JP7659783B2 - Drugs for improving fluid retention in acute heart failure - Google Patents

Description

The present invention relates to a novel use of SGLT2 inhibitors.

SGLT2 inhibitors, such as canagliflozin, are used as antidiabetic drugs. SGLT2 inhibitors are also known to be effective in improving fluid retention in chronic heart failure one month or more after the onset of heart failure (Non-Patent Document 1), and are known to be effective in reducing re-hospitalization in chronic heart failure.

After the onset of acute heart failure, dyspnea due to pulmonary congestion and fluid retention such as pleural effusion are considered to be the biggest factors that reduce a patient's quality of life. Diuretics are generally chosen as drugs to improve dyspnea and fluid retention, but they are often ineffective.

Yoshihiro Seo, et al., Effects and Safety of Sodium Glucose Cotransporter 2 Inhibitors in Diabetes Patients With Drug-Refractory Advanced Heart Failure., Circ J 2018; 82: 1959 - 1962

The treatment objectives are different between chronic and acute heart failure. That is, in the acute phase, treatment to improve symptoms is prioritized, whereas in the chronic phase, treatment to improve clinical endpoints such as suppressing re-hospitalization and total mortality is continued. Therefore, drugs that are effective in treating chronic heart failure do not necessarily show visible effects in treating acute heart failure. In order to improve patients' QOL and improve respiratory and circulatory dynamics, there is a need for therapeutic agents that improve fluid retention in the acute phase from immediately after the onset of heart failure.
An object of the present invention is to provide a therapeutic agent that improves fluid retention in acute heart failure.

The present inventors have conducted intensive research in light of the above problems and have found that sodium-dependent glucose cotransporter 2 (hereinafter referred to as "SGLT2") inhibitors, which are known as drugs for treating diabetes, can be effective in improving fluid retention in acute heart failure, thus completing the present invention.

That is, the gist of the present invention is as follows.
[1] A drug for improving fluid retention in acute heart failure, containing an SGLT2 inhibitor.
[2] The drug for improving body fluid retention according to the above-mentioned [1], wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof.
[3] SGLT2 inhibitors used as drugs to improve fluid retention in acute heart failure.
[4] The SGLT2 inhibitor according to the above-mentioned [3], which is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof.
[5] A method for ameliorating fluid retention in a patient with acute heart failure, comprising the step of administering an effective amount of an SGLT2 inhibitor to a patient in need thereof.
[6] The method for improving fluid retention according to the above-mentioned [5], wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof.
[7] Use of an SGLT2 inhibitor in the manufacture of a drug for improving fluid retention in acute heart failure.
[8] The use according to the above-mentioned [7], wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof.

The present invention can improve fluid retention in acute heart failure.

FIG. 1 shows the urine volume (mL/day) before administration of canagliflozin (Baseline), 1 day after administration, and 7 days after administration. 2 shows (a) cardiothoracic ratio, (b) the presence or absence of pulmonary congestion, and (c) the presence or absence of pleural effusion, evaluated using chest X-rays on the day before and 7 days after the start of canagliflozin administration. The white bars in the figure show the results on the day before the start of administration, and the black bars show the results 7 days after.

The drug for ameliorating fluid retention for acute heart failure of the present invention contains an SGLT2 inhibitor. The SGLT2 inhibitor can also be used in combination with a diuretic or other drug.
The present invention will now be described.

(SGLT2 inhibitor)
The SGLT2 inhibitor used in the present invention includes drugs that inhibit the reabsorption of sugar by SGLT2. More specific examples of the SGLT2 inhibitor include low molecular weight compounds, SGLT2 expression inhibitors, and SGLT2 specific binding substances.

