Adrenomedullin administration method

Abstract

Provided are an administration method that maximizes the therapeutic effect of adrenomedullin and a pharmaceutical that contains adrenomedullin which is provided via the administration method. The problem is solved by providing a pharmaceutical which is used to treat a disease and which contains, as an active ingredient, adrenomedullin, a derivative thereof having adrenomedullin activity, or the like, said pharmaceutical being characterized in that: the disease is one for which a therapeutic effect is expected upon administration of adrenomedullin, a derivative thereof having adrenomedullin activity, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of these; and the active ingredient is intermittently administered.

Description

Adrenomedullin administration method

[0001] The present invention relates to a method for administering adrenomedullin, and also to a medicament comprising adrenomedullin that is administered by intermittent administration.

[0002] Adrenomedullin (hereinafter referred to as "AM") is a physiologically active peptide that was isolated and identified from brown cell tissue in 1993. When it was first discovered, AM was found to exert a strong vasodilatory antihypertensive effect. Subsequent research has revealed that AM also exerts a variety of pharmacological actions, including anti-inflammatory, angiogenic, cardiovascular protective, and tissue repair promoting effects.

[0003] Because AM exerts the pharmacological effects described above, it is expected to be useful as a therapeutic agent for cerebrovascular disorders, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular disease, heart disease, and other conditions.

[0004] For example, Non-Patent Document 1 describes the implementation plan for the investigator-initiated AMFIS clinical trial to investigate the safety and efficacy of AM in the treatment of ischemic stroke.

[0005] Yoshimoto et al., Journal of Stroke and Cerebrovascular Diseases, vol. 30 (6), 105761, 2021

[0006] However, to date, no administration method that maximizes the therapeutic effect of AM is known.

[0007] Therefore, an object of the present invention is to provide an administration method that maximizes the therapeutic effect of AM, and to provide a medicine containing AM provided by said administration method.

[0008] As a result of intensive research to solve the above problems, the present inventors unexpectedly found for the first time that intermittent administration of AM was highly effective in treating acute cerebral infarction patients in the investigator-initiated AMFIS clinical trial, in which AM was administered to patients with acute cerebral infarction. Based on this finding, the present invention was completed.

[0009] That is, one aspect of the present invention relates to the following: [1] A pharmaceutical for treating a disease, comprising as an active ingredient adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the disease is one for which therapeutic effects are expected to be achieved by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the pharmaceutical is characterized in that the active ingredient is administered intermittently. [2] The pharmaceutical according to [1], wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond in the peptide of (ii) is replaced by an ethylene group and the peptide has adrenomedullin activity; (iv) a peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides of (i) to (iii) and the peptide has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides of (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus in any of the peptides of (i) to (iv).[3] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g), in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h), in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h), in which a glycine residue is added to the C-terminus; The pharmaceutical composition according to [1] or [2], wherein the peptide is selected from the group consisting of:[4] The pharmaceutical according to any one of [1] to [3], wherein the disease is one for which the anti-inflammatory, angiogenic, cardiovascular protective, and / or tissue repair promoting effects of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, are expected to be therapeutically effective. [5] The pharmaceutical according to any one of [1] to [4], wherein the disease is at least one selected from the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, and heart disease. [6] The pharmaceutical according to any one of [1] to [5], wherein the intermittent administration is for 23 hours or less per day. [7] The pharmaceutical according to any one of [1] to [6], wherein the intermittent administration is for 23 hours or less per day for 3 to 30 days. [8] A method for treating a disease, comprising administering to a subject a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the disease is one for which therapeutic effects are expected to be achieved by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and wherein the administration is intermittent. [9] Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of a disease, wherein the disease is one for which the administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is expected to have a therapeutic effect, and wherein the adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is administered intermittently.

[10] Use of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a pharmaceutical for treating a disease, wherein the disease is one for which therapeutic effects are expected to be achieved by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the pharmaceutical for treatment is administered intermittently.

[0010] According to the present invention, an optimized administration method of AM is provided, thereby maximizing the therapeutic effect of AM. Furthermore, by reducing the total dose of AM, it is possible to reduce side effects. Furthermore, according to the present invention, since the therapeutic effect can be obtained by intermittent administration, hospitalization is not necessarily required, and treatment can be performed on an outpatient basis. Therefore, AM can be administered not only in clinics and the like that do not have inpatient facilities, but also at home or in nursing homes.

[0011] Hereinafter, an example of an embodiment of the present invention will be described in detail, but the present invention is not limited to this.

[0012] (Summary of the present invention) As described above, AM is a substance that exhibits a variety of pharmacological actions, such as anti-inflammatory action, angiogenic action, cardiovascular protective action, and tissue repair promoting action, etc. Because of these pharmacological actions, AM is expected to be useful as a therapeutic agent for cerebrovascular disorders, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular disease, heart disease, etc.

[0013] However, because AM has a short half-life of 22 minutes in the body, it has been thought that the optimal administration method for achieving therapeutic effects is continuous administration of sufficient amounts of AM over a long period of time. However, to date, no detailed investigation has been conducted into the administration method that maximizes the therapeutic effect of AM.

[0014] The present inventors have conducted extensive research into the above-mentioned problems and have found that intermittent administration of AM can provide a significant therapeutic effect in patients with acute cerebral infarction in the investigator-initiated AMFIS clinical trial. More specifically, they unexpectedly and serendipitously discovered that intermittent administration of AM at a pace of 8 hours per day for 7 days, starting immediately after the onset of cerebral infarction, can provide a significant improvement in motor function. This surprising result was completely unpredictable based on the previously recognized understanding that, due to the short half-life of AM, sustained administration over a long period is necessary to achieve its effects.

[0015] According to the present invention, an administration method superior to conventional administration methods can be provided in terms of exerting the effects of AM. Furthermore, according to the present invention, since the therapeutic effect can be obtained by intermittent administration, hospitalization is not necessarily required and treatment can be performed on an outpatient basis, which is a great advantage. Therefore, the present invention is extremely promising in the treatment of various diseases for which therapeutic effects can be expected by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof (hereinafter sometimes referred to as "AM, etc.").

