / mL to approximately 25 μg / mL, approximately 1 μg / mL to approximately 10 μg / mL, approximately 0.1 μg / mL to approximately 5.0 μg / mL, for example, approximately 1 μg / mL to approximately 5 μg / mL, approximately 0.1 μg / mL to approximately 4.0 μg / mL, approximately 0.1 μg / mL to approximately 3.5 μg / mL, approximately 0.1 μg / mL to approximately 3.0 μg / mL, and approximately 0. 1μg / mL to approximately 2.5μg / mL, approximately 0.1μg / mL to approximately 2.0μg / mL, approximately 0.1μg / mL to approximately 1.5μg / mL, approximately 0.1μg / mL to approximately 1.0μg / mL, approximately 0.1μg / mL to approximately 0.5μg / mL, approximately 0.5μg / mL to approximately 4.5μg / mL, approximately 0.5μg / m L ~ about 4.0μg / mL, about 0.5μg / mL - about 3.5μg / mL, about 0.5μg / mL - about 3.0μg / mL, about 0.5μg / mL - about 2.5μg / mL, about 0.5μg / mL - about 2.0μg / mL, about 0.5μg / mL - about 1.5μg / mL, about 0.5μg / mL - about 1. 0μg / mL, approximately 1.0μg / mL to approximately 4.5μg / mL, approximately 1.0μg / mL to approximately 4.0μg / mL, approximately 1.0μg / mL to approximately 3.5μg / mL, approximately 1.0μg / mL to approximately 3.0μg / mL, approximately 1.0μg / mL to approximately 2.5μg / mL, approximately 1.0μg / mL to approximately 2.0μg / m L, about 1.0 μg / mL to about 1.5 μg / mL, about 1.5 μg / mL to about 4.5 μg / mL, about 1.5 μg / mL to about 4.0 μg / mL, about 1.5 μg / mL to about 3.5 μg / mL, about 1.5 μg / mL to about 3.0 μg / mL, about 1.5 μg / mL to about 2.5 μg / mL, about 1. 5μg / mL to about 2.0μg / mL, about 2.0μg / mL to about 4.5μg / mL, about 2.0μg / mL to about 4.0μg / mL, about 2.0μg / mL to about 3.5μg / mL, about 2.0μg / mL to about 3.0μg / mL, about 2.0μg / mL to about 2.5μg / mL, about 2.5μg / m L~about 4.5μg / mL, about 2.5μg / mL~about 4.0μg / mL, about 2.5μg / mL~about 3.5μg / mL, about 2.5μg / mL~about 3.0μg / mL, about 3.0μg / mL~about 4.5μg / mL, about 3.0μg / mL~about 4.0μg / mL, about 3.0μg / mL~about 3.It exists at concentrations of 5 μg / mL, approximately 3.5 μg / mL to 4.5 μg / mL, approximately 3.5 μg / mL to 4.0 μg / mL, or approximately 3.5 μg / mL to 4.5 μg / mL.

[0138] Dosage regimen In various embodiments, treatment regimens are disclosed herein. In some embodiments, the treatment regimen comprises a dosage pharmaceutical composition having about 100 μg to about 100,000 μg of each active ingredient (i.e., an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist as described herein)). The dosage may be a sustained-release dosage in which about 50 μg to about 60,000 μg of each active ingredient is an initial burst, while about 50 μg to about 60,000 μg of each active ingredient is released sustained over 2 hours.

[0139] In some embodiments, the dose of the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) may range from about 1.0 μg to about 100,000 μg.