(Low molecular weight compounds)
Examples of low molecular weight compounds that are SGLT2 inhibitors include canagliflozin [(1S)-1,5-Anhydro-1-C(-3{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-D-glucitol], empagliflozin [(1S)-1,5-Anhydro-1-C-{4-chloro-3-[(4-{[(3 S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol], ipragliflozin [(1S)-1,5-Anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol], dapagliflozin [(1S)-1,5-Anhydro-1-C-{4-c chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol], luseogliflozin [(2S,3R,4R,5S,6R)-2-{5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl}-6-(hydroxymethyl)thiane-3,4,5-triol], tofogliflozin [(1S,3'R,4'S,5'S,6'R)-6-[(4-Ethylphenyl)methyl]-6'-(hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]-3',4',5'-triol], sergliflozin etabonate [2-(4-Methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside], Remogliflozin etabonate [5-methyl-1-(propan-2-yl)-4-[[4-[(propan-2-yl)oxy]phenyl]methyl]-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside], ertugliflozin [(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol], sotagliflozin [Methyl (5S)-5-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-thio-β-L-xylopyranoside], and pharma- ceutical acceptable salts thereof. These compounds can be produced by known production methods or any production methods modified from known production methods.

Examples of pharma- ceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors include salts with alkali metals such as lithium, sodium, and potassium; salts with Group 2 metals such as calcium and magnesium; salts with zinc or aluminum; salts with amines such as ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris(hydroxymethyl)aminomethane, N-methyl-glucosamine, triethanolamine, and dehydroabietylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid; and salts with acidic amino acids such as aspartic acid and glutamic acid.

Furthermore, pharma- ceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors also include intramolecular salts, hydrates, and solvates of the low molecular weight compounds, such as L-proline and (2S)-propane-1,2-diol.

(SGLT2 expression inhibitor)
Examples of SGLT2 expression inhibitors include siRNA, shRNA, miRNA, ribozymes, antisense nucleic acids, low molecular weight compounds, etc. By administering these expression inhibitors, the expression of SGLT2 can be inhibited.

siRNA (small interfering RNA) is a small double-stranded RNA of 21-23 base pairs that is used for gene silencing by RNA interference. When siRNA is introduced into cells, it binds to the RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA with a sequence complementary to the siRNA, thereby suppressing gene expression in a sequence-specific manner.

siRNA can be prepared by synthesizing sense and antisense oligonucleotides using an automatic DNA/RNA synthesizer, denaturing them in an appropriate annealing buffer at 90-95°C for approximately 1 minute, and then annealing them at 30-70°C for approximately 1-8 hours.

shRNA (short hairpin RNA) is a hairpin-type RNA sequence used for gene silencing by RNA interference. shRNA can be introduced into cells by a vector and expressed by the U6 promoter or H1 promoter, or it can be prepared by synthesizing an oligonucleotide having an shRNA sequence using an automatic DNA/RNA synthesizer and self-annealing it in the same manner as siRNA. The hairpin structure of the shRNA introduced into the cell is cleaved into siRNA and binds to the RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA with a sequence complementary to the siRNA. This suppresses gene expression in a sequence-specific manner.

miRNA (microRNA) is a functional nucleic acid that is encoded on the genome and undergoes a multi-step production process to ultimately become a small RNA of approximately 20 bases. miRNA is classified as a functional ncRNA (non-coding RNA: a general term for RNA that is not translated into protein) and plays an important role in biological phenomena by regulating the expression of other genes. By administering miRNA with a specific base sequence to the living body, it is possible to inhibit the expression of SGLT2.

Ribozymes are RNAs with catalytic activity. Ribozymes have various activities, but research into ribozymes as enzymes that cleave RNA has made it possible to design ribozymes for site-specific cleavage of RNA. Ribozymes may be of the group I intron type, M1RNA contained in RNase P, or other types of 400 nucleotides or more in size, or may be of the hammerhead type, hairpin type, or other types of about 40 nucleotides in size.

