WO2025164712A1 - Adrenomedullin administration method - Google Patents

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

The present invention relates to a method for administering adrenomedullin. The present invention also relates to a pharmaceutical containing adrenomedullin that is administered by intermittent administration.

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 have a strong vasodilatory antihypertensive effect. Subsequent research has revealed that AM also exerts a variety of pharmacological effects, including anti-inflammatory, angiogenic, cardiovascular protective, and tissue repair promoting effects.

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, and heart disease.

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

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

However, to date, the administration method that maximizes the therapeutic effect of AM is unknown.

The present invention therefore aims to provide an administration method that maximizes the therapeutic effect of AM, and to provide a medicine containing AM provided by said administration method.

As a result of extensive research to solve the above-mentioned problems, the inventors unexpectedly and for the first time discovered 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. Based on this finding, the present invention was completed.

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,
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,
A pharmaceutical agent characterized in that the active ingredient is administered intermittently.
[2] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following:
(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 according to (ii), in which the disulfide bond is substituted with an ethylene group, and which 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 which has adrenomedullin activity.
(v) any one of the peptides (i) to (iv) in which the C-terminus is amidated; and (vi) any one of the peptides (i) to (iv) in which a glycine residue has been added to the C-terminus.
[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 according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity;
(h) A peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides (a) to (g), and which has adrenomedullin activity;
(i) any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) 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 therapeutic effects are expected to be induced by 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.
[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 agent according to any one of [1] to [5], wherein the intermittent administration is for 23 hours or less per day.
[7] The pharmaceutical agent according to any one of [1] to [6], wherein the intermittent administration is for 3 to 30 days and is administered for 23 hours or less per day.
[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,
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,
The method, wherein the administration is intermittent administration.
[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,
the disease is a disease for which a therapeutic effect 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,
1. Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, characterized in that it 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, comprising:
the disease is a disease for which a therapeutic effect 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,
The use, wherein the therapeutic drug is administered intermittently.

The present invention provides an optimized method for administering AM, thereby maximizing the therapeutic effect of AM. Furthermore, by reducing the total dose of AM, it is possible to reduce side effects. Furthermore, because the therapeutic effect can be achieved through 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 other facilities that do not have inpatient facilities, but also at home or in nursing homes.

The following describes in detail an example of an embodiment of the present invention, but the present invention is not limited to this.

(Summary of the Invention)
As mentioned above, AM is a substance that exhibits a variety of pharmacological actions, including anti-inflammatory, angiogenic, cardiovascular protective, and tissue repair promoting actions. 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.

As 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 effects of AM.

The inventors conducted extensive research into the above-mentioned problem and discovered that in the investigator-initiated AMFIS clinical trial, in which AM was administered to patients with acute cerebral infarction, intermittent administration produced a significant therapeutic effect. 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, produced a significant improvement in motor function. This is a surprising result that could never have been predicted based on the previous understanding that, due to the short half-life of AM, continuous administration over a long period of time is necessary to achieve its effects.

The present invention provides an administration method that is superior to conventional methods in terms of exerting the effects of AM. Furthermore, because the therapeutic effect can be achieved through intermittent administration, the present invention has the significant advantage of enabling outpatient treatment without the need for hospitalization. Therefore, the present invention is extremely promising for the treatment of various diseases 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 (hereinafter sometimes referred to as "AM, etc.") is expected to have a therapeutic effect.

(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 the remaining time. 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 considered as one unit, and repeating this period.

As used herein, "treatment" means achieving a desired pharmacological and/or physiological effect. The effect may be prophylactic, from the perspective of completely or partially preventing a disease or its symptoms, or therapeutic, from the perspective of partially or completely curing a disease and/or side effects caused by a disease. In other words, as used herein, "prevention" is also encompassed within the concept of "treatment."

"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., preventing 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., inhibiting progression), alleviating, repairing, and/or curing symptoms that have occurred (developed or manifested) in a subject suffering from the disease.

As used herein, a "therapeutically effective amount" means an amount of an active ingredient 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 being treated.

As used herein, "subject" refers to a test subject or patient who requires treatment by administering an AM or the like.

