Methods for Treating Cardiac Injury

Abstract

A method for treating cardiac damage in a subject is disclosed, comprising administering a therapeutically effective amount of angiotensin II to the subject. Also disclosed is a method for treating catecholamine-related cardiac damage in a subject, comprising administering a therapeutically effective amount of angiotensin II to the subject. The subject may have cardiac damage or may be at risk of having cardiac damage. The present invention provides a method for treating (including alleviating and preventing) cardiac damage in a subject, comprising administering angiotensin II to the subject.

Description

[Technical Field]

[0001] background Vasodilatory shock is a life-threatening state of circulatory failure that leads to hypotension, tissue hypoperfusion, progressive organ failure, and an increased risk of death. Patients with vasodilatory shock are typically treated with vasopressor drugs, such as catecholamines and / or vasopressin, which act as vasoconstrictors and increase blood pressure. [Background technology]

[0002] Catecholamines are monoamine neurotransmitters containing a catechol and a side-chain amine. Catecholamines include epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Catecholamines produce general physiological changes that prepare the body for physical activity (fight or flight response). Some typical effects include increases in heart rate, blood pressure, blood glucose levels, and general responses of the sympathetic nervous system. Vasopressin is a polypeptide hormone that causes vascular and other smooth muscle contraction and antidiuresis. Its chemical name is cyclo(1-6)L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-L-arginyl-L-glycinate. Administration of both catecholamines and vasopressin has been shown to be effective in maintaining mean arterial pressure at desired levels in many patients. However, administration of both catecholamines and vasopressin can have toxic effects.

[0003] Excessive exposure to catecholamines can adversely affect the function of several organs, including the heart. (Dunser MW, et al., "Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress," J Intensive Care Med 24:293-316, 2009). Human patients exposed to exogenous norepinephrine administered as a therapeutic intervention have been reported to develop myocardial lesions. Histologic lesions indicative of catecholamine-related cardiotoxicity (e.g., contraction band necrosis, myocyte lysis, and mononuclear cell infiltration) have been demonstrated in nearly all patients who died from septic shock and may correlate with the total duration and dose of catecholamine therapy. Baroldi G. et al., "Myocardial contraction bands. Definition, quantification, and significance in forensic pathology," Int J Legal Med 115:142-151, 2001; Schmittinger CA, et al., "Histologic pathologies of the myocardium in septic shock: A prospective observational study," Shock 39:329-335, 2013. Similarly, excessive exposure to vasopressin can lead to cardiac damage in some patients. Indrambarya et al., "Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice," Crit. Care, 13(3), R98, 2009.

[0004] Angiotensin II is a naturally occurring peptide hormone approved by the FDA for use as a vasoconstrictor to increase blood pressure in adults with sepsis or other distributive shock. GIAPREZA® Package Insert, December 2021.

[0005] Angiotensin II has only been studied in patients with catecholamine-refractory vasodilatory shock. In the double-blind ATHOS-3 clinical trial (Angiotensin II for the Treatment of High-Output Shock Clinical Trial), angiotensin II was administered to adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy; 70% of patients reached a MAP of 75 mmHg or greater at 3 hours without altering baseline vasopressor therapy or achieved an increase in MAP of 10 mmHg or greater (p<0.0001), compared with only 23% of subjects receiving placebo.

[0006] Chawla describes a method of administering angiotensin II to a subject having high-output shock and undergoing treatment with a catecholamine, where the angiotensin II is effective in increasing or maintaining the subject's mean arterial pressure (MAP), thereby reducing the dose of catecholamine. U.S. Patent No. 9,220,745. Chawla provides no evidence that administration of angiotensin II would be able to sufficiently reduce catecholamine administration to an extent sufficient to treat (e.g., alleviate, prevent) any catecholamine-related toxicity or, in particular, cardiac damage associated with catecholamine administration. The Surviving Sepsis Campaign's guidelines committee, which publishes guidelines reflecting global consensus on the treatment of sepsis and septic shock, consistently recommends the use of norepinephrine (a catecholamine) as the first-line treatment for hypotension in adults with septic shock, followed by vasopressin as the second-line treatment. Because both catecholamines and vasopressin are known to cause cardiac damage, the primary first- and second-line vasopressor agents are medications with a demonstrated ability to cause cardiac damage. Subarachnoid hemorrhage (SAH) is a serious cerebrovascular condition, resulting not only from the effects of the initial hemorrhage but also from the complication of delayed cerebral ischemia (DCI). Vasopressor-promoted hypertension is often initiated to prevent DCI, but it is unknown which vasopressor is most effective in improving outcomes. Williams, et al., "Vasopressor treatment and mortality following nontraumatic subarachnoid hemorrhage: a nationwide electronic health record analysis," Neurosurg. Focus, 48(5):E4 (May 1, 2020). During hypertension therapy for symptomatic vasospasm after SAH, norepinephrine is typically used to achieve target blood pressure. Concerns exist regarding the worsening of vasospasm with norepinephrine. Delayed cerebral ischemia (DCI) after SAH poses a significant challenge to treating physicians. The current standard of care consists of hypertension-directed measures to ensure preservation of cerebral blood flow to risk areas. Zeiler, et al., "Norepinephrine as a potential aggravator of symptomatic cerebral vasospasm: Two cases and Argument for Milrinone therapy," Case Reports in Critical Care (2014). [Prior art documents] [Patent documents]

[0007] [License 1] U.S. Patent No. 9,220,745 [Non-licensed literature]

[0008] [Non-licensed Document 1] Dunser MW, et al., "Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress," J Intensive Care Med 24:293-316, 2009 [Non-licensed Document 2] Baroldi G. et al., "Myocardial contraction bands. Definition, quantification and significance in forensic pathology," Int J Legal Med 115:142-151, 2001 [Non-licensed Document 3] Schmittinger CA, et al, "Histologic pathologies of the myocardium in septic shock: A prospective observational study," Shock 39:329-335, 2013 [Non-licensed Document 4] Indrambarya et al., "Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice," Crit. Care, 13(3), R98, 2009 [Non-licensed Document 5] Williams, et al., "Vasopressor treatment and mortality following nontraumatic subarachnoid hemorrhage: a nationwide electronic health record analysis," Neurosurg. Focus, 48(5):E4 (May 1, 2020) [Non-patent document 6] Zeiler, et al., "Norepinephrine as a potential aggravator of symptomatic cerebral vasospasm: Two cases and Argument for Milrinone therapy," Case Reports in Critical Care (2014) Summary of the Invention [Means for solving the problem]

[0009] Therefore, there is a need in the art for methods for preventing or treating cardiac damage, including cardiac damage caused by catecholamines and / or vasopressin.Furthermore, there is a need in the art for methods for increasing blood pressure in patients who need to maintain a hypertensive state.The present invention describes such methods.

[0010] A brief overview The present invention provides methods for treating (including alleviating and preventing) cardiac damage in a subject, comprising administering angiotensin II to the subject, wherein the subject may be at risk and in need of a vasopressor to increase blood pressure (e.g., a catecholamine and / or vasopressin, i.e., one or more catecholamines alone, in combination with vasopressin, or vasopressin alone), or the subject may be at risk and currently taking a vasopressor to increase blood pressure (e.g., a catecholamine and / or vasopressin).

[0011] The present invention includes a method for treating cardiac injury in a subject who has cardiac injury.In such a method, administering angiotensin II can act to alleviate cardiac injury.Also disclosed is a method for treating cardiac injury in a subject who does not have cardiac injury but is at risk of suffering from cardiac injury.In such a method, administering angiotensin II can act to prevent cardiac injury.

[0012] Disclosed is a method for treating cardiac damage in a subject, wherein the subject has catecholamine-related cardiac damage or has the risk of cardiac damage, for example, due to the use of exogenous hypertensive drugs, such as catecholamines and / or vasopressin.Disclosed is also a method for treating cardiac damage in a subject, wherein the cardiac damage or the risk of cardiac damage is related to the subject who is currently receiving or will be receiving a hypertensive drug, such as catecholamines and / or vasopressin.Disclosed is also a method for treating cardiac damage in a subject, wherein the cardiac damage or the risk of cardiac damage is related to the subject who has a medical condition that causes the endogenous release of catecholamines.In such a method, the subject may have cardiac damage, or the subject may not have cardiac damage, but is at risk of suffering from cardiac damage.

[0013] In some embodiments, the subject treated according to the disclosed methods is being treated with or needs to be treated with a vasopressor, such as a catecholamine and / or vasopressin, to increase and maintain blood pressure. In some embodiments, the administration of the vasopressor, such as a catecholamine and / or vasopressin, is discontinued or adjusted, for example, the dose and / or dosing frequency of the vasopressor (e.g., catecholamine) is reduced. In some embodiments, the administration of angiotensin II allows the discontinuation and / or reduction of the vasopressor administration, thereby achieving treatment (e.g., alleviation and / or prevention) of cardiac damage.

[0014] In other aspects, the disclosed methods may include determining whether a subject to be treated is suffering from cardiac damage, for example, as a result of administering catecholamines and / or vasopressin. In some embodiments, the present invention provides methods for identifying cardiac damage based on the presence of blood troponin. In other embodiments, the present invention provides methods in which administering angiotensin II prevents an increase in blood troponin and / or prevents cardiac damage and / or prevents (e.g., alleviates) the worsening of cardiac damage. In yet other embodiments, the present invention provides methods in which administering angiotensin II to a subject reduces blood troponin and / or reduces cardiac damage. In some aspects, administering angiotensin II can reduce or eliminate the administration of catecholamines and / or vasopressin.