Antisense nucleic acids are nucleic acids complementary to a target sequence. Antisense nucleic acids can inhibit the expression of a target gene by inhibiting transcription initiation through triplex formation, inhibiting transcription through hybridization with a site where an open loop structure has been formed locally by RNA polymerase, inhibiting transcription through hybridization with RNA in the process of synthesis, inhibiting splicing through hybridization at the junction of an intron and an exon, inhibiting splicing through hybridization with a spliceosome formation site, inhibiting migration from the nucleus to the cytoplasm through hybridization with mRNA, inhibiting splicing through hybridization with a capping site or poly(A) addition site, inhibiting translation initiation through hybridization with a translation initiation factor binding site, inhibiting translation through hybridization with a ribosome binding site near the initiation codon, preventing peptide chain elongation through hybridization with the translation region or polysome binding site of mRNA, and inhibiting gene expression through hybridization with a nucleic acid-protein interaction site.

siRNA, shRNA, miRNA, ribozymes, and antisense nucleic acids may contain various chemical modifications to improve stability and activity. For example, to prevent degradation by hydrolases such as nucleases, phosphate residues may be replaced with chemically modified phosphate residues such as phosphorothioate (PS), methylphosphonate, and phosphorodithioate. In addition, at least a portion of them may be composed of a nucleic acid analog such as peptide nucleic acid (PNA).

(SGLT2 specific binding substance)
The SGLT2 specific binding substance includes substances that specifically bind to SGLT2 and inhibit the function of SGLT2, such as antibodies, antibody fragments, and aptamers. The antibody can be prepared, for example, by immunizing an animal such as a mouse with an SGLT2 protein or a fragment thereof as an antigen. Alternatively, the antibody can be prepared, for example, by screening a phage library. Examples of antibody fragments include Fv, Fab, and scFv. The antibody is preferably a monoclonal antibody. The antibody may also be a commercially available antibody. An aptamer is a substance that has a specific binding ability to a target substance. Examples of aptamers include nucleic acid aptamers and peptide aptamers. The nucleic acid aptamer that has a specific binding ability to a target peptide can be selected, for example, by the systematic evolution of ligand by exponential enrichment (SFLEX) method. Furthermore, peptide aptamers having specific binding ability to a target peptide can be selected, for example, by a two-hybrid method using yeast.

(Acute Heart Failure)
Acute heart failure is specifically defined in the "Guidelines for the Treatment of Acute and Chronic Heart Failure (revised 2017)" prepared by the Japanese Circulation Society, but in the present invention, patients with acute heart failure include both the first attack of heart failure and attacks caused by acute exacerbation of chronic heart failure. In addition, the target patients in the present invention are patients with acute heart failure who have been switched from intravenous injection treatment to oral medication treatment, and whose cardiorespiratory dynamics have stabilized and who are able to take medication orally.
In addition, in the present invention, a patient to whom an SGLT2 inhibitor is administered may have diabetes mellitus, but is not limited to this.

(Improves fluid retention)
In the present invention, the degree of fluid retention can be determined by the cardiothoracic ratio using chest X-ray, the degree of pulmonary congestion and pleural effusion, and the degree of edema. In particular, for the evaluation of respiratory failure, it is useful to determine the degree of fluid retention based on the degree of pulmonary congestion.
In addition to the improvement of pulmonary congestion, it is also useful to assess the degree of improvement in the patient's own dyspnea using, for example, the seven-point Likert scale, which expresses how the patient felt when asked about dyspnea by the attending physician using a score (markedly worsened, moderately worsened, mildly worsened, no change, mildly improved, moderately improved, markedly improved).

Pharmaceutical Compositions
The present invention provides a pharmaceutical composition for improving fluid retention in acute heart failure, comprising an SGLT2 inhibitor and a pharma- ceutical acceptable carrier. By administering the pharmaceutical composition of this embodiment, fluid retention in acute heart failure can be improved.

The pharmaceutical composition of this embodiment may be formulated into a dosage form for oral use or a dosage form for parenteral use. Examples of dosage forms for oral use include tablets, capsules, elixirs, and microcapsules. Examples of dosage forms for parenteral use include injections, ointments, and patches.

As a pharma- ceutically acceptable carrier, any carrier that is normally used in the manufacture of pharmaceutical compositions can be used without particular limitation. Specific examples include binders such as gelatin, corn starch, gum tragacanth, and gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; solvents for injections such as water, ethanol, and glycerin; and adhesives such as rubber-based adhesives and silicone-based adhesives.

