A medicine for treating the symptoms of cerebral infarction in patients with acute cerebral infarction

Abstract

The present invention provides a means for treating a symptom of cerebral infarction in a cerebral infarction patient, particularly in an acute stage cerebral infarction patient, without causing undesirable side effects, by optimizing the administration and dosage of a drug that includes, as an active ingredient, adrenomedullin (AM) or a derivative thereof having adrenomedullin activity. One aspect of the present invention relates to a drug for treating a symptom of cerebral infarction in an acute stage cerebral infarction patient, said drug including, as an active ingredient, adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any of these.

Description

Technical Field

[0001] The present invention relates to a medicament for treating the symptoms of cerebral infarction in acute-phase cerebral infarction patients. In particular, one aspect of the present invention relates to a medicament for treating the symptoms of cerebral infarction in acute-phase cerebral infarction patients, which contains adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

Background Art

[0002] With the progress of the treatment of acute-phase cerebral infarction, such as recombinant tissue-type plasminogen activator (rt-PA or tPA) intravenous therapy and endovascular therapy, the recanalization rate of occluded blood vessels has become as high as 70-80%, and many patients have benefited from it. However, the number of deaths from stroke in Japan still reaches 110,000 annually. In addition, cerebral infarction is a major cause of bedriddenness and dementia, and its direct cost far exceeds 1 trillion yen annually. Therefore, two issues are (1) how to relieve the tissue damage caused by acute ischemia and (2) how to realize regenerative medicine by utilizing the reperfused blood flow.

[0003] Adrenomedullin (hereinafter also referred to as "AM") is a bioactive peptide isolated and identified from chromaffin tissue in 1993 (Non-Patent Document 1). At the beginning of its discovery, AM was found to exhibit a strong vasodilatory hypotensive effect. For example, Patent Document 1 describes a peptide having a blood pressure-lowering effect containing the amino acid sequence of human AM.

[0004] Subsequent studies have revealed that AM exhibits a variety of pharmacological effects, such as cardiovascular protective effects, anti-inflammatory effects, angiogenesis effects, and effects that promote tissue repair. In addition, with the aim of applying the pharmacological effects of AM to disease treatment, administration studies of AM have been conducted on various disease patients. Among them, the usefulness of AM as a therapeutic agent for inflammatory bowel disease, pulmonary hypertension, peripheral vascular disease, or acute myocardial infarction is expected.

[0005] For example, Patent Document 2 describes a prophylactic or therapeutic agent for non-bacterial inflammatory bowel disease containing, as an active ingredient, adrenomedullin or a derivative thereof having an activity to suppress non-bacterial inflammation, or a salt thereof having an activity to suppress non-bacterial inflammation.

[0006] Patent Document 3 describes a method for preventing or treating inflammatory bowel disease in a patient who requires prevention or treatment of inflammatory bowel disease for whom the use of a steroid preparation, immunosuppressant, or biological preparation is difficult or ineffective, the method comprising administering to the patient an effective amount of adrenomedullin, a derivative thereof having an activity to suppress inflammation, or a salt of the adrenomedullin or the derivative having an activity to suppress inflammation.

[0007] The blood concentration of AM is also proportional to the severity of cerebrovascular lesions. From this, AM is considered to be an important peptide hormone that promotes the body's defense response against cerebral infarction. For example, Non-Patent Document 2 describes that, using a chronic cerebral hypoperfusion model mouse (BCAS model: bilateral common carotid artery stenosis), AM exerted a tissue protective effect through an angiogenesis effect or an effect of suppressing the activation (inflammation) of microglia. Non-Patent Document 3 describes the effectiveness of AM administration in a middle cerebral artery occlusion (acute ischemia) model and the effect of reducing cerebral infarction in AM-overexpressing mice (AM-transgenic mice). Non-Patent Document 4 describes a decrease in ischemic tolerance in AM-deficient (AM+ / -) mice.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0010] As described above, since non-clinical findings of AM in cerebrovascular disorders have been obtained, the therapeutic effect of AM in cerebrovascular disorders, particularly cerebral infarction, has been expected. However, there were several problems in the administration of AM to patients with cerebrovascular disorders, particularly cerebral infarction.

[0011] As described above, AM has a potent vasodilatory hypotensive effect. Therefore, when administering AM over a long period, it was necessary to avoid administration at night due to concerns about blood pressure reduction from the perspective of blood pressure management. In addition, when administering AM to patients with cerebral infarction, there was a possibility that blood pressure fluctuations associated with the vasodilatory action of AM would cause the cerebral infarction to worsen, and there was also a possibility of concurrent hemorrhagic cerebral infarction due to the angiogenesis action of AM.

[0012] Therefore, an object of the present invention is to provide a means for treating the symptoms of cerebral infarction without causing undesirable side effects by optimizing the usage and dosage of a medicament containing AM or its derivative having adrenomedullin activity as an active ingredient in patients with cerebral infarction, particularly acute-phase cerebral infarction patients.

Means for Solving the Problems

[0013] The inventors have variously considered means for solving the above problems. The inventors have found that by continuously administering a predetermined dose of AM to acute cerebral infarction patients according to a predetermined administration schedule, the symptoms of cerebral infarction can be treated without causing undesirable side effects. Based on the above findings, the inventors have completed the present invention.