[0140] In some embodiments, the dosage of the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is approximately 1.0 μg to 100,000 μg, approximately 1.0 μg to 90,000 μg, approximately 1.0 μg to 80,000 μg, approximately 1.0 μg to 70,000 μg, approximately 1.0 μg to 60,000 μg, approximately 1.0 μg to 50,000 μg, approximately 1.0 μg to 40,000 μg, approximately 1.0 μg to 30,000 μg, approximately 1.0 μg to 29,000 μg, approximately 1.0 μg to 28,000 μg, approximately 1.0 μg to 27,000 μg, and approximately 1.0 μg to 2600 μg. 0μg, about 1.0μg to about 25000μg, about 1.0μg to about 24000μg, about 1.0μg to about 23000μg, about 1.0μg to about 2 2000μg, about 1.0μg~about 21000μg, about 1.0μg~about 20000μg, about 1.0μg~about 19000μg, about 1.0μg~ Approximately 18000μg, approximately 1.0μg to approximately 17000μg, approximately 1.0μg to approximately 16000μg, approximately 1.0μg to approximately 15000μg, approximately 1.0μ g ~ approx. 14000μg, approx. 1.0μg ~ approx. 13000μg, approx. 1.0μg ~ approx. 12000μg, approx. 1.0μg ~ approx. 11000μg, approx. 1. 0μg to about 10000μg, about 1.0μg to about 9000μg, about 1.0μg to about 8000μg, about 1.0μg to about 7000μg, about 1. 0 μg to approx. 6000 μg, approx. 1.0 μg to approx. 5000 μg, approx. 1.0 μg to approx. 4500 μg, approx. 1.0 μg to approx. 4000 μg, approx. 1.0 μg g ~ approx. 3500 μg, approx. 1.0 μg ~ approx. 3000 μg, approx. 1.0 μg ~ approx. 2500 μg, approx. 1.0 μg ~ approx. 2000 μg, approx. 1.0 μg ~ Approximately 1500μg, approximately 1.0μg to approximately 1250μg, approximately 1.0μg to approximately 1000μg, approximately 1.0μg to approximately 750μg, approximately 1.0μg to approximately 50 0μg, about 1.0μg to about 300μg, about 1.0μg to about 250μg, about 1.0μg to about 200μg, about 1.0μg to about 150μg, about 1.0μg to about 100μg, about 1.0μg to about 75μg, about 1.0μg to about 50μg, about 1.0μg to about 25μg, about 1.0μg to about 10 μg, about 10 μg to about 100000 μg, about 10 μg to about 90000 μg, about 10 μg to about 80000 μg, about 10 μg to about 70000 μg g, about 10μg to about 60000μg, about 10μg to about 50000μg, about 10μg to about 40000μg, about 10μg to about 30000μg,Approximately 10 μg to approximately 29,000 μg, approximately 10 μg to approximately 28,000 μg, approximately 10 μg to approximately 27,000 μg, approximately 10 μg to approximately 26,000 μg, approximately 10 μg to approximately 25,000 μg, approximately 10 μg to approximately 24,000 μg, approximately 10 μg to approximately 23,000 μg, approximately 10 μg to approximately 22,000 μg, approximately 10 μg g ~ approximately 21000μg, approximately 10μg ~ approximately 20000μg, approximately 10μg ~ approximately 19000μg, approximately 10μg ~ approximately 18000μg, approximately 10μg ~ approximately 17000μg, approximately 10μg ~ approximately 16000μg, approximately 10μg ~ approximately 15000μg, approximately 10μg ~ approximately 14000μg, approximately 10μg ~ approximately 13 000μg, approximately 10μg to approximately 12000μg, approximately 10μg to approximately 11000μg, approximately 10μg to approximately 10000μg, approximately 10μg to approximately 9000μg, approximately 10μg to approximately 8000μg, approximately 10μg to approximately 7000μg, approximately 10μg to approximately 6000μg, approximately 10μg to approximately 5000μg, approximately 10μg g ~ approximately 4500μg, approximately 10μg ~ approximately 4000μg, approximately 10μg ~ approximately 3500μg, approximately 10μg ~ approximately 3000μg, approximately 10μg ~ approximately 2500μg, approximately 10μg ~ approximately 2000μg, approximately 10μg ~ approximately 1500μg, approximately 10μg ~ approximately 1250μg, approximately 10μg ~ approximately 1000μg, approximately 10 μg ~ approx. 750μg, approx. 10μg ~ approx. 500μg, approx. 10μg ~ approx. 300μg, approx. 10μg ~ approx. 250μg, approx. 10μg ~ approx. 200μg, approx. 10μg ~ approx. 150μg, approx. 10μg ~ approx. 100μg, approx. 10μg ~ approx. 75μg, approx. 10μg ~ approx. 50μg, approx. 10μg ~ approx. 25μg, approx. 25μg~approx. 100,000μg, approx. 25μg~approx. 90,000μg, approx. 25μg~approx. 80,000μg, approx. 25μg~approx. 70,000μg, approx. 25μg~approx. 60,000μg, approx. 25μg~approx. 50,000μg, approx. 25μg~approx. 40,000μg, approx. 25μg~approx. 30,000μg, approx. 25μg ~approx. 29000μg, approx. 25μg~approx. 28000μg, approx. 25μg~approx. 27000μg, approx. 25μg~approx. 26000μg, approx. 25μg~approx. 25000μg, approx. 25μg~approx. 24000μg, approx. 25μg~approx. 23000μg, approx. 25μg~approx. 22000μg, approx. 25μg~approx. 210 0.00 μg, approximately 25 μg to approximately 20,000 μg, approximately 25 μg to approximately 19,000 μg, approximately 25 μg to approximately 18,000 μg, approximately 25 μg to approximately 17,000 μg, approximately 25 μg to approximately 16,000 μg, approximately 25 μg to approximately 15,000 μg, approximately 25 μg to approximately 14,000 μg, approximately 25 μg to approximately 13,000 μgApproximately 25 μg to approximately 12000 μg, approximately 25 μg to approximately 11000 μg, approximately 25 μg to approximately 10000 μg, approximately 25 μg to approximately 9000 μg, approximately 25 μg to approximately 8000 μg, approximately 25 μg to approximately 7000 μg, approximately 25 μg to approximately 6000 μg, approximately 25 μg to approximately 5000 μg, approximately 25 μg to approximately 45 μg 00μg, approximately 25μg to approximately 4000μg, approximately 25μg to approximately 3500μg, approximately 25μg to approximately 3000μg, approximately 25μg to approximately 2500μg, approximately 25μg to approximately 2000μg, approximately 25μg to approximately 1500μg, approximately 25μg to approximately 1250μg, approximately 25μg to approximately 1000μg, approximately 25μg to approximately 7 50μg, approximately 25μg to approximately 500μg, approximately 25μg to approximately 300μg, approximately 25μg to approximately 250μg, approximately 25μg to approximately 200μg, approximately 25μg to approximately 150μg, approximately 25μg to approximately 100μg, approximately 25μg to approximately 75μg, approximately 25μg to approximately 50μg, approximately 50μg to approximately 100000μg, approximately 5 0 μg ~ approximately 90,000 μg, approximately 50 μg ~ approximately 80,000 μg, approximately 50 μg ~ approximately 70,000 μg, approximately 50 μg ~ approximately 60,000 μg, approximately 50 μg ~ approximately 50,000 μg, approximately 50 μg ~ approximately 40,000 μg, approximately 50 μg ~ approximately 30,000 μg, approximately 50 μg ~ approximately 29,000 μg, approximately 50 μg ~ approximately 28000μg, approximately 50μg~approx. 27000μg, approximately 50μg~approx. 26000μg, approximately 50μg~approx. 25000μg, approximately 50μg~approx. 24000μg, approximately 50μg~approx. 23000μg, approximately 50μg~approx. 22000μg, approximately 50μg~approx. 21000μg, approximately 50μg~approx. 20000μg μg, approximately 50μg~approx. 19000μg, approximately 50μg~approx. 18000μg, approximately 50μg~approx. 17000μg, approximately 50μg~approx. 16000μg, approximately 50μg~approx. 15000μg, approximately 50μg~approx. 14000μg, approximately 50μg~approx. 13000μg, approximately 50μg~approx. 12000μg, approximately 5 0 μg ~ approximately 11000 μg, approximately 50 μg ~ approximately 10000 μg, approximately 50 μg ~ approximately 9000 μg, approximately 50 μg ~ approximately 8000 μg, approximately 50 μg ~ approximately 7000 μg, approximately 50 μg ~ approximately 6000 μg, approximately 50 μg ~ approximately 5000 μg, approximately 50 μg ~ approximately 4500 μg, approximately 50 μg ~ approximately 4000 μg Approximately 50 μg to 3500 μg, approximately 50 μg to 3000 μg, approximately 50 μg to 2500 μg, approximately 50 μg to 2000 μg, approximately 50 μg to 1500 μg, approximately 50 μg to 1250 μg, approximately 50 μg to 1000 μg, approximately 50 μg to 750 μg, approximately 50 μg to 500 μg.Approximately 50 μg to approximately 300 μg, approximately 50 μg to approximately 250 μg, approximately 50 μg to approximately 200 μg, approximately 50 μg to approximately 150 μg, approximately 50 μg to approximately 100 μg, approximately 50 μg to approximately 75 μg, approximately 75 μg to approximately 100,000 μg, approximately 75 μg to approximately 90,000 μg, approximately 75 μg to approximately 80,000 μg, approximately 75μg~approx. 70000μg, approx. 75μg~approx. 60000μg, approx. 75μg~approx. 50000μg, approx. 75μg~approx. 40000μg, approx. 75μg~approx. 30000μg, approx. 75μg~approx. 29000μg, approx. 75μg~approx. 28000μg, approx. 75μg~approx. 27000μg, approx. 75μg ~Approximately 26000 μg, approximately 75 μg ~ approximately 25000 μg, approximately 75 μg ~ approximately 24000 μg, approximately 75 μg ~ approximately 23000 μg, approximately 75 μg ~ approximately 22000 μg, approximately 75 μg ~ approximately 21000 μg, approximately 75 μg ~ approximately 20000 μg, approximately 75 μg ~ approximately 19000 μg, approximately 75 μg ~ approximately 18 000μg, approximately 75μg~approx. 17000μg, approximately 75μg~approx. 16000μg, approximately 75μg~approx. 15000μg, approximately 75μg~approx. 14000μg, approximately 75μg~approx. 13000μg, approximately 75μg~approx. 12000μg, approximately 75μg~approx. 11000μg, approximately 75μg~approx. 10000μg Approximately 75 μg to approximately 9000 μg, approximately 75 μg to approximately 8000 μg, approximately 75 μg to approximately 7000 μg, approximately 75 μg to approximately 6000 μg, approximately 75 μg to approximately 5000 μg, approximately 75 μg to approximately 4500 μg, approximately 75 μg to approximately 4000 μg, approximately 75 μg to approximately 3500 μg, approximately 75 μg to approximately 3000 μg μg, approximately 75μg~approx. 2500μg, approximately 75μg~approx. 2000μg, approximately 75μg~approx. 1500μg, approximately 75μg~approx. 1250μg, approximately 75μg~approx. 1000μg, approximately 75μg~approx. 750μg, approximately 75μg~approx. 500μg, approximately 75μg~approx. 300μg, approximately 75μg~approx. 250μg Approximately 75 μg to approximately 200 μg, approximately 75 μg to approximately 150 μg, approximately 75 μg to approximately 100 μg, approximately 100 μg to approximately 100,000 μg, approximately 100 μg to approximately 90,000 μg, approximately 100 μg to approximately 80,000 μg, approximately 100 μg to approximately 70,000 μg, approximately 100 μg to approximately 60,000 μg, approximately 10 0 μg ~ approximately 50,000 μg, approximately 100 μg ~ approximately 40,000 μg, approximately 100 μg ~ approximately 30,000 μg, approximately 100 μg ~ approximately 29,000 μg, approximately 100 μg ~ approximately 28,000 μg, approximately 100 μg ~ approximately 27,000 μg, approximately 100 μg ~ approximately 26,000 μg, approximately 100 μg ~ approximately 25,000 μgApproximately 100 μg to approximately 24000 μg, approximately 100 μg to approximately 23000 μg, approximately 100 μg to approximately 22000 μg, approximately 100 μg to approximately 21000 μg, approximately 100 μg to approximately 20000 μg, approximately 100 μg to approximately 19000 μg, approximately 100 μg to approximately 18000 μg, approximately 100 μg to approximately 1700 μg 0 μg, approximately 100 μg to approximately 16000 μg, approximately 100 μg to approximately 15000 μg, approximately 100 μg to approximately 14000 μg, approximately 100 μg to approximately 13000 μg, approximately 100 μg to approximately 12000 μg, approximately 100 μg to approximately 11000 μg, approximately 100 μg to approximately 10000 μg, approximately 100 μg to approximately 9 μg 000μg, approximately 100μg to approximately 8000μg, approximately 100μg to approximately 7000μg, approximately 100μg to approximately 6000μg, approximately 100μg to approximately 5000μg, approximately 100μg to approximately 4500μg, approximately 100μg to approximately 4000μg, approximately 100μg to approximately 3500μg, approximately 100μg to approximately 3000μg Approximately 100μg to approximately 2500μg, approximately 100μg to approximately 2000μg, approximately 100μg to approximately 1500μg, approximately 100μg to approximately 1250μg, approximately 100μg to approximately 1000μg, approximately 100μg to approximately 750μg, approximately 100μg to approximately 500μg, approximately 100μg to approximately 300μg, approximately 100μg~ Approximately 250 μg, approximately 100 μg to approximately 200 μg, approximately 100 μg to approximately 150 μg, approximately 150 μg to approximately 100,000 μg, approximately 150 μg to approximately 90,000 μg, approximately 150 μg to approximately 80,000 μg, approximately 150 μg to approximately 70,000 μg, approximately 150 μg to approximately 60,000 μg, approximately 150 μg to approximately 50,000 μg, approximately 150 μg to approximately 40,000 μg, approximately 150 μg to approximately 30,000 μg, approximately 150 μg to approximately 29,000 μg, approximately 150 μg to approximately 28,000 μg, approximately 150 μg to approximately 27,000 μg, approximately 150 μg to approximately 26,000 μg, approximately 150 μg to approximately 25,000 μg, approximately 150 μg g ~ approximately 24000μg, approximately 150μg ~ approximately 23000μg, approximately 150μg ~ approximately 22000μg, approximately 150μg ~ approximately 21000μg, approximately 150μg ~ approximately 20000μg, approximately 150μg ~ approximately 19000μg, approximately 150μg ~ approximately 18000μg, approximately 150μg ~ approximately 17000μg, approximately 1 50μg~approx. 16000μg, approx. 150μg~approx. 15000μg, approx. 150μg~approx. 14000μg, approx. 150μg~approx. 13000μg, approx. 150μg~approx. 12000μg, approx. 150μg~approx. 11000μg, approx. 150μg~approx. 10000μg, approx. 150μg~approx. 9000μgApproximately 150 μg to approximately 8000 μg, approximately 150 μg to approximately 7000 μg, approximately 150 μg to approximately 6000 μg, approximately 150 μg to approximately 5000 μg, approximately 150 μg to approximately 4500 μg, approximately 150 μg to approximately 4000 μg, approximately 150 μg to approximately 3500 μg, approximately 150 μg to approximately 3000 μg, approximately 150 μg to approximately 2500 μg, approximately 150 μg to approximately... 2000μg, approximately 150μg to approximately 1500μg, approximately 150μg to approximately 1250μg, approximately 150μg to approximately 1000μg, approximately 150μg to approximately 750μg, approximately 150μg to approximately 500μg, approximately 150μg to approximately 300μg, approximately 150μg to approximately 250μg, approximately 150μg to approximately 200μg, approximately 25 0 μg ~ approximately 100,000 μg, approximately 250 μg ~ approximately 90,000 μg, approximately 250 μg ~ approximately 80,000 μg, approximately 250 μg ~ approximately 70,000 μg, approximately 250 μg ~ approximately 60,000 μg, approximately 250 μg ~ approximately 50,000 μg, approximately 250 μg ~ approximately 40,000 μg, approximately 250 μg ~ approximately 30,000 μg Approximately 250 μg to approximately 29000 μg, approximately 250 μg to approximately 28000 μg, approximately 250 μg to approximately 27000 μg, approximately 250 μg to approximately 26000 μg, approximately 250 μg to approximately 25000 μg, approximately 250 μg to approximately 24000 μg, approximately 250 μg to approximately 23000 μg, approximately 250 μg to approximately 2200 μg 0 μg, approximately 250 μg to approximately 21000 μg, approximately 250 μg to approximately 20000 μg, approximately 250 μg to approximately 19000 μg, approximately 250 μg to approximately 18000 μg, approximately 250 μg to approximately 17000 μg, approximately 250 μg to approximately 16000 μg, approximately 250 μg to approximately 15000 μg, approximately 250 μg to approximately 1 4000μg, approximately 250μg~approx. 13000μg, approximately 250μg~approx. 12000μg, approximately 250μg~approx. 11000μg, approximately 250μg~approx. 10000μg, approximately 250μg~approx. 9000μg, approximately 250μg~approx. 8000μg, approximately 250μg~approx. 7000μg, approximately 250μg~approx. 6 000μg, approximately 250μg to approximately 5000μg, approximately 250μg to approximately 4500μg, approximately 250μg to approximately 4000μg, approximately 250μg to approximately 3500μg, approximately 250μg to approximately 3000μg, approximately 250μg to approximately 2500μg, approximately 250μg to approximately 2000μg, approximately 250μg to approximately 1500μg Approximately 250 μg to 1250 μg, approximately 250 μg to 1000 μg, approximately 250 μg to 750 μg, approximately 250 μg to 500 μg, approximately 250 μg to 300 μg, approximately 300 μg to 100000 μg, approximately 300 μg to 90000 μg, approximately 300 μg to 80000 μg, approximately 30 0 μg ~ approximately 70,000 μg, approximately 300 μg ~ approximately 60,000 μg, approximately 300 μg ~ approximately 50,000 μg, approximately 300 μg ~ approximately 40,000 μg, approximately 300 μg ~ approximately 30,000 μg, approximately 300 μg ~ approximately 29,000 μg, approximately 300 μg ~ approximately 28,000 μg, approximately 300 μg ~ approximately 27,000 μgApproximately 300 μg to approximately 26000 μg, approximately 300 μg to approximately 25000 μg, approximately 300 μg to approximately 24000 μg, approximately 300 μg to approximately 23000 μg, approximately 300 μg to approximately 22000 μg, approximately 300 μg to approximately 21000 μg, approximately 300 μg to approximately 20000 μg, approximately 300 μg to approximately 190 μg 00μg, approximately 300μg~approx. 18000μg, approximately 300μg~approx. 17000μg, approximately 300μg~approx. 16000μg, approximately 300μg~approx. 15000μg, approximately 300μg~approx. 14000μg, approximately 300μg~approx. 13000μg, approximately 300μg~approx. 12000μg, approximately 300μg~ Approximately 11000 μg, approximately 300 μg to approximately 10000 μg, approximately 300 μg to approximately 9000 μg, approximately 300 μg to approximately 8000 μg, approximately 300 μg to approximately 7000 μg, approximately 300 μg to approximately 6000 μg, approximately 300 μg to approximately 5000 μg, approximately 300 μg to approximately 4500 μg, approximately 300 μg to approximately 4000μg, approximately 300μg~approx. 3500μg, approximately 300μg~approx. 300μg, approximately 300μg~approx. 2500μg, approximately 300μg~approx. 2000μg, approximately 300μg~approx. 1500μg, approximately 300μg~approx. 1250μg, approximately 300μg~approx. 1000μg, approximately 300μg~approx. 750μg g, approximately 300μg~approx. 500μg, approximately 500μg~approx. 100000μg, approximately 500μg~approx. 90000μg, approximately 500μg~approx. 80000μg, approximately 500μg~approx. 70000μg, approximately 500μg~approx. 60000μg, approximately 500μg~approx. 50000μg, approximately 500μg~approx. 40 000μg, approximately 500μg~approx. 30000μg, approximately 500μg~approx. 29000μg, approximately 500μg~approx. 28000μg, approximately 500μg~approx. 27000μg, approximately 500μg~approx. 26000μg, approximately 500μg~approx. 25000μg, approximately 500μg~approx. 24000μg, approximately 500μg ~approx. 23000μg, approx. 500μg~approx. 22000μg, approx. 500μg~approx. 21000μg, approx. 500μg~approx. 20000μg, approx. 500μg~approx. 19000μg, approx. 500μg~approx. 18000μg, approx. 500μg~approx. 17000μg, approx. 500μg~approx. 16000μg, approx. 5 00μg~approx. 15000μg, approx. 500μg~approx. 14000μg, approx. 500μg~approx. 13000μg, approx. 500μg~approx. 12000μg, approx. 500μg~approx. 11000μg, approx. 500μg~approx. 10000μg, approx. 500μg~approx. 9000μg, approx. 500μg~approx. 8000μgApproximately 500 μg to approximately 7000 μg, approximately 500 μg to approximately 6000 μg, approximately 500 μg to approximately 5000 μg, approximately 500 μg to approximately 4500 μg, approximately 500 μg to approximately 4000 μg, approximately 500 μg to approximately 3500 μg, approximately 500 μg to approximately 3000 μg, approximately 500 μg to approximately 2500 μg, approximately 50 0 μg ~ approx. 2000 μg, approx. 500 μg ~ approx. 1500 μg, approx. 500 μg ~ approx. 1250 μg, approx. 500 μg ~ approx. 1000 μg, approx. 500 μg ~ approx. 750 μg, approx. 750 μg ~ approx. 100000 μg, approx. 750 μg ~ approx. 90000 μg, approx. 750 μg ~ approx. 80000 μg, approx. 750 μg~approx. 70000μg, approx. 750μg~approx. 60000μg, approx. 750μg~approx. 50000μg, approx. 750μg~approx. 40000μg, approx. 750μg~approx. 30000μg, approx. 750μg~approx. 29000μg, approx. 750μg~approx. 28000μg, approx. 750μg~approx. 27000μg Approximately 750 μg to approximately 26000 μg, approximately 750 μg to approximately 25000 μg, approximately 750 μg to approximately 24000 μg, approximately 750 μg to approximately 23000 μg, approximately 750 μg to approximately 22000 μg, approximately 750 μg to approximately 21000 μg, approximately 750 μg to approximately 20000 μg, approximately 750 μg to approximately 1900 μg 0 μg, approximately 750 μg to approximately 18000 μg, approximately 750 μg to approximately 17000 μg, approximately 750 μg to approximately 16000 μg, approximately 750 μg to approximately 15000 μg, approximately 750 μg to approximately 14000 μg, approximately 750 μg to approximately 13000 μg, approximately 750 μg to approximately 12000 μg, approximately 750 μg~ Approximately 11000 μg, approximately 750 μg to approximately 10000 μg, approximately 750 μg to approximately 9000 μg, approximately 750 μg to approximately 8000 μg, approximately 750 μg to approximately 7000 μg, approximately 750 μg to approximately 6000 μg, approximately 750 μg to approximately 5000 μg, approximately 750 μg to approximately 4500 μg, approximately 750 μg to approximately 4 000μg, approximately 750μg~approx. 3500μg, approximately 750μg~approx. 3000μg, approximately 750μg~approx. 2500μg, approximately 750μg~approx. 2000μg, approximately 750μg~approx. 1500μg, approximately 750μg~approx. 1250μg, approximately 750μg~approx. 1000μg, approximately 1000μg~approx. 1000μg 0.00 μg, approximately 1000 μg to approximately 90000 μg, approximately 1000 μg to approximately 80000 μg, approximately 1000 μg to approximately 70000 μg, approximately 1000 μg to approximately 60000 μg, approximately 1000 μg to approximately 50000 μg, approximately 1000 μg to approximately 40000 μg, approximately 1000 μg to approximately 30000 μg,Approximately 1000 μg to approximately 29000 μg, approximately 1000 μg to approximately 28000 μg, approximately 1000 μg to approximately 27000 μg, approximately 1000 μg to approximately 26000 μg, approximately 1000 μg to approximately 25000 μg, approximately 1000 μg to approximately 24000 μg, approximately 1000 μg to approximately 23000 μg, approximately 100 0 μg ~ approximately 22000 μg, approximately 1000 μg ~ approximately 21000 μg, approximately 1000 μg ~ approximately 20000 μg, approximately 1000 μg ~ approximately 19000 μg, approximately 1000 μg ~ approximately 18000 μg, approximately 1000 μg ~ approximately 17000 μg, approximately 1000 μg ~ approximately 16000 μg, approximately 1000 μg ~ approximately 15000μg, approximately 1000μg~14000μg, approximately 1000μg~13000μg, approximately 1000μg~12000μg, approximately 1000μg~11000μg, approximately 1000μg~10000μg, approximately 1000μg~9000μg, approximately 1000μg~8000μg Approximately 1000μg to 7000μg, approximately 1000μg to 6000μg, approximately 1000μg to 5000μg, approximately 1000μg to 4500μg, approximately 1000μg to 4000μg, approximately 1000μg to 3500μg, approximately 1000μg to 3000μg, approximately 1000μg to 25 00μg, approximately 1000μg~approx. 2000μg, approximately 1000μg~approx. 1500μg, approximately 1000μg~approx. 1250μg, approximately 1250μg~approx. 100000μg, approximately 1250μg~approx. 90000μg, approximately 1250μg~approx. 80000μg, approximately 1250μg~approx. 70000μg, approximately 1 250μg~approx. 60000μg, approx. 1250μg~approx. 50000μg, approx. 1250μg~approx. 40000μg, approx. 1250μg~approx. 30000μg, approx. 1250μg~approx. 29000μg, approx. 1250μg~approx. 28000μg, approx. 1250μg~approx. 27000μg, approx. 1250μg ~approx. 26000μg, approx. 1250μg~approx. 25000μg, approx. 1250μg~approx. 24000μg, approx. 1250μg~approx. 23000μg, approx. 1250μg~approx. 22000μg, approx. 1250μg~approx. 21000μg, approx. 1250μg~approx. 20000μg, approx. 1250μg~approx. 190 00μg, approximately 1250μg~approx. 18000μg, approximately 1250μg~approx. 17000μg, approximately 1250μg~approx. 16000μg, approximately 1250μg~approx. 15000μg, approximately 1250μg~approx. 14000μg, approximately 1250μg~approx. 13000μg, approximately 1250μg~approx. 12000μgApproximately 1250 μg to approximately 11000 μg, approximately 1250 μg to approximately 10000 μg, approximately 1250 μg to approximately 9000 μg, approximately 1250 μg to approximately 8000 μg, approximately 1250 μg to approximately 7000 μg, approximately 1250 μg to approximately 6000 μg, approximately 1250 μg to approximately 5000 μg, approximately 1250 μg to approximately 4 500μg, approximately 1250μg~approx. 4000μg, approximately 1250μg~approx. 3500μg, approximately 1250μg~approx. 3000μg, approximately 1250μg~approx. 2500μg, approximately 1250μg~approx. 2000μg, approximately 1250μg~approx. 1500μg, approximately 1500μg~approx. 100000μg, approximately 1500μg μg~approx. 90000μg, approx. 1500μg~approx. 80000μg, approx. 1500μg~approx. 70000μg, approx. 1500μg~approx. 60000μg, approx. 1500μg~approx. 50000μg, approx. 1500μg~approx. 40000μg, approx. 1500μg~approx. 30000μg, approx. 1500μg~approx. 29 000μg, approximately 1500μg~approx. 28000μg, approximately 1500μg~approx. 27000μg, approximately 1500μg~approx. 26000μg, approximately 1500μg~approx. 25000μg, approximately 1500μg~approx. 24000μg, approximately 1500μg~approx. 23000μg, approximately 1500μg~approx. 22000μg Approximately 1500 μg to approximately 21000 μg, approximately 1500 μg to approximately 20000 μg, approximately 1500 μg to approximately 19000 μg, approximately 1500 μg to approximately 18000 μg, approximately 1500 μg to approximately 17000 μg, approximately 1500 μg to approximately 16000 μg, approximately 1500 μg to approximately 15000 μg, approximately 1500 μg g ~ approximately 14000 μg, approximately 1500 μg ~ approximately 13000 μg, approximately 1500 μg ~ approximately 12000 μg, approximately 1500 μg ~ approximately 11000 μg, approximately 1500 μg ~ approximately 10000 μg, approximately 1500 μg ~ approximately 9000 μg, approximately 1500 μg ~ approximately 8000 μg, approximately 1500 μg ~ approximately 7000 μg g, approximately 1500μg~approx. 6000μg, approximately 1500μg~approx. 5000μg, approximately 1500μg~approx. 4500μg, approximately 1500μg~approx. 4000μg, approximately 1500μg~approx. 3500μg, approximately 1500μg~approx. 3000μg, approximately 1500μg~approx. 2500μg, approximately 1500μg~approx. 20 0.00 μg, approximately 2000 μg to approximately 100000 μg, approximately 2000 μg to approximately 90000 μg, approximately 2000 μg to approximately 80000 μg, approximately 2000 μg to approximately 70000 μg, approximately 2000 μg to approximately 60000 μg, approximately 2000 μg to approximately 50000 μg, approximately 2000 μg to approximately 40000 μg,Approximately 2000μg~30000μg, approximately 2000μg~29000μg, approximately 2000μg~28000μg, approximately 2000μg~27000μg, approximately 2000μg~26000μg, approximately 2000μg~25000μg, approximately 2000μg~24000μg, approximately 2000μg~23000μg, approximately 2000μg~22000μg Approximately 2000μg~21000μg, approximately 2000μg~20000μg, approximately 2000μg~19000μg, approximately 2000μg~18000μg, approximately 2000μg~17000μg, approximately 2000μg~16000μg, approximately 2000μg~15000μg, approximately 20 00μg~approx. 14000μg, approx. 2000μg~approx. 13000μg, approx. 2000μg~approx. 12000μg, approx. 2000μg~approx. 11000μg, approx. 2000μg~approx. 10000μg, approx. 2000μg~approx. 9000μg, approx. 2000μg~approx. 8000μg, approx. 2000μg~approx. 7000μg, approximately 2000μg~approx. 6000μg, approximately 2000μg~approx. 5000μg, approximately 2000μg~approx. 4500μg, approximately 2000μg~approx. 4000μg, approximately 2000μg~approx. 3500μg, approximately 2000μg~approx. 3000μg, approximately 2000μg~approx. 2500μg, approximately 250μg 0 μg ~ approx. 100,000 μg, approx. 2,500 μg ~ approx. 90,000 μg, approx. 2,500 μg ~ approx. 80,000 μg, approx. 2,500 μg ~ approx. 70,000 μg, approx. 2,500 μg ~ approx. 60,000 μg, approx. 2,500 μg ~ approx. 50,000 μg, approx. 