As used herein, "acute cerebral infarction" generally refers to cerebral infarction occurring within 72 hours of onset, and 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.

(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.

As used herein, "C-terminal amidation" refers to a type of post-translational modification of peptides in vivo, specifically the reaction in which the main-chain carboxyl group of the C-terminal amino acid residue of a peptide is converted to an amide group. Also, as used herein, "disulfide bond formation of cysteine residues" or "disulfidation of cysteine residues" refers to a type of post-translational modification of peptides in vivo, specifically the reaction in which two cysteine residues in the amino acid sequence of a peptide form a disulfide bond (-S-S-). 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 transport to become 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 physiologically active peptides with a C-terminal amide group, a Gly residue is bound to the C-terminal carboxyl group to be amidated in the precursor protein, and this 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 typically occurs through the action of protein disulfide isomerase on precursor proteins.

(Adrenomedullin derivative)
In various embodiments of the present invention, not only native AM itself but also its derivatives having adrenomedullin activity can be used as active ingredients. In various embodiments 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 by purchasing them, applying appropriate conversion reactions to purchased compounds, or preparing them themselves based on the above literature. 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.

In each aspect of the present invention, "adrenomedullin activity" refers to, for example, various physiological actions exemplified below, and in particular refers to physiological actions that may be involved in the treatment of symptoms of cerebral infarction, such as the inhibitory effect of inflammation in cerebral infarction via the anti-inflammatory action of AM, the alleviation of tissue damage caused by acute ischemia via the vasodilatory effect of AM, and the induction of vascular regeneration via the angiogenic action of AM.
(1) Cardiovascular system: vasodilatory effect, blood pressure lowering effect, blood pressure elevation suppression effect, cardiac output increase/heart failure improvement effect, pulmonary hypertension improvement effect, angiogenic effect, lymphangiogenic effect, vascular endothelial function improvement effect, anti-arteriosclerotic effect, myocardial protective effect (e.g., myocardial protective effect in ischemia-reperfusion injury or inflammation), remodeling suppression effect after myocardial infarction, cardiac hypertrophy suppression effect, and angiotensin converting enzyme suppression effect.
(2) Kidney and water-electrolyte system: diuretic effect, natriuretic effect, antidiuretic hormone suppression effect, aldosterone lowering effect, renal protective effect (e.g., myocardial protective effect in hypertension or ischemia-reperfusion injury), suppression of water drinking behavior, and suppression of salt requirement.
(3) Brain and nervous system: neuroprotective and brain damage suppressive effects, anti-inflammatory effects (e.g., controlling inflammation in cerebral infarction), vasodilatory effects (e.g., alleviating tissue damage caused by acute ischemia), angiogenic effects (e.g., inducing vascular regeneration), anti-apoptotic effects (e.g., inhibiting apoptosis in ischemia-reperfusion injury or inflammation), maintaining autoregulatory function, inhibiting oxidative stress, improving dementia, and suppressing sympathetic nervous system activity.
(4) Genitourinary organs: erection improvement effect, blood flow improvement effect, and implantation promotion effect.
(5) Digestive system: Antiulcer effect, tissue repair effect, mucosal regeneration effect, blood flow improvement effect, anti-inflammatory effect, and liver function improvement effect.
(6) Orthopedics: Stimulating effect on osteoblasts and improving arthritis.
(7) Endocrine metabolic system: adipocyte differentiation, lipolysis control, insulin sensitivity improvement, insulin secretion control, antidiuretic hormone secretion inhibition, and aldosterone secretion inhibition.
(8) Other: Circulation improvement 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.

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 according to (ii), in which the disulfide bond is substituted with an ethylene group, and which 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 which has adrenomedullin activity.
(v) any of the peptides (i) to (iv) in which the C-terminus is amidated; and (vi) any of the peptides (i) to (iv) in which a glycine residue has been added to the C-terminus.