[0015] Also disclosed are methods of treatment, wherein administration of angiotensin II to a subject suffering from cardiac injury provides a clinically significant decrease in blood troponin after administration of angiotensin II.

[0016] Additional advantages of the disclosed methods and compositions will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practicing the disclosed methods and compositions. The advantages of the disclosed methods and compositions will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description The disclosed methods may be more readily understood by reference to the following detailed description of specific embodiments and examples contained therein, as well as the drawings and accompanying description.

[0018] It is to be understood that the disclosed methods are not limited to particular synthetic methods, particular analytical techniques, or particular reagents, unless otherwise specified, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. A.Definition

[0019] It is understood that the disclosed methods and compositions are not limited to the particular methodology, protocols, and reagents described, as these may vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which will be limited only by the appended claims.

[0020] It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a dose" includes a plurality of such doses, a reference to "the dose" is a reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth.

[0021] As used herein, the term "subject" or "patient" refers to any living organism that may be administered with the composition of the present invention, for example, for experimental, diagnostic, and / or therapeutic purposes.Typical subjects include animals (e.g., mammals, such as non-human primates, and humans; birds; domestic animals or livestock, such as cats, dogs, sheep, goats, cows, horses, and pigs; laboratory animals, such as mice, rats, and guinea pigs; rabbits; fish; reptiles; zoo animals and wild animals).Typically, "subject" is a mammal, such as animals including humans and primates.

[0022] As used herein, the term "treating" refers to partially or completely alleviating, ameliorating, mitigating, alleviating, preventing, delaying the onset, inhibiting, or slowing the progression of, reducing the severity of, and / or reducing the incidence of cardiac damage. Treatment may be administered to subjects who do not exhibit signs of cardiac damage and / or to subjects who exhibit signs of cardiac damage.

[0023] As used herein, "preventing" refers to minimizing the chance that a subject who is susceptible to developing a disease, disorder, or condition (e.g., cardiac damage, catecholamine-related cardiac damage) will develop the disease, disorder, or condition. For example, as used herein, preventing can refer to minimizing the chance that a subject who is at risk of cardiac damage will develop it.

[0024] As used herein, the terms "administering" and "administration" refer to any method of providing a disclosed composition (e.g., angiotensin II) to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, nasal, topical, intravaginal, ocular, auricular, intracerebral, rectal, sublingual, buccal, and parenteral administration, including injectables such as intravenous, intraarterial, intramuscular, and subcutaneous administration. Administration can be continuous or intermittent. In various embodiments, the preparations can be administered therapeutically; i.e., to treat an existing disease or condition. In further various embodiments, the preparations can be administered prophylactically; i.e., to prevent a disease or condition.

[0025] The phrase "cardiac injury" refers to a condition involving myocardial injury or damage. Myocardial injury can be acute or chronic. A broad spectrum of myocardial injury exists. Myocardial injury can be associated with acute myocardial ischemia (e.g., rupture of atherosclerotic plaque with thrombosis) or acute myocardial ischemia due to an imbalance in oxygen supply / demand (e.g., reduced myocardial perfusion or increased myocardial oxygen demand). Other causes of myocardial injury include cardiac conditions (e.g., heart failure, myocarditis, cardiomyopathy, takotsubo syndrome, coronary revascularization, catheter ablation, defibrillator shock, cardiac contusion) or systemic conditions (e.g., sepsis, chronic kidney disease, stroke, pulmonary embolism, infiltrative disease, chemotherapy, critical illness, strenuous exercise). Myocardial injury includes myocardial necrosis, myocardial infarction (heart attack), cardiomyopathy, myocardial ischemia, and blunt cardiac injury.

[0026] The phrase "troponin" refers to the troponin complex, which includes three regulatory proteins: troponin C, troponin I, and troponin T. Troponin I (also referred to as cardiac troponin I, cTnI) and troponin T (also referred to as cardiac troponin T, cTnT) are used as diagnostic and prognostic indicators of myocardial injury. The diagnostic criteria for elevated troponin suggestive of myocardial infarction are currently set by the WHO at a threshold of 2 μg or greater.

[0027] Cardiac troponin T and I are measured by immunoassay. Roche Diagnostics distributes its proprietary cTnT, and various diagnostic companies make cTnI immunoassays available on many different immunoassay platforms. The 99th percentile cutoff for cardiac troponin T (cTnT) is 0.01 ng / mL. Reference ranges for high-sensitivity troponin T are normal <14 ng / L, borderline 14-52 ng / L, and elevated >52 ng / L.

[0028] The term "angiotensin II" can refer to Asp-Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO: 1], also known as 5-isoleucine angiotensin II. SEQ ID NO: 1 is an octapeptide that occurs naturally in humans and other species, such as equines and pigs. The isoleucine can be replaced by valine to form 5-valine angiotensin II, Asp-Arg-Val-Tyr-Val-His-Pro-Phe [SEQ ID NO: 2]. Other angiotensin II analogs, such as [Asn1-Phe4]-angiotensin II [SEQ ID NO: 3], the hexapeptide Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO: 4], the nonapeptide Asn-Arg-Val-Tyr-Tyr-Val-His-Pro-Phe [SEQ ID NO: 5], [Asn'-Ileu5-Ileu8]-angiotensin II [SEQ ID NO: 6], [Asn1-Ileu5-Ala8]-angiotensin II [SEQ ID NO: 7], and [Asn1-diiodoTyr4-Ileu5]-angiotensin II [SEQ ID NO: 8], may also be used. Angiotensin II may be synthesized, for example, by solid-phase peptide synthesis to incorporate modifications, such as C-terminal amidation. A C-terminal acetate group may also be added. Fragments of angiotensin II that retain the activity of angiotensin II may also be used, such as angiotensin II fragments lacking the N-terminal amino acids or C-terminal amino acids (e.g., Ang III, Ang IV, and Ang II(1-7)). The term "angiotensin II," unless further specified, is intended to refer to any of these various forms, as well as combinations thereof.

[0029] The term "catecholamine," as used herein, refers to dopamine, norepinephrine, epinephrine, phenylephrine, ephedrine, and prodrugs, structural analogs, or derivatives thereof, which induce similar physiological effects in humans, e.g., increasing mean arterial pressure in healthy human subjects. In certain embodiments, the catecholamine may be dopamine, norepinephrine, epinephrine, ephedrine, or phenylephrine.

[0030] The term "pharmaceutically acceptable salt" as used herein refers to a salt suitable for use within the scope of sound medical judgment. The physicochemical and biological properties of a drug substance are significantly affected by its salt form. The selection of a particular salt formulation is based on numerous factors, such as the chemical properties of the drug substance, the intended dosage form, pharmacokinetics, and pharmacodynamics. The selection of a counterion is based on the degree of ionization of the acidic or basic functional groups present in the drug. Consideration is given to the absence of excessive toxicity, irritation, allergic responses, etc., associated with contact of the drug substance with human and animal tissues, and to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977, and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCR, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-hydroxyethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine.

[0031] The "effective amount" of a composition is the amount of the composition that is sufficient to provide beneficial effects to the subject to which the composition is administered.The phrase "therapeutically effective amount" as used herein refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset, prevent the progression, inhibit, reduce, or reverse) a disease or condition, including alleviating the symptoms of such a disease.For example, a therapeutically effective amount of angiotensin II is an amount that is sufficient to increase blood pressure and / or treat cardiac damage.Such therapeutic effects on cardiac damage can be determined by assessing the effect on cardiac troponin levels.

[0032] "Optionally" or "as needed" means that the subsequently described event, circumstance, or material may or may not occur, or may or may not exist, and that the description includes cases where the event, circumstance, or material occurs or exists, as well as cases where it does not occur or exist.

[0033] "Vasopressor" means a drug that tends to increase low blood pressure (e.g., an antihypotensive, vasopressor, or pressor), for example, by causing vasoconstriction of blood vessels. Vasopressors include, for example, catecholamines, vasopressin, and combinations thereof.

[0034] Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed and considered to be specifically contemplated and disclosed, it ranges from one particular value and / or to the other particular value, unless the context specifically dictates otherwise. Similarly, when values ​​are expressed as approximations by use of the antecedent "about," it will be understood that the particular value forms another specific contemplated embodiment, which should be considered disclosed, unless the context specifically dictates otherwise. It will be further understood that the endpoints of each range are significant both in relation to the other endpoint and independently of the other endpoint, unless the context specifically dictates otherwise. Finally, it should be understood that all individual values ​​and subranges of values ​​falling within an expressly disclosed range are also specifically contemplated and considered to be disclosed, unless the context specifically dictates otherwise. The foregoing applies regardless of whether any or all of these embodiments are specifically disclosed in a particular instance.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed methods and compositions belong. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present methods and compositions, particularly useful methods, devices, and materials are as described. Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. No reference is admitted to constitute prior art. The discussion of references states the assertions of their authors, and the applicant reserves the right to challenge the accuracy and pertinence of the cited documents. It will be clearly understood that although several publications are referenced herein, such reference does not constitute an admission that any of these documents form part of the common general knowledge in the art.

