Angiotensin II alone or in combination for treatment of hypotension

Abstract

In particular, the present invention relates to a method comprising administering to a subject having a high output shock and undergoing treatment with catecholamine in a dose equivalent to at least about 0.2 mcg / kg / min noradrenaline, an angiotensin II in a dose effective to raise the blood pressure of the subject to a mean arterial pressure (MAP) of about 65 mm Hg or more, and which is effective to reduce the dosage of catecholamine required to maintain about 65 mm Hg of MAP to equivalent to about 0.05 to 0.2 mcg / kg / min of noradrenaline or less, or to equivalent to about 0.05 mcg / kg / min of noradrenaline or less.

Description

[0001] This application is a divisional application of an invention patent application with an application date of December 18, 2014, application number 201480075899.1, and invention name “Angiotensin II alone or in combination for the treatment of hypotension”.

[0002] This application claims the benefit of the filing dates of U.S. Provisional Application No. 61 / 917,576, filed December 18, 2013, and U.S. Provisional Application No. 61 / 955,706, filed March 19, 2014, both of which are incorporated herein by reference in their entireties.

[0003] Sequence Listing

[0004] This application contains a sequence listing filed electronically in ST.26 format and incorporated herein by reference in its entirety. A copy of the ST.26 format sequence listing created on November 25, 2024 is named BY24IM55095FFPC-CNsequencelisting.xml and is 12770 bytes in size. Background Art

[0005] Critically ill patients with shock requiring vasopressors are at high risk for death. High-output shock (also called distributive shock) is the most common form of shock and is often caused by sepsis [1]. When treating shock with vasopressors, two major classes of vasopressors are in the armamentarium of critical care medicine: catecholamines and vasopressin peptides [1]. Currently, no specific type of vasopressor (e.g., norepinephrine, vasopressin, dopamine) has been shown to improve outcomes compared to another vasopressor [2]. All vasopressors have limitations and potential side effects. Patients treated for shock with catecholamines often develop rapid resistance to medication, limiting the utility of these drugs, and high doses of catecholamines can cause direct cardiotoxicity [3]. The potential toxicity of catecholamines has recently been demonstrated in a randomized clinical trial of patients with septic shock treated with norepinephrine [4]. In this study, beta-adrenergic blockade with esmolol was shown to improve survival in these patients by reducing heart rate. Therefore, non-inotrope or non-chronotrope vasopressors can be used in patients with shock. Such a vasopressor is vasopressin, which is most commonly used as an adjuvant to catecholamines. Vasopressin has been shown to improve outcomes in patients with less severe septic shock but is toxic at high doses (e.g., cardiac and mesenteric ischemia) and interacts with hydrocortisone [5]. In high-output shock, the patient is critically ill and cannot maintain mean arterial pressure without vasopressors. High-output shock is defined as a cardiovascular sequential organ function assessment (SOFA) score greater than or equal to 3 or 4 and a cardiac index >2.4 L / min / BSA1.73m2

[10] In high-output shock, if blood pressure cannot be maintained, it is invariably fatal. In patients who are unable to maintain their blood pressure, the addition of “rescue” vasopressors to this setting may be useful.

[0006] A subgroup of patients with shock (including high-output shock and other types of shock) are catecholamine-resistant. That is, they do not respond to treatment (do not show an appropriate increase in blood pressure) with catecholamine doses equivalent to at least 0.2 mcg / kg / min of norepinephrine.

[0007] Angiotensin II (sometimes referred to herein as ATII) is a naturally occurring peptide hormone with endocrine, autocrine, paracrine and cytocrine hormone effects. It is a potent direct vasoconstrictor that constricts both arteries and veins and increases blood pressure [6]. It has a circulation half-life of approximately 30 seconds, but at the same time in tissues, its half-life is as long as 15-30 minutes. ATII increases the secretion of ADH and ACTH, and can enhance the action of sympathetic nerves through direct effects on postganglionic sympathetic nerve fibers. It also acts on the adrenal cortex, causing it to release aldosterone [6,7]. High doses of angiotensin II have been reported to cause adverse side effects, including, for example, mesenteric ischemia and bronchospasm. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 The study drug titration protocol is shown.

[0009] Figure 2 A patient flow chart is shown.

[0010] Figure 3 Variations in norepinephrine dose with concurrent angiotensin II administration are shown.

[0011] Figure 4 Angiotensin II dose titration - Quintiles is shown. DETAILED DESCRIPTION

[0012] The present invention relates in particular to the surprising discovery of the inventors that when very low doses of angiotensin II are administered to subjects with hypotension, e.g., exhibiting distributive shock (high-output shock), blood pressure can be raised to normal levels (e.g., mean arterial pressure (MAP) of about 65 mm Hg or more), and can be maintained at this level, even in the absence or with low doses of other agents, such as vasopressin or catecholamines (e.g., norepinephrine), that are typically administered to such subjects as a standard of care. Reducing or eliminating the need to administer catecholamines (e.g., norepinephrine) is sometimes referred to herein as the catecholamine-sparing (norepinephrine-sparing) effect. Administration of low doses of angiotensin II and catecholamines such as norepinephrine reduces the undesirable side effects caused by these drugs. High doses of catecholamines can be toxic, and blunting of these toxic effects has been associated with improved survival rates in patients with shock. Maintenance of blood pressure during shock is critical to survival. In addition to increasing blood pressure, heart rate and hemodynamics also improved or remained stable after administration of low-dose angiotensin II.

[0013] definition

[0014] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, treatment with "a" catecholamine as used above includes treatment with one or more types of catecholamines.

[0015] The term "about," as used herein, means within about 10% of the indicated value, preferably plus or minus 5% of the indicated value.

[0016] The term "angiotensin II" may 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 naturally occurring in humans and other species such as horses, pigs, etc. Isoleucine may be replaced by valine to produce 5-valine angiotensin II, Asp-Arg-Val-Tyr-Val-His-Pro-Phe [SEQ ID NO: 2]. Other angiotensin II analogs may also be used, such as [Asn 1 -Phe 4 ]-angiotensin II [SEQ ID NO: 3], hexapeptide Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO: 4], nonapeptide Asn-Arg-Val-Tyr-Tyr-Val-His-Pro-Phe [SEQ ID NO: 5], [Asn 1-Ileu 5 -Ileu 8 ]-angiotensin II [SEQ ID NO: 6], [Asn 1 -Ileu 5 -Ala 8 ]-angiotensin II [SEQ ID NO: 7] and [Asn 1 -DiiodoTyr 4 -Ileu 5 ]-Angiotensin II [SEQ ID NO: 8]. Angiotensin II can be synthesized, for example, by solid phase peptide synthesis, to include modifications such as C-terminal amidation. A C-terminal acetate group can also be added. The term "angiotensin II", without further specificity, is intended to refer to any of these different forms, as well as combinations thereof.

[0017] The term "catecholamine" as used herein refers to dopamine, norepinephrine, epinephrine, phenylephrine, ephedrine, and their prodrugs, structural analogs, or derivatives that induce similar physiological effects in humans, such as increasing mean arterial pressure in healthy human subjects. In certain embodiments, the catecholamine can be dopamine, norepinephrine, epinephrine, ephedrine, or phenylephrine.

[0018] As used herein, the term "catecholamine-resistant hypotension" refers to a patient who requires greater than 15 μg / kg / min of dopamine, 0.1 μg / kg / min of norepinephrine, or 0.1 μg / kg / min of epinephrine as a vasopressor. Dopamine, norepinephrine, and epinephrine may be administered at rates greater than 15 μg / kg / min, 0.1 μg / kg / min, or 0.1 μg / kg / min, respectively, but elevated rates are associated with increased mortality.

[0019] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0020] The term "including" is used to mean "including, but not limited to." "Including" and "including, but not limited to" are used interchangeably.