2,500 μg ~ Approximately 30,000 μg, approximately 2,500 μg to approximately 29,000 μg, approximately 2,500 μg to approximately 28,000 μg, approximately 2,500 μg to approximately 27,000 μg, approximately 2,500 μg to approximately 26,000 μg, approximately 2,500 μg to approximately 25,000 μg, approximately 2,500 μg to approximately 24,000 μg, approximately 2,500 μg to approximately 230 μg 0.00 μg, approximately 2500 μg to approximately 22000 μg, approximately 2500 μg to approximately 21000 μg, approximately 2500 μg to approximately 20000 μg, approximately 2500 μg to approximately 19000 μg, approximately 2500 μg to approximately 18000 μg, approximately 2500 μg to approximately 17000 μg, approximately 2500 μg to approximately 16000 μg Approximately 2500μg to 15000μg, approximately 2500μg to 14000μg, approximately 2500μg to 13000μg, approximately 2500μg to 12000μg, approximately 2500μg to 11000μg, approximately 2500μg to 10000μg, approximately 2500μg to 9000μg, approximately 250 0 μg to approximately 8000 μg, approximately 2500 μg to approximately 7000 μg, approximately 2500 μg to approximately 6000 μg, approximately 2500 μg to approximately 5000 μg, approximately 2500 μg to approximately 4500 μg, approximately 2500 μg to approximately 4000 μg, approximately 2500 μg to approximately 3500 μg, approximately 2500 μg to approximately 3000 μgApproximately 3000μg~approximately 100000μg, approximately 3000μg~approximately 90000μg, approximately 3000μg~approximately 80000μg, approximately 3000μg~approximately 70000μg, approximately 3000μg~approximately 60000μg, approximately 3000μg~approximately 50000μg, approximately 3000μg~approximately 40000μg, approximately 300 0 μg ~ approximately 30000 μg, approximately 3000 μg ~ approximately 29000 μg, approximately 3000 μg ~ approximately 28000 μg, approximately 3000 μg ~ approximately 27000 μg, approximately 3000 μg ~ approximately 26000 μg, approximately 3000 μg ~ approximately 25000 μg, approximately 3000 μg ~ approximately 24000 μg, approximately 3000 μg ~ approximately 2 3000μg, approximately 3000μg~approx. 22000μg, approximately 3000μg~approx. 21000μg, approximately 3000μg~approx. 20000μg, approximately 3000μg~approx. 19000μg, approximately 3000μg~approx. 18000μg, approximately 3000μg~approx. 17000μg, approximately 3000μg~approx. 16000μg Approximately 3000μg~15000μg, approximately 3000μg~14000μg, approximately 3000μg~13000μg, approximately 3000μg~12000μg, approximately 3000μg~11000μg, approximately 3000μg~10000μg, approximately 3000μg~9000μg, approximately 3000μg g ~ approximately 8000 μg, approximately 3000 μg ~ approximately 7000 μg, approximately 3000 μg ~ approximately 6000 μg, approximately 3000 μg ~ approximately 5000 μg, approximately 3000 μg ~ approximately 4500 μg, approximately 3000 μg ~ approximately 4000 μg, approximately 3500 μg ~ approximately 100000 μg, approximately 3500 μg ~ approximately 90000 μg Approximately 3500 μg to approximately 80000 μg, approximately 3500 μg to approximately 70000 μg, approximately 3500 μg to approximately 60000 μg, approximately 3500 μg to approximately 50000 μg, approximately 3500 μg to approximately 40000 μg, approximately 3500 μg to approximately 30000 μg, approximately 3500 μg to approximately 29000 μg, approximately 3500 μg μg ~ approx. 28000μg, approx. 3500μg ~ approx. 27000μg, approx. 3500μg ~ approx. 26000μg, approx. 3500μg ~ approx. 25000μg, approx. 3500μg ~ approx. 24000μg, approx. 3500μg ~ approx. 23000μg, approx. 3500μg ~ approx. 22000μg, approx. 3500μg ~ approx. 21 000μg, approximately 3500μg~approx. 20000μg, approximately 3500μg~approx. 19000μg, approximately 3500μg~approx. 18000μg, approximately 3500μg~approx. 17000μg, approximately 3500μg~approx. 16000μg, approximately 3500μg~approx. 15000μg, approximately 3500μg~approx. 14000μgApproximately 3500μg~13000μg, approximately 3500μg~12000μg, approximately 3500μg~11000μg, approximately 3500μg~10000μg, approximately 3500μg~9000μg, approximately 3500μg~8000μg, approximately 3500μg~7000μg, approximately 3500μg ~approx. 6000μg, approx. 3500μg~approx. 5000μg, approx. 3500μg~approx. 4500μg, approx. 3500μg~approx. 4000μg, approx. 4000μg~approx. 100000μg, approx. 4000μg~approx. 90000μg, approx. 4000μg~approx. 80000μg, approx. 4000μg~approx. 70000μg Approximately 4000μg to approximately 60000μg, approximately 4000μg to approximately 50000μg, approximately 4000μg to approximately 40000μg, approximately 4000μg to approximately 30000μg, approximately 4000μg to approximately 29000μg, approximately 4000μg to approximately 28000μg, approximately 4000μg to approximately 27000μg, approximately 400 0 μg ~ approximately 26000 μg, approximately 4000 μg ~ approximately 25000 μg, approximately 4000 μg ~ approximately 24000 μg, approximately 4000 μg ~ approximately 23000 μg, approximately 4000 μg ~ approximately 22000 μg, approximately 4000 μg ~ approximately 21000 μg, approximately 4000 μg ~ approximately 20000 μg, approximately 4000 μg ~ approximately 19000μg, approximately 4000μg~approx. 18000μg, approximately 4000μg~approx. 17000μg, approximately 4000μg~approx. 16000μg, approximately 4000μg~approx. 15000μg, approximately 4000μg~approx. 14000μg, approximately 4000μg~approx. 13000μg, approximately 4000μg~approx. 12000μg μg, approximately 4000μg~approx. 11000μg, approximately 4000μg~approx. 10000μg, approximately 4000μg~approx. 9000μg, approximately 4000μg~approx. 8000μg, approximately 4000μg~approx. 7000μg, approximately 4000μg~approx. 6000μg, approximately 4000μg~approx. 5000μg, approximately 4000μg ~approx. 4500μg, approx. 4500μg~approx. 100000μg, approx. 4500μg~approx. 90000μg, approx. 4500μg~approx. 80000μg, approx. 4500μg~approx. 70000μg, approx. 4500μg~approx. 60000μg, approx. 4500μg~approx. 50000μg, approx. 4500μg~approx. 400 00μg, approximately 4500μg~approx. 30000μg, approximately 4500μg~approx. 29000μg, approximately 4500μg~approx. 28000μg, approximately 4500μg~approx. 27000μg, approximately 4500μg~approx. 26000μg, approximately 4500μg~approx. 25000μg, approximately 4500μg~approx. 24000μgApproximately 4500 μg to approximately 23000 μg, approximately 4500 μg to approximately 22000 μg, approximately 4500 μg to approximately 21000 μg, approximately 4500 μg to approximately 20000 μg, approximately 4500 μg to approximately 19000 μg, approximately 4500 μg to approximately 18000 μg, approximately 4500 μg to approximately 17000 μg, approximately 4500 μg μg ~ approx. 16000μg, approx. 4500μg ~ approx. 15000μg, approx. 4500μg ~ approx. 14000μg, approx. 4500μg ~ approx. 13000μg, approx. 4500μg ~ approx. 12000μg, approx. 4500μg ~ approx. 11000μg, approx. 4500μg ~ approx. 10000μg, approx. 4500μg ~ approx. 90 00μg, approximately 4500μg~approx. 8000μg, approximately 4500μg~approx. 7000μg, approximately 4500μg~approx. 6000μg, approximately 4500μg~approx. 5000μg, approximately 5000μg~approx. 100000μg, approximately 5000μg~approx. 90000μg, approximately 5000μg~approx. 80000μg, approximately 50 00μg~approx. 70000μg, approx. 5000μg~approx. 60000μg, approx. 5000μg~approx. 50000μg, approx. 5000μg~approx. 40000μg, approx. 5000μg~approx. 30000μg, approx. 5000μg~approx. 29000μg, approx. 5000μg~approx. 28000μg, approx. 5000μg~approx. 27000μg, approximately 5000μg~approx. 26000μg, approximately 5000μg~approx. 25000μg, approximately 5000μg~approx. 24000μg, approximately 5000μg~approx. 23000μg, approximately 5000μg~approx. 22000μg, approximately 5000μg~approx. 21000μg, approximately 5000μg~approx. 20000μg μg, approximately 5000μg~approx. 19000μg, approximately 5000μg~approx. 18000μg, approximately 5000μg~approx. 17000μg, approximately 5000μg~approx. 16000μg, approximately 5000μg~approx. 15000μg, approximately 5000μg~approx. 14000μg, approximately 5000μg~approx. 13000μg, approximately 50 00μg~approx. 12000μg, approx. 5000μg~approx. 11000μg, approx. 5000μg~approx. 10000μg, approx. 5000μg~approx. 9000μg, approx. 5000μg~approx. 8000μg, approx. 5000μg~approx. 7000μg, approx. 5000μg~approx. 6000μg, approx. 6000μg~approx. 1000μg 000μg, approximately 6000μg~approx. 90000μg, approximately 6000μg~approx. 80000μg, approximately 6000μg~approx. 70000μg, approximately 6000μg~approx. 60000μg, approximately 6000μg~approx. 50000μg, approximately 6000μg~approx. 40000μg, approximately 6000μg~approx. 30000μgApproximately 6000μg~approximately 29000μg, approximately 6000μg~approximately 28000μg, approximately 6000μg~approximately 27000μg, approximately 6000μg~approximately 26000μg, approximately 6000μg~approximately 25000μg, approximately 6000μg~approximately 24000μg, approximately 6000μg~approximately 23000μg, approximately 6000μg g ~ approximately 22000μg, approximately 6000μg ~ approximately 21000μg, approximately 6000μg ~ approximately 20000μg, approximately 6000μg ~ approximately 19000μg, approximately 6000μg ~ approximately 18000μg, approximately 6000μg ~ approximately 17000μg, approximately 6000μg ~ approximately 16000μg, approximately 6000μg ~ approximately 150 00μg, approximately 6000μg~approx. 14000μg, approximately 6000μg~approx. 13000μg, approximately 6000μg~approx. 12000μg, approximately 6000μg~approx. 11000μg, approximately 6000μg~approx. 10000μg, approximately 6000μg~approx. 9000μg, approximately 6000μg~approx. 8000μg, approximately 60 00μg~approx. 7000μg, approx. 7000μg~approx. 100000μg, approx. 7000μg~approx. 90000μg, approx. 7000μg~approx. 80000μg, approx. 7000μg~approx. 70000μg, approx. 7000μg~approx. 60000μg, approx. 7000μg~approx. 50000μg, approx. 7000μg~approx. 40,000 μg, approximately 7,000 μg to approximately 30,000 μg, approximately 7,000 μg to approximately 29,000 μg, approximately 7,000 μg to approximately 28,000 μg, approximately 7,000 μg to approximately 27,000 μg, approximately 7,000 μg to approximately 26,000 μg, approximately 7,000 μg to approximately 25,000 μg, approximately 7,000 μg to approximately 24,000 μg g, approximately 7000μg~approx. 23000μg, approximately 7000μg~approx. 22000μg, approximately 7000μg~approx. 21000μg, approximately 7000μg~approx. 20000μg, approximately 7000μg~approx. 19000μg, approximately 7000μg~approx. 18000μg, approximately 7000μg~approx. 17000μg, approximately 700 0 μg ~ approx. 16000 μg, approx. 7000 μg ~ approx. 15000 μg, approx. 7000 μg ~ approx. 14000 μg, approx. 7000 μg ~ approx. 13000 μg, approx. 7000 μg ~ approx. 12000 μg, approx. 7000 μg ~ approx. 11000 μg, approx. 7000 μg ~ approx. 10000 μg, approx. 7000 μg ~ approx. 9 000μg, approximately 7000μg~approx. 8000μg, approximately 8000μg~approx. 100000μg, approximately 8000μg~approx. 90000μg, approximately 8000μg~approx. 80000μg, approximately 8000μg~approx. 70000μg, approximately 8000μg~approx. 60000μg, approximately 8000μg~approx. 50000μgApproximately 8000μg~approximately 40000μg, approximately 8000μg~approximately 30000μg, approximately 8000μg~approximately 29000μg, approximately 8000μg~approximately 28000μg, approximately 8000μg~approximately 27000μg, approximately 8000μg~approximately 26000μg, approximately 8000μg~approximately 25000μg, approximately 8000μg~approximately 24000μg, approximately 8000μg~approximately 23000μg μg, approximately 8000μg~approx. 22000μg, approximately 8000μg~approx. 21000μg, approximately 8000μg~approx. 20000μg, approximately 8000μg~approx. 19000μg, approximately 8000μg~approx. 18000μg, approximately 8000μg~approx. 17000μg, approximately 8000μg~approx. 16000μg, approximately 8000μg~approx. 15000μg, approx. 8000μg~approx. 14000μg, approx. 8000μg~approx. 13000μg, approx. 8000μg~approx. 12000μg, approx. 8000μg~approx. 11000μg, approx. 8000μg~approx. 10000μg, approx. 8000μg~approx. 9000μg, approx. 9000μg ~Approximately 100,000 μg, approximately 9,000 μg, approximately 9,000 μg, approximately 80,000 μg, approximately 9,000 μg, approximately 70,000 μg, approximately 9,000 μg, approximately 60,000 μg, approximately 50,000 μg, approximately 40,000 μg, approximately 9,000 μg, approximately 3 0000μg, approximately 9000μg~approx. 29000μg, approximately 9000μg~approx. 28000μg, approximately 9000μg~approx. 27000μg, approximately 9000μg~approx. 26000μg, approximately 9000μg~approx. 25000μg, approximately 9000μg~approx. 24000μg, approximately 9000μg~approx. 23000μg g, approximately 9000μg~approx. 22000μg, approximately 9000μg~approx. 21000μg, approximately 9000μg~approx. 20000μg, approximately 9000μg~approx. 19000μg, approximately 9000μg~approx. 18000μg, approximately 9000μg~approx. 17000μg, approximately 9000μg~approx. 16000μg, approximately 9 000μg~approx. 15000μg, approx. 9000μg~approx. 14000μg, approx. 9000μg~approx. 13000μg, approx. 9000μg~approx. 12000μg, approx. 9000μg~approx. 11000μg, approx. 9000μg~approx. 10000μg, approx. 10000μg~approx. 100000μg, approx. 10000μg~approx. 10000μg 0 μg ~ approximately 90,000 μg, approximately 10,000 μg ~ approximately 80,000 μg, approximately 10,000 μg ~ approximately 70,000 μg, approximately 10,000 μg ~ approximately 60,000 μg, approximately 10,000 μg ~ approximately 50,000 μg, approximately 10,000 μg ~ approximately 40,000 μg, approximately 10,000 μg ~ approximately 30,000 μg, approximately 1 0000μg~approx. 29000μg, approx. 10000μg~approx. 28000μg, approx. 10000μg~approx. 27000μg, approx. 10000μg~approx. 26000μg, approx. 10000μg~approx. 25000μg, approx. 10000μg~approx. 24000μg, approx. 10000μg~approx. 23000μgApproximately 10,000 μg to approximately 22,000 μg, approximately 10,000 μg to approximately 21,000 μg, approximately 10,000 μg to approximately 20,000 μg, approximately 10,000 μg to approximately 19,000 μg, approximately 10,000 μg to approximately 18,000 μg, approximately 10,000 μg to approximately 17,000 μg, approximately 10,000 μg to approximately 16,000 μg g, approximately 10000μg~approx. 15000μg, approximately 10000μg~approx. 14000μg, approximately 10000μg~approx. 13000μg, approximately 10000μg~approx. 12000μg, approximately 10000μg~approx. 11000μg, approximately 11000μg~approx. 100000μg, approximately 11000μg~approx. 900 00μg, approximately 11000μg~approx. 80000μg, approximately 11000μg~approx. 70000μg, approximately 11000μg~approx. 60000μg, approximately 11000μg~approx. 50000μg, approximately 11000μg~approx. 40000μg, approximately 11000μg~approx. 30000μg, approximately 11000μg~approx. 2 9000μg, approximately 11000μg~approx. 28000μg, approximately 11000μg~approx. 27000μg, approximately 11000μg~approx. 26000μg, approximately 11000μg~approx. 25000μg, approximately 11000μg~approx. 24000μg, approximately 11000μg~approx. 23000μg, approximately 11000μg~ Approximately 22000 μg, approximately 11000 μg to approximately 21000 μg, approximately 11000 μg to approximately 20000 μg, approximately 11000 μg to approximately 19000 μg, approximately 11000 μg to approximately 18000 μg, approximately 11000 μg to approximately 17000 μg, approximately 11000 μg to approximately 16000 μg, approximately 11000 μg g ~ approximately 15000 μg, approximately 11000 μg ~ approximately 14000 μg, approximately 11000 μg ~ approximately 13000 μg, approximately 11000 μg ~ approximately 12000 μg, approximately 12000 μg ~ approximately 100000 μg, approximately 12000 μg ~ approximately 90000 μg, approximately 12000 μg ~ approximately 80000 μg, approximately 120 00μg~approx. 70000μg, approx. 12000μg~approx. 60000μg, approx. 12000μg~approx. 50000μg, approx. 12000μg~approx. 40000μg, approx. 12000μg~approx. 30000μg, approx. 12000μg~approx. 29000μg, approx. 12000μg~approx. 28000μg, approx. 1 2000μg~approx. 27000μg, approx. 12000μg~approx. 26000μg, approx. 12000μg~approx. 25000μg, approx. 12000μg~approx. 24000μg, approx. 12000μg~approx. 23000μg, approx. 12000μg~approx. 22000μg, approx. 12000μg~approx. 21000μgApproximately 12,000 μg to approximately 20,000 μg, approximately 12,000 μg to approximately 19,000 μg, approximately 12,000 μg to approximately 18,000 μg, approximately 12,000 μg to approximately 17,000 μg, approximately 12,000 μg to approximately 16,000 μg, approximately 12,000 μg to approximately 15,000 μg, approximately 12,000 μg to approximately 14,000 μg g, approximately 12000μg~approx. 13000μg, approximately 13000μg~approx. 100000μg, approximately 13000μg~approx. 90000μg, approximately 13000μg~approx. 80000μg, approximately 13000μg~approx. 70000μg, approximately 13000μg~approx. 60000μg, approximately 13000μg~approx. 500 00μg, approximately 13000μg~approx. 40000μg, approximately 13000μg~approx. 30000μg, approximately 13000μg~approx. 29000μg, approximately 13000μg~approx. 28000μg, approximately 13000μg~approx. 27000μg, approximately 13000μg~approx. 26000μg, approximately 13000μg~approx. 2 5000μg, approximately 13000μg~approx. 24000μg, approximately 13000μg~approx. 23000μg, approximately 13000μg~approx. 22000μg, approximately 13000μg~approx. 21000μg, approximately 13000μg~approx. 20000μg, approximately 13000μg~approx. 19000μg, approximately 13000μg~ Approximately 18,000 μg, approximately 13,000 μg to approximately 17,000 μg, approximately 13,000 μg to approximately 16,000 μg, approximately 13,000 μg to approximately 15,000 μg, approximately 13,000 μg to approximately 14,000 μg, approximately 14,000 μg to approximately 100,000 μg, approximately 14,000 μg to approximately 90,000 μg, approximately 14,000 μg μg ~ approximately 80,000 μg, approximately 14,000 μg ~ approximately 70,000 μg, approximately 14,000 μg ~ approximately 60,000 μg, approximately 14,000 μg ~ approximately 50,000 μg, approximately 14,000 μg ~ approximately 40,000 μg, approximately 14,000 μg ~ approximately 30,000 μg, approximately 14,000 μg ~ approximately 29,000 μg, approximately 140 00μg~approx. 28000μg, approx. 14000μg~approx. 27000μg, approx. 14000μg~approx. 26000μg, approx. 14000μg~approx. 25000μg, approx. 14000μg~approx. 24000μg, approx. 14000μg~approx. 23000μg, approx. 14000μg~approx. 22000μg, approx. 1 4000μg~approx. 21000μg, approx. 14000μg~approx. 20000μg, approx. 14000μg~approx. 19000μg, approx. 14000μg~approx. 18000μg, approx. 14000μg~approx. 17000μg, approx. 14000μg~approx. 16000μg, approx. 14000μg~approx. 15000μgApproximately 15,000 μg to approximately 100,000 μg, approximately 15,000 μg to approximately 90,000 μg, approximately 15,000 μg to approximately 80,000 μg, approximately 15,000 μg to approximately 70,000 μg, approximately 15,000 μg to approximately 60,000 μg, approximately 15,000 μg to approximately 50,000 μg, approximately 15,000 μg to approximately 40,000 μg μg, approximately 15000μg~approx. 30000μg, approximately 15000μg~approx. 29000μg, approximately 15000μg~approx. 28000μg, approximately 15000μg~approx. 27000μg, approximately 15000μg~approx. 26000μg, approximately 15000μg~approx. 25000μg, approximately 15000μg~approx. 240 00μg, approximately 15000μg~approx. 23000μg, approximately 15000μg~approx. 22000μg, approximately 15000μg~approx. 21000μg, approximately 15000μg~approx. 20000μg, approximately 15000μg~approx. 19000μg, approximately 15000μg~approx. 18000μg, approximately 15000μg~approx. 1 7000μg, approximately 15000μg~approx. 16000μg, approximately 16000μg~approx. 100000μg, approximately 16000μg~approx. 90000μg, approximately 16000μg~approx. 80000μg, approximately 16000μg~approx. 70000μg, approximately 16000μg~approx. 60000μg, approximately 16000μg ~Approximately 50,000 μg, approximately 16,000 μg ~ approximately 40,000 μg, approximately 16,000 μg ~ approximately 30,000 μg, approximately 16,000 μg ~ approximately 29,000 μg, approximately 16,000 μg ~ approximately 28,000 μg, approximately 16,000 μg ~ approximately 27,000 μg, approximately 16,000 μg ~ approximately 26,000 μg, approximately 16,000 μg μg ~ approximately 25000μg, approximately 16000μg ~ approximately 24000μg, approximately 16000μg ~ approximately 23000μg, approximately 16000μg ~ approximately 22000μg, approximately 16000μg ~ approximately 21000μg, approximately 16000μg ~ approximately 20000μg, approximately 16000μg ~ approximately 19000μg, approximately 160 00μg~approx. 18000μg, approx. 16000μg~approx. 17000μg, approx. 17000μg~approx. 100000μg, approx. 17000μg~approx. 90000μg, approx. 17000μg~approx. 80000μg, approx. 17000μg~approx. 70000μg, approx. 17000μg~approx. 60000μg, approx. 17000μg~approx. 50000μg, approx. 17000μg~approx. 40000μg, approx. 17000μg~approx. 30000μg, approx. 17000μg~approx. 29000μg, approx. 17000μg~approx. 28000μg, approx. 17000μg~approx. 27000μg, approx. 17000μg~approx. 26000μgApproximately 17,000 μg to approximately 25,000 μg, approximately 17,000 μg to approximately 24,000 μg, approximately 17,000 μg to approximately 23,000 μg, approximately 17,000 μg to approximately 22,000 μg, approximately 17,000 μg to approximately 21,000 μg, approximately 17,000 μg to approximately 20,000 μg, approximately 17,000 μg to approximately 19,000 μg g, approximately 17000μg~approx. 18000μg, approximately 18000μg~approx. 100000μg, approximately 18000μg~approx. 90000μg, approximately 18000μg~approx. 80000μg, approximately 18000μg~approx. 70000μg, approximately 18000μg~approx. 60000μg, approximately 18000μg~approx. 500 00μg, approximately 18000μg~approx. 40000μg, approximately 18000μg~approx. 30000μg, approximately 18000μg~approx. 29000μg, approximately 18000μg~approx. 28000μg, approximately 18000μg~approx. 27000μg, approximately 18000μg~approx. 26000μg, approximately 18000μg~approx. 2 5000μg, approximately 18000μg~approx. 24000μg, approximately 18000μg~approx. 23000μg, approximately 18000μg~approx. 22000μg, approximately 18000μg~approx. 21000μg, approximately 18000μg~approx. 20000μg, approximately 18000μg~approx. 19000μg, approximately 19000μg~ Approximately 100,000 μg, approximately 19,000 μg to approximately 90,000 μg, approximately 19,000 μg to approximately 80,000 μg, approximately 19,000 μg to approximately 70,000 μg, approximately 19,000 μg to approximately 60,000 μg, approximately 19,000 μg to approximately 50,000 μg, approximately 19,000 μg to approximately 40,000 μg, approximately 19,000 μg μg~approx. 30000μg, approx. 19000μg~approx. 29000μg, approx. 19000μg~approx. 28000μg, approx. 19000μg~approx. 27000μg, approx. 19000μg~approx. 26000μg, approx. 19000μg~approx. 25000μg, approx. 19000μg~approx. 24000μg, approx. 190 00μg~approx. 23000μg, approx. 19000μg~approx. 22000μg, approx. 19000μg~approx. 21000μg, approx. 19000μg~approx. 20000μg~approx. 100000μg, approx. 20000μg~approx. 90000μg, approx. 20000μg~approx. 80000μg, approx. 20,000 μg ~ approximately 70,000 μg, approximately 20,000 μg ~ approximately 60,000 μg, approximately 20,000 μg ~ approximately 50,000 μg, approximately 20,000 μg ~ approximately 40,000 μg, approximately 20,000 μg ~ approximately 30,000 μg, approximately 20,000 μg ~ approximately 29,000 μg, approximately 20,000 μg ~ approximately 28,000 μgApproximately 20,000 μg to approximately 27,000 μg, approximately 20,000 μg to approximately 26,000 μg, approximately 20,000 μg to approximately 25,000 μg, approximately 20,000 μg to approximately 24,000 μg, approximately 20,000 μg to approximately 23,000 μg, approximately 20,000 μg to approximately 22,000 μg, approximately 20,000 μg to approximately 21,000 μg, approximately 21,000 μg to approximately 100,000 μg, approximately 21,000 μg to approximately 90,000 μg. Approximately 21,000 μg to approximately 80,000 μg, approximately 21,000 μg to approximately 70,000 μg, approximately 21,000 μg to approximately 60,000 μg, approximately 21,000 μg to approximately 50,000 μg, approximately 21,000 μg to approximately 40,000 μg, approximately 21,000 μg to approximately 30,000 μg, approximately 21,000 μg to approximately 29,000 μg g, approximately 21000μg~approx. 28000μg, approximately 21000μg~approx. 27000μg, approximately 21000μg~approx. 26000μg, approximately 21000μg~approx. 25000μg, approximately 21000μg~approx. 24000μg, approximately 21000μg~approx. 23000μg, approximately 21000μg~approx. 2200 0 μg, approximately 22,000 μg to approximately 100,000 μg, approximately 22,000 μg to approximately 90,000 μg, approximately 22,000 μg to approximately 80,000 μg, approximately 22,000 μg to approximately 70,000 μg, approximately 22,000 μg to approximately 60,000 μg, approximately 22,000 μg to approximately 50,000 μg, approximately 22,000 μg to approximately 4 0000μg, approximately 22000μg~approx. 30000μg, approximately 22000μg~approx. 29000μg, approximately 22000μg~approx. 28000μg, approximately 22000μg~approx. 27000μg, approximately 22000μg~approx. 26000μg, approximately 22000μg~approx. 25000μg, approximately 22000μg~ Approximately 24,000 μg, approximately 22,000 μg to approximately 23,000 μg, approximately 23,000 μg to approximately 100,000 μg, approximately 23,000 μg to approximately 90,000 μg, approximately 23,000 μg to approximately 80,000 μg, approximately 23,000 μg to approximately 70,000 μg, approximately 23,000 μg to approximately 60,000 μg, approximately 23,000 μg μg~approx. 50000μg, approx. 23000μg~approx. 40000μg, approx. 23000μg~approx. 30000μg, approx. 23000μg~approx. 29000μg, approx. 23000μg~approx. 28000μg, approx. 23000μg~approx. 27000μg, approx. 23000μg~approx. 26000μg, approx. 230 00μg~approx. 25000μg, approx. 23000μg~approx. 24000μg, approx. 24000μg~approx. 100000μg, approx. 24000μg~approx. 90000μg, approx. 24000μg~approx. 80000μg, approx. 24000μg~approx. 70000μg, approx. 24000μg~approx. 60000μg, approx. 24,000 μg ~ approximately 50,000 μg, approximately 24,000 μg ~ approximately 40,000 μg, approximately 24,000 μg ~ approximately 30,000 μg, approximately 24,000 μg ~ approximately 29,000 μg, approximately 24,000 μg ~ approximately 28,000 μg, approximately 24,000 μg ~ approximately 27,000 μg, approximately 24,000 μg ~ approximately 26,000 μgApproximately 24,000 μg to approximately 25,000 μg, approximately 25,000 μg to approximately 100,000 μg, approximately 25,000 μg to approximately 90,000 μg, approximately 25,000 μg to approximately 80,000 μg, approximately 25,000 μg to approximately 70,000 μg, approximately 25,000 μg to approximately 60,000 μg, approximately 25,000 μg to approximately 50,000 μg μg, approximately 25000μg~approx. 40000μg, approximately 25000μg~approx. 30000μg, approximately 25000μg~approx. 29000μg, approximately 25000μg~approx. 28000μg, approximately 25000μg~approx. 27000μg, approximately 25000μg~approx. 26000μg, approximately 26000μg~approx. 1000μg 00μg, approximately 26000μg~approx. 90000μg, approximately 26000μg~approx. 80000μg, approximately 26000μg~approx. 70000μg, approximately 26000μg~approx. 60000μg, approximately 26000μg~approx. 50000μg, approximately 26000μg~approx. 40000μg, approximately 26000μg~approx. 3 0000μg, approximately 26000μg~approx. 29000μg, approximately 26000μg~approx. 28000μg, approximately 26000μg~approx. 27000μg, approximately 27000μg~approx. 100000μg, approximately 27000μg~approx. 90000μg, approximately 27000μg~approx. 80000μg, approximately 27000μg~ Approximately 70,000 μg, approximately 27,000 μg to approximately 60,000 μg, approximately 27,000 μg to approximately 50,000 μg, approximately 27,000 μg to approximately 40,000 μg, approximately 27,000 μg to approximately 30,000 μg, approximately 27,000 μg to approximately 29,000 μg, approximately 27,000 μg to approximately 28,000 μg, approximately 28,000 μg g ~ approximately 100,000 μg, approximately 28,000 μg ~ approximately 90,000 μg, approximately 28,000 μg ~ approximately 80,000 μg, approximately 28,000 μg ~ approximately 70,000 μg, approximately 28,000 μg ~ approximately 60,000 μg, approximately 28,000 μg ~ approximately 50,000 μg, approximately 28,000 μg ~ approximately 40,000 μg, approximately 2800 μg 0 μg ~ approximately 30,000 μg, approximately 28,000 μg ~ approximately 29,000 μg, approximately 29,000 μg ~ approximately 100,000 μg, approximately 29,000 μg ~ approximately 90,000 μg, approximately 29,000 μg ~ approximately 80,000 μg, approximately 29,000 μg ~ approximately 70,000 μg, approximately 29,000 μg ~ approximately 60,000 μg, approximately 2 9000μg~approx. 50000μg, approx. 29000μg~approx. 40000μg, approx. 29000μg~approx. 30000μg, approx. 30000μg~approx. 100000μg, approx. 30000μg~approx. 90000μg, approx. 30000μg~approx. 80000μg, approx. 30000μg~approx. 70000μgApproximately 30,000μg to approximately 60,000μg, approximately 30,000μg to approximately 50,000μg, approximately 30,000μg to approximately 40,000μg, approximately 40,000μg to approximately 100,000μg, approximately 40,000μg to approximately 90,000μg, approximately 40,000μg to approximately 80,000μg, approximately 4 0000μg~about 70000μg, about 40000μg~about 60000μg, about 40000μg~about 50000μg, about 50000μg~about 100000μg, about 50000μg~about 90000μg, about 50000μg~about 80000μg, about 500 It can range from 00 μg to approximately 70,000 μg, from approximately 50,000 μg to approximately 60,000 μg, from approximately 60,000 μg to approximately 100,000 μg, from approximately 60,000 μg to approximately 90,000 μg, from approximately 60,000 μg to approximately 80,000 μg, from approximately 60,000 μg to approximately 70,000 μg, from approximately 70,000 μg to approximately 100,000 μg, from approximately 70,000 μg to approximately 90,000 μg, from approximately 70,000 μg to approximately 80,000 μg, from approximately 80,000 μg to approximately 100,000 μg, from approximately 80,000 μg to approximately 90,000 μg, and from approximately 90,000 μg to approximately 100,000 μg.