[0036] Throughout this description and the claims, the word "comprise" and variations of that word, such as "comprising" and "comprises," mean "including but not limited to," and are not intended to exclude, for example, other additives, components, integers, or steps. In particular, in methods defined as including one or more steps or operations, each step is specifically contemplated to include those recited (unless the step includes a limiting term, such as "consisting of"), and each step is not intended to exclude, for example, other additives, components, integers, or steps not recited in that step. B. Angiotensin II Therapy

[0037] The methods of the present invention involve the administration of angiotensin II to a subject.

[0038] Angiotensin II is a peptide hormone naturally produced by the body. Angiotensin II regulates blood pressure through vasoconstriction and sodium reabsorption. The hemodynamic effects of angiotensin II administration have been the subject of numerous clinical studies, demonstrating significant effects on systemic and renal blood flow (Harrison-Bernard, LM, The renal renin-angiotensin system. Adv Physiol Educ., (2009) 33(4): pp. 270-74). Angiotensin II is a hormone produced by the renin-angiotensin-aldosterone system (RAAS), which modulates blood pressure through regulation of vascular smooth muscle tone and extracellular fluid homeostasis. Angiotensin II mediates its effects on the vasculature by inducing vasoconstriction and sodium retention. In addition to its systemic effects, angiotensin II has pronounced effects on renal efferent arterioles, maintaining glomerular filtration when blood flow is reduced. Angiotensin II also regulates sodium reabsorption in the kidney by stimulating the Na+ / H+ exchanger in the proximal tubule and inducing the release of aldosterone and vasopressin (Harrison-Bernard, LM, The renal renin-angiotensin system. Adv. Physiol. Educ., 2009. 33(4): p. 270-4).

[0039] The angiotensin II sequences used in the compositions and methods disclosed herein may be homologous to the angiotensin II sequences described above. In certain embodiments, the invention includes isolated, synthetic, or recombinant amino acid sequences that are at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, and / or 8. Any such variant sequences may be used in place of angiotensin II as described in the preceding paragraph.

[0040] In some embodiments, angiotensin II may be selected from 5-valine angiotensin II, 5-valine angiotensin II amide, 5-L-isoleucine angiotensin II, and 5-L-isoleucine angiotensin II amide, or pharmaceutically acceptable salts thereof, which are preferably manufactured under current good manufacturing practice (cGMP). In some embodiments, the composition may contain different forms of angiotensin II, such as a mixture of hexapeptide and nonapeptide angiotensin, in different percentages. The composition containing angiotensin II may be suitable for parenteral administration, such as injection or intravenous infusion.

[0041] Similarly, angiotensin II therapeutic agents may be used as any suitable salt, deprotected form, acetylated form, deacetylated form, and / or prodrug form of the above-mentioned peptides, including pegylated forms of the peptides or conjugates disclosed in U.S. Pat. No. 7,666,408 (incorporated by reference). The term "prodrug" refers to any precursor compound capable of generating or releasing the above-mentioned peptides under physiological conditions. Such prodrugs may be larger peptides that are selectively cleaved to form the peptides of the present invention. For example, in some embodiments, the prodrug may be angiotensin I or a homolog thereof, which may yield angiotensin II through the action of certain endogenous or exogenous enzymes. Additional prodrugs include peptides with protected amino acids, e.g., having protecting groups on one or more carboxylic acid and / or amino groups. Suitable protecting groups for amino groups are benzyloxycarbonyl, t-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (FMOC), formyl, and acetyl or acyl groups. Suitable protecting groups for carboxylic acid groups are esters, such as benzyl esters or t-butyl esters. The present invention also contemplates the use of angiotensin II and / or precursor peptides having amino acid substitutions, deletions, and additions, including standard D and L amino acids and modified amino acids, such as amidated and acetylated amino acids, while maintaining the therapeutic activity of the basic peptide sequence at a pharmacologically useful level.

[0042] In some embodiments, angiotensin II is L-aspartyl-L-arginyl-L-valyl-L-tyrosyl-L-isoleucyl-L-histidyl-L-prolyl-L-phenylalanine acetate, molecular formula: C 50 H 71 N 13 O 12 (C2H4O2) n; (n = number of acetate molecules; theoretical n = 3), average molecular weight: 1046.2 (as free base). C. Therapeutically Effective Doses

[0043] Generally, angiotensin II increases blood pressure. A composition containing an angiotensin therapeutic agent (e.g., angiotensin II) may be administered at a dose and / or rate sufficient to increase blood pressure and / or achieve a target blood pressure. For example, the patient may be connected to a monitor that provides continuous, periodic, or occasional measurement of mean arterial pressure (MAP).

[0044] In some embodiments, a composition comprising an angiotensin therapeutic agent (e.g., angiotensin II) may be administered at a dose and / or rate sufficient to achieve a reduction in the dose of another vasopressor agent, e.g., a catecholamine, that is being or will be administered, while still achieving a desired increase in blood pressure and / or target blood pressure. For example, the amount of catecholamine being administered may be reduced or eliminated, thereby reducing or avoiding cardiac damage or the risk of cardiac damage associated with catecholamine administration.

[0045] In some embodiments, a composition comprising an angiotensin therapeutic agent (e.g., angiotensin II) may be administered at a dose and / or rate sufficient to treat cardiac injury, e.g., prevent the occurrence of cardiac injury, prevent an increase in cardiac injury, prevent an increase in the level of a biomarker associated with cardiac injury, and / or maintain and / or reduce the level of a biomarker associated with cardiac injury. In some embodiments, a composition comprising an angiotensin therapeutic agent (e.g., angiotensin II) may be administered at a dose and / or rate sufficient to achieve a target blood pressure and to treat cardiac injury.

[0046] The dose of angiotensin II may be administered at a rate of about 0.25 ng / kg / min to about 100 ng / kg / min, e.g., about 5 ng / kg / min to about 20 ng / kg / min, about 10 ng / kg / min to about 50 ng / kg / min, about 20 ng / kg / min to about 40 ng / kg / min, about 0.25 ng / kg / min to about 20 ng / kg / min, about 0.25 ng / kg / min to about 10 ng / kg / min, about 0.25 ng / kg / min to about 5 ng / kg / min, about 1.25 ng / kg / min to about 20 ng / kg / min, about 1.25 ng / kg / min to about 10 ng / kg / min, or about 1.25 ng / kg / min to about 5 ng / kg / min. In embodiments of the invention, the dose is about 0.25 ng / kg / min, about 0.5 ng / kg / min, about 1 ng / kg / min, about 1.25 ng / kg / min, about 1.5 ng / kg / min, about 2 ng / kg / min, about 2.5 ng / kg / min, about 3 ng / kg / min, about 3.5 ng / kg / min, about 4 ng / kg / min, about 4.5 ng / kg / min, about 5 ng / kg / min, about 5.5 ng / kg / min, about 6 ng / kg / min, about 7.5 ng / kg / min or about 10 ng / kg / min.

[0047] In some embodiments of the present invention, the starting dose of angiotensin II is 20 ng / kg / min, which is administered, for example, via continuous intravenous infusion. The dose of angiotensin II may be gradually increased and / or decreased as needed to achieve or maintain target blood pressure and / or to treat cardiac damage. Titration of the dose of angiotensin II may allow for simultaneous reduction in the dose of a vasopressor, such as a catecholamine and / or vasopressin. In some embodiments, titration of the dose of angiotensin II allows for the elimination of the administration of a vasopressor, such as a catecholamine and / or vasopressin.

[0048] The dose of angiotensin II may be titrated up by increments up to 15 ng / kg / min, with the dose not exceeding 80 ng / kg / min during the first 3 hours of treatment. The dose may also be tapered up to 15 ng / kg / min every 5 to 15 minutes. The maintenance dose should not exceed 40 ng / kg / min. Doses as low as 1.25 ng / kg / min may be used.

[0049] Doses may be administered over a duration of about 0.25 hours to about 120 hours, e.g., about 1 hour to about 7 hours, 2 hours to about 6 hours, or about 3 hours to about 5 hours. The treatment regimen may be initiated, for example, within 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, or 72 hours after the onset of acute symptoms. D. Mode of Administration

[0050] Angiotensin II may be administered by any convenient route, for example, intravenously (using either a bolus or constant infusion), intramuscularly, intraosseously, subcutaneously, or by inhalation.

[0051] The compositions of the present invention may be administered in a variety of conventional ways. In some embodiments, the compositions of the present invention are suitable for parenteral administration. These compositions may be administered, for example, intraperitoneally, intravenously, intraarterially, intrarenally, or intrathecally. In some embodiments, the compositions of the present invention are injected intravenously. Those skilled in the art will understand that the method of administering the therapeutically effective substance formulation or composition of the present invention will depend on factors such as the age, weight, and physical condition of the patient being treated, as well as the disease or condition being treated. Therefore, those skilled in the art will be able to individually select the optimal administration method for each patient. E. Target Population

[0052] The methods of the present invention involve administering angiotensin II to a subject. The subject may have hypotension, normotensive, or hypertension, depending on the clinical background and disease state.