[0021] The term "mean arterial pressure" or "MAP" refers to the mean arterial pressure during a single cardiac cycle.

[0022] As used herein, "subject" or "patient" refers to any animal (e.g., mammal), including humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably with respect to human subjects.

[0023] Angiotensin II therapy

[0024] Angiotensin II is a peptide hormone produced naturally by the body that regulates blood pressure through vasoconstriction and sodium reabsorption. The hemodynamic effects of angiotensin II administration have been the subject of numerous clinical studies, showing significant effects on systemic and renal blood flow (Harrison-Bernard, LM, The renal renin-angiotensin system. Adv Physiol Educ, (2009) 33 (4): p. 270-74). Angiotensin II is a hormone produced by the renin angiotensin aldosterone system (RAAS) that regulates blood pressure through the 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 a significant effect on the efferent arterioles of the kidney, maintaining glomerular filtration when blood flow is reduced. Angiotensin II also regulates sodium reabsorption in the kidney by stimulating Na+ / H+ exchange 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.).

[0025] The sequence of angiotensin II used in the compositions and methods disclosed herein can be homologous to the sequence of angiotensin II described above. In certain aspects, the invention includes an isolated, synthetic or recombinant amino acid sequence that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, and / or 8. Any such variant sequence can be used in place of angiotensin II as described in the preceding paragraphs.

[0026] In some aspects, angiotensin II can 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 their pharmaceutically acceptable salts, preferably produced under current good manufacturing conditions (cGMP). In some aspects, the composition can include different forms of angiotensin II in different percentages, for example, a mixture of hexapeptide and nonapeptide angiotensin. The composition comprising angiotensin II can be suitable for parenteral administration, for example, for injection or intravenous infusion.

[0027] Similarly, angiotensin II therapeutic agents can 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 peptides or conjugates disclosed in U.S. Pat. No. 7,666,408 (incorporated herein by reference). The term "prodrug" refers to any precursor compound capable of producing or releasing the above-mentioned peptides under physiological conditions. Such a prodrug can be a larger peptide that is selectively cleaved in order to form the peptides of the present invention. For example, in some aspects, the prodrug can be angiotensin I or its homologue that can lead to angiotensin II through the action of certain endogenous or exogenous enzymes. Further prodrugs include peptides with protected amino acids, such as having protective groups at one or more carboxylic acids and / or amino groups. Suitable protective groups for amino groups are benzyloxycarbonyl, tert-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (FMOC), formyl and acetyl or acyl groups. Suitable protective groups for carboxylic acid groups are esters, such as benzyl esters or tert-butyl esters. The present invention also contemplates the use of angiotensin II and / or precursor peptides having amino acid substitutions, deletions, additions, including standard D and L amino acids and modified amino acids, such as, for example, amidated amino acids and acetylated amino acids, wherein the therapeutic activity of the basic peptide sequence is maintained at pharmacologically useful levels.

[0028] Indications

[0029] The methods of the invention can be used to treat subjects exhibiting various types of shock, such as, for example, high-output shock, septic shock, or shock resulting from cardiac arrest or cardiogenic shock. Other conditions that can be treated with the indicated low doses of angiotensin II include acute kidney injury (AKI), hepatorenal syndrome (HRS), and variceal bleeding.

[0030] Therapeutically effective dose of substance

[0031] In general, angiotensin II increases blood pressure, and hypotensive patients may require larger doses to exhibit a pressor response similar to that observed in normal patients. Compositions including angiotensin therapeutic agents (e.g., angiotensin II) can be administered at a rate sufficient to achieve target blood pressure. For example, the patient can be connected to a monitor that provides continuous, periodic, or occasional measurements of MAP.

[0032] The exact amount of drug administered to a mammal to treat hypotension and shock depends on many factors known to those skilled in the art, such as the agent being administered, the general condition of the patient, the condition being treated, the desired duration of use, the type of mammal, the method of administration, etc.

[0033] The dose of angiotensin II can be administered at a rate of about 0.25 ng / kg / min to about 100 ng / kg / min, for example, from 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 an embodiment of the invention, the dosage 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.

[0034] Figure 4 The Examples show that high-output shock subjects who were administered only 1 or 2.5 ng / kg / min of angiotensin II and who required high doses of catecholamines (in the illustrated case, norepinephrine) showed an increase in blood pressure and maintained it, even in the absence or with very low doses of norepinephrine. Figure 4In the study shown in , subjects who required high doses of norepinephrine (>0.2 mcg / kg / min) responded to low doses of angiotensin II such that norepinephrine was discontinued and the action of angiotensin II converted these patients from hypotension to hypertension.

[0035] Dosage administration can continue for about 0.25 hours to about 120 hours, for example, about 1 hour to about 7 hours, 2 hours to about 6 hours, or about 3 hours to about 5 hours.

[0036] The treatment regimen can 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.

[0037] preparation

[0038] Suitable formulations (pharmaceutical compositions) for administering drugs will depend on the mode of administration. For example, formulations suitable for parenteral administration may include sterile aqueous formulations, preferably isotonic with the blood of the recipient. This aqueous formulation can be prepared using suitable dispersants or wetting agents and suspending agents according to known methods. An example of a formulation produced in this traditional manner is an aqueous formulation, Remestyp (terlipressin). The formulation may also be a sterile injectable solution or suspension in a diluent or solvent, such as a solution in 1,3-butanediol, water, Ringer's solution, and isotonic sodium chloride solution, which are exemplary acceptable diluents. Sterile fixed oils may be used as solvents or suspension media. Mild fixed oils may also be used, including synthetic mono- or di-glycerides, and fatty acids, such as oleic acid. Most of the medicaments described herein are commercially available and can be easily obtained from commercial sources.

[0039] excipient

[0040] The pharmaceutical composition of the present invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient together with the therapeutically effective substance of the present invention (such as angiotensin II) and does not destroy the pharmacological activity of the therapeutically effective substance. The term "pharmaceutically acceptable" refers to a non-toxic material that does not interfere with the effectiveness of the biological activity of (multiple) active ingredients. The characteristics of the carrier will depend on the route of administration. The term "excipient" refers to an additive in a preparation or composition that is not a pharmaceutically active ingredient.

[0041] Those skilled in the art will appreciate that the selection of any one excipient may affect the selection of any other excipient. For example, the selection of a particular excipient may exclude the use of one or more additional excipients because the combination of excipients may have an adverse effect. Those skilled in the art will be able to empirically determine which excipient, if any, to be included in the composition of the present invention. The excipient of the present invention may include, but is not limited to, cosolvents, solubilizing agents, buffers, pH adjusting agents, bulking agents, surfactants, encapsulating agents, tension regulators, stabilizers, protective agents and viscosity modifiers. In some respects, it may be beneficial to include a pharmaceutically acceptable carrier in the composition of the present invention.

[0042] Solubilizer

[0043] In some respects, it may be beneficial to include a solubilizing agent in the compositions of the present invention. A solubilizing agent may be used to increase any component of a preparation or composition, including a therapeutically effective material (e.g., angiotensin II) or the solubility of an excipient. Solubilizing agents as described herein are not intended to constitute an exhaustive list, but are provided as exemplary solubilizing agents that can be used in the compositions of the present invention. In some respects, solubilizing agents include, but are not limited to, ethanol, the tert-butyl alcohol, polyethylene glycol, glycerine, methyl parahydroxybenzoate, propyl parahydroxybenzoate, polyethylene glycol, polyvinyl pyrrolidone and any pharmaceutically acceptable salt and / or their combination.