[0141] In some embodiments, the dosage of the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is approximately 1.0 μg to 10,000 μg, approximately 1.0 μg to 5,000 μg, approximately 1.0 μg to 2,500 μg, approximately 1.0 μg to 1,000 μg, approximately 1.0 μg to 500 μg, approximately 1.0 μg to 250 μg, approximately 1.0 μg to 100 μg, approximately 1.0 μg to 75 μg, approximately 1.0 μg to 50 μg, approximately 1.0 μg to 25 μg, approximately 1.0 μg to 10 μg, approximately 10 μg to 10,000 μg, approximately 10 μg to 5,000 μg, and approximately 10 μg to 5,000 μg. 2500μg, about 10μg to about 1000μg, about 10μg to about 500μg, about 10μg to about 250μg, about 10μg to about 100μg, about 1 0μg to about 75μg, about 10μg to about 50μg, about 50μg to about 10000μg, about 50μg to about 5000μg, about 50μg to about 2500 μg, approximately 50μg to approximately 2000μg, approximately 50μg to approximately 1000μg, approximately 50μg to approximately 750μg, approximately 50μg to approximately 500μg, approximately 50μg ~about 250μg, about 50μg to about 200μg, about 50μg to about 100μg, about 100μg to about 10000μg, about 100μg to about 5000 μg, approximately 100μg to approximately 2500μg, approximately 100μg to approximately 2000μg, approximately 100μg to approximately 1500μg, approximately 100μg to approximately 1250μg , about 100μg to about 1000μg, about 100μg to about 750μg, about 100μg to about 500μg, about 100μg to about 250μg, about 100 μg ~ approx. 200 μg, approx. 250 μg ~ approx. 10000 μg, approx. 250 μg ~ approx. 5000 μg, approx. 250 μg ~ approx. 2500 μg, approx. 250 μg ~2000μg, 250μg~1500μg, 250μg~1250μg, 250μg~1000μg, 250μg~approx. 750μg, about 250μg to about 500μg, about 500μg to about 10000μg, about 500μg to about 7000μg, about 500μg to about 500 0μg, about 500μg to about 3000μg, about 500μg to about 2500μg, about 500μg to about 2000μg, about 500μg to about 1500μg g, about 500μg to about 1250μg, about 500μg to about 1000μg, about 500μg to about 750μg, about 750μg to about 20000μg, Approximately 750μg to approximately 15000μg, approximately 750μg to approximately 10000μg, approximately 750μg to approximately 7000μg, approximately 750μg to approximately 5000μg,Approximately 750 μg to approximately 3000 μg, approximately 750 μg to approximately 2500 μg, approximately 750 μg to approximately 2000 μg, approximately 750 μg to approximately 1500 μg, approximately 750 μg to approximately 1250 μg, approximately 750 μg to approximately 1000 μg, approximately 1000 μg to approximately 25000 μg, approximately 1000 μg to approximately 20000 μg, approximately 1000μg~approx. 15000μg, approx. 1000μg~approx. 10000μg, approx. 1000μg~approx. 7000μg, approx. 1000μg~approx. 5000μg, approx. 1000μg~approx. 3000μg, approx. 1000μg~approx. 2500μg, approx. 1000μg~approx. 2000μg, approx. 1000μg~approx. 1500μg 0 μg, approximately 1500 μg to approximately 25000 μg, approximately 1500 μg to approximately 20000 μg, approximately 1500 μg to approximately 15000 μg, approximately 1500 μg to approximately 10000 μg, approximately 1500 μg to approximately 7000 μg, approximately 1500 μg to approximately 5000 μg, approximately 1500 μg to approximately 3000 μg, approximately 1500 μg μg ~ approximately 2500μg, approximately 1500μg ~ approximately 2000μg, approximately 2000μg ~ approximately 30000μg, approximately 2000μg ~ approximately 25000μg, approximately 2000μg ~ approximately 20000μg, approximately 2000μg ~ approximately 15000μg, approximately 2000μg ~ approximately 10000μg, approximately 2000μg ~ approximately 7000μg μg, approximately 2000μg~approx. 5000μg, approximately 2000μg~approx. 4000μg, approximately 2000μg~approx. 3000μg, approximately 2000μg~approx. 2500μg, approximately 2500μg~approx. 30000μg, approximately 2500μg~approx. 2500μg~approx. 20000μg, approximately 2500μg ~15000μg, approximately 2500μg~approx. 12000μg, approximately 2500μg~approx. 10000μg, approximately 2500μg~approx. 7000μg, approximately 2500μg~approx. 5000μg, approximately 2500μg~approx. 4000μg, approximately 2500μg~approx. 3000μg, approximately 3000μg~approx. 50000μg Approximately 3000μg~approximately 25000μg, approximately 3000μg~approximately 20000μg, approximately 3000μg~approximately 15000μg, approximately 3000μg~approximately 12000μg, approximately 3000μg~approximately 10000μg, approximately 3000μg~approximately 7000μg, approximately 3000μg~approximately 6000μg, approximately 3000μg~ Approximately 5000 μg, approximately 3000 μg to approximately 4000 μg, approximately 4000 μg to approximately 50000 μg, approximately 4000 μg to approximately 30000 μg, approximately 4000 μg to approximately 25000 μg, approximately 4000 μg to approximately 20000 μg, approximately 4000 μg to approximately 15000 μg, approximately 4000 μg to approximately 12000 μg,Approximately 4000μg~approximately 10000μg, approximately 4000μg~approximately 8000μg, approximately 4000μg~approximately 6000μg, approximately 4000μg~approximately 5000μg, approximately 5000μg~approximately 50000μg, approximately 5000μg~approximately 40000μg, approximately 5000μg~approximately 30000μg, approximately 5000μg ~approx. 25000μg, approx. 5000μg~approx. 20000μg, approx. 5000μg~approx. 15000μg, approx. 5000μg~approx. 12000μg, approx. 5000μg~approx. 10000μg, approx. 5000μg~approx. 8000μg, approx. 5000μg~approx. 7000μg, approx. 5000μg~approx. 6000μg, approx. 6000μg~approx. 50000μg, approx. 6000μg~approx. 30000μg, approx. 6000μg~approx. 25000μg, approx. 6000μg~approx. 20000μg, approx. 6000μg~approx. 17000μg, approx. 6000μg~approx. 15000μg, approx. 6000μg~approx. 12000μg, approx. 6000μg~approx. 10000μg, approx. 6000μg~approx. 9000μg, approx. 6000μg~approx. 8000μg, approx. 6000μg~approx. 7000μg, approx. 7000μg~approx. 70000μg, approx. 7000μg~approx. 50000μg, approx. 7000μg~approx. 40000μg, approx. 7000μg~approx. 30000μg, approximately 7000μg~approx. 25000μg, approximately 7000μg~approx. 20000μg, approximately 7000μg~approx. 17000μg, approximately 7000μg~approx. 15000μg, approximately 7000μg~approx. 12000μg, approximately 7000μg~approx. 10000μg, approximately 7000μg~approx. 8000μg μg, approximately 8000μg~approx. 80000μg, approximately 8000μg~approx. 60000μg, approximately 8000μg~approx. 50000μg, approximately 8000μg~approx. 30000μg, approximately 8000μg~approx. 25000μg, approximately 8000μg~approx. 20000μg, approximately 8000μg~approx. 17000μg, approximately 8 000μg~approx. 15000μg, approx. 8000μg~approx. 12000μg, approx. 8000μg~approx. 10000μg, approx. 10000μg~approx. 10000μg~approx. 80000μg, approx. 10000μg~approx. 70000μg, approx. 10000μg~approx. 60000μg, approx. 10,000 μg ~ approximately 50,000 μg, approximately 10,000 μg ~ approximately 40,000 μg, approximately 10,000 μg ~ approximately 30,000 μg, approximately 10,000 μg ~ approximately 25,000 μg, approximately 10,000 μg ~ approximately 20,000 μg, 10,000 μg ~ approximately 18,000 μg, approximately 10,000 μg ~ approximately 16,000 μgApproximately 10,000 μg to approximately 15,000 μg, approximately 10,000 μg to approximately 12,000 μg, approximately 12,000 μg to approximately 100,000 μg, approximately 12,000 μg to approximately 90,000 μg, approximately 12,000 μg to approximately 80,000 μg, approximately 12,000 μg to approximately 70,000 μg, approximately 12,000 μg to approximately 60,000 μg μg, approximately 12000μg~approx. 50000μg, approximately 12000μg~approx. 40000μg, approximately 12000μg~approx. 30000μg, approximately 12000μg~approx. 25000μg, approximately 12000μg~approx. 20000μg, approximately 12000μg~approx. 18000μg, approximately 12000μg~approx. 1600μg 0 μg, approximately 12000 μg to approximately 15000 μg, approximately 12000 μg to approximately 14000 μg, approximately 15000 μg to approximately 100000 μg, approximately 15000 μg to approximately 90000 μg, approximately 15000 μg to approximately 80000 μg, approximately 15000 μg to approximately 70000 μg, approximately 15000 μg to approximately 6 0000μg, approximately 15000μg~approx. 50000μg, approximately 15000μg~approx. 40000μg, approximately 15000μg~approx. 30000μg, approximately 15000μg~approx. 25000μg, approximately 15000μg~approx. 20000μg, approximately 20000μg~approx. 100000μg, approximately 20000μg~ Approximately 90,000 μg, approximately 20,000 μg to approximately 80,000 μg, approximately 20,000 μg to approximately 70,000 μg, approximately 20,000 μg to approximately 60,000 μg, approximately 20,000 μg to approximately 50,000 μg, approximately 20,000 μg to approximately 40,000 μg, approximately 20,000 μg to approximately 30,000 μg, approximately 20,000 μg g ~ approximately 25000 μg, approximately 25000 μg ~ approximately 100000 μg, approximately 25000 μg ~ approximately 90000 μg, approximately 25000 μg ~ approximately 80000 μg, approximately 25000 μg ~ approximately 70000 μg, approximately 25000 μg ~ approximately 60000 μg, approximately 25000 μg ~ approximately 50000 μg, approximately 2500 0 μg ~ approximately 40,000 μg, approximately 25,000 μg ~ approximately 30,000 μg, approximately 30,000 μg ~ approximately 100,000 μg, approximately 30,000 μg ~ approximately 90,000 μg, approximately 30,000 μg ~ approximately 80,000 μg, approximately 30,000 μg ~ approximately 70,000 μg, approximately 30,000 μg ~ approximately 60,000 μg, approximately 30 000μg~approx. 50000μg, approx. 30000μg~approx. 40000μg, approx. 40000μg~approx. 100000μg, approx. 40000μg~approx. 80000μg, approx. 40000μg~approx. 60000μg, approx. 40000μg~approx. 50000μg, approx. 50000μg~approx. 100000μgIt could be approximately 50,000 μg to 70,000 μg, approximately 60,000 μg to 100,000 μg, or approximately 70,000 μg to 100,000 μg.