[0053] The subject is typically at risk (e.g., hypotensive) and requires treatment with a vasopressor to raise the subject's blood pressure, for example, one or more catecholamines, vasopressin, or a combination thereof.Such a subject may be a critically ill patient with shock, for example, high-output shock or distributive shock (septic shock), or shock due to cardiac arrest or cardiogenic shock.The subject may also have acute kidney injury, hepatorenal syndrome, and / or variceal hemorrhage.The subject may also require intentional hypertension, or may require vasopressor therapy to increase blood pressure, for example, to increase intracranial perfusion pressure to avoid delayed cerebral ischemia.For example, the subject may have suffered from stroke, subarachnoid hemorrhage, or traumatic brain injury.

[0054] One aspect of the present invention is a method comprising administering to a subject, wherein the subject has cardiac injury. A subject with cardiac injury may be identified based on the presence of a detectable amount of troponin in the blood. A subject with cardiac injury may also be identified based on the presence of an elevated amount of troponin in the blood. Diagnosis of cardiac injury is often based on detecting the presence of troponin I (cardiac troponin I, designated cTnI) and / or troponin T (cardiac troponin T, designated cTnT). Myocardial injury is defined as present when blood levels of cTn increase above the 99th percentile upper reference limit (URL). Injury may be acute, as evidenced by newly detected dynamic rising and / or falling patterns of cTn values ​​above the 99th percentile URL, or chronic, in the setting of persistently elevated cTn levels. Cardiac troponin T and I are measured by immunoassay. Roche Diagnostics distributes its proprietary cTnT, and various diagnostic equipment companies make cTnI immunoassays available on many different immunoassay platforms. The 99th percentile cutoff for cardiac troponin T (cTnT) is 0.01 ng / mL. Reference ranges for high-sensitivity troponin T include normal values ​​below 14 ng / L, borderline values ​​between 14 and 52 ng / L, and elevated values ​​above 52 ng / L. Subjects with cardiac injury may also be identified based on echocardiography, for example, by the presence of regional wall motion abnormalities (RWMA) observed on an echocardiogram. Alternatively, subjects with cardiac injury may be identified based, for example, on a combination of the presence of elevated cardiac troponin and the presence of regional wall motion abnormalities (RWMA).

[0055] In some embodiments, a subject with cardiac damage may be a subject whose cardiac damage is associated with, e.g., a result of, being administered or having been administered catecholamines (e.g., catecholamine-induced cardiac damage) and / or vasopressin. Such a subject may be administered or have been administered catecholamines and / or vasopressin at a dose level that causes cardiac damage, or may be administered or have been administered catecholamines and / or vasopressin for a period of time sufficient to cause cardiac damage. In yet other embodiments, a subject with cardiac damage may be a subject who is in need of, or is in need of, administration of catecholamines and / or vasopressin at a dose level that causes cardiac damage, or may be administered or have been administered catecholamines and / or vasopressin for a period of time sufficient to cause cardiac damage.

[0056] In some embodiments, the subject has sepsis or other distributive shock and has cardiac damage. For example, the subject may have been administered catecholamines and / or vasopressin to treat sepsis or other distributive shock, and may have catecholamine-induced and / or vasopressin-induced cardiac damage.

[0057] Another aspect of the present invention is a method comprising administering to a subject without cardiac injury.A subject without cardiac injury may be identified based on the absence of detectable amounts of troponin in blood.A subject without cardiac injury may also be identified based on the absence of elevated levels of troponin in blood, for example, the absence of troponin I (cardiac troponin I, referred to as cTnI) and / or troponin T (cardiac troponin T, referred to as cTnT), or the subject has a blood level of cTn that is less than or equal to the 99th percentile upper reference limit (URL).A subject without cardiac injury may also be identified based on echocardiography, for example, by the absence of regional wall motion abnormalities (RWMA) observed in echocardiograms.Alternatively, a subject with cardiac injury may be identified based on, for example, the combination of the absence of elevated cardiac troponin and the absence of regional wall motion abnormalities (RWMA).

[0058] In some embodiments, a subject without cardiac injury may be at risk for cardiac injury. A subject at risk for cardiac injury may be a subject with cardiac risk factors, including hypertension, diabetes, heart failure, coronary artery disease, atrial fibrillation / flutter, and cerebrovascular disease, old age, smoking history, a history of lung or kidney disease, and / or a diagnosis of COVID-19. Alternatively, or in addition, a subject at risk for cardiac injury may be a subject who is or has been administered catecholamines. Such a subject may be administered or may have been administered a vasopressor, such as catecholamines and / or vasopressin, at a dose level that causes cardiac injury, or may be administered or may have been administered a vasopressor, such as catecholamines and / or vasopressin, for a period long enough to cause cardiac injury. In still other embodiments, a subject at risk for cardiac damage may be a subject in need of catecholamines and / or vasopressin, in need of being administered catecholamines and / or vasopressin at a dose level that causes cardiac damage, or may be or have been administered catecholamines and / or vasopressin for a period of time long enough to cause cardiac damage.

[0059] In some embodiments, the subject without cardiac injury is one with sepsis or other distributive shock. For example, the subject may have been administered catecholamines and / or vasopressin to treat sepsis or other distributive shock, and may be at risk of having catecholamine-induced and / or vasopressin-induced cardiac injury.

[0060] In some embodiments, the subject with or without cardiac injury is the subject with medical condition that causes the endogenous release of catecholamines.For example, the subject can have neuroendocrine tumor (for example, pheochromocytoma), neuroblastoma, convulsive status epilepticus, cerebrovascular disease (for example, ischemic stroke, cerebral hemorrhage and subarachnoid hemorrhage), or the subject can experience a surge in catecholamines after craniotomy. F. Methods Related to the Administration of Angiotensin II

[0061] One aspect of the present invention is a method of treatment, comprising administering a therapeutically effective dose of angiotensin II to a subject with cardiac damage. In some aspects, the therapeutically effective dose of angiotensin II prevents further progression of cardiac damage. In such embodiments, the prevention of cardiac damage may be achieved by reducing the subject's need for treatment with other hypertensive drugs, such as catecholamines and / or vasopressin.

[0062] Another aspect of the present invention is a method of treatment, comprising administering a therapeutically effective dose of angiotensin II to a subject having cardiac damage, wherein the subject's cardiac damage is associated with the administration of catecholamines and / or vasopressin. In some embodiments, the therapeutically effective amount of angiotensin II prevents further progression of cardiac damage, for example, by allowing a reduction in catecholamine and / or vasopressin dose while maintaining an acceptable blood pressure in the subject.

[0063] In some embodiments, the subject is receiving standard care treatment with a hypertensive drug, such as a catecholamine (e.g., epinephrine, norepinephrine, dopamine, phenylephrine, ephedrine) and / or vasopressin, at or before the time when angiotensin II is administered.These drugs may be administered at a dose equivalent to at least 0.05mcg / kg / min of catecholamine, norepinephrine (norepinephrine equivalent dose, NED).Typical equivalent doses are as follows: [Table 4]

[0064] In some embodiments, the dose of a vasopressor, e.g., a catecholamine (e.g., epinephrine, norepinephrine, dopamine, phenylephrine, ephedrine) and / or vasopressin, at or before the time angiotensin II is administered exceeds the typical equivalent dose.

[0065] In some aspects, the subject has previously been administered a conventional vasopressor (e.g., a catecholamine and / or vasopressin), and the method may further include adjusting (e.g., decreasing or tapering) the dose of the conventional vasopressor (e.g., a catecholamine and / or vasopressin) compared to the dose the subject was taking before administration of angiotensin II. Such adjustment may involve decreasing the amount of catecholamine being administered or may involve decreasing the dosing frequency of the catecholamine. In some embodiments, administration of the catecholamine is discontinued upon administration of angiotensin II.

[0066] In other embodiments, the subject requires treatment with a vasopressor (e.g., catecholamines and / or vasopressin), and the method may include administering angiotensin II in the absence of catecholamines and / or vasopressin to achieve a target blood pressure. The method may also include administering angiotensin II in combination with a conventional vasopressor (e.g., catecholamines and / or vasopressin), and then adjusting (e.g., reducing, tapering, or discontinuing) the dose of the conventional vasopressor (e.g., catecholamines and / or vasopressin) compared to the starting dose of the conventional vasopressor. Additionally or alternatively, the method may include administering angiotensin II in combination with a conventional vasopressor (e.g., catecholamines and / or vasopressin), and then adjusting (e.g., increasing or tapering) the dose of angiotensin II. Titration of the dose of angiotensin II and / or the conventional vasopressor may be performed to achieve desired blood pressure control and to treat or prevent cardiac damage.