[0044] pH Adjusters

[0045] In some aspects, it may be beneficial to include a pH adjusting agent in the composition of the present invention to adjust the pH of the composition. Changing the pH of a preparation or composition may have a beneficial effect on, for example, the stability or solubility of a therapeutically effective substance, or may be used to prepare a preparation 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 exemplary pH adjusting agents that can be used in the composition of the present invention. pH adjusting agents may include, for example, acids and bases. In some aspects, pH adjusting agents include, but are not limited to, acetic acid, hydrochloric acid, phosphoric acid, sodium hydroxide, sodium carbonate, and combinations thereof.

[0046] The pH of the composition of the present invention can be any pH that provides the desired properties for the preparation or composition. The desired properties can include, for example, therapeutically effective substance (e.g., angiotensin II) stability, therapeutically effective substance retention compared to compositions increased at other pH values, and improved filtration efficiency. In certain aspects, the pH of the composition of the present invention can be from about 3.0 to about 9.0, for example from about 5.0 to about 7.0. In specific aspects, the pH of the composition of the present invention can 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.

[0047] Buffer

[0048] In some aspects, it may be beneficial to buffer pH by including one or more buffers in the composition. In some aspects, the buffer may have, for example, a pKa of about 5.5, about 6.0, or about 6.5. Those skilled in the art will recognize that suitable buffers may be selected to be included in the composition of the present invention based on their pKa and other properties. Buffers are well known in the art. Therefore, the buffer described herein is not intended to constitute an exhaustive list, but is provided as an exemplary buffer used in the composition of the present invention. In some aspects, the buffer may include one or more of the following: Tris, Tris HCl, potassium phosphate, sodium phosphate, sodium citrate, sodium ascorbate, a combination of sodium phosphate and potassium, Tris / Tris HCl, sodium bicarbonate, arginine phosphate, arginine hydrochloride, histidine hydrochloride, dimethyl arsonate, succinate, 2-(N-morpholino) ethanesulfonic acid (MES), maleate, Bis-Tris, phosphate, carbonate, and any pharmaceutically acceptable salt and / or a combination thereof.

[0049] Surfactants

[0050] In some aspects, it may be beneficial to include a surfactant in the composition of the present invention. Surfactants, in general, reduce the surface tension of a liquid composition. This may provide beneficial properties, such as making filtration easier. Surfactants may also serve 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 provided only as exemplary surfactants that can be used in the composition of the present invention. Surfactants may include, but are not limited to, sorbitol esters, such as polysorbates (e.g., polysorbate 20 and polysorbate 80), lipopolysaccharides, polyethylene glycols (e.g., PEG 400 and PEG 3000), poloxamers (i.e., pluronics), ethylene oxide and polyethylene oxide (e.g., Triton X-100), saponins, phospholipids (e.g., lecithin), and combinations thereof.

[0051] Tonicity regulator

[0052] In some aspects, it may be beneficial to include a tension regulator in the composition of the present invention. When administering, for example, a composition to a patient via parenteral administration, the tension of the liquid composition is an important consideration. Therefore, tension regulators can be used to help the formulation or composition be suitable for administration. Tension regulators are well known in the art. Therefore, the tension regulators described herein are not intended to constitute an exhaustive list, but are provided only as exemplary tension regulators that can be used in the composition of the present invention. Tension regulators can be ionic or non-ionic, including but not limited to inorganic salts, amino acids, carbohydrates, sugars, sugar alcohols and carbohydrates. Exemplary inorganic salts can include sodium chloride, potassium chloride, sodium sulfate and potassium sulfate. An exemplary amino acid is glycine. Exemplary sugars can include sugar alcohols such as glycerol, propylene glycol, glucose, sucrose, lactose and mannitol.

[0053] Stabilizer

[0054] In some aspects, it may be beneficial to include a stabilizer in the composition of the present invention. Stabilizers help to improve the stability of the therapeutically effective substance in the composition of the present invention. This can occur by, for example, reducing the degradation of the therapeutically effective substance or preventing the 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 anthracycline compounds. Stabilizers are well known in the art. Therefore, the stabilizers described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary stabilizers that can be used in the composition of the present invention. Stabilizers may include, but are not limited to, emulsifiers and surfactants.

[0055] Mode of administration

[0056] Angiotensin II or the catecholamines may be administered by any convenient route, for example intravenously (using a bolus or by steady infusion), intramuscularly, subcutaneously or by inhalation. Angiotensin II and the catecholamines may be administered together or separately.

[0057] The compositions of the present invention can be used in various conventional ways. In some aspects, the compositions of the present invention are suitable for parenteral administration. These compositions can be used, for example, intraperitoneally, intravenously, intrarenally or intrathecally. In some aspects, the compositions of the present invention are intravenously injected. It will be appreciated by those skilled in the art that the method of using the therapeutically effective material preparation or composition of the present invention will depend on various factors, such as the age, weight and physical condition of the patient being treated and the disease or illness being treated. Therefore, a skilled worker can select the best method for the patient as appropriate.

[0058] Unless otherwise defined herein, the scientific and technical terms used in this application should have the meanings commonly understood by those of ordinary skill in the art. In general, the nomenclature and techniques related to chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0059] Methods involving administration of angiotensin II

[0060] One aspect of the invention is a method comprising administering to a subject having high-output shock (e.g., catecholamine-resistant high-output shock) and undergoing treatment with a catecholamine dose equivalent to at least about 0.2 mcg / kg / min norepinephrine, a dose of angiotensin II that is effective to increase the subject's blood pressure to a mean arterial pressure (MAP) of about 65 mm Hg or above and that is effective to reduce the dose of catecholamine required to maintain a MAP of about 65 mm Hg to the equivalent of about 0.05-0.2 mcg / kg / min norepinephrine or less.

[0061] Another aspect of the invention is a method comprising administering to a subject having high-output shock (e.g., catecholamine-resistant high-output shock) and undergoing treatment with a catecholamine dose equivalent to at least about 5 mcg / min norepinephrine, a dose of angiotensin II effective to increase the subject's blood pressure to a mean arterial pressure (MAP) above about 80 mm Hg and effective to reduce the dose of catecholamines required to maintain a MAP above about 80 mm Hg to an equivalent of less than about 5-10 mcg / min norepinephrine. In certain such embodiments, the dose of angiotensin II is at least about 20 ng / kg / min.

[0062] In various embodiments, the dose of angiotensin II is effective to reduce the dose of catecholamines required to maintain a MAP of about 65 mm Hg to an equivalent of about 0.05 mcg / kg / min of norepinephrine or less.

[0063] In an embodiment of the present invention,

[0064] a. The catecholamine is norepinephrine, or

[0065] b. the catecholamine is epinephrine and the dose equivalent to 0.1 mcg / kg / min of norepinephrine is 0.1 mcg / kg / min; or

[0066] c. the catecholamine is dopamine and the dose of norepinephrine equivalent to 0.1 mcg / kg / min is 15 mcg / kg / min; or

[0067] d. The catecholamine is phenylephrine and the dose of norepinephrine equivalent to 0.1 mcg / kg / min is 1.0 mcg / kg / min.

[0068] In embodiments of the invention, the dose of angiotensin II is 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 ng / kg / min; about 2 ng / kg / min or about 3 ng / kg / min.

[0069] Another aspect of the invention is a method comprising administering to a subject having high-output shock (e.g., catecholamine-resistant high-output shock) and undergoing treatment with a catecholamine dose equivalent to at least about 0.2 mcg / kg / min of norepinephrine, a dose of angiotensin II effective to increase the subject's blood pressure to a mean arterial pressure (MAP) of about 65 mm Hg or above and effective to reduce the dose of catecholamine required to maintain a MAP of about 0.05 mcg / kg / min or less of norepinephrine, further comprising

[0070] identifying subjects (selecting subjects) as belonging to a subset of subjects who are adequately responsive to angiotensin II by titrating the amount of angiotensin about a fixed dose of norepinephrine so that an angiotensin II dose of about 0.25 ng / kg / min to about 5 ng / kg / min is effective to reduce the amount of norepinephrine required to maintain a mean arterial pressure (MAP) of about 65 mm Hg or above to about 0.05 mcg / kg / min of epinephrine or less; and

[0071] Angiotensin II is continuously administered to the subject at the dose determined above.