In one embodiment of the present invention, 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;
More preferably, the peptide is selected from the group consisting of (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 has been added to the C-terminus.
Among the peptides (i) to (vi), the peptide included in (v) consisting of the amino acid sequence of adrenomedullin, having amidated C-terminus and having two cysteine residues in the amino acid sequence form a disulfide bond, corresponds to mature native adrenomedullin. The peptide consisting of the amino acid sequence of adrenomedullin (i) corresponds to native adrenomedullin in its pre-translational (i.e., immature) form prior to post-translational modifications of C-terminal amidation and disulfidation of cysteine residues. Among the peptides (i) to (vi), the other peptides, excluding those described above, correspond to derivatives (modified forms) of adrenomedullin.

The peptide (ii) can be formed by air-oxidizing the thiol groups of the two cysteine residues of the peptide (i) or by oxidizing them with an appropriate oxidizing agent to form disulfide bonds. By using the peptide (ii), the three-dimensional structure of the peptide can be made similar to that of native adrenomedullin. This makes it possible to make the adrenomedullin activity of the peptide (ii) substantially equivalent to that of native adrenomedullin.

The peptide (iii) can be formed by converting the disulfide bond of the peptide (ii) to 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). The use of the peptide (iii) can stabilize the three-dimensional structure of the peptide. This allows the peptide (iii) to continuously express adrenomedullin activity in vivo.

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 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 (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 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 has adrenomedullin activity. The suitable peptides may further include deletion, substitution, or addition of one or more (e.g., 1 to 5, 1 to 3, or 1 or 2) amino acid residues. By using the peptide (iv), the adrenomedullin activity of the peptide can be made substantially equivalent to that of native adrenomedullin. Furthermore, by using the peptide (iv), the peptide can continuously express adrenomedullin activity in vivo.

The peptide (vi) can be converted to the peptide (v) by the action of a C-terminal amidating enzyme, converting the C-terminal glycine residue into 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 has passed. This allows the peptide (vi) to continuously express adrenomedullin activity in the body.

The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of:
(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 according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity;
(h) A peptide in which 1 to 15 amino acids are deleted, substituted, or added in any of the peptides (a) to (g), and which has adrenomedullin activity;
(i) any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) 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:

In one embodiment of the present invention, the adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of:
(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) any of the peptides (a) to (f) in which the C-terminus is amidated; and (j) any of the peptides (a) to (f) in which a glycine residue is added to the C-terminus;
It is more preferred that the peptide is selected from the group consisting of:

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.

(Salt of adrenomedullin or its derivative)
In each aspect of the present invention, AM or a derivative thereof having adrenomedullin activity used as an active ingredient includes not only the compound itself but also its salt.When AM or a derivative thereof having adrenomedullin activity is in the form of a salt, it is preferably a pharmaceutically acceptable salt.The counter ion of the salt of AM or a derivative thereof having adrenomedullin activity includes, but is not limited to, cations such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, or chloride ion, bromide ion, iodide ion, phosphate ion, nitrate ion, sulfate ion, carbonate ion, bicarbonate 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- 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.

(Solvate 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 the 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 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 a derivative thereof having adrenomedullin activity, or a salt thereof, is in the form of a solvate with the solvent, the adrenomedullin activity of the compound can be substantially equivalent to that of native adrenomedullin.

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

(disease)
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 a disease is one 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 (be treated).

Diseases for which AM administration is expected to have a therapeutic effect include, for example, cerebrovascular disorders, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular disease, and heart disease.

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.

Examples of dementia include 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.

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

Examples of autoimmune diseases include rheumatoid arthritis, collagen diseases (e.g., systemic lupus erythematosus), multiple sclerosis, and neuromyelitis optica.

Examples of infectious diseases include respiratory infections (e.g., sepsis, pneumonia, etc.), urinary tract infections (e.g., pyelitis, etc.), gastrointestinal infections (e.g., peritonitis, cholecystitis, etc.), burns, infections that occur after surgery, and viral infections (e.g., COVID-19, etc.). In one embodiment of the present invention, the infectious disease may be a severe infection.

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.

Peripheral vascular diseases include, for example, carotid artery stenosis, subclavian artery stenosis, renal artery stenosis, arteriosclerosis obliterans, acute arterial occlusion, Buerger's disease, and varicose veins of the lower extremities.

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 standpoint of therapeutic effect, acute myocardial infarction is preferred.

(Pharmaceuticals)
In the pharmaceutical 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 pharmaceutical 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.