[0067] In some embodiments, methods involving administration of angiotensin II are effective to increase the subject's blood pressure to a mean arterial pressure (MAP) of about 65 mmHg or greater, or about 70 mmHg or greater, or about 75 mmHg or greater, or about 80 mmHg, or about 85 mmHg or greater, or about 90 mmHg or greater, or about 95 mmHg or greater, or about 100 mmHg or greater. In yet other embodiments, methods comprising administration of angiotensin II are effective to raise a subject's blood pressure to a mean arterial pressure (MAP) of greater than about 65 mmHg and to reduce the dose of catecholamines and / or vasopressin required to maintain a MAP of greater than about 65 mmHg to the equivalent of less than about 0.05-0.10 mcg / kg / min of NED, or are effective to raise a subject's blood pressure to a mean arterial pressure (MAP) of greater than about 70 mmHg and to reduce the dose of catecholamines and / or vasopressin required to maintain a MAP of greater than about 70 mmHg to the equivalent of less than about 0.05-0.10 mcg / kg / min of NED, or are effective to raise a subject's blood pressure to a mean arterial pressure (MAP) of greater than about 75 mmHg. or is effective to raise a subject's blood pressure to a mean arterial pressure (MAP) of greater than about 80 mmHg and reduce the dose of catecholamines and / or vasopressin required to maintain a MAP above about 80 mmHg to the equivalent of about 0.05 to 0.10 mcg / kg / min of less than NED; or is effective to raise a subject's blood pressure to a mean arterial pressure (MAP) of greater than about 85 mmHg and reduce the dose of catecholamines and / or vasopressin required to maintain a MAP above about 85 mmHg to the equivalent of about 0.05 to 0.10 mcg / kg / min of less than NED.or is effective to increase the subject's blood pressure to a mean arterial pressure (MAP) of greater than about 90 mmHg and reduce the dose of catecholamines and / or vasopressin required to maintain a MAP of greater than about 90 mmHg to the equivalent of less than about 0.05-0.10 mcg / kg / min NED, or is effective to increase the subject's blood pressure to a mean arterial pressure (MAP) of greater than about 95 mmHg and reduce the dose of catecholamines and / or vasopressin required to maintain a MAP of greater than about 95 mmHg to the equivalent of less than about 0.05-0.10 mcg / kg / min NED. Effective to reduce the dose of catecholamines and / or vasopressin required to maintain a mean arterial pressure (MAP) above about 100 mmHg to the equivalent of less than about 0.05 to 0.10 mcg / kg / min of NED, or effective to increase the subject's blood pressure to a mean arterial pressure (MAP) above about 100 mmHg and effective to reduce the dose of catecholamines and / or vasopressin required to maintain a MAP above about 100 mmHg to the equivalent of less than about 0.05 to 0.10 mcg / kg / min of NED.

[0068] In some embodiments, the subject's blood troponin level is elevated upon administration of angiotensin II (e.g., high-sensitivity cardiac troponin, troponin I, etc. is increased). In some aspects of these embodiments, administering a therapeutically effective amount of angiotensin II to a subject prevents a further increase in the amount of blood troponin in the subject. In other aspects of these embodiments, administering a therapeutically effective amount of angiotensin II to a subject reduces a further increase in the amount of blood troponin in the subject (e.g., compared to an increase that would be observed in the absence of angiotensin administration). In still other embodiments, administering a therapeutically effective amount of angiotensin II to a subject has the effect of reducing the amount of blood troponin in the subject.

[0069] Thus, in some aspects of the present invention, the method further comprises determining the subject's blood troponin level before administration of angiotensin II. In some aspects of the present invention, the method further comprises determining the subject's blood troponin level after administration of angiotensin II. In other aspects of the present invention, the method further comprises comparing the subject's blood troponin level before administration of angiotensin II with the subject's blood troponin level after administration of angiotensin II. Furthermore, in some aspects, the method comprises adjusting the dose of angiotensin II based on the subject's blood pressure, catecholamine utilization, and blood troponin level determined after administration of angiotensin II. For example, in some embodiments, the dose of angiotensin II is titrated up when the blood troponin level determined after administration of angiotensin II exceeds a predetermined threshold level, 99% URL. Other considerations for adjusting the dose of angiotensin II may include the subject's blood pressure and catecholamine utilization.

[0070] In some embodiments, a subject with catecholamine-related cardiac damage has elevated blood troponin levels (e.g., elevated high-sensitivity cardiac troponin, troponin I, etc.) upon administration of angiotensin II. In some aspects of these embodiments, administering a therapeutically effective amount of angiotensin II to a subject prevents a further increase in the amount of blood troponin in the subject. In other aspects of these embodiments, administering a therapeutically effective amount of angiotensin II to a subject reduces a further increase in the amount of blood troponin in the subject (e.g., compared to an increase that would be observed in the absence of angiotensin administration). In still other embodiments, administering a therapeutically effective amount of angiotensin II to a subject has the effect of reducing the amount of blood troponin in the subject.

[0071] Thus, in some aspects of the invention, the method further comprises determining the subject's blood troponin level before administration of angiotensin II. In some aspects of the invention, the method further comprises determining the subject's blood troponin level after administration of angiotensin II. In other aspects of the invention, the method further comprises comparing the subject's blood troponin level before administration of angiotensin II with the subject's blood troponin level after administration of angiotensin II. Furthermore, in some aspects, the method comprises adjusting the dose of angiotensin II based on the subject's blood pressure, catecholamine dose, and blood troponin level determined after administration of angiotensin II. For example, in some embodiments, the dose of angiotensin II is increased or titrated if the blood troponin level determined after administration of angiotensin II exceeds or equals the amount of troponin present before administration of angiotensin II.

[0072] In other embodiments, the methods of the present invention include each of the following methods: 1. A method for treating cardiac damage in a subject, comprising administering a therapeutically effective amount of angiotensin II to a subject in need thereof. 2. The method of item 1, wherein the subject has cardiac damage. 3. The method according to any one of items 1 to 2, wherein the subject has increased blood troponin. 4. The method of item 3, wherein the blood troponin is high-sensitivity cardiac troponin (hs-cTn). 5. The method according to item 3 or 4, wherein the blood troponin is troponin I. 6. The method of any one of items 3 to 5, wherein the increased blood troponin is a blood troponin level above the 99th percentile upper reference value. 7. The method of any one of items 1 to 6, wherein the subject has a wall motion abnormality determined by echocardiography. 8. The method according to any one of items 1 to 7, wherein the therapeutically effective amount of angiotensin II prevents further progression of the cardiac damage. 9. The method of item 1, wherein the subject does not have cardiac damage. 10. The method of items 1 and 9, wherein the administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin that needs to be administered to the subject. 11. The method according to any one of items 9 to 10, wherein the therapeutically effective amount of angiotensin II prevents cardiac damage. 12. A method for treating catecholamine-related or vasopressin-related cardiac damage in a subject, comprising administering angiotensin II to a subject in need thereof. 13. The method of claim 12, wherein the subject has cardiac damage. 14. The method of claim 13, wherein the subject has increased blood troponin. 15. The method of item 14, wherein the blood troponin is high-sensitivity cardiac troponin (hs-cTn). 16. The method according to any one of items 14 to 15, wherein the blood troponin is troponin I. 17. The method of any one of items 14 to 16, wherein the increased blood troponin is a blood troponin level above the 99th percentile upper reference value. 18. The method according to any one of items 12 to 17, wherein the administration of angiotensin II is effective in preventing an increase in blood troponin. 19. The method of any one of items 1 to 18, wherein the subject is taking or in need of taking a catecholamine, vasopressin, or a combination thereof. 20. The method according to item 19, wherein the administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin being administered. 21. The method according to item 19, wherein the administration of angiotensin II allows for the interruption of the administration of catecholamines and / or vasopressin. 22. The method of any one of items 12 to 21, wherein the therapeutically effective amount of angiotensin II prevents further progression of the cardiac damage. 23. A method for treating catecholamine-related or vasopressin-related cardiac damage in a subject without cardiac damage, comprising administering angiotensin II to a subject in need thereof. 24. The method of item 23, wherein the subject is taking or needs to take a catecholamine, vasopressin, or a combination thereof. 25. The method of any one of items 23 to 24, wherein the therapeutically effective amount of angiotensin II prevents catecholamine-related and / or vasopressin-related cardiac damage. 26. A method according to any one of items 23 to 25, wherein the administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin that needs to be administered to the subject. 27. A method for treating catecholamine-related and / or vasopressin-related cardiac damage in a subject who has previously been administered a catecholamine and / or vasopressin, comprising the steps of (1) administering angiotensin II to the subject, and (2) discontinuing the administration of the catecholamine and / or vasopressin. 28. A method for treating catecholamine-related cardiac damage, comprising administering angiotensin II to a subject receiving an initial dose of catecholamines and / or vasopressin, the method comprising the steps of: (1) administering angiotensin II to the subject; and (2) administering catecholamines and / or vasopressin to the subject at a dose lower than the initial dose. 29. The method of item 27 or 28, wherein the subject is suffering from cardiac damage. 30. The method of item 29, wherein the angiotensin II prevents further progression of the cardiac damage. 31. The method of item 27 or 28, wherein the subject does not suffer from cardiac damage. 32. The method of claim 31, wherein the angiotensin II prevents cardiac damage. 33. The method of any one of items 28 to 32, wherein two or more doses of catecholamine and / or vasopressin are administered to the subject after the initial dose. 34. The method according to item 33, wherein each dose of catecholamine and / or vasopressin is lower than the previous dose. 35. The method of any one of items 28 to 45, wherein the angiotensin II and the catecholamine and / or vasopressin are administered as separate compositions. 36. The method of any one of items 28 to 45, wherein the angiotensin II and the catecholamine and / or vasopressin are administered as a single composition. 37. The method of any one of items 12 to 36, wherein the catecholamine is norepinephrine. 38. The method of any one of items 1 to 37, further comprising measuring the amount of troponin present in a sample obtained from the subject before administering angiotensin II. 39. The method of any one of items 1 to 37, further comprising: (1) measuring the amount of troponin present in a sample obtained from the subject before administering angiotensin II; and (2) measuring the amount of troponin present in a sample obtained from the subject after administering angiotensin II. 40. The method of item 39, wherein angiotensin II can be increased in a subject if the amount of troponin present in a sample obtained from the subject after administering angiotensin II is greater than or equal to the amount of troponin present in a sample obtained from the subject before administering angiotensin II. 41. The method of any one of items 1 to 40, wherein said administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin being administered, resulting in a clinically significant decrease in blood troponin. 42. A method of increasing blood pressure in a subject in need of maintenance of a hypertensive condition, comprising administering angiotensin II. 43. The method of item 42, wherein said increase in blood pressure requires increasing intracranial perfusion pressure. 44. The method of any one of items 42 to 43, wherein the subject has suffered from a stroke, subarachnoid hemorrhage, or traumatic brain injury. 45. The method of any one of items 1 to 44, wherein angiotensin II is administered via intravenous infusion. 46. ​​The method of item 45, wherein angiotensin II is administered via continuous intravenous infusion. 47. The method of any one of paragraphs 1 to 46, wherein angiotensin II is administered at a rate of about 1 ng / kg / min to 20 ng / kg / min. 48. The method of item 47, further comprising gradually increasing the rate to a maximum rate of about 30 ng / kg / min to about 40 ng / kg / min. 49. The method of any one of items 1 to 48, wherein the administration of angiotensin II is effective to increase the subject's blood pressure to a mean arterial pressure (MAP) of about 65 mmHg or greater. 50. The method of any one of items 1 to 49, wherein the administration of angiotensin II is effective to increase the subject's blood pressure to a mean arterial pressure (MAP) of greater than about 65 mmHg and is effective to reduce the dose of catecholamines and / or vasopressin required to maintain a MAP greater than about 65 mmHg to the equivalent of less than about 0.05-0.10 mcg / kg / min NED. G. Combination Therapy