[0072] In the various methods of the present invention, angiotensin II and catecholamines may be administered intravenously, intramuscularly, subcutaneously, or by inhalation; and they may be administered together or separately.

[0073] Another aspect of the invention is a method comprising administering to a subject having shock (e.g., septic shock or other causes such as shock resulting from cardiac arrest or cardiogenic shock) and undergoing treatment with a catecholamine dose equivalent to at least about 0.2 mcg / kg / min of norepinephrine, a dose of angiotensin II effective to increase the subject's blood pressure to a MAP of about 65 mm Hg or above, effective to reduce the dose of catecholamine required to maintain a MAP of about 65 mm Hg to the equivalent of about 0.05-0.2 mcg / kg / min of norepinephrine or less, or to the equivalent of about 0.05 mcg / kg / min of norepinephrine or less.

[0074] In preferred methods of the invention, the subject is a human.

[0075] In certain embodiments, angiotensin II and catecholamines are administered jointly. As used herein, the phrase "administered in combination" refers to any form of administration of two agents, such that the previously administered agent is still effective in vivo while the second agent is administered (e.g., the two agents act simultaneously in the subject, which may include the synergistic effect of the two agents). For example, the two agents can be administered in the same preparation or a separate preparation, simultaneously or sequentially. In certain embodiments, different agents can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or a week of each other. Therefore, individuals receiving this treatment can benefit from the combined effect of the two agents.

[0076] In various methods of the invention, the subject is undergoing standard of care treatment with catecholamines (e.g., epinephrine, norepinephrine, dopamine, phenylephrine, ephedrine) or with vasopressin at or before the administration of angiotensin II. These agents are administered at doses equivalent to at least 0.2 mcg / kg / min of catecholamines, norepinephrine. Typical equivalent doses are:

[0077]

[0078] In some embodiments, the patient is catecholamine-resistant. That is, the patient does not respond (does not show an increase in blood pressure) to catecholamines administered at a dose equivalent to a norepinephrine dose of at least about 0.2 mcg / kg / min.

[0079] It will be readily appreciated by those skilled in the art that the present invention is well adapted to achieve the objects and obtain the purposes and advantages set forth above, as well as those inherent therein. The embodiments described herein are not intended to limit the scope of the invention. The present description is further illustrated by the following examples, which should not be construed as limiting in any way. In the foregoing and following examples, all temperatures are stated in uncorrected degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.

[0080] Example

[0081] Example I - Intravenous Angiotensin II for Treatment of High-Output Shock

[0082] A. method

[0083] Study Patients

[0084] Patients were older than 21 years and considered to have high-output shock, defined as a cardiovascular sequential organ function assessment (SOFA) score of 4 and a cardiac index >2.4 L / min / BSA 1.73 m 2

[10] . Patients also had an indwelling arterial line and urinary catheter as part of standard care. In addition, each subject was found to be adequately volume resuscitated and clinically assessed as not volume responsive (i.e., a fluid bolus would fail to increase cardiac index by 15%). The standard of care is initial resuscitation with 20-30cc / kg of crystalloids. Exclusion criteria included patients with an acute coronary syndrome, a known history of vasospasm or asthma, any patient currently experiencing bronchospasm, or patients with active bleeding anticipated to require transfusion of >4 units of packed red blood cells, hemoglobin <7g / dL, or for whom serial blood samples would be contraindicated.

[0085] Treatment allocation

[0086] Once enrolled in the study, patients were randomly assigned following a randomization procedure (computerized random number) to receive either angiotensin II acetate infusion (Clinalfa, Bachem AG, Hauptstrasse 144, 4416 Bubendorf, Switzerland) or a placebo infusion (hereinafter referred to as study drug and placebo, respectively). Investigators, clinical support staff, patients, and families were unaware of the treatment assignments during the study.

[0087] Drug infusion

[0088] Enrolled patients were randomized to receive an infusion of study drug in normal saline at a drip rate calculated to correspond to an initial concentration of 20 ng / kg / min, plus standard of care treatment for high-output shock. Study drug was prepared in opaque cellophane bags, the contents of which were unknown to the study staff, nurses, or anyone else in direct patient care. Administration of the study drug took a total of 6 hours, with doses (and corresponding drip rates) adjusted hourly. Study drug dose adjustments were determined per the prespecified trial protocol based on concomitant requirements for standard of care therapy (in all cases, norepinephrine infusion plus vasopressin, epinephrine, and / or phenylephrine infusions) required to maintain a mean arterial pressure (MAP) at or above 65 mmHg, which is standard practice at our institution. The study drug titration regimen was designed to elucidate the ATII dose required to achieve the above standard MAP goal of 65 mmHg (along with norepinephrine doses between 5-10 mcg / min). The dose titration regimen is shown in Figure 1 The maximum allowed dose of ATII titration was 40 ng / kg / min and the minimum was 5 ng / kg / min. At the end of 6 hours, the study drug infusion was titrated off by halving every 10 minutes until the study drug infusion dose was below 5 ng / kg / min, after which the titration was stopped.

[0089] end

[0090] The primary endpoint was the effect of ATII infusion on the standing dose of norepinephrine required to maintain a MAP of 65 mmHg. Secondary endpoints included the effect of ATII infusion on urine output, serum lactate, cardiac output, and 30-day mortality.

[0091] Statistical analysis

[0092] A small patient population was analyzed, consistent with similar studies of this nature. A population of 20 patients (10 patients in each group) was determined to generate a basis for determining whether ATII would affect the dose of norepinephrine at the doses outlined herein. An independent data and safety monitor (DSM) was assigned and reviewed all adverse events.

[0093] The distribution of demographic and clinical variables was also assessed. Differences between the proportions of patients with certain variables were assessed using chi-square, Fisher's exact test, Student's t, and Mann-Whitney tests, as appropriate. The primary endpoint of the effect of study drug infusion on the fixed dose of norepinephrine was calculated using generalized estimating equation analysis and expressed as the mean dose of norepinephrine (mcg / min) and study drug infusion (in ng / kg / min) per hourly interval.

[0094] Generalized estimating equations were used to model the response to study drug over time, with hourly readings of standard-of-care vasopressors starting 1 hour before study drug initiation until 8 hours after study drug initiation, using the SAS Genmod program (Version 9.3, Cary, NC). The correlation structure was defined as autoregressive to account for potentially higher correlations between time points that were closer together. In this model, the main effect of drug examined the mean response to each drug averaged over time. The main effect of time examined the mean response at each time point averaged over drug, and the drug times time interaction examined whether changes over time differed between drugs.

[0095] All values ​​are reported as mean ± SD unless otherwise specified. All other statistical analyses were performed using SPSS 18, Chicago, IL, USA.

[0096] B. result

[0097] Figure 2 The process of patient entry into the study is reported in . Twenty patients underwent randomization and all 20 patients were enrolled and completed the study ( Figure 1 ). The baseline characteristics of the two groups are shown in Table 1. The mean age of all study subjects was 62.9±15.8 years. Among these patients, 75% were male, 45% were white and 40% were African American. Baseline SOFA and APACHE II scores were 15.9±3.0 and 30.6±8.9, respectively. Nineteen of the 20 patients received concomitant vasopressin at a dose of 0.02 to 0.08 U / min. The vasopressin dose was not adjusted during the study.