The dosage form of the pharmaceutical of this embodiment may be a formulation for intravenous administration, and is not particularly limited. Examples of formulations for intravenous administration include injections, such as sterile solutions or suspensions in water or other pharmaceutically acceptable liquids. Additives that can be mixed with 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 (e.g., a vial or an ampule) and stored in an appropriate environment until use.

The pharmaceutical of this embodiment can also be used in combination with one or more other pharmaceutical agents. In this case, the pharmaceutical of this embodiment may be provided in the form of a single pharmaceutical agent containing an AM or a derivative thereof having adrenomedullin activity and one or more other pharmaceutical agents, or it may be provided in the form of a pharmaceutical combination or kit containing multiple formulations in which an AM or a derivative thereof having adrenomedullin activity and one or more other pharmaceutical agents are separately formulated. When in the form of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (e.g., sequentially).

When AM or a derivative thereof having adrenomedullin activity is applied to pharmaceutical purposes, 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 purpose.

The AM or a derivative thereof having adrenomedullin activity used as the active ingredient of the pharmaceutical 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 has low toxicity. Therefore, the pharmaceutical of this embodiment can be applied to a variety of subjects requiring treatment for diseases for which administration of an AM or the like is expected to have a therapeutic effect. 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. By intermittently administering the pharmaceutical of this embodiment to the subject, the disease in the subject can be treated.

When administering the pharmaceutical of this embodiment to a subject, particularly a human patient, the exact dosage and administration method should ultimately be determined by the attending physician, taking into account many factors, such as the subject's age, sex, the 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 pharmaceutical 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 route of administration).

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 injection, for example, 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 active ingredient/kg body weight/minute, and more preferably at a rate of 6.0 to 12.0 ng active ingredient/kg body weight/minute, 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 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, a sufficient therapeutic effect may not be obtained. Therefore, by intermittently administering the pharmaceutical agent of this embodiment intravenously at an administration rate within the above range, it is possible to treat the disease without causing undesirable side effects.

In this embodiment of the pharmaceutical, intermittent administration is not limited to the cerebrovascular disorder described in the examples, but can be similarly applied to any disease for which the administration of 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.). In other words, the examples of the present application use cerebrovascular disorder as an example of a disease for which the AM of the present invention is administered intermittently, and confirm its effectiveness.

In this pharmaceutical embodiment, the intravenous administration is preferably performed intermittently for no more than 23 hours per day, more preferably for no more than 15 hours, even more preferably for no more than 12 hours, particularly preferably for no more than 10 hours, and particularly preferably for no more than 8 hours per day. For example, after continuous intravenous administration in the morning for no more than 8 hours, a drug-free period of 16 hours or more is allowed before 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 no more than 23 hours, no more than 15 hours, no more than 12 hours, no more than 10 hours, or no more than 8 hours 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, particularly 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 pharmaceutical of this embodiment intravenously for an administration period within the above-mentioned range, it is possible to treat the disease with a greater therapeutic effect.

In the pharmaceutical of this embodiment, 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 previous administration methods, it was generally believed that continuous administration for several days immediately after the onset of a disease (e.g., cerebral infarction) and then transitioning to intermittent administration was effective, but according to the present invention, intermittent administration initiated immediately after onset can enhance the therapeutic effect.

In this embodiment of the pharmaceutical, the active ingredient, AM or a derivative thereof having adrenomedullin activity, is preferably administered intravenously at a rate in the range of 1.0 to 20.0 ng active ingredient/kg body weight/minute, more preferably 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 over a period of 7 days after the start of administration. By administering the pharmaceutical of this embodiment intravenously based on this dosing regimen intermittently, it is possible to treat the disease with greater therapeutic effectiveness.

In each aspect of the present invention, when a subject to be treated by administering AM or a derivative thereof having adrenomedullin activity is, for example, a subject with acute cerebral infarction, the therapeutic effect can be determined, for example, by administering a pharmaceutical agent containing AM or a derivative thereof having adrenomedullin activity as an active ingredient to the subject with acute cerebral infarction, and evaluating 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 hemorrhage, infarction, and severe stenosis), nuclear medicine tests, or ultrasound tests. For example, when the symptoms of cerebral infarction in a subject with acute cerebral infarction are evaluated using the NIHSS, the mean change in the NIHSS score one week later is, for example, in the range of -1.5 to -4.5.