[0073] Disclosed is a method for treating cardiac injury in a subject, comprising administering a therapeutically effective amount of angiotensin II alone or in combination with a catecholamine. In some embodiments, angiotensin II and a catecholamine are administered as separate compositions. In other embodiments, angiotensin II and a catecholamine are formulated together. In various methods of the present invention, angiotensin II and a catecholamine may be administered together or independently, intravenously, intramuscularly, subcutaneously, or by inhalation. Separate administration of angiotensin II and a catecholamine is particularly advantageous in methods in which the dose of angiotensin II is titrated to achieve target blood pressure, thereby achieving a reduction and / or elimination of catecholamine administration, and treating cardiac injury. H. Pharmaceutical Compositions

[0074] Suitable formulations (pharmaceutical compositions) for administering a drug (e.g., angiotensin II and / or one or more catecholamines and / or vasopressin) will depend on the mode of administration. For example, formulations adapted for parenteral administration may comprise a sterile aqueous preparation, preferably isotonic with the blood of the recipient. This aqueous preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. Preparations may also be sterile injectable solutions or suspensions as diluents or solvents, such as solutions containing exemplary acceptable diluents such as mannitol, 1,3-butanediol, water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils may also be used as solvents or suspending media. Bland fixed oils may also be used, including synthetic mono- or diglycerides and fatty acids, such as oleic acid. Most of the agents described herein are commercially available and readily available from commercial sources.

[0075] The pharmaceutical compositions of the present invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient together with a therapeutically active substance of the present invention (e.g., angiotensin II) and does not destroy the pharmacological activity of the therapeutically active substance. The term "pharmaceutically acceptable" refers to a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient. The characteristics of the carrier will depend on the route of administration. The term "excipient" refers to an additive that is not a pharmaceutically active ingredient in a formulation or composition. One of ordinary skill in the art will understand that the selection of any one excipient may affect the selection of any other excipient. For example, the selection of a particular excipient may preclude the use of one or more additional excipients because the combination of excipients would produce undesirable effects. One of ordinary skill in the art will be able to empirically determine which, if any, excipients to include in the compositions of the present invention. Excipients of the present invention may include, but are not limited to, cosolvents, solubilizers, buffers, pH adjusters, bulking agents, surfactants, encapsulating agents, tonicity agents, stabilizers, protectants, and viscosity modifiers. In some embodiments, it may be beneficial to include a pharmaceutically acceptable carrier in the compositions of the present invention.

[0076] In some embodiments, it may be beneficial to include a solubilizer in the compositions of the present invention.Solubilizers may be useful for increasing the solubility of any of the components of formulations or compositions, including therapeutically effective substances (e.g., angiotensin II and / or catecholamines) or excipients.The solubilizers described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary solubilizers that may be used in the compositions of the present invention.In certain embodiments, solubilizers include, but are not limited to, ethyl alcohol, tert-butyl alcohol, polyethylene glycol, glycerol, methylparaben, propylparaben, polyethylene glycol, polyvinylpyrrolidone, and any pharmaceutically acceptable salt and / or combination thereof.

[0077] In some embodiments, it may be beneficial to adjust the pH of the composition by including a pH adjusting agent in the composition of the present invention. Modifying the pH of a formulation or composition may, for example, have a beneficial effect on the stability or solubility of a therapeutically effective substance, or may be useful in preparing a formulation or composition suitable for parenteral administration. pH adjusting agents are well known in the art. Therefore, the pH adjusting agents described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary pH adjusting agents that may be used in the composition of the present invention. pH adjusting agents may include, for example, acids and bases. In some embodiments, pH adjusting agents include, but are not limited to, acetic acid, hydrochloric acid, phosphoric acid, sodium hydroxide, sodium carbonate, and combinations thereof.

[0078] The pH of the compositions of the present invention may be any pH that provides the formulation or composition with desired properties. Desirable properties may include, for example, stability of the therapeutically active substance (e.g., angiotensin II), enhanced retention of the therapeutically active substance compared to compositions at other pHs, and improved filtration efficiency. In some embodiments, the pH of the compositions of the present invention may be about 3.0 to about 9.0, e.g., about 5.0 to about 7.0. In certain embodiments, the pH of the compositions of the present invention may be 5.5±0.1, 5.6±0.1, 5.7±0.1, 5.8±0.1, 5.9±0.1, 6.0±0.1, 6.1±0.1, 6.2±0.1, 6.3±0.1, 6.4±0.1, or 6.5±0.1.

[0079] In some embodiments, it may be beneficial to buffer pH by including one or more buffers in the composition.In certain embodiments, the buffer may have a pKa of, for example, about 5.5, about 6.0, or about 6.5.Those skilled in the art will understand that suitable buffers may be selected for inclusion in the compositions of the present invention based on their pKa and other properties.Buffers are well known in the art.

[0080] Therefore, the buffer solution described herein is not intended to constitute an exhaustive list, but merely serves as the exemplary buffer solution that can be used in the compositions of the present invention.In certain embodiments, the buffer solution can be one or more of: Tris, TrisHCl, potassium phosphate, sodium phosphate, sodium citrate, sodium ascorbate, the combination of sodium phosphate and potassium phosphate, Tris / TrisHCl, sodium bicarbonate, arginine phosphate, arginine hydrochloride, histidine hydrochloride, cacodylate, succinate, 2-(N-morpholino)ethanesulfonic acid (MES), maleate, bis-trismethane, phosphate, carbonate, and any pharmaceutically acceptable salt, and / or any combination thereof.

[0081] In some embodiments, it may be beneficial to include a surfactant in the compositions of the present invention. Surfactants generally reduce the surface tension of liquid compositions. This can provide beneficial properties, such as improved ease of filtration. Surfactants may also act as emulsifiers and / or solubilizers. Surfactants are well known in the art. Therefore, the surfactants described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary surfactants that may be used in the compositions of the present invention. Surfactants that may be included include, but are not limited to, sorbitan esters, such as polysorbates (e.g., polysorbate 20 and polysorbate 80), lipopolysaccharides, polyethylene glycols (e.g., PEG 400 and PEG 3000), poloxamers (i.e., pluronic®), ethylene oxides and polyethylene oxides (e.g., Triton® X-100), saponins, phospholipids (e.g., lecithin), and combinations thereof.

[0082] In some embodiments, it may be beneficial to include an isotonicity agent in the compositions of the present invention. The tonicity of a liquid composition is an important consideration, for example, when administering the composition to a patient via parenteral administration. Therefore, isotonicity agents may be used to aid in the preparation of a formulation or composition suitable for administration. Isotonicity agents are well known in the art. Therefore, the isotonicity agents described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary isotonicity agents that may be used in the compositions of the present invention. Isotonicity agents may be ionic or nonionic, and include, but are not limited to, inorganic salts, amino acids, carbohydrates, sugars, sugar alcohols, and carbohydrates. Exemplary inorganic salts may include sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate. An exemplary amino acid is glycine. Exemplary sugars may include sugar alcohols, such as glycerol, propylene glycol, glucose, sucrose, lactose, and mannitol.

[0083] In some embodiments, it may be beneficial to include a stabilizer in the compositions of the present invention. The stabilizer helps to increase the stability of the therapeutically effective substance in the compositions of the present invention. This can occur, for example, by reducing degradation or preventing aggregation of the therapeutically effective substance. Without wishing to be bound by theory, mechanisms for enhancing stability may include isolating the therapeutically effective substance from the solvent or inhibiting free radical oxidation of the anthracycline compound. Stabilizers are well known in the art. Therefore, the stabilizers described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary stabilizers that may be used in the compositions of the present invention. Stabilizers may include, but are not limited to, emulsifiers and surfactants.