[0098] ATII resulted in a reduction in norepinephrine dose in all patients ( Figure 3 ). The mean norepinephrine dose at hour 1 in the placebo population was 27.6±29.3 mcg / min, versus 7.4±12.4 mcg / min in the ATII population (p=0.06). The norepinephrine dose at hour 2 in the placebo population was 28.6±30.2 mcg / min, versus 7.3±11.9 mcg / min in the ATII population (p=0.06). Throughout the study, the mean ATII dose decreased from 20 ng / kg / min at hour zero to 5 ng / kg / min at hour 6, prior to the titration stop at hour 7 (one hour after infusion). Despite the reduction in ATII titration, norepinephrine doses remained significantly lower in the ATII population than in the placebo population, although the effect approached statistical significance only at hours 1 and 2. Once the ATII infusion was stopped, mean norepinephrine rebounded concomitantly.

[0099] Using a generalized estimating equation model with time defined as a continuous variable to obtain a global test of interaction, the main effect of treatment (study drug vs. placebo) was not significant (p = 0.13), the time effect was not significant (p = 0.30), and the treatment times time interaction was not significant (p = .76). When time was defined as a categorical variable and hour 1 was defined as the reference group to examine specific time points, both the drug effect (p = .14) and the time effect (p = .18 at time 0 and p = .51 at time 1) remained nonsignificant. The product of the drug times time interaction showed a trend toward significance at 1-hour and 2-hour (p = 0.06).

[0100] The most common adverse event experienced by all patients was metabolic disease, with alkalosis occurring in four patients in the ATII group and in zero in the placebo group (p=0.09). The most common adverse event considered attributable to ATII was hypertension,

[0101] This occurred in 20% of patients receiving ATII (p=0.58). In both patients, study drug infusion was stopped to achieve MAP target per the trial protocol. Table 2 lists the adverse events

[0102] Urine output, cardiac output, central venous pressure, and mean arterial pressure are shown in Table 3. The 30-day mortality rate was similar for the ATII and placebo populations (50% vs. 60%, p=1.00).

[0103] Table 1 - Demographic and clinical baseline data

[0104]

[0105]

[0106] Results are expressed as mean and SD or numerical values. 1 Student's t test was used to calculate P values ​​for continuous variables, and Fisher's exact test was used to calculate P values ​​for discrete variables. 2 One patient in the placebo group versus no patient in the ATII group received a phenylephrine infusion before starting ATII. One patient in the placebo group versus no patient in the ATII group received epinephrine. SOFA, sequential organ function assessment; APACHE, acute physiology chronic health evaluation II; IHD = ischemic heart disease. CHF = congestive heart failure. COPD = chronic obstructive pulmonary disease. DM = diabetes mellitus. CKD = chronic kidney disease. HD = hemodialysis. IS = immunocompromised state. CVA = cerebrovascular accident. AKI = acute kidney injury; Hgb, hemoglobin; NA, not analyzed, not applicable, or not available.

[0107] Table 2 Adverse events

[0108]

[0109] ATII infusion was discontinued in two patients due to hypertension.

[0110] Y Seventeen of the 20 patients presented with pre-existing AKI, of which eight patients received placebo and nine received ATII. Of the three patients without pre-existing AKI, one patient developed AKI and received ATII.

[0111] These included worsening multi-organ system failure, fever, lower extremity edema, and thigh hematoma.

[0112] AKI = acute kidney injury. MOSF = multiple organ system failure. P values ​​were calculated using Fisher's exact test.

[0113] Urine output, cardiac output, central venous pressure, and mean arterial pressure are shown in Table 3. The 30-day mortality rate was similar for the ATII and placebo populations (50% vs. 60%, p=1.00).

[0114]

[0115] Further studies have shown that subjects administered only 1.25 or 2.5 ng / kg / min of angiotensin II showed an increase in blood pressure and maintained it, even in the absence or with very low doses of catecholamines, such as norepinephrine. The standard of care for patients with high-output shock is to maintain a mean arterial pressure of 65 mmHg with catecholamines and / or vasopressin. Failure to maintain blood pressure in a mammal for an extended period of time is uniformly fatal. Figure 4 In the studies presented, the standard of care was to administer norepinephrine. 20% of patients responded to very low doses of angiotensin II (1.25-2.5 ng / kg / min) with a significant rise in MAP. The catecholamine dose was reduced as per standard protocol, as pushing MAP above normal in patients with high-output shock is nonstandard. Even with complete weaning of catecholamines, low doses of angiotensin II still resulted in MAP > 85 mm Hg.

[0116] ATII has been shown to be an effective vasopressor in a dose range of 1-40 ng / kg / min. More specifically, a starting dose of 2-10 ng / kg / min may be an appropriate starting dose in the treatment of high-output shock when used in combination with standard of care vasopressors.

[0117] Although all patients in the study responded to ATII infusion, significant heterogeneity was observed. Of the 10 patients who received ATII, two had modest responses, while two were very sensitive to ATII, an unexpected finding. In these two highly sensitive patients, the norepinephrine infusion was withheld per the protocol, and the ATII dose was at its lowest allowed dose of 5 ng / kg / min, yet the patients remained hypertensive with a MAP > 90 mm Hg despite the withholding of the norepinephrine infusion. As hypertension was not part of our standard of care, the investigators stopped the infusion and weaned off ATII. In both cases, the requirement for norepinephrine was rapidly reestablished.

[0118] ATII appears to have synergistic effects with other vasopressors (i.e., catecholamines and vasopressin). ATII appears to be particularly useful for patients who require norepinephrine and have tachycardia. For patients with severe hypotension, lower doses of multiple vasopressors with different mechanisms of action may be more effective and less toxic than large doses of one type of vasopressor (i.e., catecholamines).

[0119] The multiple strengths of this study are as follows. First, this study was a randomized, double-blind, controlled trial with an appropriate placebo control group. Second, this was a pragmatic design as the investigators' intent was to enroll patients receiving standard of care treatment for high-output shock. Therefore, all patients had received a priori appropriate monitoring and therapeutic interventions (including central venous catheters, bladder catheters, arterial lines, and cardiac output monitoring devices). There was no additional need for any specialized procedural equipment prior to enrollment in this study. Third, despite volume therapy, all enrolled patients had a documented need for high-dose vasopressor therapy as demonstrated by cardiac index entry criteria. This is consistent with current practice of addressing volume responsiveness in hypotensive patients before initiating vasopressor therapy. Finally, as part of the study protocol, a data safety monitor was used with the ability to unblind the data and assess adverse events and study discontinuation, neither of which occurred.

[0120] Initiation of ATII infusion in septic shock patients receiving norepinephrine resulted in a significant reduction in norepinephrine dose. ATII improves blood pressure in patients with high-output shock and multiple vasopressors. ATII is effective as a pressor for the treatment of high-output shock. The initial dose can be between 2-10 ng / kg / min. Finally, ATII has been shown to be well tolerated.

[0121] Another aspect of the invention relates inter alia to formulations (compositions, pharmaceutical compositions) comprising angiotensin II in combination with one or more additional peptides and / or compounds, and methods of using those formulations in the treatment of subjects in need of increased blood pressure (having hypotension), for example, as present in various types of shock, such as, for example, high output shock, septic shock, or shock from other forms of shock such as cardiac arrest or cardiogenic shock. The above formulations may also be used to treat other diseases, including acute kidney injury, hepatorenal syndrome (HRS), or variceal bleeding.

[0122] Specific embodiments include, for example, angiotensin II in combination with other vasopressor peptides or analogs or derivatives thereof; and angiotensin II in combination with other vasopressor peptides or analogs or derivatives thereof and catecholamines. Additional embodiments include any of the foregoing peptides or combinations further combined with the compound methylene blue, also referred to herein as 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride or MB.