[0142] In some embodiments, the dose of an ETBR antagonist as described herein (e.g., a specifically deuterated ETBR antagonist) is about 1.0 μg to about 10,000 μg. In some embodiments, the dose is about 1.0 μg to about 5,000 μg. In some embodiments, the dose is about 1.0 μg to about 2,500 μg. In some embodiments, the dose is about 1.0 μg to about 1,000 μg. In some embodiments, the dose is about 1.0 μg to about 500 μg. In some embodiments, the dose is about 1.0 μg to about 250 μg. In some embodiments, the dose is about 1.0 μg to about 100 μg. In some embodiments, the dose is about 1.0 μg to about 75 μg. In some embodiments, the dose is about 1.0 μg to about 50 μg. In some embodiments, the dose is about 1.0 μg to about 25 μg. In some embodiments, the dose is approximately 1.0 μg to approximately 10 μg. In some embodiments, the dose is approximately 10 μg to approximately 10,000 μg. In some embodiments, the dose is approximately 10 μg to approximately 5,000 μg. In some embodiments, the dose is approximately 10 μg to approximately 2,500 μg. In some embodiments, the dose is approximately 10 μg to approximately 1,000 μg. In some embodiments, the dose is approximately 10 μg to approximately 500 μg. In some embodiments, the dose is approximately 10 μg to approximately 250 μg. In some embodiments, the dose is approximately 10 μg to approximately 100 μg. In some embodiments, the dose is approximately 10 μg to approximately 75 μg. In some embodiments, the dose is approximately 10 μg to approximately 50 μg. In some embodiments, the dose is approximately 50 μg to approximately 10,000 μg. In some embodiments, the dose is approximately 50 μg to approximately 5,000 μg. In some embodiments, the dose is approximately 50 μg to approximately 2500 μg. In some embodiments, the dose is approximately 50 μg to approximately 2000 μg. In some embodiments, the dose is approximately 50 μg to approximately 1000 μg. In some embodiments, the dose is approximately 50 μg to approximately 750 μg. In some embodiments, the dose is approximately 50 μg to approximately 500 μg. In some embodiments, the dose is approximately 50 μg to approximately 250 μg.In some embodiments, the dose is approximately 50 μg to approximately 200 μg. In some embodiments, the dose is approximately 50 μg to approximately 100 μg. In some embodiments, the dose is approximately 100 μg to approximately 10000 μg. In some embodiments, the dose is approximately 100 μg to approximately 5000 μg. In some embodiments, the dose is approximately 100 μg to approximately 2500 μg. In some embodiments, the dose is approximately 100 μg to approximately 2000 μg. In some embodiments, the dose is approximately 100 μg to approximately 1500 μg. In some embodiments, the dose is approximately 100 μg to approximately 1250 μg. In some embodiments, the dose is approximately 100 μg to approximately 1000 μg. In some embodiments, the dose is approximately 100 μg to approximately 750 μg. In some embodiments, the dose is approximately 100 μg to approximately 500 μg. In some embodiments, the dose is approximately 100 μg to approximately 250 μg. In some embodiments, the dose is approximately 100 μg to approximately 200 μg. In some embodiments, the dose is approximately 250 μg to approximately 10,000 μg. In some embodiments, the dose is approximately 250 μg to approximately 5,000 μg. In some embodiments, the dose is approximately 250 μg to approximately 2,500 μg. In some embodiments, the dose is approximately 250 μg to approximately 2,000 μg. In some embodiments, the dose is approximately 250 μg to approximately 1,500 μg. In some embodiments, the dose is approximately 250 μg to approximately 1,250 μg. In some embodiments, the dose is approximately 250 μg to approximately 1,000 μg. In some embodiments, the dose is approximately 250 μg to approximately 750 μg. In some embodiments, the dose is approximately 250 μg to approximately 500 μg. In some embodiments, the dose is approximately 500 μg to approximately 10,000 μg. In some embodiments, the dose is approximately 500 μg to approximately 7,000 μg. In some embodiments, the dose is approximately 500 μg to approximately 5,000 μg. In some embodiments, the dose is approximately 500 μg to approximately 3,000 μg. In some embodiments, the dose is approximately 500 μg to approximately 2,500 μg. In some embodiments, the dose is approximately 500 μg to approximately 2,000 μg. In some embodiments, the dose is approximately 500 μg to approximately 1,500 μg.In some embodiments, the dose is approximately 500 μg to approximately 1250 μg. In some embodiments, the dose is approximately 500 μg to approximately 1000 μg. In some embodiments, the dose is approximately 500 μg to approximately 750 μg. In some embodiments, the dose is approximately 750 μg to approximately 20000 μg. In some embodiments, the dose is approximately 750 μg to approximately 15000 μg. In some embodiments, the dose is approximately 750 μg to approximately 10000 μg. In some embodiments, the dose is approximately 750 μg to approximately 7000 μg. In some embodiments, the dose is approximately 750 μg to approximately 5000 μg. In some embodiments, the dose is approximately 750 μg to approximately 3000 μg. In some embodiments, the dose is approximately 750 μg to approximately 2500 μg. In some embodiments, the dose is approximately 750 μg to approximately 2000 μg. In some embodiments, the dose is approximately 750 μg to approximately 1500 μg. In some embodiments, the dose is approximately 750 μg to approximately 1250 μg. In some embodiments, the dose is approximately 750 μg to approximately 1000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 20000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 15000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 10000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 7000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 5000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 3000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 2500 μg. In some embodiments, the dose is approximately 1000 μg to approximately 2000 μg. In some embodiments, the dose is approximately 1000 μg to approximately 1500 μg. In some embodiments, the dose is approximately 1500 μg to approximately 25000 μg. In some embodiments, the dose is approximately 1500 μg to approximately 20000 μg. In some embodiments, the dose is approximately 1500 μg to approximately 15000 μg. In some embodiments, the dose is approximately 1500 μg to approximately 10000 μg.In some embodiments, the dose is approximately 1500 μg to approximately 7000 μg. In some embodiments, the dose is approximately 1500 μg to approximately 5000 μg. In some embodiments, the dose is approximately 1500 μg to approximately 3000 μg. In some embodiments, the dose is approximately 1500 μg to approximately 2500 μg. In some embodiments, the dose is approximately 1500 μg to approximately 2000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 30000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 20000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 15000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 10000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 7000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 5000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 4000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 3000 μg. In some embodiments, the dose is approximately 2000 μg to approximately 2500 μg. In some embodiments, the dose is approximately 2500 μg to approximately 30000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 25000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 20000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 15000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 12000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 10000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 7000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 5000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 4000 μg. In some embodiments, the dose is approximately 2500 μg to approximately 3000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 50000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 20000 μg.In some embodiments, the dose is approximately 3000 μg to approximately 15000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 12000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 10000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 7000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 6000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 5000 μg. In some embodiments, the dose is approximately 3000 μg to approximately 4000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 50000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 30000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 20000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 15000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 12000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 10000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 8000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 6000 μg. In some embodiments, the dose is approximately 4000 μg to approximately 5000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 50000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 40000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 30000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 20000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 15000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 12000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 10000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 8000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 7000 μg. In some embodiments, the dose is approximately 5000 μg to approximately 6000 μg.In some embodiments, the dose is approximately 6000 μg to approximately 50000 μg. In some embodiments, the dose is approximately 6000 μg to approximately 30000 μg. In some embodiments, the dose is approximately 6000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 6000 μg to approximately 20000 μg. In some embodiments, the dose is approximately 6000 μg to approximately 17000 μg. In some embodiments, the dose is approximately 6000 μg. ~Approximately 15,000 μg. In some embodiments, the dose is approximately 6,000 μg to approximately 12,000 μg. In some embodiments, the dose is approximately 6,000 μg to approximately 10,000 μg. In some embodiments, the dose is approximately 6,000 μg to approximately 9,000 μg. In some embodiments, the dose is approximately 6,000 μg to approximately 8,000 μg. In some embodiments, the dose is approximately 6,000 μg to approximately 7,000 μg. In some embodiments, the dose is approximately 7,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 7,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 7,000 μg to approximately 40,000 μg. In some embodiments, the dose is approximately 7,000 μg to approximately 30,000 μg. In some embodiments, the dose is approximately 7000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 7000 μg to approximately 20000 μg. In some embodiments, the dose is approximately 7000 μg to approximately 17000 μg. In some embodiments, the dose is approximately 7000 μg to approximately 15000 μg. In some embodiments, the dose is approximately 7000 μg to approximately 12000 μg. In some embodiments, the dose is approximately 7000 μg to approximately 10000 μg. In some embodiments, the dose is approximately 7000 μg to approximately 8000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 80000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 60000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 50000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 30000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 25000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 20000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 17000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 15000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 12000 μg. In some embodiments, the dose is approximately 8000 μg to approximately 10000 μg. In some embodiments, the dose is approximately 10000 μg to approximately 100000 μg.In some embodiments, the dose is approximately 10,000 μg to approximately 80,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 60,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 40,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 30,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 25,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 20,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 18,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 16,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 15,000 μg. In some embodiments, the dose is approximately 10,000 μg to approximately 12,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 100,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 90,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 80,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 60,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 40,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 30,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 25,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 20,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 18,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 16,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 15,000 μg. In some embodiments, the dose is approximately 12,000 μg to approximately 14,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 100,000 μg.In some embodiments, the dose is approximately 15,000 μg to approximately 90,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 80,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 60,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 40,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 30,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 25,000 μg. In some embodiments, the dose is approximately 15,000 μg to approximately 20,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 100,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 90,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 80,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 60,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 40,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 30,000 μg. In some embodiments, the dose is approximately 20,000 μg to approximately 25,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 100,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 90,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 80,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 60,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 40,000 μg. In some embodiments, the dose is approximately 25,000 μg to approximately 30,000 μg.In some embodiments, the dose is approximately 30,000 μg to approximately 100,000 μg. In some embodiments, the dose is approximately 30,000 μg to approximately 90,000 μg. In some embodiments, the dose is approximately 30,000 μg to approximately 80,000 μg. In some embodiments, the dose is approximately 30,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 30,000 μg to approximately 60,000 μg. In some embodiments, the dose is approximately 30,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 30,000 μg to approximately 40,000 μg. In some embodiments, the dose is approximately 40,000 μg to approximately 100,000 μg. In some embodiments, the dose is approximately 40,000 μg to approximately 80,000 μg. In some embodiments, the dose is approximately 40,000 μg to approximately 60,000 μg. In some embodiments, the dose is approximately 40,000 μg to approximately 50,000 μg. In some embodiments, the dose is approximately 50,000 μg to approximately 100,000 μg. In some embodiments, the dose is approximately 50,000 μg to approximately 70,000 μg. In some embodiments, the dose is approximately 60,000 μg to approximately 100,000 μg or approximately 70,000 μg to approximately 100,000 μg.

