WO2022030665A1 - Pharmaceutical composition for preventing or treating contrast media-induced nephrotoxicity - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating contrast media-induced nephrotoxicity. More particularly, a pharmaceutical composition containing paricalcitol prevents renal dysfunction by controlling mitophagy and aging, and reduces tissue damage, thereby exhibiting a preventive or therapeutic effect on contrast media-induced nephrotoxicity.

Description

Pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity

The present invention relates to a pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity.

Contrast media is injected into the stomach, intestinal tract, blood vessels, etc. to artificially measure the difference in the absorption of X-rays in each tissue so that the tissue or blood vessels can be seen accurately during radiological examinations such as magnetic resonance imaging (MRI) or computed tomography (CT). It is a drug that increases the contrast of the image by increasing the For accurate and safe diagnosis and treatment, most tests require a radiographic contrast agent, so the use of contrast agent has greatly increased over the past few years. As such, the radiation contrast agent is essential for diagnosis and treatment, but the incidence of side effects due to the use of the contrast agent is not as low as 1-15%. Contrast agents are known to damage the kidneys by inducing intracellular mitochondrial damage and cellular senescence due to excessive mitophagy generation by acting on the renal tubular cells of the kidney tissue.

Contrast-induced nephropathy (CIN) is the third most common cause of acute renal failure in hospitals. The incidence of acute renal failure induced by contrast agents has been reported to vary from 0 to 24% depending on the patient's risk factors. Although generally known to be reversible, active prevention and treatment are required as it can lead to complications and increased mortality. As a treatment to prevent contrast agent-induced nephrotoxicity, it has been reported that, in general, preventing electrolyte imbalance while providing sufficient fluids is helpful in recovery. Sometimes it is necessary. Therefore, more research is needed to develop a preventive method to suppress the occurrence at an early stage.

An object of the present invention is to provide a pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity.

1. A pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity, comprising paricalcitol or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition for the prevention or treatment of contrast agent-induced nephrotoxicity according to the above 1, wherein the contrast agent is ioversol, iohexol, iobitridol, iopromide, iomeprol, or iopamidol.

3. The pharmaceutical for the prevention or treatment of contrast agent-induced nephrotoxicity according to the above 1, wherein the contrast agent-induced nephrotoxicity is a state in which the blood creatinine level is increased by 25% or 0.3mg/dL or more compared to before administration within 48 hours after administration of the contrast agent to the subject composition.

4. The pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity according to 1 above, wherein the composition is administered 30 minutes to 24 hours before contrast agent administration.

5. The pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity according to the above 1, wherein the composition is administered in combination with a contrast agent.

6. Paricalcitol or a pharmaceutically acceptable salt thereof; And a contrast composition for mitigating nephrotoxic side effects comprising a contrast agent.

7. The contrast composition according to the above 6, wherein the contrast agent is ioversol, iohexol, iobitridol, iopromide, iomeprol, or iopamidol.

The pharmaceutical composition of the present invention may have the effect of controlling mitophagy and cellular aging, preventing renal dysfunction, and reducing tissue damage. Accordingly, it is possible to prevent and treat contrast agent-induced nephrotoxicity.

1 shows the measured values of the concentrations of BUN and creatine 6 hours, 12 hours, 24 hours, and 48 hours after administration of ioversol. shows the results.

FIG. 2 shows that the increase in BUN and creatine concentrations 12 hours after ioversol administration was significantly reduced by paricalcitol pretreatment, and severe coronary damage after ioversol administration was inhibited by paricalcitol pretreatment. indicates

FIG. 3 shows that immunochemical staining for 8-OHdG (a marker for ROS-induced DNA damage) was performed. As a result, 8-OHdG staining was evident in the nuclei of renal renal tubular epithelial cells exposed to ioversol, flies Calcitol pretreatment inhibited such signals. In addition, TUNEL-positive signals (apoptotic markers) were confirmed in the epithelial cells of the dilated renal tubules, and the number increased 12 hours after ioversol administration, whereas paricalcitol pretreatment suppressed such increase.

4 shows the expression of Pink1 and Parkin (a mitochondrial autophagy marker) increased by ioversol, but the expression was suppressed when paricalcitol was pretreated. Similarly, the level of autophagy marker LC3II/LC31 is significantly increased after ioversol administration, but when paricalcitol is administered, the expression level is suppressed.

5 shows that the expression of SA-βgal and p16 ^INK4A (a biomarker for aging) in the renal tract increased after administration of ioversol, but the expression was suppressed in the case of paricalcitol administration.

6 shows that ioversole increases the expression of LC3BII and HMGB1 (a marker of senescent cells), but paricalcitol significantly reduces the expression at all concentrations tested.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity, comprising paricalcitol or a pharmaceutically acceptable salt thereof:

Paricalcitol (CAS: 131918-61-1) is a synthetic vitamin D analog, which is 19-nor-1,25-(OH)2-vitamin D2 or 19-nor-1,25-dihydride. As hydroxyvitamin D2, it is an analogue of 1,25-dihydroxy cholecalciferol, an active form of vitamin D2 (ergocalciferol), and its chemical structure is as follows:

The “contrast-induced nephrotoxicity” refers to an increase in serum creatinine level by 25% or 0.3 mg/dL or more compared to the existing level within 48 hours after contrast-induced nephropathy (CIN). do.