The pharmaceutical composition may contain additives. Examples of additives include lubricants such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin, and maltitol; flavorings such as peppermint and saffron oil; stabilizers such as benzyl alcohol and phenol; buffers such as phosphates and sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; and preservatives.

The pharmaceutical composition can be formulated by appropriately combining an SGLT2 inhibitor, a pharma- ceutically acceptable carrier, and optionally an additive, and mixing them in a unit dosage form required for generally accepted pharmaceutical practice.

Subjects to which SGLT2 inhibitors are administered include, but are not limited to, humans, monkeys, dogs, cows, horses, sheep, pigs, rabbits, mice, rats, guinea pigs, hamsters, and cells thereof. Among these, mammals or mammalian cells are preferred, and humans or human cells are particularly preferred.

The dosage of the SGLT2 inhibitor varies depending on the specific subject to which it is administered, the subject's symptoms, body weight, age, sex, etc., and cannot be determined in general, but in the case of oral administration, for example, about 0.1 mg/kg to about 100 mg/kg of body weight of the SGLT2 inhibitor may be administered per dosage unit for adults. In the case of injection, for example, about 0.01 mg to about 50 mg of the SGLT2 inhibitor may be administered per dosage unit for adults.

In addition, the daily dose of the SGLT2 inhibitor may be any amount effective in improving fluid retention, and varies depending on the specific subject to which it is administered, the subject's symptoms, body weight, age, sex, etc., and cannot be determined in general terms. For example, for adults, a dose of about 0.1 mg/kg to about 100 mg/kg of body weight of the SGLT2 inhibitor may be administered once a day or in divided doses about two to three times a day.

The SGLT2 inhibitor of the present invention may be used in combination with at least one selected from the group consisting of fluid retention improving drugs other than SGLT2 inhibitors and drugs for treating other diseases. The SGLT2 inhibitor and the other drug may be in the same formulation or in separate formulations. Furthermore, each formulation may be administered by the same administration route or by separate administration routes. Examples of the administration route include oral or injection. Furthermore, each formulation may be administered simultaneously, sequentially, or separately at a certain time or period. In one embodiment, the SGLT2 inhibitor and the other drug may be in the form of a kit including them.

The present invention will be explained in more detail below using examples, but the present invention is not limited to these in any way.

Example 1
Effect of canagliflozin on patients with decompensated heart failure Thirty-four type 2 diabetes patients were hospitalized with decompensated heart failure and were administered 100 mg/day of canagliflozin for 7 days after initial treatment and stabilization of their condition. During the canagliflozin administration period, the dose of furosemide was adjusted appropriately.
As a result of the 7-day treatment with canagliflozin, body weight was significantly reduced (mean body weight before the start of treatment was 58.7±14.4 kg, but after 7 days it was 57.2±14.4 kg, P<0.001). As shown in Figure 1, urine volume increased after 1 day but returned to normal after 7 days. Dyspnea was also improved in most patients.
The cardiothoracic ratio, pulmonary congestion, and pleural effusion were evaluated using chest X-rays on the day before and 7 days after the start of canagliflozin administration. As a result, significant improvements were observed in all items, including (a) cardiothoracic ratio, (b) pulmonary congestion, and (c) pleural effusion, as shown in Figure 2. The white bars in Figure 2 show the results on the day before the start of administration, and the black bars show the results 7 days later.

From the above, it has become clear that according to the present invention, administration of an SGLT2 inhibitor can improve fluid retention during the acute phase of heart failure.

The present invention provides a novel medicine that is effective and safe to use to improve fluid retention in acute heart failure.

Claims (2)

A drug for improving fluid retention in acute heart failure, comprising canagliflozin and/or a pharma- ceutically acceptable salt thereof . The drug for improving fluid retention according to claim 1, for improving at least one selected from the group consisting of cardiothoracic ratio, pulmonary congestion, and pleural effusion .

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