[0084] The compositions of the present invention may be administered in a variety of conventional ways. In some embodiments, the compositions of the present invention are suitable for parenteral administration. These compositions may be administered, for example, intraperitoneally, intravenously, intraarterially, intrarenally, or intrathecally. In some embodiments, the compositions of the present invention are injected intravenously. Those skilled in the art will understand that the method of administering the therapeutically effective substance formulation or composition of the present invention will depend on factors such as the age, weight, and physical condition of the patient being treated, as well as the disease or condition being treated. Therefore, those skilled in the art will be able to individually select the optimal administration method for each patient.

[0085] The pharmaceutical compositions are sterile and can be sterilized by conventional sterilization techniques or sterile filtration. Aqueous solutions may be packaged for use as is or lyophilized; lyophilized preparations are encompassed by the present disclosure and may be combined with a sterile aqueous carrier prior to administration. The pH of the pharmaceutical composition will typically be between 3 and 11 (e.g., between about 5 and 9) or between 6 and 8 (e.g., between about 7 and 8). Compositions obtained in solid form may be packaged as multiple single-dose units, each containing a fixed amount of the above-mentioned drug in a sealed package, for example, tablets or capsules. Compositions in solid form may also be packaged in flexible dispensers, for example, squeezable tubes designed for topically applicable creams or ointments.

[0086] The following examples are included to illustrate the invention, but the invention should not be understood as being limited to these exemplified embodiments. [Example]

[0087] A prospective observational study was conducted to evaluate the efficacy, safety, and feasibility of using angiotensin II as the primary vasopressor agent for treating critically ill patients with vasodilatory shock.

[0088] Study Population: A total of 40 patients receiving angiotensin II were matched with 80 control patients receiving conventional vasopressors (norepinephrine, vasopressin, metaraminol, epinephrine, or a combination of these). Patients were adult patients (≥18 years) presenting with vasodilatory shock, admitted to the intensive care unit, receiving vasopressor therapy for <24 hours, and with in situ arterial, central venous, and bladder catheters. The mean age of the patients was 63 years (SD 14 years), two-thirds were male, and the median APACHE III score was 65 (IQR 49-80). Baseline characteristics of the patient cohort are shown in Table 1. No significant differences were observed between groups in terms of demographics, clinical characteristics, disease severity, baseline vasopressor type and dose, physiological parameters, or biochemistry. [Table 1-1] [Table 1-2] Abbreviations: ACE, angiotensin-converting enzyme; ANZROD, Australian and New Zealand mortality risk; ARB, angiotensin receptor blocker; CRRT, continuous renal replacement therapy; ICU, intensive care unit; IQR, interquartile range; INR, international normalized ratio; RAAS, renin-angiotensin-aldosterone system; SD, standard deviation;

[0089] Vasodilatory shock was diagnosed as a cardiac index of 2.3 L / min / m in the presence of adequate fluid resuscitation and preservation of cardiac output. 2 Patients were defined as having a mean arterial pressure of <65 mmHg, either based on a central venous oxygen saturation of 70% or greater, or a clinician's judgment. Patients were excluded from the study if they had renal failure (i.e., chronic hemodialysis, peritoneal dialysis, or a baseline estimated glomerular filtration rate of 15 mL / min / 1.73 m). 2Patients were excluded if they had a history of thrombosis (<10 years) or if they had been diagnosed with arterial thrombosis (acute coronary syndrome, ischemic stroke, or mesenteric ischemia) or venous thrombosis (deep vein thrombosis or pulmonary embolism) within the previous 6 months. Patients were also excluded if they had a contraindication to chemical thromboprophylaxis within the first 48 hours. The mean age of the patients was 63 (SD 14) years, two-thirds were male, and the median APACHE III score was 65 (IQR 49-80). No significant differences were observed between the angiotensin II and conventional vasopressor groups in terms of demographics, clinical characteristics, disease severity, type and use of vasopressor medications, physiological parameters, or biochemistry.

[0090] Intervention: Angiotensin II infusion was initiated and delivered at a dose between 5 and 10 ng / kg / min. The dose was adjusted every 5 minutes according to a protocolized titration scheme to achieve a mean arterial pressure (MAP) of 65 mmHg or greater (dose range: 1.25 to 40 ng / kg / min). During the titration period, the infusion of other vasopressors was gradually reduced and, if possible, discontinued. If MAP was insufficient despite the maximum dose of angiotensin II, additional vasopressors were prescribed at the clinician's discretion. The use of vasopressin (dose range: 0.01 to 0.04 IU / min) was preferred over norepinephrine (dose range: 0 to 40 mcg / min). Angiotensin II was continued until shock resolved, death occurred, or for a maximum of 7 days. If ongoing vasopressor therapy was required after this time, norepinephrine was used.

[0091] Controls: The control group included critically ill patients with vasodilatory shock who received conventional vasopressors. To address confounding by indication and other sources of bias arising from the use of nonrandomized data, propensity scores were imputed for the likelihood of treatment with angiotensin II, and patients in the intervention group were matched to their closest counterparts in the control group without replacement using a 1:2 ratio. Propensity scores were generated based on age, sex, APACHE II score, serum creatinine level, type and dose of vasopressor at enrollment, and the time from ICU admission and initiation of any vasopressor to initiation of angiotensin II.

[0092] Primary Outcome: The primary outcome was peak serum creatinine level on day 7, censored at time of ICU discharge. Serum creatinine levels were measured every 4 to 8 hours via a blood gas analyzer using an enzymatic method (ABL800 FLEX, Radiometer Medical). Patients who received CRRT during the first 7 days were not included in the primary analysis.

[0093] Secondary Outcomes: Secondary renal outcomes included new or progressive AKI, creatinine trajectory, need for CRRT, time to CRRT weaning, and occurrence of major adverse renal events at day 7 (MAKE7). New AKI was defined and staged according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria when serum creatinine increased to 26.5 μmol / L or greater at 48 hours or when serum creatinine increased by 50% or greater from baseline within 7 days. Progressive AKI was defined as at least one KDIGO stage increase in AKI severity. MAKE7 was a composite of death, dialysis dependence, and a sustained 50% increase in serum creatinine level. Other secondary outcomes included all-cause mortality (ICU, in-hospital, 28th and 90th days), physiological parameters (heart rate [HR], systolic blood pressure [SBP], mean arterial pressure [MAP], diastolic blood pressure [DBP], cardiac index [CI], and serum troponin elevation (defined as TnI level ≥ 20 ng / L)), acid-base balance (pH, bicarbonate, lactate); gas exchange (P:F ratio and P a CO2); urine output and fluid balance; and the occurrence of any thromboembolic events (deep vein thrombosis, pulmonary embolism) during hospitalization.

[0094] Statistical Analysis: Baseline characteristics were expressed as frequencies (n, %), means (standard deviation, SD), or medians (interquartile range, IQR), as determined by data type. Between-group comparisons were performed using the chi-square test, unpaired t-test, and Wilcoxon rank-sum test, as appropriate. Mean peak serum creatinine levels were compared by unpaired t-test; the incidence and stage of new or progressive AKI were explored using the chi-square test. Multilevel mixed-effects linear regression analysis was used to evaluate serum creatinine over time, physiological, and biochemical parameters. Competing risk regression analysis was used to examine time to weaning from CRRT (death was treated as a competing risk). Death was examined by Kaplan-Meier and logistic regression. Patients were examined by age subgroups (dichotomized at 65 years), sepsis (yes / no), and previous exposure to RAAS inhibitors. Analyses were performed using Stata MP 16.0. A two-sided p value of less than 0.05 was considered statistically significant.

[0095] Catecholamine exposure: Over the first 7 days, patients in the angiotensin II group received less norepinephrine (305 vs. 446 mcg per patient) and epinephrine (12 vs. 31 mcg per patient) than patients in the control group. Total vasopressin administration was higher in patients receiving angiotensin II than in control patients (0.35 vs. 0.27 IU per patient), while metaraminol administration was similar between groups (80 vs. 85 mcg per patient). Angiotensin II initiation was associated with a decrease in catecholamine exposure over the first 24 hours, most pronounced in the first 6 hours of therapy. Time to vasopressor discontinuation was similar in patients receiving angiotensin II and conventional vasopressors (45.5 vs. 42.5 hours, p=0.84).

[0096] Renal Results: Peak serum creatinine levels within the first 7 days were not different in patients receiving angiotensin II compared with matched controls (median 128 vs. 126 μmol / L, p = 0.78, Table 2). The median number of hours between intervention initiation and creatinine peak was 8.5 (4.5 to 37.5) in patients receiving angiotensin II compared with 9 (IQR 3 to 29) in the control group. No differences were observed in the incidence of new or progressive AKI or peak AKI stage at day 7. The course of serum creatinine levels over the first 7 days was similar between groups (β coefficient 2.96, 95% CI -24.64 to 30.55). There was no significant reduction in the risk of MAKE7 in patients receiving angiotensin II compared with controls (48% vs. 30%, p = 0.07). The incidence of new CRRT and the time to new CRRT initiation were also similar. Time to withdrawal was not different in patients receiving CRRT (SHR 1.38, 95% CI 0.60 to 3.17).