[0123] The present inventors have unexpectedly discovered that the use of angiotensin II in combination with other vasopressors, such as vasopressin and / or vasopressin analogs and / or catecholamines, allows the use of much lower doses of vasopressin and / or vasopressin analogs and / or catecholamines than are currently administered as a standard of care, thereby reducing the side effects of these agents and increasing their effectiveness. Methylene blue also exhibits synergistic effects with any of these agents. That is, a combination of two or more of these agents (in combination with angiotensin II) at low doses is more effective than a conventional large dose of one of these agents.

[0124] One aspect of the invention is a composition comprising angiotensin II or an analog thereof and at least one additional vasopressor and / or methylene blue. Such a combination is sometimes referred to herein as a "multi-component composition of the invention".

[0125] In an embodiment of the present invention, the multi-component composition comprises the following combination of agents:

[0126] Angiotensin II + vasopressin

[0127] Angiotensin II + vasopressin + norepinephrine

[0128] Angiotensin II + vasopressin + any catecholamine,

[0129] Methylene blue (MB) + angiotensin II

[0130] MB + Angiotensin II + Vasopressin

[0131] MB + angiotensin II + vasopressin + norepinephrine

[0132] MB + angiotensin II + vasopressin + any catecholamine

[0133] Angiotensin II + terlipressin

[0134] Angiotensin II + terlipressin + norepinephrine

[0135] Angiotensin II + terlipressin + any catecholamine

[0136] Methylene blue (MB) + angiotensin II

[0137] MB+Angiotensin II+Terlipressin

[0138] MB + angiotensin II + terlipressin + norepinephrine

[0139] MB + Angiotensin II + Terlipressin + Any catecholamine

[0140] Another aspect of the present invention is a pharmaceutical composition comprising the above multi-component composition and a pharmaceutically acceptable carrier.

[0141] Another aspect of the invention is a kit comprising angiotensin II and at least one additional vasopressor and / or methylene blue in one or more containers.

[0142] Another aspect of the invention is a method (e.g., a method for treating a subject in need, such as a subject in need of increased blood pressure, such as shock), comprising administering to the subject a therapeutically effective amount of a multi-component composition comprising angiotensin II and at least one additional vasopressor and / or methylene blue, or a pharmaceutical composition comprising the composition and a pharmaceutically acceptable carrier.

[0143] As discussed above, agents such as the above-mentioned agents can be co-administered, which refers to any form of administration of two (or more) agents such that the second agent (or other (multiple) agents) is administered while the previously administered agent is still effective in vivo (e.g., the two (or more) agents are simultaneously effective in the patient's body). For example, two (or more) agents can be administered simultaneously or sequentially with the same formulation or separate formulations. In certain embodiments, different agents can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or a week of each other. Therefore, individuals receiving such treatment can benefit from the combined effects of these two or more agents. Two, three, or four of the above-mentioned agents can be co-administered.

[0144] Compositions for administering a combination of two or more of the medicaments shown can take any various forms. For example, two of the multiple medicaments can be packaged together and administered together. In another embodiment, one or more medicaments in the composition are packaged separately from each other, so it can be administered independently of the others, for example with a separate intravenous infusion line. In this way, for example, the dosage of each medicament can be controlled individually. In one embodiment, for example, when a patient has an emergency situation of cardiac arrest, a combination of, for example, angiotensin II, vasopressin and catecholamines can be administered to a subject outside a hospital, for example, in an ambulance. Afterwards, when the patient arrives at the hospital, a more accurate dosage and combination of medicaments can be administered.

[0145] Angiotensin II is discussed above. The dose of angiotensin II administered to a subject in the case of multi-component administration can be determined (titrated when used in combination with catecholamines, vasopressin and / or methylene blue) by methods as discussed elsewhere herein. Typically, the dose of angiotensin II administered to a subject in the case of multi-component administration is from about 1 or 1.25 ng / kg to about 20 ng / kg, from about 1 or 1.25 ng / kg / min to about 10 ng / kg / min, from about 1 or 1.25 ng / kg / min to about 5 ng / kg / min, from about 0.25 ng / kg / min to about 20 ng / kg / min, from about 0.25 ng / kg / min to about 10 ng / kg / min, or from about 0.25 ng / kg / min to about 5 ng / kg / min. In an embodiment of the invention, the dosage 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.

[0146] As discussed above, the catecholamines that can be used in the methods of the present invention include norepinephrine, epinephrine, dopamine or phenylephrine or ephedrine. The dosage of catecholamines administered to a subject in the case of multi-component administration can be determined (titrated when used in combination with angiotensin II, vasopressin and / or methylene blue) by methods as discussed elsewhere herein. Typically, the dosage of catecholamines administered to a subject in the case of multi-component administration is equivalent to a norepinephrine dosage of about 0.01mcg / kg / min to about 0.1mcg / kg / min (e.g., about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.1mcg / kg / min). The equivalent dosages of catecholamines are summarized above.

[0147] Vasopressin or any of its various suitable analogs or derivatives can be used in the methods of the present invention; suitable analogs or derivatives will be apparent to the skilled person. These suitable analogs or derivatives are: terlipressin, arginine vasopressin, desmopressin, felypressin, lysine vasopressin and ornithine vasopressin. A suitable analog terlipressin is a synthetic triglycyl lysine derivative of vasopressin, which is an inactive prodrug. It has a pressor and antidiuretic effect. After intravenous (IV) injection, lysine vasopressin is released after enzymatic cleavage of the 3 glycyl moiety. The dose of vasopressin or its analogs administered to a subject in the case of multi-component administration can be determined by methods as discussed elsewhere herein (titration when used in combination with angiotensin II, catecholamines and / or methylene blue). Typically, the dose of vasopressin administered to a subject in the case of multi-component administration is about 0.01 U / minute to about 0.04 U / minute (e.g., about 0.01, about 0.02, about 0.03 or about 0.04 U / min). Typically, the dose of terlipressin administered to a subject in the case of multi-component administration is about 0.1 mg to about 1 mg, such as about 0.1, 0.3, 0.7 or 1 mg, for about 4-6 hours.

[0148] Methylene blue (MB) can also be administered to a subject in the multi-component administration method of the present invention. Methylene blue is a selective inhibitor of the second messenger guanylate cyclase involved in nitric oxide-mediated vasodilation, and therefore can enhance the effect of vasopressor. As an experimental pharmaceutical drug, the international non-proprietary name (INN) of methylene blue is methylene blue (methylthioninium chloride). The dosage of methylene blue administered to a subject in the case of multi-component administration can be determined (titrated when used in combination with angiotensin II, catecholamines and / or methylene blue) by methods as discussed elsewhere herein. Typically, the dosage of methylene blue administered to a subject in the case of multi-component administration is about 0.01 to about 3 mg / kg, every 2-8 hours.

[0149] Treatment with low doses of two or more of these agents as described above (including angiotensin II) is more effective than conventional high doses of one of these agents. For example, the standard of care for administering catecholamines themselves is in the range of about 0.01 to about 0.3 mcg / kg / min, and the standard of care for administering vasopressin is in the range of about 0.01 to about 0.08 U / min. By combining two or more of these components, any one of these is reduced by at least about 20% to about 25% relative to the conventional standard of care, which represents a significant advantage.

[0150] The inventors show herein that smaller doses of multiple vasoconstrictors work more effectively than larger doses of one vasopressor. Without wishing to be bound by any particular mechanism, it is proposed that this synergistic effect is due, at least in part, to the observation that vasopressin and angiotensin II affect different vascular beds than catecholamines, so by attacking different targets, these agents act synergistically. For example, vasopressin tends to cause more mesenteric vasoconstriction than catecholamines, and therefore, vasopressin / vasopressin analogs are typically stopped if a patient develops mesenteric ischemia. In diseases such as hepatorenal syndrome, the disease problem is mesenteric vasodilation, and vasopressin and / or vasopressin analogs are used to counteract this particular region of vasodilation.