[0143] In some embodiments, the doses are approximately 5 μg, 10 μg, 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, and 450 μg. g, about 475μg, about 500μg, about 550μg, about 600μg, about 650μg, about 700μg, about 750μg, about 800μg, about 850μg, about 1000μg, about 1250μg, about 1500μg, about 1750μg, about 2000μg, about 2500μg, about 3000μg, about 3500μg, about 4000μg, about 4500μg, about 50 00μg, about 6000μg, about 7000μg, about 8000μg, about 9000μg, about 10000μg, about 11000μg, about 12000μg, about 13000μg, about 14000μg, about 15000μg, about 16000μg, about 17000μg, about 18000μg, about 19000μg, about 20000μg, about 21000μg, about 22 These amounts are approximately 000 μg, 23000 μg, 24000 μg, 25000 μg, 26000 μg, 27000 μg, 28000 μg, 29000 μg, 30000 μg, 40000 μg, 50000 μg, 60000 μg, 70000 μg, 80000 μg, 90000 μg, or 100000 μg.

[0144] In some embodiments, the dosage is approximately 100 μg, approximately 150 μg, approximately 300 μg, approximately 500 μg, approximately 750 μg, approximately 1000 μg, approximately 1500 μg, approximately 2500 μg, approximately 300 μg, approximately 3000 μg, approximately 3500 μg, approximately 4000 μg, approximately 4500 μg, approximately 5000 μg, approximately 6000 μg, approximately 7000 μg, approximately 8000 μg, approximately 9000 μg, approximately 10000 μg, approximately 11000 μg, approximately 12000 μg, approximately 1 The amounts are approximately 3000 μg, 14000 μg, 15000 μg, 16000 μg, 17000 μg, 18000 μg, 19000 μg, 20000 μg, 21000 μg, 22000 μg, 23000 μg, 24000 μg, 25000 μg, 26000 μg, 27000 μg, 28000 μg, 29000 μg, 30000 μg, 40000 μg, or 50000 μg.

[0145] In some embodiments, the doses are approximately 300 μg, 300 μg, 750 μg, 1000 μg, 1500 μg, 2000 μg, 2500 μg, 3000 μg, 4000 μg, or 5000 μg. In some embodiments, the doses are approximately 100 μg, 150 μg, 300 μg, 750 μg, 1000 μg, 1500 μg, 2000 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 6000 μg, 7000 μg, 8000 μg, 9000 μg, or 1000 μg. The values ​​are 0 μg, approximately 11,000 μg, approximately 12,000 μg, approximately 13,000 μg, approximately 14,000 μg, approximately 15,000 μg, approximately 16,000 μg, approximately 17,000 μg, approximately 18,000 μg, approximately 19,000 μg, approximately 20,000 μg, approximately 21,000 μg, approximately 22,000 μg, approximately 23,000 μg, approximately 24,000 μg, or approximately 25,000 μg.

[0146] In some embodiments, the dosages are approximately 100 μg, 150 μg, 300 μg, 750 μg, 1000 μg, 1500 μg, 2000 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 6000 μg, 7000 μg, 8000 μg, 9000 μg, 10000 μg, 11000 μg, 12000 μg, 13000 μg, These amounts are approximately 14,000 μg, 15,000 μg, 16,000 μg, 17,000 μg, 18,000 μg, 19,000 μg, 20,000 μg, 21,000 μg, 22,000 μg, 23,000 μg, 24,000 μg, 25,000 μg, 26,000 μg, 27,000 μg, 28,000 μg, 29,000 μg, 30,000 μg, 40,000 μg, or 50,000 μg.

[0147] In some embodiments, the dose is approximately 2000 μg, 2500 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 6000 μg, 7000 μg, 8000 μg, 9000 μg, 10000 μg, 11000 μg, 12000 μg, 13000 μg, 14000 μg, 15000 μg, 16000 μg, 17000 μg, 18000 μg, 19000 μg, 20000 μg, 21000 μg, 22000 μg, 23000 μg, 24000 μg, or 25000 μg.

[0148] In some embodiments, the dose is approximately 2000 μg, 2500 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 6000 μg, 7000 μg, 8000 μg, 9000 μg, or 10000 μg.

[0149] In some embodiments, the dose is approximately 5000 μg, approximately 6000 μg, approximately 7000 μg, approximately 8000 μg, approximately 9000 μg, or approximately 10000 μg.

[0150] In some embodiments, the dose is approximately 7000 μg, approximately 8000 μg, approximately 9000 μg, or approximately 10000 μg, approximately 11000 μg, approximately 12000 μg, approximately 13000 μg, approximately 14000 μg, approximately 15000 μg, approximately 16000 μg, approximately 17000 μg, approximately 18000 μg, approximately 19000 μg, approximately 20000 μg, approximately 21000 μg, approximately 22000 μg, approximately 23000 μg, approximately 24000 μg, approximately 25000 μg, approximately 26000 μg, approximately 27000 μg, approximately 28000 μg, approximately 29000 μg, approximately 30000 μg, approximately 40000 μg, or approximately 50000 μg.

[0151] In some embodiments, the dose is approximately 100 μg, 150 μg, 300 μg, 750 μg, 1000 μg, 1500 μg, 2000 μg, 25000 μg, 3000 μg, 4000 μg, or 5000 μg.

[0152] In some embodiments, the dose is about 10 μg, about 50 μg, about 100 μg, about 150 μg, about 300 μg, about 750 μg, or about 1000 μg. In some embodiments, the dose is about 50 μg, about 100 μg, about 150 μg, about 300 μg, about 750 μg, or about 1000 μg. In some embodiments, the dose is about 100 μg, about 150 μg, about 300 μg, about 750 μg, about 1000 μg, about 1500 μg, about 2000 μg, about 3000 μg, about 4000 μg, or about 5000 μg. In some embodiments, the dose is about 100 μg, about 150 μg, about 300 μg, about 750 μg, about 1000 μg, about 1500 μg, about 2000 μg, or about 3000 μg. In some embodiments, the dose is about 300 μg, about 750 μg, about 1000 μg, about 1500 μg, or about 2000 μg. In some embodiments, the dose is about 150 μg, about 300 μg, about 750 μg, or about 1000 μg. In some embodiments, the dose is about 300 μg, about 750 μg, or about 1000 μg. In some embodiments, the dose is about 150 μg, about 300 μg, or about 750 μg. In some embodiments, the dose is about 300 μg, about 750 μg, or about 1000 μg. In some embodiments, the dose is about 150 μg or about 300 μg. In some embodiments, the dose is about 300 μg or about 750 μg. In some embodiments, the dose is about 750 μg or about 1000 μg.

[0153] In some embodiments, the dose is approximately 5 μg. In some embodiments, the dose is approximately 10 μg. In some embodiments, the dose is approximately 25 μg. In some embodiments, the dose is approximately 50 μg. In some embodiments, the dose is approximately 75 μg. In some embodiments, the dose is approximately 100 μg. In some embodiments, the dose is approximately 125 μg. In some embodiments, the dose is approximately 150 μg. In some embodiments, the dose is approximately 175 μg. In some embodiments, the dose is approximately 200 μg. In some embodiments, the dose is approximately 225 μg. In some embodiments, the dose is approximately 250 μg. In some embodiments, the dose is approximately 275 μg. In some embodiments, the dose is approximately 300 μg. In some embodiments, the dose is approximately 325 μg. In some embodiments, the dose is approximately 350 μg. In some embodiments, the dose is approximately 375 μg. In some embodiments, the dose is approximately 400 μg. In some embodiments, the dose is approximately 425 μg. In some embodiments, the dose is approximately 450 μg. In some embodiments, the dose is approximately 475 μg. In some embodiments, the dose is approximately 500 μg. In some embodiments, the dose is approximately 550 μg. In some embodiments, the dose is approximately 600 μg. In some embodiments, the dose is approximately 650 μg. In some embodiments, the dose is approximately 700 μg. In some embodiments, the dose is approximately 750 μg. In some embodiments, the dose is approximately 800 μg. In some embodiments, the dose is approximately 850 μg. In some embodiments, the dose is approximately 1000 μg. In some embodiments, the dose is approximately 1250 μg. In some embodiments, the dose is approximately 1500 μg. In some embodiments, the dose is approximately 1750 μg. In some embodiments, the dose is approximately 2000 μg. In some embodiments, the dose is approximately 2500 μg. In some embodiments, the dose is approximately 3000 μg. In some embodiments, the dose is approximately 3500 μg. In some embodiments, the dose is approximately 4000 μg. In some embodiments, the dose is approximately 4500 μg.In some embodiments, the dose is approximately 5000 μg. In some embodiments, the dose is approximately 6000 μg. In some embodiments, the dose is approximately 7000 μg. In some embodiments, the dose is approximately 8000 μg. In some embodiments, the dose is approximately 9000 μg. In some embodiments, the dose is approximately 10000 μg. In some embodiments, the dose is approximately 11000 μg. In some embodiments, the dose is approximately 12000 μg. In some embodiments, the dose is approximately 13000 μg. In some embodiments, the dose is approximately 14000 μg. In some embodiments, the dose is approximately 15000 μg. In some embodiments, the dose is approximately 16000 μg. In some embodiments, the dose is approximately 17000 μg. In some embodiments, the dose is approximately 18000 μg. In some embodiments, the dose is approximately 19000 μg. In some embodiments, the dose is approximately 20000 μg. In some embodiments, the dose is approximately 21000 μg. In some embodiments, the dose is approximately 22,000 μg. In some embodiments, the dose is approximately 23,000 μg. In some embodiments, the dose is approximately 24,000 μg. In some embodiments, the dose is approximately 25,000 μg. In some embodiments, the dose is approximately 26,000 μg. In some embodiments, the dose is approximately 27,000 μg. In some embodiments, the dose is approximately 28,000 μg. In some embodiments, the dose is approximately 29,000 μg. In some embodiments, the dose is approximately 30,000 μg. In some embodiments, the dose is approximately 40,000 μg. In some embodiments, the dose is approximately 50,000 μg. In some embodiments, the dose is approximately 60,000 μg. In some embodiments, the dose is approximately 70,000 μg. In some embodiments, the dose is approximately 80,000 μg. In some embodiments, the dose is approximately 90,000 μg. In some embodiments, the dose is approximately 100,000 μg.

[0154] In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered daily. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every other day. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every four days. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every three days. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every five days. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every six days. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered weekly. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every 10 days. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every 2 weeks. In some embodiments, the ETBR antagonist (e.g., a specifically deuterated ETBR antagonist) is administered every 3 weeks.

[0155] Route of administration Various routes of administration of the pharmaceutical compositions disclosed herein are disclosed herein. Compounds such as those described herein may be administered in single or divided doses via oral, parenteral, or topical routes in accordance with this disclosure. Administration of the active compound may range from continuous (intravenous infusion) to multiple oral administrations per day (e.g., QOD or QID), and other routes of administration may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (may include penetration enhancers), oral, sublingual, and suppository administration. Enteric-coated oral tablets may also be used to enhance the bioavailability of the compound from the oral route of administration. The most effective dosage form depends on the pharmacokinetics of the selected specific drug(s) and the severity of the patient's disease. Administration of the compounds relating to this disclosure as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration is also possible. Accordingly, this disclosure also covers pharmaceutical compositions comprising an effective amount of the compounds relating to this disclosure in combination with optionally pharmaceutically acceptable carriers, excipients, or additives. The compounds relating to this disclosure may be administered in immediate-release, intermediate-release, or sustained-release or controlled-release forms. In some embodiments, the sustained-release or controlled-release forms are administered orally, but may also be administered in suppositories and transdermally or in other topical forms. Intramuscular injection in liposomal form may also be used to control or sustain the release of the compound at the injection site.

[0156] In some embodiments, pharmaceutical compositions as described herein are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implanted reservoir. The term “parenterally” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-sacral, intrasternal, intramedullary, intrahepatic, intrafocal, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0157] In some embodiments, the sterile injectable form of compositions described herein is an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, as well as naturally pharmaceutically acceptable oils such as olive oil, castor oil, or soybean oil, particularly their polyoxyethylated forms, are useful in the preparation of injectable preparations. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0158] In some embodiments, the pharmaceutical compositions described herein are administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or liquids. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. Useful diluents for oral administration in capsule form include lactose and dried corn starch. When aqueous suspensions are used orally, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavorings, or colorings may be added, if desired.

[0159] In some embodiments, pharmaceutical compositions such as those described herein are administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0160] In some embodiments, the pharmaceutical compositions described herein are administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestine can be done with rectal suppositories (see above) or suitable enema formulations. Topically acceptable transdermal patches may also be used.

[0161] In some embodiments, for topical application, the pharmaceutical composition is formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, DMSO, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. In some embodiments, the compounds may be coated onto a stent surgically implanted in a patient to inhibit or reduce the possibility of occlusion occurring within the patient's stent.

[0162] In some embodiments, the pharmaceutical composition is formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0163] In some embodiments, for ophthalmic use, the pharmaceutical composition is formulated as a finely powdered suspension in isotonic pH-adjusted sterile saline with or without a preservative such as benzylalkonium chloride, or as a solution in isotonic pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment such as petrolatum.

[0164] In some embodiments, pharmaceutical compositions as described herein are administered by nasal aerosol or inhalation. Such compositions may be prepared according to the techniques described herein with respect to pharmaceutical compositions and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants. In some embodiments, this description provides formulations comprising liposomes containing an effective amount (e.g., a synergistically effective amount) of an ETBR antagonist.

[0165] In some embodiments, the compositions are formulated to contain about 0.05 milligrams to about 750 milligrams or more of the active ingredient, for example, about 1 milligram to about 600 milligrams, or about 10 milligrams to about 500 milligrams, either alone or in combination with other compounds relating to this disclosure. It should also be understood that specific dosages and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combination, and the judgment of the treating physician and the severity of the specific disease or illness being treated.

[0166] In some embodiments, patients or subjects requiring treatment using compounds according to the methods described herein are treated by administering to the patient (subject) an effective amount of the compounds according to this disclosure, either alone or in combination with other known erythropoiesis-stimulating agents otherwise identified herein, including, optionally, pharmaceutically acceptable salts, solvates, or polymorphs thereof in a pharmaceutically acceptable carrier or diluent.

[0167] In some embodiments, the compounds or compositions described herein are administered orally, parenterally, intradermally, by injection (intravenously, subcutaneously, or intramuscularly), topically including transdermally, in the form of a liquid, cream, gel, or solid, or in the form of an aerosol.