[0014] That is, the present invention includes the following aspects and embodiments. (1) A medicament for treating the symptoms of cerebral infarction in acute cerebral infarction patients, containing adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. (2) The medicament according to the above embodiment (1), further containing one or more pharmaceutically acceptable carriers. (3) The above adrenomedullin or a derivative thereof having adrenomedullin activity is as follows: (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, (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group and has adrenomedullin activity, (iv) In any of the peptides of (i) to (iii), 1 to 15 amino acid residues are deleted, substituted or added, and has adrenomedullin activity, (v) In any of the peptides of (i) to (iv), a peptide in which the C-terminus is amidated, and (vi) In any of the peptides of (i) to (iv), a peptide in which a glycine residue is added to the C-terminus The medicament according to the above embodiment (1) or (2), which is a peptide selected from the group consisting of. (4) The above adrenomedullin or a derivative thereof having adrenomedullin activity is as follows: (i) A peptide consisting of the amino acid sequence of adrenomedullin, (ii) A peptide consisting of the amino acid sequence of adrenomedullin and having two cysteine residues in the amino acid sequence forming a disulfide bond, (v) A peptide in which the C-terminus is amidated in the peptide of (i) or (ii), and (vi) A peptide in which a glycine residue is added to the C-terminus in the peptide of (i) or (ii) The medicament according to the above-mentioned embodiment (3), which is a peptide selected from the group consisting of (5) The adrenomedullin or its derivative having adrenomedullin activity is as follows: (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (g) A peptide in any one of (a) to (f), wherein the disulfide bond is replaced by an ethylene group and has adrenomedullin activity; (h) A peptide in any one of (a) to (g), wherein 1 to 15 amino acid residues are deleted, substituted or added and has adrenomedullin activity; (i) A peptide in any one of (a) to (h), wherein the C-terminus is amidated; and (j) A peptide in any one of (a) to (h), wherein a glycine residue is added to the C-terminus; The medicament according to any one of the above embodiments (1) to (3), which is a peptide selected from the group consisting of: (6) The adrenomedullin or a derivative thereof having adrenomedullin activity is as follows: (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (i) In any of the peptides of (a) to (f), a peptide in which the C-terminus is amidated; and (j) In any of the peptides of (a) to (f), a peptide having a glycine residue added to the C-terminus; The pharmaceutical according to the above-mentioned embodiment (5), which is a peptide selected from the group consisting of; (7) The pharmaceutical according to any one of the above-mentioned embodiments (1) to (6), wherein adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is continuously administered intravenously. (8) The pharmaceutical according to the above-mentioned embodiment (7), wherein the intravenous administration is continuously performed at a rate in the range of 1.0 to 20.0 ng of the active ingredient / kg body weight / min. (9) The pharmaceutical according to the above-mentioned embodiment (7) or (8), wherein the intravenous administration is continuously performed for 6 to 24 hours per day. (10) The pharmaceutical according to any one of the above-mentioned embodiments (7) to (9), wherein the intravenous administration is performed for 3 to 14 days. (11) The pharmaceutical according to any one of the above-mentioned embodiments (7) to (10), wherein the intravenous administration is a repetition of 8-hour continuous administration and 16-hour continuous administration of only physiological saline on the 1st to 3rd days after the start of administration, and a repetition of 8-hour continuous administration and 16-hour non-administration on the 4th to 7th days after the start of administration, or the intravenous administration is 72-hour continuous administration on the 1st to 3rd days after the start of administration, and a repetition of 8-hour continuous administration and 16-hour non-administration on the 4th to 7th days after the start of administration, and is performed according to the administration schedule. (12) The pharmaceutical according to any one of the above-mentioned embodiments (1) to (11), wherein the acute cerebral infarction patient is a patient within 24 hours from the onset of cerebral infarction. (13) The pharmaceutical according to any one of the above-mentioned embodiments (1) to (12), wherein the acute cerebral infarction patient is a patient suffering from non-embolic cerebral infarction. A method for treating symptoms of the cerebral infarction, comprising administering to a subject in need of treatment for acute cerebral infarction an effective amount of adrenomedullin or an adrenomedullin derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. (15) Adrenomedullin or an adrenomedullin derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in treating symptoms of cerebral infarction in patients with acute cerebral infarction. (16) Use of adrenomedullin or an adrenomedullin derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for treating symptoms of cerebral infarction in patients with acute cerebral infarction. (17) Use of adrenomedullin or an adrenomedullin derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for treating symptoms of cerebral infarction in patients with acute cerebral infarction.

Advantages of the Invention

[0015] According to the present invention, by optimizing the usage and dosage of a medicament containing, as an active ingredient, AM or its derivative having adrenomedullin activity in patients with cerebral infarction, particularly patients with acute cerebral infarction, it becomes possible to provide a means for treating symptoms of cerebral infarction without causing undesirable side effects.

[0016] This specification incorporates the content described in the specification of Japanese Patent Application No. 2019-220015, which is the basis of the priority of this application.

Modes for Carrying Out the Invention

[0017] As used herein, "acute cerebral infarction" generally means a cerebral infarction within 72 hours, particularly within 24 hours, from onset. Cerebral infarction is classified into embolic cerebral infarction and non-embolic (e.g., thrombotic or hemodynamic) cerebral infarction based on the onset mechanism, and is also classified into lacunar infarction, atherosclerotic thrombotic cerebral infarction, cardiogenic cerebral embolism, etc. based on the clinical disease type.

[0018] Adrenomedullin (AM) is a bioactive peptide isolated and identified from pheochromocytoma in 1993 (Non-Patent Document 1). At the time of its discovery, AM was found to exhibit a potent vasodilatory hypotensive effect. Subsequent studies have revealed that AM exerts diverse pharmacological effects such as cardiovascular protective effects, anti-inflammatory effects, angiogenesis effects, and tissue repair promoting effects. In addition, administration studies of AM to various disease patients have been conducted with the aim of applying the pharmacological effects of AM to disease treatment.

[0019] To date, the association between AM and cerebrovascular disorders has been reported (Non-Patent Documents 2 to 4). For this reason, the therapeutic effect of AM in cerebrovascular disorders, particularly cerebral infarction, has been expected. However, AM has a potent vasodilatory hypotensive effect. Therefore, when administering AM over a long period, it was necessary to avoid administration at night due to concerns about blood pressure reduction from the perspective of blood pressure management. In addition, when administering AM to patients with cerebral infarction, there was a possibility that blood pressure fluctuations associated with the vasodilatory action of AM would cause the cerebral infarction to deteriorate, and a possibility of concurrent hemorrhagic cerebral infarction due to the angiogenesis effect of AM. Therefore, when administering AM to patients with cerebral infarction, it was necessary to optimize the dosage form and dosage.