[0016] (Definition) As used herein, "intermittent administration" means continuous intravenous administration of a therapeutic agent for a certain period of time, with no administration of the therapeutic agent during other times. Typically, intermittent administration is performed by setting a period of continuous intravenous administration of a therapeutic agent for a certain period of time and a drug-free period for the remaining period of time, with one day being used as one unit, and repeating this period.

[0017] As used herein, "treatment" means obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, from the viewpoint of completely or partially preventing a disease or its symptoms, or therapeutic, from the viewpoint of partially or completely curing a disease and / or side effects caused by the disease. That is, as used herein, "prevention" is also encompassed within the concept of "treatment."

[0018] "Treatment" refers to any treatment of disease in mammals, particularly humans, and includes, for example: (a) preventing the onset of disease in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease; (b) suppressing the disease, i.e., arresting the onset of the disease; and (c) alleviating the disease (i.e., causing regression of the disease). When "treatment" is a therapeutic treatment as described above, it can be, for example, suppressing (e.g., suppressing progression), alleviating, repairing, and / or curing symptoms that have occurred (onset or manifestation) in a subject suffering from the disease.

[0019] As used herein, the term "therapeutically effective amount" refers to the amount of an active ingredient that is sufficient to effectively treat a disease when administered to a subject. The "therapeutically effective amount" varies depending on the active ingredient, the disease and its severity, and the age, weight, etc. of the subject to be treated.

[0020] As used herein, the term "subject" refers to a test subject or patient in need of treatment by administration of an AM or the like.

[0021] As used herein, "acute cerebral infarction" generally refers to cerebral infarction occurring within 72 hours, particularly within 24 hours, of onset. Cerebral infarction is classified into embolic cerebral infarction and non-embolic (e.g., thrombotic or hemodynamic) cerebral infarction based on the mechanism of onset, and into lacunar infarction, atherothrombotic cerebral infarction, cardiogenic cerebral embolism, etc. based on the clinical disease type.

[0022] (Adrenomedullin) In each aspect of the present invention, the AM may be a human-derived peptide (SEQ ID NO: 1) isolated and identified from human brown cell tissue, or a peptide (orthologue) derived from other non-human mammals (e.g., warm-blooded animals), such as pig (SEQ ID NO: 4), dog (SEQ ID NO: 6), cow (SEQ ID NO: 8), rat (SEQ ID NO: 10), or mouse (SEQ ID NO: 12). In vivo, these peptides have two cysteine ​​residues in their amino acid sequences that form a disulfide bond, and the C-terminus is amidated. Herein, the peptide having a disulfide bond and a C-terminal amide group may be referred to as "native adrenomedullin" or simply "adrenomedullin." In each aspect of the present invention, any of the above peptides may be used as an active ingredient.

[0023] As used herein, "C-terminal amidation" refers to one aspect of post-translational modification of peptides in vivo, specifically, a reaction in which the main-chain carboxyl group of the C-terminal amino acid residue of a peptide is converted to an amide group. Furthermore, as used herein, "formation of a disulfide bond at a cysteine ​​residue" or "disulfidation of a cysteine ​​residue" refers to one aspect of post-translational modification of peptides in vivo, specifically, a reaction in which two cysteine ​​residues in the amino acid sequence of a peptide form a disulfide bond (-SS-). Many physiologically active peptides produced in vivo are initially biosynthesized as precursor proteins with larger molecular weights, which undergo post-translational modification reactions such as C-terminal amidation and / or disulfidation of cysteine ​​residues during intracellular translocation to mature physiologically active peptides. C-terminal amidation typically occurs through the action of a C-terminal amidating enzyme on the precursor protein. In the case of a physiologically active peptide having a C-terminal amide group, a Gly residue is bound to the C-terminal carboxyl group to be amidated in the precursor protein, and the Gly residue is converted to a C-terminal amide group by a C-terminal amidating enzyme. Furthermore, the C-terminal propeptide of the precursor protein contains a repeating sequence of a combination of basic amino acid residues, such as Lys-Arg or Arg-Arg (Mizuno, Biochemistry, Vol. 61, No. 12, pp. 1435-1461 (1989)). Disulfide formation of cysteine ​​residues can occur under oxidative conditions. In vivo, disulfide formation of cysteine ​​residues usually occurs through the action of protein disulfide isomerase on precursor proteins.

[0024] (Adrenomedullin Derivatives) In each embodiment of the present invention, not only native AM itself but also its derivatives having adrenomedullin activity can be used as active ingredients. In each embodiment of the present invention, "adrenomedullin derivative" or "adrenomedullin derivative" refers to a compound having a peptide chain corresponding to AM in its partial structure. Examples of AM derivatives having adrenomedullin activity include, but are not limited to, compounds disclosed in the specifications of International Publication Nos. 2015 / 141819, 2017 / 047788, and 2018 / 181638. Those skilled in the art can prepare AM derivatives having adrenomedullin activity based on the above literature by purchasing them, applying appropriate conversion reactions to purchased compounds, or preparing them themselves. The AM derivatives disclosed in the above literature can sustain the pharmacological effects of adrenomedullin without causing any undesirable side effects. Therefore, in each aspect of the present invention, by using the AM derivatives disclosed in the above-mentioned literature as active ingredients, it is possible to treat diseases for which the administration of AM, etc., is expected to have a therapeutic effect, through the adrenomedullin activity of the AM derivatives, while substantially avoiding the occurrence of undesirable side effects.