(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,
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,
The method, wherein the administration is intermittent administration.
[8a] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following:
(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 according to (ii), in which the disulfide bond is substituted with an ethylene group, and which 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 which has adrenomedullin activity.
(v) any one of the peptides (i) to (iv) in which the C-terminus is amidated; and (vi) any one of the peptides (i) to (iv) in which a glycine residue has been added to the C-terminus.
[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 according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity;
(h) A peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides (a) to (g), and which has adrenomedullin activity;
(i) any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) 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 according to 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 according to 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 according to any one of [8] to [8d], wherein the intermittent administration is administration for 23 hours or less per day.
[8f] The method according to any one of [8] to [8e], wherein the intermittent administration is for 23 hours or less per day for 3 to 30 days.

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.

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 the treatment of a disease,
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,
1. Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, characterized in that it is administered intermittently.
[9a] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following:
(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 according to (ii), in which the disulfide bond is substituted with an ethylene group, and which 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 which has adrenomedullin activity.
(v) a peptide selected from the group consisting of any of the peptides (i) to (iv) in which the C-terminus is amidated, and (vi) a peptide selected from the group consisting of any of the peptides (i) to (iv) in which a glycine residue is added to the C-terminus. The adrenomedullin or a derivative thereof having adrenomedullin activity according to [9], or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
[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 according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity;
(h) A peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides (a) to (g), and which has adrenomedullin activity;
(i) any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) 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] Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, described in any of [9] to [9b], wherein the disease is a disease for which therapeutic effects are expected due to 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, described in 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] Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, described in any of [9] to [9d], wherein the intermittent administration is administration for 23 hours or less per day.
[9f] 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 within 23 hours per day and is administered for 3 to 30 days.

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 in this embodiment described above. Furthermore, the AM, etc. in this embodiment can be administered in the same manner and dosage as the medicament in this embodiment described above. Furthermore, the AM, etc. in this embodiment can treat the same diseases as the medicament in this embodiment described above.

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, comprising:
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,
The use, wherein the therapeutic drug is administered intermittently.
[10a] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following:
(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 according to (ii), in which the disulfide bond is substituted with an ethylene group, and which 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 which has adrenomedullin activity.
(v) any one of the peptides (i) to (iv) in which the C-terminus is amidated; and (vi) any one of the peptides (i) to (iv) in which a glycine residue has been added to the C-terminus.
[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 according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity;
(h) A peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides (a) to (g), and which has adrenomedullin activity;
(i) any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) 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 have a therapeutic effect.
[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 administration for 23 hours or less per day.
[10f] The use according to any one of [10] to [10e], wherein the intermittent administration is within 23 hours per day and is administered for 3 to 30 days.

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.

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, comprising:
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,
A use 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.
[11a] The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of the following:
(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 according to (ii), in which the disulfide bond is substituted with an ethylene group, and which 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 which has adrenomedullin activity.
(v) any one of the peptides (i) to (iv) in which the C-terminus is amidated; and (vi) any one of the peptides (i) to (iv) in which a glycine residue has been added to the C-terminus.
[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 according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity;
(h) A peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides (a) to (g), and which has adrenomedullin activity;
(i) any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) 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 have a therapeutic effect.
[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 administration for 23 hours or less per day.
[11f] The use according to any one of [11] to [11e], wherein the intermittent administration is within 23 hours per day and is administered for 3 to 30 days.

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.

The present invention will be explained in more detail below using examples, but these are not intended to limit the scope of the present invention. In this example, an example of the application of the present invention to a patient with "acute cerebral infarction," a type of cerebrovascular disorder, will be 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."