[0168] In some embodiments, the active ingredient is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient for the desired indication without causing serious toxic effects in the patient being treated. Exemplary doses of the active compound for all diseases mentioned herein are in the range of about 10 ng / kg to 300 ng / kg, about 10 ng / kg to 1 μg / kg, about 1 μg / kg to 10 μg / kg, about 10 μg / kg to 100 μg / kg, about 100 μg / kg to 1000 μg / kg, about 1 mg / kg to 30 mg / kg, about 1 mg / kg to 300 mg / kg, or 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Typical topical doses are in the range of 0.01 to 5% wt / wt in a suitable carrier.

[0169] In some embodiments, the active ingredients described herein are conveniently administered in any suitable unit dosage form, including but not limited to those containing less than 1 μg, 1 μg to 5000 μg, for example, 50 to 3000 μg of the active compound per unit dosage form.

[0170] In some embodiments, the active ingredient is administered to achieve a peak plasma concentration of the active compound of approximately 0.00001–30 mM, for example, approximately 0.1–30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient in physiological saline or an aqueous medium, or by administration as a bolus of the active ingredient. Oral administration is also suitable for producing an effective plasma concentration of the active agent.

[0171] Chimeric antigen receptor-expressing immune cells The combination therapies and methods disclosed herein generally involve chimeric antigen receptor (CAR) expressing immune cells. A “chimeric antigen receptor” (CAR) refers to a synthetic receptor that mimics immune receptor activation to induce immune cell activity against a target of interest. A CAR substantially consists of (a) an extracellular domain that binds to the target of interest (e.g., a single-chain variable fragment (scFv)), (b) a transmembrane domain, and (c) an intracellular domain that activates immune signaling (e.g., a CD3z domain). CARs may be expressed in several different types of immune cells useful for the methods described herein. In some embodiments, CARs are expressed in T cells (e.g., CD4 T cells, CD8 T cells, T cells). C 1 cell, T C 2 cells, γδT cells, T H 1 cell, T H 2 cells, T H 3, T H 17 cells, T FH cell, T reg CAR can be expressed in cells (memory T cells, NK T cells) or NK cells. In some embodiments, CAR is expressed in T cells ("CAR-T cells"). In some embodiments, CAR is expressed in NK cells ("CAR-NK cells").

[0172] In some embodiments, the CAR useful in the methods described herein specifically binds to tumor-associated antigens. A "tumor-associated antigen" is a protein produced by tumor cells that elicits an immune response. Examples of tumor-associated antigens include human epidermal growth factor receptor 2 (HER2). In some embodiments, the tumor-associated antigen is (human epidermal growth factor receptor 2)HER2.

[0173] In some embodiments, the dose of CAR-expressing immune cells is 10 4 ~10 9 cells / kg body weight, 10 5 ~10 9 cells / kg body weight, 10 6 ~10 9 cells / kg body weight, 10 7 ~10 9 cells / kg body weight, 10 8~10 9 cells / kg body weight, 10 4 ~10 8 cells / kg body weight, 10 5 ~10 8 cells / kg body weight, 10 6 ~10 8 cells / kg body weight, 10 7 ~10 8 cells / kg body weight, 10 4 ~10 7 cells / kg body weight, 10 5 ~10 7 cells / kg body weight, 10 6 ~10 7 cells / kg body weight, 10 4 ~10 6 cells / kg body weight, 10 5 ~10 6 cells / kg body weight, or 10 4 ~10 5 It is expressed as cells per kg of body weight.

[0174] In some embodiments, CAR-expressing immune cells are administered as a single infusion. In some embodiments, CAR-expressing immune cells are administered as multiple infusions (e.g., 2 to 20 infusions). In some embodiments, CAR-expressing immune cells are administered as two infusions. In some embodiments, CAR-expressing immune cells are administered as three infusions. In some embodiments, CAR-expressing immune cells are administered as four infusions. In some embodiments, CAR-expressing immune cells are administered as five infusions. In some embodiments, CAR-expressing immune cells are administered as six infusions. In some embodiments, CAR-expressing immune cells are administered as seven infusions. In some embodiments, CAR-expressing immune cells are administered as eight infusions. In some embodiments, CAR-expressing immune cells are administered as nine infusions. In some embodiments, CAR-expressing immune cells are administered as ten infusions. In some embodiments, CAR-expressing immune cells are administered as eleven infusions. In some embodiments, CAR-expressing immune cells are administered as twelve infusions. In some embodiments, CAR-expressing immune cells are administered as thirteen infusions. In some embodiments, CAR-expressing immune cells are administered as fourteen infusions. In some embodiments, CAR-expressing immune cells are administered in 16 infusions. In some embodiments, CAR-expressing immune cells are administered in 17 infusions. In some embodiments, CAR-expressing immune cells are administered in 18 infusions. In some embodiments, CAR-expressing immune cells are administered in 19 infusions. In some embodiments, CAR-expressing immune cells are administered in 20 infusions.

[0175] In some embodiments, CAR-expressing immune cells are administered at one-week intervals. In some embodiments, CAR-expressing immune cells are administered at two-week intervals. In some embodiments, CAR-expressing immune cells are administered at three-week intervals. In some embodiments, CAR-expressing immune cells are administered at four-week intervals. In some embodiments, CAR-expressing immune cells are administered at five-week intervals. In some embodiments, CAR-expressing immune cells are administered at six-week intervals. In some embodiments, CAR-expressing immune cells are administered at seven-week intervals. In some embodiments, CAR-expressing immune cells are administered at eight-week intervals. In some embodiments, CAR-expressing immune cells are administered at nine-week intervals. In some embodiments, CAR-expressing immune cells are administered at ten-week intervals. In some embodiments, CAR-expressing immune cells are administered at eleven-week intervals. In some embodiments, CAR-expressing immune cells are administered at twelve-week intervals.

[0176] In some embodiments, CAR-expressing immune cells are administered at one-month intervals. In some embodiments, CAR-expressing immune cells are administered at two-month intervals. In some embodiments, CAR-expressing immune cells are administered at three-month intervals. In some embodiments, CAR-expressing immune cells are administered at four-month intervals. In some embodiments, CAR-expressing immune cells are administered at five-month intervals. In some embodiments, CAR-expressing immune cells are administered at six-month intervals. In some embodiments, CAR-expressing immune cells are administered at seven-month intervals. In some embodiments, CAR-expressing immune cells are administered at eight-month intervals. In some embodiments, CAR-expressing immune cells are administered at nine-month intervals. In some embodiments, CAR-expressing immune cells are administered at ten-month intervals. In some embodiments, CAR-expressing immune cells are administered at eleven-month intervals. In some embodiments, CAR-expressing immune cells are administered at twelve-month intervals.

[0177] Immune checkpoint inhibitors In various embodiments, the methods disclosed herein include the step of administering a combination therapy comprising an immune checkpoint inhibitor (ICPI) to a target. In some embodiments, the ICPI is an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, or a CISH inhibitor. In some embodiments, the ICPI is an anti-PD1 antibody. In some embodiments, the anti-PD1 antibody is nivolumab, pembrolizumab, pizilizumab, or any combination thereof. In some embodiments, the anti-PD1 antibody is nivolumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1 antibody is pizilizumab. In some embodiments, the ICPI is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, avelumab, durvalumab, or any combination thereof. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is MDX-1105. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0178] In some embodiments, the dose of ICPI is approximately 0.1 mg / kg to approximately 9.0 mg / kg. For example, the dose of anti-PD1 antibody is approximately 0.1 mg / kg to approximately 9.0 mg / kg, approximately 0.1 mg / kg to approximately 8.0 mg / kg, approximately 0.1 mg / kg to approximately 7.0 mg / kg, approximately 0.1 mg / kg to approximately 6.0 mg / kg, approximately 0.1 mg / kg to approximately 5.0 mg / kg, approximately 0.1 mg / kg to approximately 4.0 mg / kg, approximately 0.1 mg / kg to approximately 3.0 mg / kg, approximately 0.1 mg / kg to approximately 2.0 mg / kg, approximately 0.1 mg / kg to approximately 1.0 mg / kg, approximately 1.0 mg / kg to approximately 9.0 mg / kg, and approximately 1.0 mg / kg to approximately 8.0 mg / kg. mg / kg, approximately 1.0 mg / kg to approximately 7.0 mg / kg, approximately 1.0 mg / kg to approximately 6.0 mg / kg, approximately 1.0 mg / kg to approximately 5.0 mg / kg, approximately 1.0 mg / kg to approximately 4.0 mg / kg, approximately 1.0 mg / kg to approximately 3.0 mg / kg, approximately 1.0 mg / kg to approximately 2.0 mg / kg, approximately 2.0 mg / kg to approximately 9.0 mg / kg, approximately 2.0 mg / kg to approximately 8.0 mg / kg, approximately 2.0 mg / kg to approximately 7.0 mg / kg, approximately 2.0 mg / kg to approximately 6.0 mg / kg, approximately 2.0 mg / kg to approximately 5.0 mg / kg, approximately 2.0 mg g / kg ~ approximately 4.0 mg / kg, approximately 2.0 mg / kg ~ approximately 3.0 mg / kg, approximately 3.0 mg / kg ~ approximately 9.0 mg / kg, approximately 3.0 mg / kg ~ approximately 8.0 mg / kg, approximately 3.0 mg / kg ~ approximately 7.0 mg / kg, approximately 3.0 mg / kg ~ approximately 6.0 mg / kg, approximately 3.0 mg / kg ~ approximately 5.0 mg / kg, approximately 3.0 mg / kg ~ approximately 4.0 mg / kg, approximately 4.0 mg / kg ~ approximately 9.0 mg / kg, approximately 4.0 mg / kg ~ approximately 8.0 mg / kg, approximately 4.0 mg / kg ~ approximately 7.0 mg / kg, approximately 4.0 mg / kg ~ approximately 6.0 mg The values ​​are approximately g / kg, 4.0 mg / kg to 5.0 mg / kg, 5.0 mg / kg to 9.0 mg / kg, 5.0 mg / kg to 8.0 mg / kg, 5.0 mg / kg to 7.0 mg / kg, 5.0 mg / kg to 6.0 mg / kg, 6.0 mg / kg to 9.0 mg / kg, 6.0 mg / kg to 8.0 mg / kg, 6.0 mg / kg to 7.0 mg / kg, 7.0 mg / kg to 9.0 mg / kg, 7.0 mg / kg to 8.0 mg / kg, or 8.0 mg / kg to 9.0 mg / kg.

[0179] In some embodiments, the dose of ICPI is approximately 10 mg to approximately 5000 mg. In some embodiments, the dose of ICPI is approximately 10 mg to approximately 900 mg. For example, the dose of anti-PD1 antibody is approximately 10 mg to approximately 900 mg, approximately 10 mg to approximately 800 mg, approximately 10 mg to approximately 700 mg, approximately 10 mg to approximately 600 mg, approximately 10 mg to approximately 500 mg, approximately 10 mg to approximately 400 mg, approximately 10 mg to approximately 300 mg, approximately 10 mg to approximately 200 mg, approximately 10 mg to approximately 100 mg, approximately 100 mg to approximately 900 mg, and approximately 100 mg to approximately 800 mg. , about 100mg to about 700mg, about 100mg to about 600mg, about 100mg to about 500mg, about 100mg to about 400mg, about 100mg to about 300mg, about 100mg to about 2 00mg, about 200mg to about 900mg, about 200mg to about 800mg, about 200mg to about 700mg, about 200mg to about 600mg, about 200mg to about 500mg, about 200mg ~about 400mg, about 200mg to about 300mg, about 300mg to about 900mg, about 300mg to about 800mg, about 300mg to about 700mg, about 300mg to about 600mg, about 3 00mg to about 500mg, about 300mg to about 400mg, about 400mg to about 900mg, about 400mg to about 800mg, about 400mg to about 700mg, about 400mg to about 600mg The amounts are approximately 400mg to 500mg, 500mg to 900mg, 500mg to 800mg, 500mg to 700mg, 500mg to 600mg, 600mg to 900mg, 600mg to 800mg, 600mg to 700mg, 700mg to 900mg, 700mg to 800mg, or 800mg to 900mg.

[0180] In some embodiments, the dosage of ICPI is approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, and 750 mg. g, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 mg, approximately 2000 mg, approximately 2500 mg, approximately 3000 mg, approximately 3500 mg, approximately 4000 mg, approximately 4500 mg, or approximately 5000 mg. In some embodiments, the dosage of ICPI is approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg.

[0181] In some embodiments, the dose of ICPI is approximately 10 mg. In some embodiments, the dose of ICPI is approximately 20 mg. In some embodiments, the dose of ICPI is approximately 30 mg. In some embodiments, the dose of ICPI is approximately 40 mg. In some embodiments, the dose of ICPI is approximately 50 mg. In some embodiments, the dose of ICPI is approximately 70 mg. In some embodiments, the dose of ICPI is approximately 75 mg. In some embodiments, the dose of ICPI is approximately 80 mg. In some embodiments, the dose of ICPI is approximately 90 mg. In some embodiments, the dose of ICPI is approximately 100 mg. In some embodiments, the dose of ICPI is approximately 150 mg. In some embodiments, the dose of ICPI is approximately 200 mg. In some embodiments, the dose of ICPI is approximately 250 mg. In some embodiments, the dose of ICPI is approximately 300 mg. In some embodiments, the dose of ICPI is approximately 350 mg. In some embodiments, the dose of ICPI is approximately 400 mg. In some embodiments, the dose of ICPI is approximately 450 mg. In some embodiments, the dose of ICPI is approximately 500 mg. In some embodiments, the dose of ICPI is approximately 550 mg. In some embodiments, the dose of ICPI is approximately 600 mg. In some embodiments, the dose of ICPI is approximately 650 mg. In some embodiments, the dose of ICPI is approximately 700 mg. In some embodiments, the dose of ICPI is approximately 750 mg. In some embodiments, the dose of ICPI is approximately 800 mg. In some embodiments, the dose of ICPI is approximately 850 mg. In some embodiments, the dose of ICPI is approximately 900 mg. In some embodiments, the dose of ICPI is approximately 950 mg. In some embodiments, the dose of ICPI is approximately 1000 mg. In some embodiments, the dose of ICPI is approximately 1100 mg. In some embodiments, the dose of ICPI is approximately 1200 mg. In some embodiments, the dose of ICPI is approximately 1300 mg. In some embodiments, the dose of ICPI is approximately 1400 mg.In some embodiments, the dose of ICPI is approximately 1500 mg. In some embodiments, the dose of ICPI is approximately 1600 mg. In some embodiments, the dose of ICPI is approximately 1700 mg. In some embodiments, the dose of ICPI is approximately 1800 mg. In some embodiments, the dose of ICPI is approximately 1900 mg. In some embodiments, the dose of ICPI is approximately 2000 mg. In some embodiments, the dose of ICPI is approximately 2500 mg. In some embodiments, the dose of ICPI is approximately 3000 mg. In some embodiments, the dose of ICPI is approximately 3500 mg. In some embodiments, the dose of ICPI is approximately 4000 mg. In some embodiments, the dose of ICPI is approximately 4500 mg. In some embodiments, the dose of ICPI is approximately 5000 mg.

[0182] In some embodiments, ICPI is administered daily. In some embodiments, ICPI is administered every other day. In some embodiments, ICPI is administered every three days. In some embodiments, ICPI is administered every four days. In some embodiments, ICPI is administered every five days. In some embodiments, ICPI is administered every six days. In some embodiments, ICPI is administered every seven days. In some embodiments, ICPI is administered every eight days. In some embodiments, ICPI is administered every nine days. In some embodiments, ICPI is administered every ten days. In some embodiments, ICPI is administered every eleven days. In some embodiments, ICPI is administered every twelve days. In some embodiments, ICPI is administered every thirteen days. In some embodiments, ICPI is administered every fourteen days. In some embodiments, ICPI is administered every fifteen days. In some embodiments, ICPI is administered every sixteen days. In some embodiments, ICPI is administered every seventeen days. In some embodiments, ICPI is administered every eighteen days. In some embodiments, ICPI is administered every nineteen days. In some embodiments, ICPI is administered every 20 days. In some embodiments, ICPI is administered every 21 days. In some embodiments, ICPI is administered weekly. In some embodiments, ICPI is administered every 2 weeks. In some embodiments, ICPI is administered every 3 weeks. In some embodiments, ICPI is administered every 4 weeks. In some embodiments, ICPI is administered every 5 weeks. In some embodiments, ICPI is administered every 6 weeks. In some embodiments, ICPI is administered every 7 weeks. In some embodiments, ICPI is administered every 8 weeks. In some embodiments, ICPI is administered every 9 weeks. In some embodiments, ICPI is administered every 10 weeks. In some embodiments, ICPI is administered every 11 weeks. In some embodiments, ICPI is administered every 12 weeks.