The contrast agent-induced nephrotoxicity according to the present invention may be induced by various known contrast agents, for example, induced by ioversol, iohexol, iobitridol, iopromide, iomeprol, iopamidol, and the like. may be, but is not limited thereto.

The term "pharmaceutically acceptable" means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.

The pharmaceutically acceptable salt may be, for example, an acid addition salt or a metal salt.

Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It can be formed from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propylate, oxalate, malonate, succinate, suberate, Sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, benzenesulfonate, etuenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, β_hydroxybutyrate, glycol lactate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate. For example, an acid addition salt of a compound represented by formula (1) can be obtained by dissolving the compound in an excess aqueous acid solution, and precipitating the salt using a hydrating organic solvent such as methanol, ethanol, acetone or acetonitrile. .

The metal salt may be a sodium, potassium or calcium salt. Metal salts can be prepared using a base, for example an alkali metal or alkaline earth metal salt by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt and evaporating the filtrate and/or Or it can be obtained by drying.

Formula 1 and a pharmaceutically acceptable salt thereof may exhibit the effect of controlling mitophagy and cellular aging, preventing renal dysfunction, and reducing tissue damage.

The term "prevention" refers to any action that inhibits or delays contrast agent-induced nephrotoxicity.

The term "treatment" refers to any action in which the symptoms of the subject suspected of nephrotoxicity induced by the contrast agent and the symptoms of the subject are improved or changed to a beneficial effect.

The pharmaceutical composition of the present invention may be administered in combination with a known contrast agent. When administered in combination, they may be administered by mixing them, or they may be administered separately.

Known contrast agents include, but are not limited to, ioversol, iohexol, iobitlidol, iopromide, omeprol, and iopamidol.

The term "administration" means introducing a predetermined substance to a subject by an appropriate method, and the term "subject" refers to all animals, including humans, rats, mice, livestock, etc., which have or may develop contrast agent-induced nephrotoxicity. do. As a specific example, it may be a mammal including a human.

If necessary, the pharmaceutical composition of the present invention may additionally include a known contrast agent.

Examples of the contrast agent include, but are not limited to, ioversol, iohexol, iobitridol, iopromide, omeprol, and iopamidol.

The pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages.

The pharmaceutical composition of the present invention may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and injections.

The pharmaceutical composition of the present invention may include an active ingredient alone, or may further include one or more pharmaceutically acceptable carriers, excipients or diluents.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may be binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc., for oral administration, and in the case of injections, buffering agents, preservatives, analgesic agents, Solubilizers, isotonic agents, stabilizers, etc. can be mixed and used. For topical administration, bases, excipients, lubricants, preservatives, etc. can be used.

The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, when administered orally, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. It may be prepared in the form of injections, and in the case of injections, it may be prepared in the form of unit dose ampoules or multiple doses. In addition, the dosage form of the pharmaceutical composition of the present invention may be prepared as a solution, suspension, tablet, capsule, sustained release formulation, and the like.

Carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, filler, anticoagulant, lubricant, wetting agent, flavoring, emulsifying agent or preservative and the like.

The route of administration of the pharmaceutical composition of the present invention may be oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal. not limited

The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, external or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection injection method may be selected. have.

The dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art.

For example, the pharmaceutical composition of the present invention may be administered in an amount of 0.0001 mg to 1000 mg/kg or 0.001 mg to 500 mg/kg per day. Administration of the pharmaceutical composition of the present invention may be administered once a day, may be administered several times divided. The above dosage does not limit the scope of the present invention in any way.

In addition, paricalcitol or a pharmaceutically acceptable salt thereof; And it relates to a contrast composition for which side effects of nephrotoxicity are alleviated, including a contrast agent.

The contrast agent may cause renal toxic side effects by its administration. The composition for contrast of the present invention contains paricalcitol or a pharmaceutically acceptable salt thereof together with the contrast medium, thereby alleviating renal toxic side effects caused by the contrast medium.

Paricalcitol or a pharmaceutically acceptable salt thereof may be within the range exemplified above.

As the contrast agent, any known contrast agent that induces or does not induce renal toxicity may be used without limitation, and may be, for example, ioversol, iohexol, iovitridol, iopromide, omeprol, or iopamidol.

The mixing ratio of paricalcitol or a pharmaceutically acceptable salt thereof and the contrast agent is not particularly limited, and for example, 0.001 to 10 parts by weight of paricalcitol or a pharmaceutically acceptable salt thereof relative to 100 parts by weight of the contrast agent may be included. have.