[0020] The present inventors have found that by continuously administering a predetermined dose of AM to acute cerebral infarction patients according to a predetermined administration schedule, the symptoms of cerebral infarction can be treated without causing undesirable side effects. Therefore, one aspect of the present invention relates to a medicament for treating the symptoms of cerebral infarction in acute cerebral infarction patients, which contains AM or a derivative thereof having adrenomedullin activity as an active ingredient.

[0021] In each aspect of the present invention, a subject having acute cerebral infarction to be treated, for example, a patient with acute cerebral infarction, is usually a patient within 72 hours from the onset of cerebral infarction, particularly a patient within 24 hours from the onset. Further, a patient with acute cerebral infarction is usually a patient suffering from non-embolic cerebral infarction, for example, a patient suffering from non-cardioembolic cerebral infarction, that is, lacunar infarction or atherosclerotic thrombotic cerebral infarction. In each aspect of the present invention, by administering to a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, a medicament or the like containing as an active ingredient AM or a derivative thereof having adrenomedullin activity, the symptoms of the cerebral infarction can be treated without causing undesirable side effects.

[0022] Examples of the symptoms of cerebral infarction in a subject having acute cerebral infarction to be treated, for example, a patient with acute cerebral infarction, include, but are not limited to, inflammation caused by cerebral infarction, tissue damage due to acute ischemia, and vascular injury. In each aspect of the present invention, by administering to a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, a medicament or the like containing as an active ingredient AM or a derivative thereof having adrenomedullin activity, it is possible to obtain a therapeutic effect on the symptoms of cerebral infarction, such as control of inflammation of cerebral infarction through the anti-inflammatory action of AM, alleviation of tissue damage due to acute ischemia through the vasodilatory action of AM, and induction of angiogenesis through the angiogenic action of AM.

[0023] Examples of undesirable side effects that may occur when administering AM or a derivative thereof having adrenomedullin activity to a subject having acute cerebral infarction to be treated, for example, a patient with acute cerebral infarction, include, but are not limited to, blood pressure decrease or fluctuation, deterioration of cerebral infarction, or complication of hemorrhagic cerebral infarction. In each aspect of the present invention, by administering to a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, a medicament or the like containing as an active ingredient AM or a derivative thereof having adrenomedullin activity, the symptoms of cerebral infarction can be treated without causing the undesirable side effects exemplified above.

[0024] In each aspect of the present invention, the therapeutic effect on the symptoms of cerebral infarction in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, can be determined, for example, by administering a medicament containing, as an active ingredient, AM or a derivative thereof having adrenomedullin activity to the subject having acute cerebral infarction, and evaluating the symptoms of cerebral infarction in the subject using, for example, the Stroke Severity Assessment Scale (NIHSS), the modified Rankin Scale (mRS), clinical examinations (for example, hematological examinations and blood biochemical examinations), vital signs (for example, blood pressure and electrocardiogram), head imaging findings (for example, evaluation of the presence or absence of bleeding, infarction, and severe stenosis by CT and / or MR examinations), nuclear medicine examinations, or ultrasonic examinations. For example, when evaluating the symptoms of cerebral infarction in a subject having acute cerebral infarction using NIHSS, the change in NIHSS after one week is, on average, in the range of, for example, -1.5 to -4.5. Further, in each aspect of the present invention, the occurrence of undesirable side effects (for example, blood pressure decrease or fluctuation, exacerbation of cerebral infarction, or complication of hemorrhagic cerebral infarction) when administering a medicament containing, as an active ingredient, AM or a derivative thereof having adrenomedullin activity to a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, can be determined by the same means as described above.

[0025] As used herein, "treatment" means suppressing (for example, suppressing progression), alleviating, repairing, and / or curing the symptoms of cerebral infarction that have occurred (onset or manifestation) in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction.

[0026] In each aspect of the present invention, AM is not only a human-derived peptide (SEQ ID NO: 1, Non-Patent Document 1) isolated and identified from human brown adipose tissue, but also a peptide (ortholog) derived from other non-human mammals (e.g., warm-blooded animals) such as pigs (SEQ ID NO: 4), dogs (SEQ ID NO: 6), cows (SEQ ID NO: 8), rats (SEQ ID NO: 10) or mice (SEQ ID NO: 12). In vivo, in these peptides, two cysteine residues in their amino acid sequences form a disulfide bond, and the C-terminus is amidated. In the present specification, a peptide having a disulfide bond and a C-terminal amide group may be described as "native adrenomedullin" or simply "adrenomedullin". In each aspect of the present invention, any of the above peptides can be applied as an active ingredient.

[0027] As used herein, "C-terminal amidation" means a form of post-translational modification of a peptide in vivo. Specifically, it refers to the reaction in which the main-chain carboxyl group of the C-terminal amino acid residue of a peptide is converted into an amide group. Also, as used herein, "formation of a disulfide bond of a cysteine residue" or "disulfidization of a cysteine residue" means a form of post-translational modification of a peptide in vivo. Specifically, it refers to the reaction in which two cysteine residues in the amino acid sequence of a peptide form a disulfide bond (-S-S-). Many bioactive peptides produced in vivo are initially biosynthesized as precursor proteins with a larger molecular weight, and during the process of intracellular translocation, they undergo post-translational modification reactions such as C-terminal amidation and / or disulfidization of cysteine residues to become mature bioactive peptides. C-terminal amidation usually proceeds by the action of a C-terminal amidating enzyme on the precursor protein. In the case of a bioactive peptide having a C-terminal amide group, in its precursor protein, a Gly residue is bound to the C-terminal carboxyl group to be amidated, and this Gly residue is converted into a C-terminal amide group by a C-terminal amidating enzyme. Also, in the C-terminal propeptide of the precursor protein, there is a repetitive 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)). The disulfidization of cysteine residues can proceed under oxidative conditions. In vivo, the disulfidization of cysteine residues usually proceeds by the action of a protein disulfide isomerase on the precursor protein.