[0025] In each aspect of the present invention, "adrenomedullin activity" refers to, for example, various physiological actions exemplified below, and particularly refers to physiological actions that may be involved in the treatment of symptoms of cerebral infarction, such as the control of inflammation in cerebral infarction via the anti-inflammatory action of AM, the alleviation of tissue damage caused by acute ischemia via the vasodilatory action of AM, and the induction of vascular regeneration via the angiogenic action of AM. (1) Cardiovascular system: vasodilatory action, blood pressure lowering action, blood pressure elevation suppression action, increased cardiac output / improvement of heart failure, improvement of pulmonary hypertension, angiogenic action, lymphangiogenic action, improvement of vascular endothelial function, anti-arteriosclerotic action, myocardial protective action (e.g., myocardial protective action against ischemia-reperfusion injury or inflammation), suppression of remodeling after myocardial infarction, suppression of cardiac hypertrophy, and angiotensin-converting enzyme suppression action. (2) Kidneys and water-electrolyte system: diuretic, natriuretic, antidiuretic hormone suppressive, aldosterone-reducing, renal protective (e.g., myocardial protective effect in hypertension or ischemia-reperfusion injury), suppressive of drinking behavior, and suppressive of salt requirement. (3) Brain and nervous system: neuroprotective and brain damage suppressive, anti-inflammatory (e.g., controlling inflammation in cerebral infarction), vasodilatory (e.g., alleviating tissue damage caused by acute ischemia), angiogenic (e.g., inducing vascular regeneration), apoptosis suppressive (e.g., apoptosis suppressive effect in ischemia-reperfusion injury or inflammation), maintaining autoregulation, suppressing oxidative stress, improving dementia, and sympathetic nervous system suppression. (4) Genitourinary system: erectile improvement, blood flow improvement, and implantation promotion. (5) Digestive system: antiulcer, tissue repair, mucosal regeneration, blood flow improvement, anti-inflammatory, and liver function improvement. (6) Orthopedic system: Osteoblast stimulating effect and arthritis improving effect. (7) Endocrine metabolism system: Adipocyte differentiation effect, lipolysis control effect, insulin sensitivity improving effect, insulin secretion control effect, antidiuretic hormone secretion suppression effect, and aldosterone secretion suppression effect. (8) Other: Circulation improving effect, anti-inflammatory effect, cytokine control effect, organ protection effect, oxidative stress suppression effect, tissue repair effect (e.g., anti-bedsore effect), septic shock improvement effect, multiple organ failure suppression effect, autoimmune disease suppression effect, antibacterial effect, hair growth effect, and hair care effect.

[0026] The adrenomedullin or a derivative thereof having adrenomedullin activity is preferably a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond in the peptide (ii) is replaced with an ethylene group and the peptide has adrenomedullin activity; (iv) a peptide in which 1 to 15 amino acids are deleted, substituted, or added in any of the peptides (i) to (iii) and the peptide has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus in any of the peptides (i) to (iv).

[0027] In one embodiment of the present invention, the adrenomedullin or a derivative thereof having adrenomedullin activity is preferably a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin, (ii) a peptide consisting of the amino acid sequence of adrenomedullin and in which two cysteine ​​residues in the amino acid sequence form a disulfide bond, (v) a peptide of (i) or (ii) in which the C-terminus is amidated, and (vi) a peptide of (i) or (ii) in which a glycine residue is added to the C-terminus. Among the peptides (i) to (vi), a peptide consisting of the amino acid sequence of adrenomedullin, in which the C-terminus is amidated, and in which two cysteine ​​residues in the amino acid sequence form a disulfide bond, which is included in (v), corresponds to mature native adrenomedullin. The peptide (i) consisting of the amino acid sequence of adrenomedullin corresponds to the native adrenomedullin in its immature form before post-translational modifications such as C-terminal amidation and disulfidation of cysteine ​​residues are made. Of the peptides (i) to (vi), the other peptides, excluding those described above, correspond to derivatives (modified forms) of adrenomedullin.

[0028] The peptide (ii) can be formed by converting the thiol groups of the two cysteine ​​residues of the peptide (i) into disulfide bonds by air oxidation or oxidation with an appropriate oxidizing agent. By using the peptide (ii), the three-dimensional structure of the peptide can be made similar to that of native adrenomedullin. This allows the adrenomedullin activity of the peptide (ii) to be substantially equivalent to that of native adrenomedullin.

[0029] The peptide (iii) can be formed by converting the disulfide bond of the peptide (ii) to an ethylene group. The substitution of the disulfide bond with an ethylene group can be performed by methods well known in the art (O. Keller et al., Helv. Chim. Acta, 1974, Vol. 57, p. 1253). The use of the peptide (iii) can stabilize the three-dimensional structure of the peptide. This allows the peptide (iii) to sustainably express adrenomedullin activity in vivo.

[0030] In the peptide (iv), the number of deleted, substituted, or added amino acid residues is preferably in the range of 1 to 15, more preferably 1 to 10, even more preferably 1 to 8, particularly preferably 1 to 5, and most preferably 1 to 3. A preferred peptide (iv) is any of the peptides (i) to (iii) in which amino acid residues at positions 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3 from the N-terminus have been deleted, and the peptide still has adrenomedullin activity. A more preferred peptide (iv) is any of the peptides (i) to (iii) in which amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5 from the N-terminus have been deleted, and the peptide still has adrenomedullin activity. The preferred peptides may further have one or more (e.g., 1 to 5, 1 to 3, or 1 or 2) amino acid residues deleted, substituted, or added. By using the peptide (iv), the adrenomedullin activity of the peptide can be made substantially equivalent to that of natural adrenomedullin.Furthermore, by using the peptide (iv), the peptide can continuously express adrenomedullin activity in vivo.

[0031] The peptide (vi) can be converted to the peptide (v) by the action of a C-terminal amidating enzyme, which converts the C-terminal glycine residue to a C-terminal amide group. Therefore, by administering the peptide (vi) to a subject, a C-terminally amidated peptide can be formed in the subject's body after a certain period of time. This allows the peptide (vi) to continuously exert adrenomedullin activity in the body.