[0151] One embodiment of the invention is a kit comprising angiotensin II and the agent vasopressin or its analog (e.g., terlipressin), and / or one or more of catecholamines and / or methylene blue. The agents in the kit may be present in separate containers (e.g., vials), or two or more agents may be present together in a single container. In one embodiment, each container contains a unit dose of the agent. In other embodiments, multiple dose units are present in each container. The agents may be in liquid form or they may be solid (e.g., powdered or lyophilized form) that may be reconstituted with saline or a similar diluent solution before administration to the patient. For example, in one embodiment, the following agents are present in a single vial in solid form: about 0.25 mg to about 1 mg of the catecholamine epinephrine; about 10 U to about 40 U of vasopressin; and about 0.01 micrograms to about 100 micrograms of angiotensin II. These ingredients are then suspended in a suitable volume of diluent before use. Suitable diluents and suitable amounts of other agent combinations will be apparent to the skilled person.

[0152] The kits of the invention may include instructions for carrying out the methods, e.g., methods for reconstituting a solid form of a pharmaceutical agent or diluting a liquid form. Other optional components of the kits of the invention include suitable buffers or other diluents for reconstituting a solid form of a pharmaceutical agent or diluting a liquid form of a pharmaceutical agent; or packaging materials. The reagents of the kit may be in containers in which the reagents are stable, e.g., in freeze-dried form or powder form or in a stable liquid.

[0153] The compositions or pharmaceutical compositions of the present invention can be used to treat any of a variety of diseases or conditions. These include, for example, shock, including septic shock, shock caused by cardiac arrest or cardiogenic shock or high output shock. Other indications include acute kidney injury, hepatorenal syndrome (HRS) and varicose bleeding.

[0154] Acute kidney injury

[0155] Patients with inflammation / sepsis may develop acute kidney injury (AKI), in part due to vasodilation of the glomerular afferent arterioles and loss of GFR leading to intraglomerular hypotension. Parenteral use of agents such as angiotensin II and vasopressin leads to vasoconstriction of the afferent arterioles, thereby attenuating this effect.

[0156] Hepatorenal syndrome (HRS)

[0157] HRS is a disease in which mesenteric vasodilation is so severe that blood flows preferentially to the intestines and away from the kidneys. HRS commonly occurs in patients with cirrhosis. Angiotensin II alone or in combination with vasopressin and / or catecholamines causes vasoconstriction and a consequent improvement in renal function. In addition, patients with cirrhosis often have vasodilation due to increased nitric oxide levels and can therefore be treated with methylene blue in combination with angiotensin II and vasopressin (e.g., terlipressin) and / or catecholamines.

[0158] Varicose vein bleeding

[0159] Patients with portal hypertension, usually due to cirrhosis of the liver, are prone to bleeding from their esophageal varices. It would be desirable to formulate a drug that reduces portal pressure. Treatment with the composition of the present invention results in reduced bleeding, so fewer transfusions or procedures to stop bleeding are required, and deaths caused by the condition are reduced.

[0160] References

[0161] 1.Vincent JL,De Backer D:Circulatory shock.N Engl J Med 2013,369(18):1726–1734.

[0162] 2. Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J, CAT Study investigators: A comparison of epinephrine and norepinephrine incritically ill patients. Intensive Care Med 2008, 34(12): 2226–2234.

[0163] 3.Rona G:Catecholamine cardiotoxicity.J Mol Cell Cardiol 1985,17(4):291–306.4.Morelli A,Ertmer C,Westphal M,Rehberg S,Kampmeier T,Ligges S,OrecchioniA,D'Egidio A,D'Ippoliti F,Raffone C,Venditti M,Guarracino F,Girardis M,Tritapepe L,Pietropaoli P,Mebazaa A,Singer M:Effect of heart ratecontrol withesmolol on hemodynamic and clinical outcomes in patients withseptic shock:arandomized clinical trial.JAMA 2013,310(16):1683–1691.

[0164] 5.Russell JA,Walley KR,Singer J,Gordon AC,Hebert PC,Cooper DJ,HolmesCL,Mehta S,Granton JT,Storms MM,Cook DJ,Presneill JJ,Ayers D,VASSTInvestigators:Vasopressin versus norepinephrine infusion in patientswith septicshock.N Engl J Med 2008,358(9):877–887.

[0165] 6.Basso N,Terragno NA:History about the discovery of the renin-angiotensinsystem.Hypertension 2001,38(6):1246–1249.

[0166] 7.Struthers AD,MacDonald TM:Review of aldosterone-and angiotensin II-induced target organ damage and prevention.Cardiovasc Res 2004,61(4):663–670.8.Jackson T,Corke C,Agar J:Enalapril overdose treated with angiotensininfusion.Lancet 1993,341(8846):703.

[0167] 9.Trilli LE,Johnson KA:Lisinopril overdose and management withintravenousangiotensin II.Ann Pharmacother 1994,28(10):1165–1168.

[0168] 10.Vincent JL,Moreno R,Takala J,Willatts S,De Mendonca A,Bruining H,ReinhartCK,Suter PM,Thijs LG:The SOFA(Sepsis-related Organ FailureAssessment)score to describe organ dysfunction / failure.On behalf of theWorking Group onSepsis-Related Problems of the European Society of IntensiveCare Medicine.Intensive Care Med 1996,22(7):707–710.

[0169] 11.Newby DE,Lee MR,Gray AJ,Boon NA:Enalapril overdose and thecorrective effect of intravenous angiotensin II.Br J Clin Pharmacol 1995,40(1):103–104.

[0170] 12.Wray GM,Coakley JH:Severe septic shock unresponsive tonoradrenaline.Lancet 1995,346(8990):1604.

[0171] 13.Whiteley SM,Dade JP:Treatment of hypotension in septicshock.Lancet 1996,347(9001):622.

[0172] 14.Ryding J,Heslet L,Hartvig T,Jonsson V:Reversal of‘refractoryseptic shock’by infusion of amrinone and angiotensin II in an anthracycline-treated patient.Chest 1995,107(1):201–203.

[0173] 15.Thomas VL,Nielsen MS:Administration of angiotensin II inrefractory septic shock.Crit Care Med 1991,19(8):1084–1086.

[0174] 16.Yunge M,Petros A:Angiotensin for septic shock unresponsive tonoradrenaline.Arch Dis Child 2000,82(5):388–389.

[0175] 17.Correa TD,Jeger V,Pereira AJ,Takala J,Djafarzadeh S,Jakob SM:Angiotensin II in Septic Shock:Effects on Tissue Perfusion,Organ Function,andMitochondrial Respiration in a Porcine Model of Fecal Peritonitis.Crit CareMed 2014.Aug;42(8):e550-9

[0176] 18.Wan L, Langenberg C, Bellomo R, May CN: Angiotensin II in experimentalhyperdynamic sepsis. Crit Care 2009,13(6):R190.

[0177] 19.Goldsmith SR,Hasking GJ:Effect of a pressor infusion ofangiotensin II on sympathetic activity and heart rate in normal humans.CircRes 1991,68(1):263–268.

[0178] According to the foregoing, those skilled in the art can easily determine the basic characteristics of the present invention without departing from its spirit and scope, can make changes and modifications of the present invention to adapt it to various uses and conditions, and utilize the present invention to its maximum extent. The aforementioned preferred specific embodiments should be interpreted as being merely illustrative, and not limiting the scope of the present invention in any way. Those skilled in the art will recognize or be able to use no more than routine experiments to determine many equivalents of the compounds described herein and the methods used. These equivalents are considered to be within the scope of the present invention and are covered by the following claims. Those skilled in the art will also recognize that all combinations of the embodiments described herein are within the scope of the present invention.