[0028] In each aspect of the present invention, the AM used as an active ingredient includes not only the native adrenomedullin itself but also its modified forms having adrenomedullin activity. In each aspect of the present invention, the "modified form of adrenomedullin" means a peptide obtained by chemically modifying the native adrenomedullin described above. Further, in each aspect of the present invention, "adrenomedullin activity" means, for example, various physiological actions exemplified below, and in particular, the action of controlling inflammation of cerebral infarction through the anti-inflammatory action of AM, the action of alleviating tissue damage due to acute ischemia through the vasodilatory action of AM, and the action of inducing angiogenesis through the angiogenic action of AM, which are physiological actions that can be involved in the treatment of symptoms of cerebral infarction. Even when the pharmaceutical composition of this aspect contains, as an active ingredient, a modified form of AM having the above-described adrenomedullin activity, it can treat the symptoms of cerebral infarction in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, through substantially the same biological activity (i.e., adrenomedullin activity) as native adrenomedullin.

[0029] (1) Cardiovascular system: Vasodilatory action, blood pressure lowering action, blood pressure elevation inhibitory action, increased cardiac output and improvement of heart failure, improvement of pulmonary hypertension, angiogenic action, lymphangiogenic action, improvement of vascular endothelial function, anti-atherosclerotic action, myocardial protective action (e.g., myocardial protective action in ischemia-reperfusion injury or inflammation), suppression of remodeling after myocardial infarction, suppression of cardiac hypertrophy, and angiotensin-converting enzyme inhibitory action. (2) Kidney and electrolyte system: Diuretic action, natriuretic action, antidiuretic hormone inhibitory action, aldosterone lowering action, renal protective action (e.g., myocardial protective action in hypertension or ischemia-reperfusion injury), suppression of drinking behavior, and suppression of salt appetite. (3) Brain and nervous system: Neuroprotective and brain damage inhibitory action, anti-inflammatory action (e.g., action of controlling inflammation of cerebral infarction), vasodilatory action (e.g., action of alleviating tissue damage due to acute ischemia), angiogenic action (e.g., action of inducing angiogenesis), apoptosis inhibitory action (e.g., apoptosis inhibitory action in ischemia-reperfusion injury or inflammation), maintenance of autoregulatory function, suppression of oxidative stress, improvement of dementia, and sympathetic nerve inhibitory action. (4) Genitourinary system: Erection improvement effect, blood flow improvement effect, and implantation promotion effect. (5) Digestive system: Anti-ulcer effect, tissue repair effect, mucosal regeneration effect, blood flow improvement effect, anti-inflammatory effect, and liver function improvement effect. (6) Orthopedic system: Osteoblast stimulation effect and arthritis improvement effect. (7) Endocrine and metabolic system: Adipocyte differentiation effect, lipolysis control effect, insulin sensitivity improvement effect, insulin secretion control effect, antidiuretic hormone secretion inhibition effect, and aldosterone secretion inhibition effect. (8) Others: Circulation improvement effect, anti-inflammatory effect, cytokine control effect, organ protection effect, oxidative stress suppression effect, tissue repair effect (e.g., anti-bedsore effect), improvement effect of septic shock, suppression effect of multiple organ failure, suppression effect of autoimmune diseases, antibacterial effect, hair growth promoting effect, and hair nourishing effect.

[0030] In each aspect of the present invention, not only AM itself but also its derivatives having adrenomedullin activity can be used as an active ingredient. In each aspect of the present invention, the "derivative of adrenomedullin" or "adrenomedullin derivative" means 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, the compounds disclosed in the specifications of International Publication No. WO2015 / 141819, International Publication No. WO2017 / 047788, and International Publication No. WO2018 / 181638. Those skilled in the art can prepare the compound by purchasing an AM derivative having adrenomedullin activity based on the above-mentioned documents, applying an appropriate conversion reaction to the purchased compound, or preparing it by themselves. The AM derivatives disclosed in the above-mentioned documents can continuously exhibit the pharmacological effects of adrenomedullin without substantially causing undesirable side effects. Therefore, in each aspect of the present invention, by using the AM derivatives disclosed in the above-mentioned documents as an active ingredient, it is possible to treat the symptoms of cerebral infarction in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, while substantially avoiding the occurrence of undesirable side effects through the adrenomedullin activity of the AM derivative.

[0031] The adrenomedullin or its derivative having adrenomedullin activity is as follows: (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, (iii) In the peptide of (ii), the disulfide bond is substituted by an ethylene group and has adrenomedullin activity, (iv) In any of the peptides of (i) to (iii), a peptide in which 1 to 15 amino acids are deleted, substituted or added and has adrenomedullin activity, (v) In any of the peptides of (i) to (iv), a peptide in which the C-terminus is amidated, and (vi) In any of the peptides of (i) to (iv), a peptide in which a glycine residue is added to the C-terminus is preferably a peptide selected from the group consisting of.

[0032] In one embodiment, the adrenomedullin or its derivative having adrenomedullin activity is as follows: (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) In the peptide of (i) or (ii), a peptide in which the C-terminus is amidated, and (vi) In the peptide of (i) or (ii), a peptide in which a glycine residue is added to the C-terminus is more preferably a peptide selected from the group consisting of.

[0033] Among the peptides (i) to (vi), the peptide consisting of the amino acid sequence of adrenomedullin included in (v), with its C-terminus amidated and the two cysteine residues in the amino acid sequence forming a disulfide bond, corresponds to mature native adrenomedullin. The peptide consisting of the amino acid sequence of adrenomedullin in (i) corresponds to the native form of adrenomedullin in an immature form (i.e., before undergoing post-translational modifications of C-terminal amidation and disulfide formation of cysteine residues). Among the peptides (i) to (vi), other peptides excluding the peptides described above correspond to modified forms of adrenomedullin.

[0034] The peptide in (ii) can be formed by air-oxidizing the thiol groups of the two cysteine residues of the peptide in (i) or by oxidizing them using an appropriate oxidant to convert them into a disulfide bond. By using the peptide in (ii), the three-dimensional structure of the peptide can be made similar to that of native adrenomedullin. Thereby, the adrenomedullin activity of the peptide in (ii) can be made substantially equivalent to that of native adrenomedullin.