Paricalcitol was administered intraperitoneally at 0.3ug/kg 24 hours or 30 minutes before other drugs. After the initial administration of indomethacin (10 mg/kg) to rats, 15 and 30 minutes later, N-ω nitro-L-arginine methyl ester (10 mg/kg) and ioversol (8.3 mL/kg) were administered to the tail. It was administered via intravenous injection. The control group was administered with PBS. Mice are sacrificed 6,12,24 and 48 hours after ioversol injection, and blood and kidney tissue are harvested.

The dosage form of the contrast composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., when administered orally. It may be prepared in the form of injections, and in the case of injections, it may be prepared in the form of unit dose ampoules or multiple doses. In addition, the dosage form of the pharmaceutical composition of the present invention may be prepared as a solution, suspension, tablet, capsule, sustained release formulation, and the like.

Carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, filler, anticoagulant, lubricant, wetting agent, flavoring, emulsifying agent or preservative and the like.

Hereinafter, examples will be given to describe the present invention in detail.

Example

Confirmation of the effect of paricalcitol in preventing renal dysfunction and reducing tissue damage

(1) Changes in renal function and pathology with time after administration of ioversol

The 28-week-old white rats were divided into 4 groups. : Control group (n=7), paricalcitol alone (PC, n=7), contrast agent alone (CONT, n=7), and paricalcitol treatment before contrast agent administration (PC+CONT, n=7) ). Paricalcitol was intraperitoneally administered at 0.3ug/kg 24 hours or 30 minutes before contrast agent treatment. Contrast treatment was performed on white rats in the following order. After administration of indomethacin (10mg/kg), 15 and 30 minutes later, N-ωnitro-L-arginine methyl ester (10mg/kg) and ioversol (8.3mL/kg) were administered via tail vein injection. did. The control group was administered PBS. After 6, 12, 24 and 48 hours after ioversol injection, mice were sacrificed to obtain blood and kidney tissue.

(2) Confirmation of the effect of paricalcitol on reducing renal dysfunction and morphological changes

The increase in BUN and creatine concentrations 12 hours after ioversol administration was significantly reduced by paricalcitol pretreatment. It was confirmed that severe kidney tissue damage was seen after ioversol administration, and paricalcitol pretreatment inhibited such damage. (See Fig. 2)

(3) Confirmation of apoptosis and oxidative stress reduction effect of paricalcitol

Immunochemical staining for 8-OHdG, a DNA damage marker induced by ROS, was performed, and it was confirmed that the renal tubular epithelial cells in the renal tissue exposed to ioversol showed a positive reaction for 8-OHdG in the nucleus. It was confirmed that the positive reaction of 8-OHdG was inhibited by sitol pretreatment. In the TUNEL staining performed to investigate apoptosis, a TUNEL positive reaction was confirmed 12 hours after ioversol administration, and it was confirmed that paricalcitol pretreatment suppressed such a positive reaction. (See Fig. 3)

(4) Confirmation of CI-AKI improvement effect by mitophagy regulation of paricalcitol

Ioversole increased the protein expression of Pink1 and Parkin, but pretreatment with paricalcitol suppressed this increase. The levels of LC3II/LC31, a marker of autophagy, were significantly increased after administration of ioversol, and paricalcitol inhibited this increase. After administration of ioversol, LC3-positive renal tubular epithelial cells were observed in the renal tissue, whereas the number was decreased by paricalcitol pretreatment. (See Fig. 4)

(5) Confirmation of aging reduction effect induced by contrast agent of paricalcitol

After administration of ioversol, the positivity of SA-β-gal, a biomarker for aging, increased in renal tubular cells of the kidney, and the expression of senescence-related p16 ^INK4A and HMGB1 proteins also increased. Paricalcitol inhibits their positive reaction and protein expression, suggesting that nephrotoxicity induced by contrast agent treatment and senescence of renal tubule cells may be functionally related. (See Fig. 5)

From the above experimental results, paricalcitol is judged to be able to prevent and treat contrast agent-induced nephrotoxicity by regulating mitophagy and aging-promoting signaling system.

Claims (7)

1. A pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity, comprising paricalcitol or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity according to claim 1, wherein the contrast agent is ioversol, iohexol, iobitridol, iopromide, iomeprol, or iopamidol.
3. The pharmaceutical composition for preventing or treating contrast agent-induced nephrotoxicity according to claim 1, wherein the contrast agent-induced nephrotoxicity is a condition in which blood creatinine levels are increased by 25% or 0.5 mg/dL or more compared to before administration within 48 hours after administration of the contrast agent to the subject.
4. The method according to claim 1, wherein the composition is administered 30 minutes to 24 hours before contrast agent administration, contrast agent-induced nephrotoxicity prevention or treatment pharmaceutical composition.
5. The method according to claim 1, wherein the composition is administered in combination with a contrast agent, contrast agent-induced nephrotoxicity prevention or treatment pharmaceutical composition.
6. paricalcitol or a pharmaceutically acceptable salt thereof; And a contrast composition for mitigating nephrotoxic side effects comprising a contrast agent.
7. The method according to claim 6, wherein the contrast agent is ioversol, iohexol, iobitridol, iopromide, iomeprol, or iopamidol, the nephrotoxic side effect of the contrast composition is alleviated.

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