[0179] The entire disclosures of all applications, patents, and publications cited above, including U.S. Provisional Application No. 61 / 917,576 filed on December 18, 2013, and U.S. Provisional Application No. 61 / 955,706 filed on March 19, 2014, including the drawings, are hereby incorporated by reference in their entireties, particularly with respect to the disclosures cited therein.

Claims

1. Use of synthetic human angiotensin II in the preparation of a medicament for treating high-output shock in a subject undergoing treatment with a vasopressor selected from catecholamines and vasopressin at a rate equivalent to greater than 5 mcg / min norepinephrine, wherein: The treatment comprises administering the medicament comprising angiotensin II at a rate of 0.25 ng / kg / min to 20 ng / kg / min of angiotensin II, and reducing the rate at which the vasopressor is administered; the medicament is effective to increase and / or maintain the mean arterial pressure (MAP) of the subject above 80 mm Hg.

2. Use of synthetic human angiotensin II in the preparation of a medicament for treating high-output shock in a subject undergoing treatment with a vasopressor selected from catecholamines and vasopressin at a rate equivalent to greater than 10 mcg / min norepinephrine, wherein: The treatment comprises administering the medicament comprising angiotensin II at an initial rate of angiotensin II of 0.25 ng / kg / min to 20 ng / kg / min, and reducing the rate at which the vasopressor is administered; the medicament is effective to increase and / or maintain the mean arterial pressure (MAP) of the subject above 80 mm Hg.

3. The use of claim 2, wherein the treatment comprises reducing the rate of administration of the vasopressor to the equivalent of 5 mcg / min of norepinephrine or less, and reducing the rate of administration of the drug while maintaining the subject's MAP above 80 mm Hg.

4. The use according to claim 2, wherein Reducing the rate at which the vasopressor is administered comprises maintaining MAP above 80 mm Hg while reducing the rate to the equivalent of 0.05 mcg / kg / min to 0.2 mcg / kg / min or less.

5. Use of synthetic human angiotensin II in the preparation of a medicament for treating hypotension or shock in a subject receiving a vasopressor selected from catecholamines and vasopressin at a rate equivalent to at least 0.2 mcg / kg / min of norepinephrine, wherein: The treatment comprises administering the medicament comprising angiotensin II at a rate of 0.25 ng / kg / min to 20 ng / kg / min of angiotensin II, and reducing the rate at which the vasopressor is administered; the medicament being effective to achieve and / or maintain a mean arterial pressure (MAP) of 65 mm Hg or greater in the subject.

6. The use of claim 5, wherein reducing the rate of administration of the vasopressor comprises maintaining MAP at 65 mmHg or greater while reducing the rate to the equivalent of 0.05 mcg / kg / min-0.2 mcg / kg / min of norepinephrine or less.

7. The use of claim 5, wherein reducing the rate of administration of the vasopressor comprises maintaining MAP at 65 mmHg or greater while reducing the rate to the equivalent of 0.05 mcg / kg / min norepinephrine or less.

8. Use of synthetic human angiotensin II in the preparation of a medicament for treating shock or hypotension in a subject receiving a vasopressor selected from catecholamines and vasopressin at a rate equivalent to at least 1 mcg / kg / min of norepinephrine, wherein: The treatment comprises administering the drug comprising angiotensin II at a rate of 0.25 ng / kg / min to 20 ng / kg / min of angiotensin II, and reducing the rate at which the vasopressor is administered; The medicament is effective to achieve and / or maintain a mean arterial pressure (MAP) of 65 mm Hg or greater in the subject.

9. The use of claim 8, wherein reducing the rate at which the vasopressor is administered comprises reducing the rate to the equivalent of 0.05 mcg / kg / min-0.2 mcg / kg / min of norepinephrine or less while maintaining MAP at 65 mmHg or greater.

10. The use of claim 8, wherein reducing the rate at which the vasopressor is administered comprises reducing the rate to the equivalent of 0.05 mcg / kg / min norepinephrine or less while maintaining MAP at 65 mm Hg or greater.

11. The use according to any one of claims 1 to 10, wherein The subject is a human.

12. The use of claim 11, wherein reducing the rate at which the vasopressor is administered comprises reducing the rate to the equivalent of 0.05 mcg / kg / min-0.2 mcg / kg / min of norepinephrine or less while maintaining MAP at 65 mm Hg or greater.

13. The use of claim 11, wherein reducing the rate at which the vasopressor is administered comprises reducing the rate to the equivalent of 0.05 mcg / kg / min norepinephrine or less while maintaining MAP at 65 mm Hg or greater.

14. The use of claim 11, wherein the subject is resistant to catecholamines.

15. The use according to claim 1, wherein The vasopressor is a catecholamine, and the catecholamine is norepinephrine, or The vasopressor is a catecholamine, and the catecholamine is epinephrine and the dose equivalent to 0.1 mcg / kg / min of norepinephrine is 0.1 mcg / kg / min; or The vasopressor is a catecholamine, and the catecholamine is dopamine and the dose of norepinephrine equivalent to 0.1 mcg / kg / min is 15 mcg / kg / min; or The vasopressor is a catecholamine and the catecholamine is phenylephrine and the dose of norepinephrine equivalent to 0.1 mcg / kg / min is 1.0 mcg / kg / min.

16. The use according to any one of claims 1 to 10, wherein The administration to the subject comprises administering angiotensin II at an initial rate of 0.25 ng / kg / min to 10 ng / kg / min.

17. The use according to any one of claims 1 to 10, wherein The administration to the subject comprises administering angiotensin II at an initial rate of 0.25 ng / kg / min to 5 ng / kg / min.

18. The use according to claim 17, wherein The administration to the subject comprises administering angiotensin II at an initial rate of 1 ng / kg / min.

19. The use according to claim 17, wherein The administration to the subject includes administering angiotensin II at an initial rate of 2 ng / kg / min.

20. The use according to claim 17, wherein The administration to the subject includes administering angiotensin II at an initial rate of 3 ng / kg / min.

21. The use according to any one of claims 1 to 10, wherein The administration to the subject comprises administering angiotensin II at an initial rate of 2 ng / kg / min to 10 ng / kg / min.

22. The use according to any one of claims 1 to 10, wherein Angiotensin II and vasopressors are administered intravenously, intramuscularly, subcutaneously, or by inhalation.

23. The use according to claim 22, wherein Angiotensin II and vasopressors were administered intravenously.

24. The use according to any one of claims 12 to 15, wherein The subject is a human.

25. The use according to claim 5, wherein The treatment comprises reducing the rate at which a vasopressor is administered while maintaining the subject's MAP at 65 mm Hg or above, and reducing the rate at which the drug is administered while maintaining the subject's MAP at 65 mm Hg or above.

26. The use according to claim 25, wherein The treatment involves reducing the rate at which the vasopressor is administered and then reducing the rate at which the drug is administered.

27. The use according to claim 25, wherein The treatment involves reducing the rate at which the drug is administered and then reducing the rate at which the vasopressor is administered.

28. The use according to claim 25, wherein The treatment comprises reducing the rate at which the drug is administered while simultaneously reducing the rate at which the vasopressor is administered.

29. The use according to claim 5, wherein The drug is effective to maintain the subject's MAP at 65 mmHg or greater at a rate of 2 ng / kg / min to 10 ng / kg / min angiotensin II.

30. The use according to claim 5, wherein The medicament is effective to maintain the subject's MAP at 65 mmHg or greater at a rate of at least 20 ng / kg / min angiotensin II.

31. The use according to claim 5, wherein The drug is effective to maintain the subject's MAP at 65 mmHg or greater at a rate of 20 ng / kg / min to 40 ng / kg / min angiotensin II.

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