[0035] The peptide in (iii) can be formed by converting the disulfide bond of the peptide in (ii) into an ethylene group. The substitution of a disulfide bond with an ethylene group can be carried out by methods well-known in the art (O. Keller et al., Helv. Chim. Acta, 1974, Vol. 57, p. 1253). By using the peptide in (iii), the three-dimensional structure of the peptide can be stabilized. Thereby, the peptide in (iii) can continuously exhibit adrenomedullin activity in vivo.

[0036] In the peptide of (iv) above, the number of amino acid residues that are deleted, substituted or added is preferably in the range of 1 to 15, 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 of (iv) is a peptide in which the 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-terminal side are deleted in any of the peptides of (i) to (iii) and which has adrenomedullin activity. A more preferred peptide of (iv) is a peptide in which the amino acid residues at positions 1 to 15, 1 to 10 or 1 to 5 from the N-terminal side are deleted in any of the peptides of (i) to (iii) and which has adrenomedullin activity. In the above-mentioned preferred peptide, one or more (for example, 1 to 5, 1 to 3, or 1 or 2) amino acid residues may be further deleted, substituted or added. By using the peptide of (iv) above, the adrenomedullin activity of the peptide can be made substantially equivalent to that of natural adrenomedullin. Further, by using the peptide of (iv) above, the peptide can continuously express adrenomedullin activity in vivo.

[0037] The peptide of (vi) above can be converted into the peptide of (v) by converting the glycine residue at the C-terminal into a C-terminal amide group by the action of a C-terminal amidating enzyme. Therefore, by administering the peptide of (vi) above to a subject, a C-terminal amidated peptide can be formed in the subject's body after a certain period of time. Thereby, the peptide of (vi) above can continuously express adrenomedullin activity in vivo.

[0038] The adrenomedullin or its derivative having adrenomedullin activity is as follows: (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (g) A peptide in any one of (a) to (f), wherein the disulfide bond is substituted by an ethylene group and has adrenomedullin activity; (h) A peptide in any one of (a) to (g), wherein 1 to 15 amino acids are deleted, substituted or added and has adrenomedullin activity; (i) A peptide in any one of (a) to (h), wherein the C-terminus is amidated; and (j) A peptide in any one of (a) to (h), wherein a glycine residue is added to the C-terminus; It is more preferable that the peptide is selected from the group consisting of.

[0039] In one embodiment, the adrenomedullin or a derivative thereof having adrenomedullin activity is as follows: (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (i) In any of the peptides (a) to (f), a peptide having an amidated C-terminus; and (j) In any of the peptides (a) to (f), a peptide having a glycine residue added to the C-terminus; It is more preferably a peptide selected from the group consisting of.

[0040] In the peptide of (h), the number of amino acid residues that are deleted, substituted or added is preferably in the range of 1 to 12, more preferably in the range of 1 to 10, still 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 of (h) is a peptide in which the 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-terminal side are deleted in any of the peptides of (a) to (g) and which has adrenomedullin activity. A more preferred peptide of (h) is a peptide in which the amino acid residues at positions 1 to 15, 1 to 10 or 1 to 5 from the N-terminal side are deleted in any of the peptides of (a) to (d) and which has adrenomedullin activity, or a peptide in which the amino acid residues at positions 1 to 13, 1 to 8 or 1 to 5 from the N-terminal side are deleted in the peptide of (e) or (f) and which has adrenomedullin activity. In the above-mentioned preferred peptide, one or more (for example, 1 to 5, 1 to 3, or 1 or 2) amino acids may be further deleted, substituted or added. By using the peptide of (h), the adrenomedullin activity of the peptide can be made substantially equivalent to that of natural adrenomedullin. Further, by using the peptide of (h), the peptide can continuously exhibit adrenomedullin activity in vivo.

[0041] In each aspect of the present invention, the AM or its derivative having adrenomedullin activity used as an active ingredient includes not only the compound itself but also its salts. When the derivative having AM or adrenomedullin activity is in the form of a salt, it is preferably a pharmaceutically acceptable salt. Examples of the counterions of the salts of the derivative having AM or adrenomedullin activity include, but are not limited to, cations such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, or anions such as chloride ion, bromide ion, iodide ion, phosphate ion, nitrate ion, sulfate ion, carbonate ion, hydrogen carbonate ion, perchlorate ion, formate ion, acetate ion, trifluoroacetate ion, propionate ion, lactate ion, maleate ion, hydroxymaleate ion, methylmaleate ion, fumarate ion, adipate ion, benzoate ion, 2-acetoxybenzoate ion, p-aminobenzoate ion, nicotinate ion, cinnamate ion, ascorbate ion, pamoate ion, succinate ion, salicylate ion, bismethylenesalicylic acid 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, or naphthalenesulfonate ion. When the derivative having AM or adrenomedullin activity is in the form of a salt with the above counterions, the adrenomedullin activity of the compound can be made substantially equivalent to that of native adrenomedullin.

[0042] In each aspect of the present invention, the AM or its derivative having adrenomedullin activity used as an active ingredient includes not only the compound itself but also solvates of the compound or its salt. When the AM or its derivative having adrenomedullin activity, or its salt, is in the form of a solvate, it is preferably a pharmaceutically acceptable solvate. Examples of solvents capable of forming a solvate with the compound or its salt include, 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 the AM or its derivative having adrenomedullin activity, or its salt, is in the form of a solvate with the above solvents, the adrenomedullin activity of the compound can be made substantially equivalent to that of native adrenomedullin.

[0043] In each aspect of the present invention, the AM or its derivative 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.

[0044] By having the above characteristics, the AM or its derivative having adrenomedullin activity can treat the symptoms of cerebral infarction in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, while maintaining the pharmacological action of native adrenomedullin.