[0032] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g), in which 1 to 15 amino acids are deleted, substituted, or added, and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h), in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h), in which a glycine residue is added to the C-terminus; More preferably, the peptide is selected from the group consisting of:

[0033] In one embodiment of the present invention, the adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (i) a peptide in which the C-terminus is amidated in any of the peptides (a) to (f); and (j) a peptide in which a glycine residue is added to the C-terminus in any of the peptides (a) to (f).

[0034] In the peptide (h), the number of deleted, substituted or added amino acid residues is preferably in the range of 1 to 12, more preferably in the range of 1 to 10, even more preferably in the range of 1 to 8, particularly preferably in the range of 1 to 5, and most preferably in the range of 1 to 3. A preferred peptide (h) is any of the peptides (a) to (g) in which amino acids at positions 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3 from the N-terminus have been deleted, and the peptide still has adrenomedullin activity. A more preferred peptide (h) is any of the peptides (a) to (d) in which amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5 from the N-terminus have been deleted, and the peptide still has adrenomedullin activity, or a peptide (e) or (f) in which amino acid residues at positions 1 to 13, 1 to 8, or 1 to 5 from the N-terminus have been deleted, and the peptide still has adrenomedullin activity. The preferred peptides may further have one or more (e.g., 1 to 5, 1 to 3, or 1 or 2) amino acids deleted, substituted, or added. By using the peptide (h), the adrenomedullin activity of the peptide can be made substantially equivalent to that of natural adrenomedullin.Furthermore, by using the peptide (h), the peptide can continuously express adrenomedullin activity in vivo.

[0035] (Salts of Adrenomedullin or Derivatives Thereof) In each aspect of the present invention, the AM or derivatives thereof having adrenomedullin activity used as active ingredients include not only the compounds themselves but also salts thereof. When AM or derivatives thereof having adrenomedullin activity are in the form of a salt, it is preferably a pharmaceutically acceptable salt. Counter ions in salts of AM or derivatives thereof having adrenomedullin activity include, but are not limited to, cations such as sodium ions, potassium ions, calcium ions, magnesium ions, or substituted or unsubstituted ammonium ions, or chloride ions, bromide ions, iodide ions, phosphate ions, nitrate ions, sulfate ions, carbonate ions, bicarbonate ions, perchlorate ions, formate ions, acetate ions, trifluoroacetate ions, propionate ions, lactate ions, maleate ions, hydroxymaleate ions, methylmaleate ions, fumarate ions, adipate ions, benzoate ions, 2-acetoxybenzoate ions, p- Preferred anions include aminobenzoate ion, nicotinate ion, cinnamate ion, ascorbate ion, pamoate ion, succinate ion, salicylate ion, bismethylenesalicylate ion, oxalate ion, tartrate ion, malate ion, citrate ion, gluconate ion, aspartate ion, stearate ion, palmitate ion, itaconate ion, glycolate ion, glutamate ion, benzenesulfonate ion, cyclohexylsulfamate ion, methanesulfonate ion, ethanesulfonate ion, isethionate ion, benzenesulfonate ion, p-toluenesulfonate ion, and naphthalenesulfonate ion. When AM or a derivative thereof having adrenomedullin activity is in the form of a salt with the above counter ion, the adrenomedullin activity of the compound can be substantially equivalent to that of natural adrenomedullin.

[0036] (Solvates of Adrenomedullin or Its Salt) In each aspect of the present invention, the AM or a derivative thereof having adrenomedullin activity used as an active ingredient includes not only the compound itself but also solvates of the compound or its salt. When AM or a derivative thereof having adrenomedullin activity, or a salt thereof, is in the form of a solvate, it is preferably a pharmaceutically acceptable solvate. Solvents that can form solvates with the compound or its salt are, but are not limited to, water, or organic solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, acetonitrile, or ethyl acetate. When AM or a derivative thereof having adrenomedullin activity, or a salt thereof, is in the form of a solvate with the above solvent, the adrenomedullin activity of the compound can be substantially equivalent to that of native adrenomedullin.

[0037] In addition, in each aspect of the present invention, AM or a derivative thereof having adrenomedullin activity used as an active ingredient also includes mixtures of stereoisomers of the compound, such as individual enantiomers and diastereomers of the compound, as well as racemates.

[0038] (Diseases) In each aspect of the present invention, the disease is one for which the administration of an AM is expected to have a therapeutic effect. Because the present invention provides an administration method that maximizes the therapeutic effect of an AM, the present invention is applicable to all diseases that can be treated by the administration of an AM. In other words, the disease for which the administration of an AM is expected to have a therapeutic effect may be any disease that can be treated by the administration of an AM. In other words, such diseases are diseases for which the anti-inflammatory effect, angiogenic effect, cardiovascular protective effect, and / or tissue repair promoting effect of an AM can have a therapeutic effect (are treated).

[0039] Examples of diseases for which the administration of AM is expected to have a therapeutic effect include cerebrovascular disorders, dementia, inflammatory bowel diseases, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular diseases, and heart diseases.

[0040] Examples of cerebrovascular disorders include stroke, cerebral infarction (e.g., cerebral thrombosis, cerebral embolism, etc.), cerebral hemorrhage (e.g., intracerebral hemorrhage, subarachnoid hemorrhage, etc.), acute epidural hematoma, acute subdural hematoma, and chronic subdural hematoma.

[0041] Dementia includes, for example, Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, Pick's disease, frontotemporal dementia (FTD), AIDS-related dementia, age-related cognitive impairment, age-related memory impairment, and other neurodegenerative diseases associated with dementia.

[0042] Examples of inflammatory bowel diseases include ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious enteritis, drug-induced enteritis, ischemic enteritis, and intestinal tuberculosis.

[0043] Examples of autoimmune diseases include rheumatoid arthritis, collagen diseases (such as systemic lupus erythematosus), multiple sclerosis, and neuromyelitis optica.