<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, with the C-terminus amidated and with two cysteine residues in the amino acid sequence forming a disulfide bond to form a ring structure).
(b) Dosage form, content and properties:
This is an injection (lyophilized product) containing 500 μg of synthetic human adrenomedullin white mass or powder 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 the test drug with a syringe and dissolve it without creating bubbles. Take 10 mL of the dissolved test drug into the syringe and add 20 mL of saline to dilute it 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) does not contain any active ingredients (it contains only 50 mg of D-mannitol) and is prepared to have the same dosage form and properties as the test drug. The test drug and control drug cannot be distinguished by appearance.
[I-2: Target]
Patients with acute cerebral infarction will be selected as subjects for this study at the National Cerebral and Cardiovascular Center. Patients must meet the following inclusion criteria: Therapeutic drug administration can be initiated within 24 hours of the onset of cerebral infarction; The patient has neurological symptoms with an NIHSS score of 1 or higher; and excluding the following exclusion criteria: The patient 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: Dosage regimen]
(a) Study drug (first half cohort)
9 ng/kg/min will be administered intravenously for 8 hours for 7 days. During the washout period up to 72 hours later, saline alone will be administered intravenously (AM intermittent administration group).
(later cohort)
The dose will be administered intravenously at a rate of 9 ng/kg/min for 72 hours, followed by 8-hour intravenous infusion for four days (AM continuous/intermittent administration group).
(b) Control drug (placebo)
(First half cohort)
Same as the test drug.
(later 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 endpoints:
Safety endpoint: adverse events (AEs)
Efficacy endpoint: modified Rankin Scale (mRS)
(c) Other evaluation items:
Clinical testing (hematology and blood chemistry tests)
Vital signs (measure blood pressure and electrocardiogram)
Head imaging findings (CT and/or MR examination to evaluate the presence or absence of bleeding, infarction, and severe stenosis)
Maximum blood concentration and efficacy endpoints (d) Exploratory endpoints:
AM blood concentration

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

(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. This indicates that the AM intermittent administration of the present invention can be performed safely.

(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.

Furthermore, in 60 patients with non-cardiogenic acute cerebral infarction, outcomes were compared between the AM intermittent administration group (20 patients), the AM continuous/intermittent administration group (20 patients), and the placebo group (20 patients). The results showed that 15 patients (75.0%) in the AM intermittent administration group, 13 patients (65.0%) in the AM continuous/intermittent administration group, and 13 patients (68.4%) in the placebo group had a good functional outcome (mRS 0-2). Furthermore, 18 patients (90.0%) in the AM intermittent administration group, 17 patients (85.0%) in the AM continuous/intermittent administration group, and 14 patients (73.7%) in the placebo group had a functional outcome of being able to walk (mRS 0-3).

These results indicate that the AM intermittent administration group showed favorable outcomes.

[Result-2]
Considering the imbalance in age, sex, and the 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.

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

According to the present invention, AM has a high therapeutic effect and is therefore extremely useful in treating diseases for which AM is expected to be effective. This application is based on patent application No. 2024-011993 filed in Japan (filing date: January 30, 2024), the contents of which are incorporated in their entirety herein.

Claims (10)

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,
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,
A pharmaceutical agent characterized in that the active ingredient is administered intermittently. 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 according to (ii), in which the disulfide bond is substituted with an ethylene group, and which 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 which has adrenomedullin activity.
The pharmaceutical composition according to claim 1, wherein the peptide is selected from the group consisting of: (v) any one of the peptides (i) to (iv) in which the C-terminus is amidated; and (vi) any one of the peptides (i) to (iv) in which a glycine residue has been added to the C-terminus. The adrenomedullin or a derivative thereof having adrenomedullin activity is selected from the group consisting of:
(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 according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity;
(h) A peptide in which 1 to 15 amino acid residues are deleted, substituted, or added in any of the peptides (a) to (g), and which has adrenomedullin activity;
(i) any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) 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: 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 be therapeutically effective. 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. The pharmaceutical agent described in claim 1 or 2, wherein the intermittent administration is for no more than 23 hours per day. The pharmaceutical agent according to claim 1 or 2, wherein the intermittent administration is for 3 to 30 days and is administered for no more than 23 hours per day. 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,
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,
The method, wherein the administration is intermittent administration. 1. 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,
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,
1. Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, characterized in that it is administered intermittently. 1. 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, comprising:
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,
The use, characterized in that the therapeutic medicament is administered intermittently.