[0045] In the medicine of this aspect, AM or its derivative having adrenomedullin activity used as an active ingredient may be used alone, or may be used in combination with one or more pharmaceutically acceptable ingredients. The medicine of this aspect can be formulated into various dosage forms commonly used in the art according to the desired administration method. Therefore, the medicine of this aspect can also be provided in the form of a pharmaceutical composition containing adrenomedullin or its derivative having adrenomedullin activity and one or more pharmaceutically acceptable carriers. In the case of this embodiment, in addition to the above components, the pharmaceutical composition may contain one or more pharmaceutically acceptable media (for example, a solvent such as sterilized water or a solution such as physiological saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (for example, vegetable oils), suspending agents, buffering agents, soothing agents, antioxidants, sweeteners, flavoring agents and other additives.

[0046] The dosage form of the medicament of this aspect is not particularly limited and may be a formulation for parenteral administration, or may be a formulation for administration via the mucosa (e.g., nasal, sublingual, or oral mucosa, etc.), transdermal, transanal (enema), or vaginal, etc., or may be a formulation for oral administration. Also, the dosage form of the medicament of this aspect may be a formulation in a unit dosage form or a formulation in a multiple dosage form. Examples of formulations for parenteral administration include, for example, injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable liquids. Additives that can be incorporated into the injection include, but are not limited to, vehicles such as isotonic solutions containing physiological saline, glucose, or other adjuvants (e.g., D-sorbitol, D-mannitol, or sodium chloride), solubilizing agents such as alcohols (e.g., ethanol or benzyl alcohol), esters (e.g., benzyl benzoate), polyalcohols (e.g., propylene glycol or polyethylene glycol), nonionic surfactants such as polysorbate 80 or polyoxyethylene hydrogenated castor oil, oily liquids 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, etc. The prepared injection is usually filled into a suitable container (e.g., vial or ampoule) and stored in a suitable environment until use.

[0047] The medicament of this aspect can also be used in combination with one or more other drugs useful as medicaments. In this case, the medicament of this aspect may be provided in the form of a single medicament containing AM or its derivative having adrenomedullin activity and one or more other drugs, or may be provided in the form of a pharmaceutical combination or kit containing a plurality of formulations in which AM or its derivative having adrenomedullin activity and one or more other drugs are separately formulated. In the case of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (e.g., sequentially).

[0048] When applying AM or its derivatives having adrenomedullin activity to pharmaceutical use, AM or its derivatives having adrenomedullin activity include not only the compound itself, but also pharmaceutically acceptable salts of the compound, and their pharmaceutically acceptable solvates. Pharmaceutically acceptable salts of AM or its derivatives having adrenomedullin activity, and their pharmaceutically acceptable solvates include, but are not limited to, for example, the salts or solvates exemplified above. When AM or its derivatives having adrenomedullin activity are in the form of the above salts or solvates, the compound can be applied to the desired pharmaceutical use.

[0049] The pharmaceutical of this embodiment can be used to treat the symptoms of cerebral infarction in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, and is usually preferably used to treat the symptoms of cerebral infarction in a patient with acute cerebral infarction suffering from non-embolic cerebral infarction, for example, non-cardioembolic cerebral infarction, that is, lacunar infarction or atherosclerotic thrombotic cerebral infarction. By using the pharmaceutical of this embodiment to treat the symptoms of cerebral infarction exemplified above in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, the symptoms of cerebral infarction can be treated.

[0050] The AM or its derivatives having adrenomedullin activity used as the active ingredient of the pharmaceutical of this embodiment are derived from adrenomedullin, a natural bioactive peptide. Therefore, AM or its derivatives having adrenomedullin activity are safe and low-toxic. Therefore, the pharmaceutical of this embodiment can be applied to various subjects in need of treatment for the symptoms of acute cerebral infarction. The subject is preferably a subject or patient of a human or non-human mammal (for example, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon or chimpanzee, etc.), and more preferably a human patient. By administering the pharmaceutical of this embodiment to the subject, the symptoms of acute cerebral infarction in the subject can be treated.

[0051] When administering the medicament of the present aspect to a subject, particularly a human patient, the exact usage and dosage should be finally determined by the attending physician to be therapeutically effective, taking into account many factors such as the age, sex of the subject, the exact condition (e.g., severity) of the symptoms, diseases and / or disorders to be prevented or treated, and the route of administration. Therefore, in the medicament of the present aspect, AM or its derivative having adrenomedullin activity as the active ingredient is administered to the subject at a therapeutically effective usage and dosage (e.g., dosage and route of administration).

[0052] The medicament of the present aspect may be administered by any route of administration. For example, the medicament of the present aspect is preferably administered by a parenteral route such as intravenous administration, enema administration, subcutaneous administration, intramuscular administration or intraperitoneal administration, more preferably by intravenous administration, and even more preferably by continuous intravenous infusion.

[0053] When administering the medicament of the present aspect to a subject having acute cerebral infarction, for example, a human patient suffering from acute cerebral infarction, it has been found that the symptoms of cerebral infarction can be treated without causing undesirable side effects (e.g., blood pressure decrease or fluctuation, deterioration of cerebral infarction or complication of hemorrhagic cerebral infarction) by continuously administering a predetermined dose of AM according to a predetermined administration schedule by intravenous injection.

[0054] In the medicine of this aspect, it is preferable that AM or its derivative having adrenomedullin activity as an active ingredient is continuously administered intravenously. In the case of this embodiment, the dosage form of the medicine of this aspect is, for example, an injection such as a sterile solution or suspension with water or other pharmaceutically acceptable liquids (for example, physiological saline). The intravenous administration is preferably continuously performed at a rate in the range of 1.0 to 20.0 ng active ingredient / kg body weight / min in terms of AM, and more preferably continuously performed at a rate in the range of 6.0 to 12.0 ng active ingredient / kg body weight / min. When the administration rate of AM or its derivative having adrenomedullin activity exceeds the upper limit value, it may cause undesirable side effects such as blood pressure decrease or fluctuation, deterioration of cerebral infarction, or complication of hemorrhagic cerebral infarction. Also, when the administration rate of AM or its derivative having adrenomedullin activity is less than the lower limit value, a sufficient therapeutic effect may not be obtained. Therefore, by continuously administering the medicine of this aspect intravenously at the administration rate within the above range, the symptoms of cerebral infarction can be treated without causing undesirable side effects.