[0044] Examples of infectious diseases include respiratory infections (e.g., sepsis, pneumonia, etc.), urinary tract infections (e.g., pyelitis, etc.), digestive infections (e.g., peritonitis, cholecystitis, etc.), burns, post-operative infections, viral infections (e.g., COVID-19, etc.), etc. In one embodiment of the present invention, the infectious disease may be a severe infection.

[0045] Examples of pulmonary hypertension include pulmonary arterial hypertension, pulmonary hypertension associated with left heart disease, pulmonary hypertension due to lung disease or hypoxemia, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension due to multiple factors of unknown cause.

[0046] Examples of peripheral vascular diseases include carotid artery stenosis, subclavian artery stenosis, renal artery stenosis, arteriosclerosis obliterans, acute arterial occlusion, Buerger's disease, and varicose veins of the lower limbs.

[0047] Examples of cardiac diseases include myocardial infarction (e.g., acute myocardial infarction, subacute myocardial infarction, old myocardial infarction, etc.), angina pectoris, heart failure, valvular disease, etc. From the viewpoint of therapeutic effect, acute myocardial infarction is preferred.

[0048] (Pharmaceuticals) In the pharmaceuticals of this embodiment, AM or a derivative thereof having adrenomedullin activity used as an active ingredient may be used alone or in combination with one or more pharmaceutically acceptable ingredients. The pharmaceuticals of this embodiment may also be provided in the form of a pharmaceutical composition containing adrenomedullin or a derivative thereof having adrenomedullin activity and one or more pharmaceutically acceptable carriers. In this embodiment, the pharmaceutical composition may contain, in addition to the ingredients, one or more pharmaceutically acceptable additives such as one or more pharmaceutically acceptable vehicles (e.g., solvents such as sterile water or solutions such as physiological saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, bulking agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners, and flavoring agents.

[0049] The dosage form of the pharmaceutical of this embodiment may be any formulation suitable for intravenous administration, and is not particularly limited. Examples of formulations suitable for intravenous administration include injections, such as sterile solutions or suspensions in water or other pharmaceutically acceptable liquids. Additives that can be incorporated into injections include, but are not limited to, vehicles such as isotonic solutions containing saline, glucose, or other adjuvants (e.g., D-sorbitol, D-mannitol, or sodium chloride); solubilizers such as alcohols (e.g., ethanol or benzyl alcohol), esters (e.g., benzyl benzoate), and polyalcohols (e.g., propylene glycol or polyethylene glycol); nonionic surfactants such as polysorbate 80 or polyoxyethylene hydrogenated castor oil; oily solutions such as sesame oil or soybean oil; buffers such as phosphate buffer or sodium acetate buffer; soothing agents such as benzalkonium chloride or procaine hydrochloride; stabilizers such as human serum albumin or polyethylene glycol; preservatives; and antioxidants. The prepared injection is usually filled into an appropriate container (for example, a vial or an ampoule) and stored under an appropriate environment until use.

[0050] The medicament of this embodiment can also be used in combination with one or more other medicaments useful as a medicine. In this case, the medicament of this embodiment may be provided in the form of a single medicine containing an AM or a derivative thereof having adrenomedullin activity and one or more other drugs, or may be provided in the form of a pharmaceutical combination or kit containing multiple preparations in which an AM or a derivative thereof having adrenomedullin activity and one or more other drugs are separately formulated. In the case of a pharmaceutical combination or kit, the respective preparations can be administered simultaneously or separately (for example, consecutively).

[0051] When AM or a derivative thereof having adrenomedullin activity is applied to a pharmaceutical use, AM or a derivative thereof having adrenomedullin activity includes not only the compound itself but also pharmaceutically acceptable salts of the compound and pharmaceutically acceptable solvates thereof. Pharmaceutically acceptable salts of AM or a derivative thereof having adrenomedullin activity and pharmaceutically acceptable solvates thereof are not limited to, but are preferably, for example, the salts or solvates exemplified above. When AM or a derivative thereof having adrenomedullin activity is in the form of the above-mentioned salt or solvate, the compound can be applied to the desired pharmaceutical use.

[0052] The AM or a derivative thereof having adrenomedullin activity used as the active ingredient of the medicament of this embodiment is derived from the natural physiologically active peptide adrenomedullin. Therefore, the AM or a derivative thereof having adrenomedullin activity is safe and low-toxic. Therefore, the medicament of this embodiment can be applied to various subjects requiring treatment for diseases for which administration of an AM or the like is expected to be therapeutically effective. The subject is preferably a human or non-human mammalian subject or patient (e.g., a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, hamadryas baboon, or chimpanzee), and more preferably a human patient. Diseases in the subject can be treated by intermittently administering the medicament of this embodiment to the subject.

[0053] When the medicament of this embodiment is administered to a subject, particularly a human patient, the exact dosage and administration method should ultimately be determined by the attending physician, taking into consideration many factors such as the subject's age, sex, symptoms to be prevented or treated, the exact state (e.g., severity) of the disease and / or disorder, and the route of administration. Therefore, in the medicament of this embodiment, the active ingredient AM or a derivative thereof having adrenomedullin activity is administered to the subject at a therapeutically effective dosage and administration method (e.g., dosage amount and administration route).

[0054] In the pharmaceutical of this embodiment, the active ingredient, AM or a derivative thereof having adrenomedullin activity, is preferably administered intravenously intermittently. In this embodiment, the pharmaceutical of this embodiment is in the form of an injectable preparation, such as a sterile solution or suspension in water or another pharmaceutically acceptable liquid (e.g., physiological saline). The intravenous administration is preferably carried out at a rate of 1.0 to 20.0 ng of active ingredient / kg body weight / min, and more preferably at a rate of 6.0 to 12.0 ng of active ingredient / kg body weight / min, calculated as AM. If the administration rate of AM or a derivative thereof having adrenomedullin activity exceeds the upper limit, undesirable side effects such as decreased or fluctuating blood pressure, worsening of cerebral infarction, or the occurrence of hemorrhagic cerebral infarction may occur. Furthermore, if the administration rate of AM or a derivative thereof having adrenomedullin activity is below the lower limit, sufficient therapeutic effects may not be achieved. Therefore, by intermittently administering the pharmaceutical of this embodiment intravenously at an administration rate within the above range, diseases can be treated without causing undesirable side effects.