[0183] kit Disclosed herein are kits or pharmaceutical compositions for the treatment of solid tumors in a subject, e.g., a human subject, comprising an effective amount of an ETBR antagonist for use in combination therapy with CAR-expressing immune cells, and a pharmaceutically acceptable carrier. In some embodiments, the kit or pharmaceutical composition further comprises an ICPI (e.g., an anti-PD1 antibody). In some embodiments, the ETBR antagonist is a specifically deuterated ETBR antagonist, e.g., deuterated BQ-788 as described herein. In some embodiments, the ETBR antagonist, e.g., deuterated BQ-788, is placed in a single container together with CAR-expressing immune cells. In some embodiments, the ETBR antagonist, e.g., deuterated BQ-788, is placed in a first container, and the CAR-expressing immune cells are placed in a second container, and the ETBR antagonist and CAR-expressing immune cells are administered almost simultaneously.

[0184] In some embodiments, this description provides a kit for the treatment of solid tumor cancer in human subjects, comprising a certain amount of CAR-expressing immune cells, a synergistically effective amount of an ETBR antagonist (e.g., a specifically deuterated ETBR antagonist as described herein), and a pharmaceutically acceptable carrier or excipient. In some embodiments, the kit or pharmaceutical composition further comprises an ICPI (e.g., an anti-PD1 antibody). In some embodiments, the ETBR antagonist is deuterated BQ-788. In some embodiments, the ETBR antagonist is BQ-788-B (ENB-003). In some embodiments, the ICPI is an anti-PD1 antibody or an anti-PD-L1 antibody.

[0185] Treatment method Methods for treating or improving cancer in a subject or patient, such as a human or other animal, are disclosed herein, the methods comprising the step of administering a combination therapy as described herein to the subject in an effective amount, such as a therapeutically effective amount or a synergistically effective amount, where the combination therapy is an effective amount for treating or improving the disease or disorder or symptoms of the subject. In some embodiments, the combination therapy comprises CAR-expressing immune cells and an ETBR antagonist (e.g., a deuterated ETBR antagonist). In some embodiments, the combination therapy comprises CAR-expressing immune cells, ICPI, and an ETBR antagonist (e.g., a deuterated ETBR antagonist). In some embodiments, the ETBR antagonist (e.g., a deuterated ETBR antagonist) is administered at 2, 3, 4, or 5 times the frequency of CAR-expressing immune cells or ICPI, for example, CAR-expressing immune cells are administered once or twice over a period of 1 to 3 weeks (e.g., 2 to 3 weeks or about 21 days), while the ETBR antagonist is administered three times over a period of 1 to 3 weeks (e.g., 2 to 3 weeks or about 21 days).

[0186] In some embodiments, the disease or disorder is a cancer expressing a target. In some embodiments, the cancer is refractory, or insensitive to immunotherapy (e.g., checkpoint inhibitors and / or CAR expression immunotherapy, e.g., treatment with CAR-T therapy), or both. In some embodiments, the cancer is newly diagnosed. In some embodiments, the cancer is recurrent or refractory. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is refractory.

[0187] In some embodiments, the cancer is ETBR-related cancer. In some embodiments, the cancer is HER2-expressing cancer. In some embodiments, the cancer is HER2+ cancer. In some embodiments, the cancer is HER2-low expressing cancer. In some embodiments, the cancer is a malignant hematological disorder. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from malignant melanoma, malignant squamous cell carcinoma, glioblastoma, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer, and kidney cancer. In some embodiments, the cancer is selected from breast cancer, gastric cancer, esophageal cancer, ovarian cancer, endometrial cancer, bladder cancer, lung cancer, cervical cancer, colon cancer, and head and neck cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is head and neck cancer.

[0188] In some embodiments, the cancer is HER2+ breast cancer, HER2+ gastric cancer, HER2+ esophageal cancer, HER2+ ovarian cancer, HER2+ endometrial cancer, HER2+ bladder cancer, HER2+ lung cancer, HER2+ cervical cancer, HER2+ colon cancer, HER2+ and head and neck cancer.

[0189] In some embodiments, the cancer is HER2-low-expressing breast cancer, HER2-low-expressing gastric cancer, HER2-low-expressing esophageal cancer, HER2-low-expressing ovarian cancer, HER2-low-expressing endometrial cancer, HER2-low-expressing bladder cancer, HER2-low-expressing lung cancer, HER2-low-expressing cervical cancer, HER2-low-expressing colon cancer, and HER2-low-expressing head and neck cancer. In some embodiments, the cancer is HER2-low-expressing breast cancer. In some embodiments, the cancer is HER2-low-expressing gastric cancer. In some embodiments, the cancer is HER2-low-expressing esophageal cancer. In some embodiments, the cancer is HER2-low-expressing ovarian cancer. In some embodiments, the cancer is HER2-low-expressing endometrial cancer. In some embodiments, the cancer is HER2-low-expressing bladder cancer. In some embodiments, the cancer is HER2-low-expressing lung cancer. In some embodiments, the cancer is HER2-low-expressing cervical cancer. In some embodiments, the cancer is HER2-low-expressing colon cancer. In some embodiments, the cancer is HER2-low-expressing head and neck cancer.

[0190] In some embodiments, cancer is metastatic. In some embodiments, cancer is progressive. [Examples]

[0191] Example 1. Combination of deuterated ETBR antagonist, ICPI, and CAR-T therapy in an in vivo model. Generation of anti-HER2 mouse CAR-T cells Lentiviruses for anti-HER2 CAR expression were produced by co-transfecting 293T-17 cells with the lentiviral vector pLVX-EF1α-CAR-IRES-ZsGreen1 together with the packaging plasmids pSPAX2 and pMD2.G. Splenocytes from 6-week-old female BALB / c mice were isolated by density gradient centrifugation using lymphocyte isolation medium Histopaque and 1 × 10⁶ cells were collected in 24-well plates using a mouse T cell activation / proliferation kit. 6The cells were activated at a density of cells / ml for 2-3 days, and then transduced with the pLVX-EF1α-CAR-IRES-ZsGreen1 lentivirus by centrifugation at 1,500×g, 32°C for 2 hours in the presence of 8 μg / mL polyblen at an infection multiplicity of 20. The GFP+ transduced T cells were analyzed by flow cytometry to evaluate the lentiviral transduction efficiency.

[0192] To evaluate the cytotoxicity of anti-HER2 mouse CAR-T cells against HER2-positive breast cancer cells in vitro, CAR-T cells were incubated in triplicates with 4T1-HER2 cells at effector:target ratios of 2:1, 4:1, and 8:1. Specific lactate dehydrogenases (LDHs) released from target cells into the culture medium supernatant were measured using an LDH cytotoxicity detection kit according to the manufacturer's instructions. In addition, IL-2 secretion from anti-HER2 mouse CAR-T cells was assayed by incubating CAR-T cells with 4T1-HER2 cells in triplicates for 24 hours at E:T ratios of 2:1, 4:1, and 8:1. IL-2 concentrations in the culture medium supernatant were analyzed using an IL-2 ELISA kit (R&D Systems) according to the manufacturer's instructions.

[0193] Generation of 4T1-HER2 mammary tumors in isomorphosed female BALB / c mice 4T1-HER2 cells (4×10 6 The drug was resuspended in 0.1 mL of PBS, mixed with 0.1 mL of Matrigel, and subcutaneously injected into the right dorsal region of BALB / c female mice (6 weeks old, body weight 17-20 g). Tumor growth was monitored every 3 days by caliper measurement.

[0194] Treatment of 4T1-HER2 mammary tumors using anti-HER2 CAR-T cells and BQ-788-B Approximately 14 days after injection of 4T1-HER2 cells, when the tumor diameter reached approximately 6 mm, the mice were randomized into eight groups (6 mice per group) for treatment.

[0195] Blank T cells or CAR-T cells (1 × 10⁻¹⁰ 7Cells ( / mouse) were intravenously injected into each mouse on days 11 and 18 after tumor inoculation. BQ-788-B (24g) or PBS was administered to each mouse via subcutaneous injection, starting on day 10 and every 2 or 3 days for a total of 9 injections. All mice received 20,000 IU of IL-2 intraperitoneally every 2 days from day 14 to day 34 (Note: Day 0 is defined as the day the 4T1-HER2 cells were injected into the mouse). Anti-PD1 or isotype control Ig (230ug / mouse) was administered via IP injection every 4 days, starting on day 11 after tumor inoculation (a total of 4 injections). The eight treatment groups are listed below. 1) Blank T + PBS + Isotype 2) CAR-T + PBS + Isotype 3) BQ-788-B + Blank T + Iso Type 4) Blank T + PBS + Anti-PD1 5) BQ-788-B+CAR-T+Isotype 6)CAR-T+PBS+anti-PD1 7) BQ-788-B + Blank T + Anti-PD1 8)BQ-788-B+CAR-T+anti-PD1

[0196] Tumor growth was monitored every three days using caliper measurements. Thirty days after injection of 4T1-HER2 cells, all mice were euthanized by CO2 asphyxiation followed by cervical dislocation. All tumors were dissected, photographed, and fixed in 10% formalin.

[0197] result Compared to blank T+PBS+isotype control, all treatment groups showed a reduction in overall tumor growth (Figure 2). On day 17, treatment with a combination of CAR-T, BQ-788-B, and anti-PD-1 demonstrated the greatest reduction in tumor growth, particularly compared to control or CAR-T alone (Figures 3A and 3B). At later time points, the addition of BQ-788-B enhanced tumor suppression in mice treated with either anti-PD1 or CAR-T therapy. On day 29 (Figure 4), groups treated with BQ-788-B in combination with anti-PD1 and / or CAR-T therapy showed a significant reduction in tumor volume compared to control, CAR-T alone, or PD-1 alone. On day 30 (Figures 5A and 5B), groups treated with BQ-788-B in combination with anti-PD1 and / or CAR-T therapy showed a significant reduction in tumor weight compared to control, CAR-T alone, or PD-1 alone. These experiments demonstrate that the addition of BQ-788-B significantly enhances the antitumor effects of CAR-T cells, anti-PD-1 antibody therapy, and combinations of CAR-T and anti-PD-1 therapy.

[0198] Example 2. Treatment of solid tumors in human subjects using combination therapy including CAR-expressing immune cells and a deuterated ETBR antagonist. In human patients with cancer expressing a target, such as HER2-expressing cancer, such as breast cancer, a combination therapy regimen comprising CAR-expressing immune cells (e.g., CAR-T cells or CAR-NK cells) and a deuterated ETBR antagonist (e.g., BQ-788-A, BQ-788-B, or BQ-788-C) is administered according to the methods disclosed herein. This treatment reduces tumor volume or mass or eradicates the tumor within the patient.

[0199] Example 3. Treatment of solid tumors in human subjects using a combination therapy comprising CAR-expressing immune cells, an immune checkpoint inhibitor, and a deuterated ETBR antagonist. In human patients with cancer, such as HER2-expressing cancer, such as breast cancer, a combination therapy regimen comprising CAR-expressing immune cells (e.g., CAR-T cells or CAR-NK cells), ICPI (e.g., anti-PD1 antibody), and a deuterated ETBR antagonist (e.g., BQ-788-A, BQ-788-B, or BQ-788-C) is administered according to the methods disclosed herein. This treatment reduces tumor volume or mass or eradicates the tumor within the patient.

[0200] While several embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will be able to conceive of numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternative forms to the embodiments of the present invention described herein may be employed when carrying out the present invention. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

1. A method for treating cancer that expresses a target substance requiring treatment, (a) Chimeric antigen receptor (CAR) expressing immune cells in which the CAR specifically binds to the target, and (b) an effective dose of ETBR antagonist A method comprising the step of administering a combination including the above to the subject.

2. A method for treating cancer expressing a target of a subject requiring treatment, using chimeric antigen receptor (CAR) expressing immune cells in which the CAR specifically binds to the target, wherein the improvement includes the simultaneous administration of an effective amount of ETBR antagonist to the subject.

3. The method according to claim 1 or 2, wherein the target is a tumor-associated antigen.

4. The method according to claim 3, wherein the tumor-associated antigen is HER2.

5. The method according to any one of claims 1 to 4, further comprising the step of co-administering an effective amount of an immune checkpoint inhibitor (ICPI) to a patient.

6. A method for treating cancer that expresses a target substance requiring treatment, (a) Chimeric antigen receptor (CAR) expressing immune cells, wherein the CAR specifically binds to the target, (b) Immune checkpoint inhibitors (ICPIs), and (c) an effective dose of ETBR antagonist A method comprising the step of administering a combination including the above to the subject.

7. A method for treating cancer expressing a target of a subject requiring treatment, using chimeric antigen receptor (CAR) expressing immune cells in which the CAR specifically binds to the target, and an immune checkpoint inhibitor (ICPI), wherein the improvement includes the simultaneous administration of an effective amount of ETBR antagonist to the subject.

8. The method according to claim 6 or 7, wherein the target is a tumor-associated antigen.

9. The method according to claim 8, wherein the tumor-associated antigen is HER2.

10. A method for treating HER2-expressing cancers that require treatment, (a) Chimeric antigen receptor (CAR) expressing immune cells in which the CAR specifically binds to HER2, and (b) an effective amount of deuterated ETBR antagonist A method comprising the step of administering a combination including the above to the subject.

11. A method for treating a target HER2-expressing cancer requiring treatment using chimeric antigen receptor (CAR)-expressing immune cells in which the CAR specifically binds to HER2, wherein the improvement includes the simultaneous administration of an effective amount of ETBR antagonist to the target.

12. The method according to claim 10 or 11, further comprising the step of co-administering an effective amount of an immune checkpoint inhibitor (ICPI) to a patient.

13. The method according to any one of claims 5 to 9 and 12, wherein the ICPI is an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or a variant or functional fragment thereof.

14. The method according to claim 13, wherein the ICPI is an anti-PD1 antibody.

15. The method according to any one of claims 1 to 14, wherein the ETBR antagonist is a deuterated ETBR antagonist.

16. The deuterated ETBR antagonist is given by formula (I): 【Chemistry 1】 A compound or stereoisomer thereof, in which, n is an integer from 0 to 4, m is an integer between 0 and 3. X is a positively charged counterion, R １ and R ３ These are independently -H, -D, and -CH ３ ien-CH ２ D, -CHD ２ , or -CD ３ And, R ２ａ 、 R ２ｂ 、 R ４ 、 R ５ 、 and R ６ are independently, -CH ３ 、 -CH ２ D, -CHD ２ 、 or -CD ３ and at least one of R １ 、 R ２ａ 、 R ２ｂ 、 or R ３ contains deuterium. The method according to claim 15, wherein the compound or its stereoisomer.

17. The aforementioned compound is of formula (1a): 【Chemistry 2】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

18. The aforementioned compound is of formula (2): 【Transformation 3】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

19. The aforementioned compound is of formula (2a): 【Chemistry 4】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

20. The aforementioned compound is of formula (3): 【Transformation 5】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

21. The aforementioned compound is of formula (3a): 【Transformation 6】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

22. The aforementioned compound is of formula (4): 【Transformation 7】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

23. The aforementioned compound is of formula (4a): 【Transformation 8】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

24. The aforementioned compound is of formula (5): 【Chemistry 9】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

25. The compound has formula (5a): 【Chemistry 10】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

26. The aforementioned compound is of formula (6): 【Chemistry 11】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

27. The aforementioned compound is of formula (6a): 【Chemistry 12】 The method according to claim 16, wherein the compound is the same or a stereoisomer thereof.

28. n is 1, R １ -D, and R ２ａ and R ２ｂ Each of these is -CH ３ The method according to any one of claims 16, 18, 20, 22, 24, and 26.

29. R ２ａ ga-CH ３ , and R ２ｂ ga-CH ２ The method according to any one of claims 16 to 27, wherein the method is D.

30. R ２ａ and R ２ｂ Each of these is -CH ２ The method according to any one of claims 16 to 27, wherein the method is D.

31. n is 1, R １ -D, and R ２ａ and R ２ｂ Each of these is -CH ２ The method according to claim 16, which is D.

32. Deuterated ETBR antagonists BQ-788-B 【Chemistry 13】 BQ-788-A 【Chemistry 14】 and BQ-788-C 【Chemistry 15】 The method according to any one of claims 1 to 31, or selected from stereoisomers thereof.

33. The aforementioned ETBR antagonist is BQ-788-B: 【Chemistry 16】 The method according to any one of claims 1 to 32, or a stereoisomer thereof.

34. The method according to any one of claims 1 to 33, wherein the ETBR antagonist is in a pharmaceutically acceptable excipient comprising dimethyl sulfoxide (DMSO).

35. The method according to any one of claims 1 to 34, wherein the CAR-expressing immune cells are CAR-T cells or CAR-NK cells.

36. The method according to claim 35, wherein the CAR-expressing immune cells are CAR-T cells.

37. The method according to any one of claims 1 to 36, wherein the cancer is ETBR-related cancer.

38. The method according to any one of claims 1 to 37, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, esophageal cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, cervical cancer, colon cancer, and head and neck cancer.

39. The method according to any one of claims 1 to 9 and 13 to 32, wherein the cancer is a HER2-expressing cancer.

40. The method according to claim 39, wherein the HER2-expressing cancer is a HER2+ cancer.

41. The method according to claim 39, wherein the HER2-expressing cancer is a HER2-low-expressing cancer.

42. The method according to any one of claims 39 to 41, wherein the HER2-expressing cancer is selected from the group consisting of breast cancer, gastric cancer, esophageal cancer, ovarian cancer, endometrial cancer, bladder cancer, lung cancer, cervical cancer, colon cancer, and head and neck cancer.

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