[0055] In the case of the above embodiment, the intravenous administration is preferably continuously performed for 6 to 24 hours per day, and more preferably continuously performed for 6 to 8 hours. Also, the intravenous administration is preferably performed for 3 to 14 days, and more preferably performed for 3 to 7 days, under the condition of the duration per day within the above range. When the administration period of AM or its derivative having adrenomedullin activity is less than the lower limit value, a sufficient therapeutic effect may not be obtained. Therefore, by continuously administering the medicine of this aspect intravenously for the administration period within the above range, the symptoms of cerebral infarction can be treated without causing undesirable side effects.

[0056] The medicine of this embodiment is preferably intravenously administered continuously at a rate in the range of 1.0 to 20.0 ng active ingredient / kg body weight / min, more preferably in the range of 6.0 to 12.0 ng active ingredient / kg body weight / min, with the active ingredient being AM or its derivative having adrenomedullin activity, and the intravenous administration is repeated with 8-hour continuous administration and 16-hour continuous administration of only physiological saline on the 1st to 3rd days after the start of administration, and repeated with 8-hour continuous administration and 16-hour non-administration on the 4th to 7th days after the start of administration, or, preferably, based on an administration schedule in which it is continuously administered for 72 hours on the 1st to 3rd days after the start of administration and repeated with 8-hour continuous administration and 16-hour non-administration on the 4th to 7th days after the start of administration. By continuously intravenously administering the medicine of this embodiment based on the said administration schedule, the symptoms of cerebral infarction can be treated without causing undesirable side effects.

[0057] AM or its derivative having adrenomedullin activity used as the active ingredient of the medicine of this embodiment can be used for treating the symptoms of cerebral infarction in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction. Therefore, another aspect of the present invention relates to a therapeutic agent for acute cerebral infarction containing, as an active ingredient, AM or its derivative having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The therapeutic agent of this embodiment has the same characteristics as the medicine of this embodiment described above. Also, the therapeutic agent of this embodiment can be used in the same usage and dosage as the medicine of this embodiment described above. The therapeutic agent of this embodiment can be used for treating the symptoms of cerebral infarction in a subject having acute cerebral infarction, for example, a patient with acute cerebral infarction, and is usually preferably used for treating the symptoms of cerebral infarction in an acute cerebral infarction patient suffering from non-embolic cerebral infarction, for example, non-cardioembolic cerebral infarction, that is, lacunar infarction or atherosclerotic thrombotic cerebral infarction. By administering an effective amount of AM or its derivative having adrenomedullin activity to a subject in need of treatment for acute cerebral infarction, for example, a patient with acute cerebral infarction, the symptoms of cerebral infarction exemplified above can be treated.

[0058] Another aspect of the present invention is a method for treating symptoms of cerebral infarction, which comprises administering to a subject in need of treatment for acute cerebral infarction, such as a patient with acute cerebral infarction, an effective amount of AM or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. 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 aspect has the same characteristics as the active ingredient of the pharmaceutical of this aspect described above. Further, the method of this aspect can be carried out with the same usage and dosage as the pharmaceutical of this aspect described above. In the method of this aspect, the acute cerebral infarction is preferably usually non-embolic cerebral infarction, such as non-cardioembolic cerebral infarction, that is, lacunar infarction or atherosclerotic thrombotic cerebral infarction. By administering an effective amount of AM or a derivative thereof having adrenomedullin activity to a subject in need of treatment for acute cerebral infarction, such as a patient with acute cerebral infarction, the symptoms of cerebral infarction exemplified above can be treated.

[0059] Another aspect of the present invention is AM or its derivative having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in treating symptoms of cerebral infarction in a subject in need of treatment for acute cerebral infarction, such as a patient with acute cerebral infarction. Yet another aspect of the present invention is the use of AM or its derivative having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for treating symptoms of cerebral infarction in a subject in need of treatment for acute cerebral infarction, such as a patient with acute cerebral infarction. Still another aspect of the present invention is the use of an AM or adrenomedullin derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for treating symptoms of cerebral infarction in a subject in need of treatment for acute cerebral infarction, such as a patient with acute cerebral infarction. Compounds and the like of this aspect have the same characteristics as the active ingredients of the medicaments of this aspect described above. Also, compounds and the like of this aspect can be used in the same usage and dosage as the medicaments of this aspect described above. In this aspect of the compound or the use, the acute cerebral infarction is preferably usually non-embolic cerebral infarction, such as non-cardioembolic cerebral infarction, that is, lacunar infarction or atherosclerotic thrombotic cerebral infarction. By administering an effective amount of AM or its derivative having adrenomedullin activity to a subject in need of treatment for acute cerebral infarction, such as a patient with acute cerebral infarction, the symptoms of cerebral infarction exemplified above can be treated.

Example

[0060] Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

[0061] <Test I: Effect of adrenomedullin on symptoms of cerebral infarction in patients with acute cerebral infarction>

[0062] [I-1: Test drug] (a) Active ingredient: Synthetic human adrenomedullin (a peptide consisting of the amino acid sequence of SEQ ID NO: 1, with an amidated C-terminus and in which two cysteine residues in the amino acid sequence form a disulfide bond). (b) Dosage form, content, and properties: An injection (lyophilized product) in which 500 μg of synthetic human adrenomedullin in the form of a white mass or powder is enclosed in one vial. (c) Preparation: At the time of use, inject 10 mL of physiological saline into the vial of the test drug with a syringe and dissolve it without foaming. Take 10 mL of the dissolved test drug into a syringe and add 20 mL of physiological saline to dilute it to a total volume of 30 mL. (d) Storage: After dissolution, store it in a sealed container protected from light and refrigerated (2 - 8°C).

[0063] The control drug (placebo) does not contain an active ingredient and is prepared to have the same dosage form and properties as the test drug. The test drug and the control drug cannot be distinguished from each other by appearance.