[0055] In the pharmaceutical of this embodiment, intermittent administration is not limited to the cerebrovascular disorder described in the examples, and can be similarly applied to any disease for which the administration of an AM is expected to have a therapeutic effect (e.g., cerebrovascular disorder, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, heart disease, etc.) That is, the examples of the present application employ cerebrovascular disorder as an example of a disease for which the AM according to the present invention is intermittently administered, and the effects were confirmed.

[0056] In this pharmaceutical embodiment, the intravenous administration is preferably performed intermittently for 23 hours or less per day, more preferably for 15 hours or less, even more preferably for 12 hours or less, even more preferably for 10 hours or less, and particularly preferably for 8 hours or less per day. For example, after continuous intravenous administration for 8 hours or less, a drug-free period of 16 hours or more is allowed until the start of the next administration, and this cycle is repeated thereafter. Furthermore, the intravenous administration is preferably performed under the above-mentioned conditions (i.e., intermittent administration for 23 hours, 15 hours, 12 hours, 10 hours, or 8 hours or less per day) for 3 to 30 days, more preferably for 4 to 25 days, even more preferably for 5 to 20 days, even more preferably for 6 to 16 days, especially preferably for 7 to 14 days, and most preferably for 7 days. If the administration period of AM or a derivative thereof having adrenomedullin activity is less than the above-mentioned lower limit, a sufficient therapeutic effect may not be obtained. Therefore, by intermittently administering the medicament of this embodiment intravenously for an administration period within the above-mentioned range, the disease can be treated with a higher therapeutic effect.

[0057] In the pharmaceutical of this embodiment, the intermittent administration of AM or a derivative thereof having adrenomedullin activity is preferably initiated immediately after the onset of a disease (e.g., cerebral infarction). In conventional administration methods, for example, continuous administration for several days immediately after the onset of a disease (e.g., cerebral infarction) followed by a transition to intermittent administration was generally considered effective, but according to the present invention, the therapeutic effect can be enhanced by starting intermittent administration immediately after the onset of the disease.

[0058] In the pharmaceutical of this embodiment, the active ingredient, AM or a derivative thereof having adrenomedullin activity, is administered intravenously, preferably at a rate of 1.0 to 20.0 ng active ingredient / kg body weight / minute, more preferably at a rate of 6.0 to 12.0 ng active ingredient / kg body weight / minute, and the intravenous administration is preferably carried out based on a dosing regimen of 8 hours of continuous administration and 16 hours of no administration, repeated over a period of 7 days after the start of administration. By intermittently administering the pharmaceutical of this embodiment intravenously based on this dosing regimen, diseases can be treated with greater therapeutic efficacy.

[0059] In various aspects of the present invention, when a subject to be treated with AM or a derivative thereof having adrenomedullin activity is, for example, a subject with acute cerebral infarction, the therapeutic effect can be determined by, for example, administering a pharmaceutical containing AM or a derivative thereof having adrenomedullin activity as an active ingredient to the subject, and assessing the symptoms of cerebral infarction in the subject using, for example, the Stroke Severity Scale (SS), the modified Rankin Scale (mRS), clinical tests (e.g., hematology tests and blood biochemistry tests), vital signs (e.g., blood pressure and electrocardiogram), head imaging findings (e.g., CT and / or MR tests to evaluate the presence or absence of bleeding, infarction, and severe stenosis), nuclear medicine tests, or ultrasound tests. For example, when assessing the symptoms of cerebral infarction in a subject with acute cerebral infarction using the NIHSS, the change in NIHSS score after one week is, for example, in the range of -1.5 to -4.5 on average.

[0060] (Other Embodiments) The present invention also relates to the following: [8] A method for treating a disease, comprising administering to a subject a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the disease is one for which therapeutic effects can be expected by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and wherein the administration is intermittent administration. [8a] The method according to [8], wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond in the peptide of (ii) is replaced by an ethylene group and the peptide has adrenomedullin activity; (iv) a peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides of (i) to (iii), and the peptide has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides of (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus in any of the peptides of (i) to (iv).[8b] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g), in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h), in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h), in which a glycine residue is added to the C-terminus; The method according to [8] or [8a], wherein the peptide is selected from the group consisting of:[8c] The method of any one of [8] to [8b], wherein the disease is one for which the anti-inflammatory, angiogenic, cardiovascular protective, and / or tissue repair promoting effects of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, are expected to be therapeutically effective. [8d] The method of any one of [8] to [8c], wherein the disease is at least one selected from the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, and heart disease. [8e] The method of any one of [8] to [8d], wherein the intermittent administration is for 23 hours or less per day. [8f] The method of any one of [8] to [8e], wherein the intermittent administration is for 23 hours or less per day for 3 to 30 days.

[0061] The AM or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof administered in the method of this embodiment has the same characteristics as the active ingredient of the medicament of this embodiment described above. Furthermore, the method of this embodiment can be carried out in the same manner and dosage as the medicament of this embodiment described above. Furthermore, the method of this embodiment can treat the same diseases as the medicament of this embodiment described above.