[0097] Nonrenal outcomes: Median ICU stay (median 3.5 vs. 3.8 days, p = 0.49) and median hospital stay (median 13.8 vs. 11.8 days, p = 0.31) did not differ between patients receiving angiotensin II or conventional vasopressors. ICU mortality was significantly reduced in patients receiving angiotensin II, but the difference between in-hospital and 28-day mortality was not statistically significant (Table 2). The number of days alive and free of renal replacement therapy at 28 and 90 days also did not differ significantly. However, the incidence of troponin elevation was lower in patients receiving angiotensin II. In terms of arterial and venous thromboembolic complications, the incidence of deep vein thrombosis and pulmonary embolism was similar. No significant differences were observed between the groups in terms of hemodynamic, respiratory, metabolic, or fluid parameters. [Table 2-1] [Table 2-2] AKI, acute kidney injury; CRRT, continuous renal replacement therapy; ICU, intensive care unit; IQR, interquartile range; RRT, renal replacement therapy; SD, standard deviation. Elevated serum troponin was defined as a troponin I level ≥20 ng / L.

[0098] Subgroup analysis: The results of the subgroup analysis are shown in Table 3. No qualitative differences were observed in the primary outcome analysis across subgroups of age (dichotomized at 65 years) or cause of shock (sepsis vs. non-sepsis). Patients who received an ACE inhibitor or angiotensin II receptor blocker before hospital admission who also received angiotensin II had lower peak serum creatinine levels compared with those receiving control vasopressors, whereas peak serum creatinine was higher in patients who did not receive renin-angiotensin aldosterone system inhibitors if they received angiotensin II compared with controls (p-value for interaction 0.03). [Table 3]

[0099] Key findings: Peak serum creatinine levels over the first 7 days were not different in patients receiving angiotensin II compared with conventional vasopressors. Creatinine trajectories, incidence of AKI and MAKE7, and need for and duration of CRRT were comparable. ICU mortality was lower in patients receiving angiotensin II, but 28-day and 90-day mortality rates were similar. The incidence of troponin elevation was lower in the angiotensin II group compared with controls, but there was no difference in the rate of thromboembolic complications. Findings did not differ by age or presence of sepsis; patients with previous exposure to RAAS inhibitors who received angiotensin II had lower peak serum creatinine than those receiving control vasopressors.

[0100] Serum Troponin Measurement: The incidence of elevated serum troponin in patients in the angiotensin II group was 3 (8%, n = 40), while the incidence of elevated serum troponin in patients in the control group was 18 (22%, n = 80). This clinically important difference was also statistically significant (P value 0.04). The results demonstrate that administration of angiotensin II is effective in reducing the incidence of elevated troponin levels in patients compared with patients receiving conventional vasopressor medications (norepinephrine, vasopressin, metaraminol, epinephrine).

Claims

1. A method of treating cardiac injury in a subject, comprising administering a therapeutically effective amount of angiotensin II to a subject in need thereof.

2. The method of claim 1 , wherein the subject has cardiac damage.

3. The method according to any one of claims 1 to 2, wherein the subject has increased blood troponin.

4. The method of claim 3, wherein the blood troponin is high-sensitivity cardiac troponin (hs-cTn).

5. The method according to claim 3 or 4, wherein the blood troponin is troponin I.

6. 6. The method of any one of claims 3 to 5, wherein the increased blood troponin is a blood troponin level above the 99th percentile upper reference value.

7. The method of any one of claims 1 to 6, wherein the subject has a wall motion abnormality determined by echocardiography.

8. The method of any of claims 1 to 7, wherein the therapeutically effective amount of angiotensin II prevents further progression of the cardiac damage.

9. The method of claim 1 , wherein the subject does not have cardiac damage.

10. 10. The method of claims 1 and 9, wherein the administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin that needs to be administered to the subject.

11. The method of any of claims 9 to 10, wherein the therapeutically effective amount of angiotensin II prevents cardiac damage.

12. A method for treating catecholamine-related or vasopressin-related cardiac damage in a subject, comprising administering angiotensin II to a subject in need thereof.

13. 13. The method of claim 12, wherein the subject has cardiac damage.

14. 14. The method of claim 13, wherein the subject has elevated blood troponin.

15. The method of claim 14, wherein the blood troponin is high-sensitivity cardiac troponin (hs-cTn).

16. The method according to any one of claims 14 to 15, wherein the blood troponin is troponin I.

17. 17. The method of any one of claims 14 to 16, wherein the increased blood troponin is a blood troponin level above the 99th percentile upper reference value.

18. 18. The method of any one of claims 12 to 17, wherein said administration of angiotensin II is effective to prevent an increase in blood troponin.

19. 19. The method of any one of claims 1 to 18, wherein the subject is taking or is in need of taking a catecholamine, vasopressin, or a combination thereof.

20. 20. The method of claim 19, wherein said administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin being administered.

21. 20. The method of claim 19, wherein said administration of angiotensin II allows for the interruption of administration of catecholamines and / or vasopressin.

22. 22. The method of any one of claims 12 to 21, wherein the therapeutically effective amount of angiotensin II prevents further progression of the cardiac damage.

23. A method for treating catecholamine-related or vasopressin-related cardiac damage in a subject without cardiac damage, comprising administering angiotensin II to a subject in need thereof.

24. 24. The method of claim 23, wherein the subject is taking or is in need of taking a catecholamine, vasopressin, or a combination thereof.

25. 25. The method of any one of claims 23-24, wherein the therapeutically effective amount of angiotensin II prevents catecholamine-related and / or vasopressin-related cardiac damage.

26. 26. The method of any one of claims 23 to 25, wherein said administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin that needs to be administered to said subject.

27. A method for treating catecholamine-related and / or vasopressin-related cardiac damage in a subject who has previously been administered catecholamines and / or vasopressin, comprising the steps of: (1) administering angiotensin II to the subject; and (2) discontinuing the administration of the catecholamines and / or vasopressin.

28. A method for treating catecholamine-related cardiac damage, comprising administering angiotensin II to a subject receiving an initial dose of catecholamines and / or vasopressin, the method comprising the steps of: (1) administering angiotensin II to the subject; and (2) administering catecholamines and / or vasopressin to the subject at a dose lower than the initial dose.

29. 29. The method of claim 27 or 28, wherein the subject is suffering from cardiac damage.

30. 30. The method of claim 29, wherein the angiotensin II prevents further progression of the cardiac damage.

31. 29. The method of claim 27 or 28, wherein the subject does not suffer from cardiac damage.

32. 32. The method of claim 31, wherein the angiotensin II prevents cardiac damage.

33. 33. The method of any one of claims 28 to 32, wherein two or more doses of catecholamine and / or vasopressin are administered to the subject after the initial dose.

34. 34. The method of claim 33, wherein each dose of catecholamine and / or vasopressin is lower than the previous dose.

35. 46. ​​The method of any one of claims 28 to 45, wherein the angiotensin II and the catecholamine and / or vasopressin are administered as separate compositions.

36. 46. ​​The method of any one of claims 28 to 45, wherein the angiotensin II and the catecholamine and / or vasopressin are administered as a single composition.

37. 37. The method of any one of claims 12 to 36, wherein the catecholamine is norepinephrine.

38. 38. The method of any one of claims 1 to 37, further comprising measuring the amount of troponin present in a sample obtained from the subject prior to administering angiotensin II.

39. 38. The method of any one of claims 1 to 37, further comprising: (1) measuring the amount of troponin present in a sample obtained from the subject before administering angiotensin II; and (2) measuring the amount of troponin present in a sample obtained from the subject after administering angiotensin II.

40. 40. The method of claim 39, wherein angiotensin II can be increased in a subject if the amount of troponin present in a sample obtained from the subject after administering angiotensin II is greater than or equal to the amount of troponin present in a sample obtained from the subject before administering angiotensin II.

41. 41. The method of any one of claims 1 to 40, wherein said administration of angiotensin II can reduce the amount of catecholamines and / or vasopressin being administered, resulting in a clinically significant reduction in blood troponin.

42. 1. A method of increasing blood pressure in a subject in need of maintenance of a hypertensive condition, comprising administering angiotensin II.

43. 43. The method of claim 42, wherein said increase in blood pressure requires increasing intracranial perfusion pressure.

44. 44. The method of any one of claims 42-43, wherein the subject has suffered a stroke, subarachnoid hemorrhage, or traumatic brain injury.

45. 45. The method of any one of claims 1 to 44, wherein angiotensin II is administered via intravenous infusion.

46. 46. ​​The method of claim 45, wherein the angiotensin II is administered via continuous intravenous infusion.

47. 47. The method of any one of claims 1 to 46, wherein angiotensin II is administered at a rate of about 1 ng / kg / min to 20 ng / kg / min.

48. 48. The method of claim 47, further comprising gradually increasing the rate to a maximum rate of about 30 to about 40 ng / kg / min.

49. 49. The method of any one of claims 1-48, wherein the administration of angiotensin II is effective to raise the blood pressure of the subject to a mean arterial pressure (MAP) of about 65 mmHg or greater.

50. 50. The method of any one of claims 1-49, wherein the administration of angiotensin II is effective to raise the blood pressure of the subject to a mean arterial pressure (MAP) of greater than about 65 mmHg and is effective to reduce the dose of catecholamines and / or vasopressin required to maintain a MAP above about 65 mmHg to the equivalent of less than about 0.05-0.10 mcg / kg / min NED.

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