[0064] [I-2: Subjects] At the National Cerebral and Cardiovascular Center, an incorporated administrative agency for national research and development, patients with acute cerebral infarction are selected as subjects for this study. In the selection of patients, administration of the therapeutic drug can be started within 24 hours after the onset of cerebral infarction; having neurological symptoms with a NIHSS of 1 or more; meeting the selection criteria and not conflicting with the exclusion criteria where an embolic mechanism is suspected. Patients selected based on the above criteria are assigned to the AM administration group or the control group.

[0065] [I-3: Administration schedule] (Cohort (a)) (a-1) From the 1st day to the 3rd day of the start of the test: The test drug (9 ng active ingredient / kg body weight / min) is continuously administered intravenously for 8 hours together with physiological saline. Only physiological saline is continuously administered intravenously until the next administration (16 hours). A total of 24 hours of continuous intravenous administration is carried out from the start of the test to the 3rd day. (a-2) From the 4th day to the 7th day of the start of the test: The test drug (9 ng active ingredient / kg body weight / min) is continuously administered intravenously for 8 hours together with physiological saline. After the administration is completed, no administration is carried out until the start of the next day's administration (16 hours). (Cohort (b)) (b-1) From the first day to the third day of the start of the test: The test drug (9 ng active ingredient / kg body weight / min) is continuously administered intravenously for 8 hours together with physiological saline. The above continuous intravenous administration is carried out 3 times a day (total 24 hours) continuously. By the third day from the start of the test, a total of 72 hours of continuous intravenous administration is carried out. (b-2) From the fourth day to the seventh day of the start of the test: The test drug (9 ng active ingredient / kg body weight / min) is continuously administered intravenously for 8 hours together with physiological saline. After the administration is completed, no administration is carried out until the start of the next day's administration (16 hours).

[0066] [I-4: Evaluation Items] (a) Primary evaluation item: Stroke severity assessment scale (NIHSS) (b) Secondary evaluation item: Modified Rankin scale (mRS) (c) Other evaluation items: Clinical tests (hematological tests and blood biochemical tests are carried out) Vital signs (blood pressure and electrocardiogram are measured) Head imaging findings (evaluate the presence or absence of bleeding, infarction, and severe stenosis by CT and / or MR examinations) (d) Exploratory evaluation item: AM blood concentration

[0067] Based on the dosing schedule of this trial, for acute cerebral infarction patients, AM, which is the active ingredient drug, is administered early, and the drug concentration is maintained continuously. Conventionally, from the perspective of blood pressure management, nighttime administration of AM, which raises concerns about blood pressure drop, has been avoided. However, in acute cerebral infarction patients, generally the blood pressure is elevated, and even if AM is continuously administered including at night, it is considered that the risk of blood pressure dropping to a certain extent is small. Also, the dosage of AM itself is an amount that does not directly cause blood pressure drop. Therefore, by administering AM based on the dosing schedule of this trial, it is possible to achieve rapid drug efficacy and safety of AM while realizing usage and dosages that cannot be achieved in conventional AM clinical administration.

[0068] By administering AM based on the dosing schedule of this trial, it is expected to obtain therapeutic effects such as inflammation control at the disease site, alleviation of tissue damage due to acute ischemia, and angiogenesis. Therefore, according to each aspect of the present invention, by administering AM or its derivative having adrenomedullin activity to acute cerebral infarction patients, the symptoms of cerebral infarction in acute cerebral infarction patients can be significantly treated. Also, thereby, the prognosis of acute cerebral infarction patients can be improved.

[0069] Note that the present invention is not limited to the above-described embodiments and includes various modifications. For example, the above-described embodiments have been described in detail for easy understanding of the present invention and are not necessarily limited to those having all the configurations described. Also, for a part of the configuration of each embodiment, it is possible to add, delete, and / or substitute other configurations.

[0070] All publications, patents, and patent applications cited in this specification are hereby incorporated herein by reference in their entirety.

Claims

1. A medicament for treating symptoms of cerebral infarction in acute-phase cerebral infarction patients, which contains adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient, wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is as follows: (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (g) a peptide in any one of the peptides of (a) to (f), wherein the disulfide bond is substituted by an ethylene group and has adrenomedullin activity; (h) a peptide in any one of the peptides of (a) to (g), wherein 1 to 5 amino acid residues are deleted, substituted or added and has adrenomedullin activity; (i) a peptide in any one of the peptides of (a) to (h), wherein the C-terminus is amidated; and (j) a peptide in any one of the peptides of (a) to (h), wherein a glycine residue is added to the C-terminus; is a peptide selected from the group consisting of The adremedullin which is an active ingredient, or its derivative having an adremedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is continuously administered intravenously, wherein the intravenous administration is continuously performed at a rate in the range of 1.0 to 20.0 ng of the active ingredient / kg body weight / min, wherein the intravenous administration is a repetition of 8-hour continuous administration and 16-hour continuous administration of only physiological saline on the 1st to 3rd days after the start of administration, and a repetition of 8-hour continuous administration and 16-hour non-administration on the 4th to 7th days after the start of administration, or, based on an administration schedule in which the intravenous administration is 72-hour continuous administration on the 1st to 3rd days after the start of administration, and a repetition of 8-hour continuous administration and 16-hour non-administration on the 4th to 7th days after the start of administration, the said medicament.

2. The medicament according to claim 1, further containing one or more pharmaceutically acceptable carriers.

3. The adremedullin or its derivative having an adremedullin activity is as follows: (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (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 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (i) in any of the peptides of (a) to (f), a peptide in which the C-terminus is amidated; and (j)A peptide in which a glycine residue is added to the C-terminus in any of the peptides (a) to (f); The medicament according to claim 1 or 2, which is a peptide selected from the group consisting of

4. The medicament according to any one of claims 1 to 3, wherein the acute cerebral infarction patient is a patient within 24 hours from the onset of cerebral infarction.

5. The medicament according to any one of claims 1 to 4, wherein the acute cerebral infarction patient is a patient suffering from non-embolic cerebral infarction.