[0062] The present invention also relates to the following: [9] Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in treating a disease, wherein the disease is one for which therapeutic effects are expected to be achieved by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered intermittently. [9a] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond in the peptide of (ii) is substituted with an ethylene group and the peptide has adrenomedullin activity; (iv) a peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides of (i) to (iii), and the peptide has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides of (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus in any of the peptides of (i) to (iv). The adrenomedullin or a derivative thereof having adrenomedullin activity according to [9], or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is a peptide selected from the group consisting of:[9b] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g), in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h), in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h), in which a glycine residue is added to the C-terminus; The adrenomedullin or a derivative thereof having adrenomedullin activity according to [9] or [9a], which is a peptide selected from the group consisting of:[9c] The adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to any of [9] to [9b], wherein the disease is a disease for which the anti-inflammatory, angiogenic, cardiovascular protective, and / or tissue repair promoting effects of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. [9d] The adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to any of [9] to [9c], wherein the disease is at least one selected from the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, and heart disease. [9e] The adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to any of [9] to [9d], wherein the intermittent administration is administration for 23 hours or less per day. [9f] The adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to any of [9] to [9e], wherein the intermittent administration is administration for 23 hours or less per day for 3 to 30 days.

[0063] The AM or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof in this embodiment has the same characteristics as the active ingredient of the medicament of this embodiment described above. Furthermore, the AM, etc. in this embodiment can be administered in the same manner and dosage as the medicament of this embodiment described above. Furthermore, the AM, etc. in this embodiment can treat the same diseases as the medicament of this embodiment described above.

[0064] The present invention also relates to the following:

[10] Use of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for treating a disease, wherein the disease is one for which therapeutic effects can be expected by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the medicament for treatment is administered intermittently. [10a] The use according to

[10] , wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond in the peptide of (ii) is replaced by an ethylene group and the peptide has adrenomedullin activity; (iv) a peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides of (i) to (iii), and the peptide has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides of (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus in any of the peptides of (i) to (iv).[10b] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g), in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h), in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h), in which a glycine residue is added to the C-terminus; The use according to

[10] or [10a], wherein the peptide is selected from the group consisting of:[10c] The use according to any one of

[10] to [10b], wherein the disease is one for which the anti-inflammatory, angiogenic, cardiovascular protective, and / or tissue repair promoting effects of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, are expected to be therapeutically effective. [10d] The use according to any one of

[10] to [10c], wherein the disease is at least one selected from the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, and heart disease. [10e] The use according to any one of

[10] to [10d], wherein the intermittent administration is within 23 hours per day. [10f] The use according to any one of

[10] to [10e], wherein the intermittent administration is within 23 hours per day for 3 to 30 days.

[0065] The AM or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof used in this embodiment has the same characteristics as the active ingredient of the medicament of this embodiment described above. Furthermore, the use of this embodiment can be carried out in the same manner and dosage as the medicament of this embodiment described above. Furthermore, the use of this embodiment can treat the same diseases as the medicament of this embodiment described above.

[0066] Furthermore, in one embodiment of the present invention, the following is provided:

[11] Use of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the treatment of a disease, wherein the disease is one for which therapeutic effects are expected to be achieved by administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and wherein the adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is administered intermittently. [11a] The use according to

[11] , wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond in the peptide of (ii) is replaced by an ethylene group and the peptide has adrenomedullin activity; (iv) a peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides of (i) to (iii), and the peptide has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides of (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus in any of the peptides of (i) to (iv).[11b] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g), in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h), in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h), in which a glycine residue is added to the C-terminus; The use according to

[11] or [11a], wherein the peptide is selected from the group consisting of:[11c] The use according to any one of

[11] to [11b], wherein the disease is one for which the anti-inflammatory, angiogenic, cardiovascular protective, and / or tissue repair promoting effects of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, are expected to be therapeutically effective. [11d] The use according to any one of

[11] to [11c], wherein the disease is at least one selected from the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, and heart disease. [11e] The use according to any one of

[11] to [11d], wherein the intermittent administration is within 23 hours per day. [11f] The use according to any one of

[11] to [11e], wherein the intermittent administration is within 23 hours per day for 3 to 30 days.

[0067] The AM or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof used in this embodiment has the same characteristics as the active ingredient of the medicament of this embodiment described above. Furthermore, the use of this embodiment can be carried out in the same manner and dosage as the medicament of this embodiment described above. Furthermore, the use of this embodiment can treat the same diseases as the medicament of this embodiment described above.

[0068] The present invention will be described in more detail below using examples, but the scope of the present invention is not limited thereto. In these examples, an example of the application of the present invention to a patient with "acute cerebral infarction," which is a type of cerebrovascular disorder, is shown as an example of "a disease for which the administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is expected to have a therapeutic effect."

[0069] <Study I: Effect of intermittent administration of adrenomedullin on symptoms of cerebral infarction in patients with acute cerebral infarction> [I-1: Test drug] (a) Active ingredient: Synthetic human adrenomedullin (a peptide consisting of the amino acid sequence of SEQ ID NO: 1, amidated at the C-terminus, and in which two cysteine ​​residues in the amino acid sequence form a disulfide bond to form a ring structure). (b) Dosage form, content, and properties: An injection (lyophilized product) in which 500 μg of white mass or powder of synthetic human adrenomedullin is sealed in one vial. It also contains 50 mg of D-mannitol. (c) Preparation: At the time of use, inject 10 mL of saline into the vial of test drug with a syringe and dissolve without creating bubbles. Transfer 10 mL of the dissolved test drug into the syringe and add 20 mL of saline to dilute to a total volume of 30 mL. (d) Storage: After dissolution, store in a sealed container protected from light and refrigerated (2-8°C). The control drug (placebo) will contain no active ingredients (only 50 mg of D-mannitol) and will be prepared to have the same dosage form and properties as the test drug. The test drug and control drug will be indistinguishable from each other by appearance. [I-2: Subjects] Patients with acute cerebral infarction will be selected as subjects for this study at the National Cerebral and Cardiovascular Center, a national research and development organization. Patients must meet the following inclusion criteria: treatment can be initiated within 24 hours of the onset of cerebral infarction; neurological symptoms with an NIHSS score of 1 or higher; and do not meet the exclusion criteria: suspected embolic mechanism. Patients selected based on the above criteria will be assigned to the AM intermittent administration group (20 patients), the AM continuous / intermittent administration group (20 patients), or the placebo group (20 patients). [I-3: Administration plan] (a) Test drug (first half cohort) Continuous intravenous administration at 9 ng / kg / min for 8 hours continued for 7 days. During the washout period until 72 hours later, only saline was administered intravenously (AM intermittent administration group). (second half cohort) Continuous intravenous administration at 9 ng / kg / min for 72 hours. Thereafter, continuous intravenous administration for 8 hours continued for 4 days (AM continuous / intermittent administration group). (b) Control drug (placebo) (first half cohort) Same as the test drug. (second half cohort) Same as the test drug.[I-4: Evaluation items] (a) Primary endpoint: Safety endpoint: Serious adverse events (SAEs) for which a causal relationship cannot be denied Efficacy endpoint: National Institutes of Health Stroke Scale (NIHSS) (b) Secondary endpoint: Safety endpoint: Adverse events (AEs) Efficacy endpoint: Modified Rankin Scale (mRS) (c) Other endpoints: Clinical tests (hematology tests and blood chemistry tests will be performed) Vital signs (blood pressure and electrocardiogram will be measured) Head imaging findings (CT and / or MR scans will be used to evaluate the presence or absence of bleeding, infarction, and severe stenosis) Maximum blood concentration and efficacy endpoints (d) Exploratory endpoint: AM blood concentration.

[0070] [Results-1] The primary and secondary endpoints regarding safety and efficacy are shown in Table 1.

[0071]

[0072] (Safety Evaluation Items) The primary endpoint was "serious adverse events (SAEs) for which a causal relationship cannot be denied," but no such events were observed in the AM intermittent administration group, AM continuous / intermittent administration group, or placebo group. In other words, it was demonstrated that the AM intermittent administration of the present invention can be performed safely.

[0073] (Efficacy evaluation items) The LSM (95% CI) of the NIHSS scores in the AM intermittent, AM continuous / intermittent, and placebo groups was 2.77 (2.35-3.19), 3.85 (3.38-4.32), and 3.07 (2.72-3.42) at 8 hours after the start of intervention; 2.32 (1.69-2.95), 3.50 (2.91-4.09), and 2.77 (2.41-3.13) at 24 hours; 2.52 (1.35-3.69), 3.40 (2.69-4.11), and 2.62 (1.55-3.68) at 72 hours; and 1.97 (0.92-3.03), 3.20 (2.46-3.93), and 2.27 (1.23-3.30) at the last day of intervention, respectively. Early neurological improvement in NIHSS scores was observed in 8 cases (40.0%) in the AM intermittent administration group, 3 cases (15.0%) in the AM continuous / intermittent administration group, and 7 cases (35.0%) in the placebo group.

[0074] In addition, in 60 patients with non-cardiogenic acute cerebral infarction, the outcomes were compared among 20 patients in the AM intermittent group, 20 patients in the AM continuous / intermittent group, and 20 patients in the placebo group. The number of patients with a good functional outcome (mRS 0-2) was 15 (75.0%) in the AM intermittent group, 13 (65.0%) in the AM continuous / intermittent group, and 13 (68.4%) in the placebo group. Furthermore, the number of patients with a functional outcome of being able to walk (mRS 0-3) was 18 (90.0%) in the AM intermittent group, 17 (85.0%) in the AM continuous / intermittent group, and 14 (73.7%) in the placebo group.

[0075] These results indicated that the AM intermittent administration group showed good outcomes.

[0076] [Results-2] Considering the imbalance in age, sex, and proportion of patients receiving intravenous rt-PA therapy in each group, we performed a multivariate analysis of the change in NIHSS score after adjusting for these factors. The results are shown in Table 2.

[0077]

[0078] As is clear from Table 2, the AM intermittent administration group showed statistically significantly better results in terms of NIHSS values ​​8 hours and 24 hours after the start of administration of the study drug.

[0079] According to the present invention, because the therapeutic effect of AM is high, it is extremely useful in the treatment of diseases for which AM is expected to be effective. This application is based on Japanese Patent Application No. 2024-011993 (filing date: January 30, 2024), the contents of which are incorporated in full herein.

Claims

1. A pharmaceutical for treating a disease, comprising as an active ingredient adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the disease is one for which therapeutic effects can be expected from the administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and wherein the active ingredient is administered intermittently.

2. The pharmaceutical according to claim 1, wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond in peptide (ii) is replaced with an ethylene group and the peptide has adrenomedullin activity; (iv) a peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides (i) to (iii), and the peptide has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus in any of the peptides (i) to (iv).

3. The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the cysteine residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, in which the cysteine residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, in which the cysteine residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8, in which the cysteine residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10, in which the cysteine residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12, in which the cysteine residues at positions 14 and 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g), in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h), in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h), in which a glycine residue is added to the C-terminus; The pharmaceutical composition according to claim 1 or 2, which is a peptide selected from the group consisting of:

4. The pharmaceutical composition according to claim 1 or 2, wherein the disease is one for which the anti-inflammatory, angiogenic, cardiovascular protective and / or tissue repair promoting effects of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, are expected to have a therapeutic effect.

5. The pharmaceutical composition according to claim 1 or 2, wherein the disease is at least one selected from the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, and heart disease.

6. The pharmaceutical composition according to claim 1 or 2, wherein the intermittent administration is for no more than 23 hours per day.

7. The pharmaceutical composition according to claim 1 or 2, wherein the intermittent administration is within 23 hours per day for 3 to 30 days.

8. A method for treating a disease, comprising administering to a subject a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the disease is one for which therapeutic effects can be expected from the administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and wherein the administration is intermittent.

9. Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of a disease, wherein the disease is one for which therapeutic effects are expected to be achieved by administering adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, characterized in that the adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered intermittently.

10. Use of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for treating a disease, wherein the disease is one for which therapeutic effects can be expected from the administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the medicament for treatment is administered intermittently.

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