Composition for preventing or treating cardiopulmonary bypass-induced vasoplegic syndrome or systemic inflammatory response syndrome, containing taurodeoxycholic acid or pharmaceutically acceptable salt thereof as active ingredient

Abstract

The present invention relates to a composition for preventing or treating cardiopulmonary bypass-induced vasoplegic syndrome or systemic inflammatory response syndrome (SIRS), the composition containing taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, taurodeoxycholic acid was found to inhibit systemic inflammatory cytokine release induced by cardiopulmonary bypass (CPB), and inhibit CPB-induced vasoplegia. Thus, taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be easily used as an active ingredient in a composition for preventing or treating cardiopulmonary bypass-induced vasoplegic syndrome or systemic inflammatory response syndrome that can be induced during surgeries such as CPB.

Description

Composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome containing taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient

[0001] The present invention relates to a composition for preventing or treating cardiopulmonary bypass-induced vasoplegic syndrome or systemic inflammatory response syndrome (SIRS), which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002] Systemic inflammatory response syndrome (SIRS) is a complex response that occurs when the body responds to various insults, including infection, trauma, burns, pancreatitis, and other injuries. SIRS is extremely common in intensive care units (ICUs) and can occur in non-infected patients. Up to 93% of surgical ICU patients meet criteria for SIRS, and the non-infectious mortality rate is reported to be 7-9%. Furthermore, SIRS has been shown to act as a precursor to sepsis. SIRS may be caused by an excessive inflammatory response to cytokine release from damaged tissues and is associated with circulating pro- and anti-inflammatory cytokines. Although not yet proven, high levels of pro-inflammatory cytokines have been closely associated with postoperative adverse outcomes. While a direct causal relationship has not been established, elevated levels of pro-inflammatory cytokines are strongly associated with adverse postoperative outcomes. Among these cytokines, IL-6 levels have been proposed as a marker directly related to the risk of postoperative complications.

[0003] Until the 1950s, when cardiopulmonary bypass (CPB) systems were developed, cardiovascular surgery was associated with high mortality and morbidity. However, the use of CPB is associated with the activation of various inflammatory pathways, including cellular components such as red blood cells, platelets, and leukocytes, as well as soluble proteins. Complement activation typically occurs during surgery, but is more pronounced in cardiac surgery using CPB. The degree of complement activation is directly proportional to the duration of CPB. Cardiovascular surgery using CPB induces a systemic inflammatory response syndrome (SIRS), which significantly impacts postoperative mortality and morbidity. Critically ill patients have a limited ability to counteract the inflammatory response, making them more susceptible to endothelial damage and capillary leak syndrome. While tissue edema can increase in any organ, the lungs, brain, kidneys, and myocardium are particularly vulnerable. Therefore, post-CPB syndrome can manifest as non-cardiogenic pulmonary edema, myocardial dysfunction, severe vasoconstriction, hemodynamic instability, renal dysfunction, and, in severe cases, multi-organ failure. Consequently, long-term CPB in large animals may be a beneficial controlled experimental model for systemic inflammatory responses.

[0004] Meanwhile, pharmacological approaches have been explored to minimize organ damage during CPB procedures. Pharmacological strategies to suppress the systemic inflammatory response to surgery have already advanced significantly, with the use of agents such as aprotinin and heparin-coated circuits used for hemostasis and coagulation management. However, the development of dedicated anti-inflammatory agents targeting the inflammatory response is limited, and those that have been developed often exhibit narrow targeting. This narrow targeting may hinder their ability to effectively mitigate the multisystemic pathogenesis of the systemic inflammatory response. Furthermore, to address safety concerns associated with the use of antifibrinolytics in cardiac surgery, appropriately supported future clinical trials are essential to detect well-defined adverse events, such as stroke, myocardial injury, and acute renal failure requiring dialysis.

[0005] Furthermore, vasoplegia is a common complication of cardiac surgery using CPB, and multiple mechanisms are implicated, including activation of the inflammatory response, oxidative stress, and catecholamine depletion. Reducing vasoplegia can positively impact postoperative outcomes in several ways. First, it can improve organ perfusion and oxygenation by maintaining vascular tone and blood pressure, thereby reducing the incidence of postoperative organ dysfunction and failure. Second, reducing vasoplegia can reduce the need for vasoconstrictors, such as norepinephrine, which are associated with adverse effects such as myocardial ischemia and arrhythmias. Third, it can reduce the incidence of postoperative complications and prolong hospital stays, ultimately improving patient outcomes and reducing healthcare costs.

[0006] Therefore, the present inventors have made efforts to develop a formulation that can reduce complications that may be caused by surgery, and as a result, in an animal model administered sodium salt of taurodeoxycholic acid during cardiopulmonary bypass (CPB), they confirmed that the level of proinflammatory cytokines was stably maintained during and after CPB discontinuation, the amount of norepinephrine required to maintain mean blood pressure after CPB discontinuation was reduced, and systemic vascular resistance (SVR) was maintained. Therefore, taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be easily utilized as an active ingredient in a composition for preventing or treating systemic inflammatory response syndrome or vasoplegic syndrome that may be induced during surgery such as CPB.

[0007] [Prior Art Literature]

[0008] [Non-patent literature]

[0009] Rangel-Frausto, M. S. et al. The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. JAMA 273, 117-123 (1995).

[0010] Prochazka, V. et al. Serum concentrations of proinflammatory biomarker interleukin-6 (IL-6) as a predictor of postoperative complications after elective colorectal surgery. World J. Surg. Oncol. 21, 384 (2023).

[0011] Tantri, A. R.et al. Comparison of postoperative IL-6 and IL-10 levels following Erector Spinae Plane Block (ESPB) and classical Thoracolumbar Interfascial Plane (TLIP) block in a posterior lumbar decompression and stabilization procedure: A randomized controlled trial. BMC Anesthesiol. 23, 13 (2023).

[0012] Hirai, S. Systemic inflammatory response syndrome after cardiac surgery under cardiopulmonary bypass. Ann. Thorac. Cardiovasc. Surg. 9, 365-370 (2003).

[0013] Lambden, S., Creagh-Brown, B. C., Hunt, J., Summers, C. & Forni, L. G. Definitions and pathophysiology of vasoplegic shock. Crit. Care (2018).

[0014] Smith, P. K.et al. Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: Combined results from the PRIMO-CABG I and II trials. J. Thorac. Cardiovasc. Surg. 142, 89-98 (2011).

[0015] Jawa, RS, Anillo, S., Huntoon, K., Baumann, H. & Kulaylat, M. Interleukin-6 in surgery, trauma, and critical care part II: Clinical implications. J. Intensive Care Med. 26, 73-87 (2011).

[0016] De Somer, F. End-organ protection in cardiac surgery. Minerva Anestesiol. 79, 285-293 (2013).

[0017] Hutton, B. et al. Risks of harms using antifibrinolytics in cardiac surgery: Systematic review and network meta-analysis of randomized and observational studies. BMJ 345, e5798 (2012).

[0018] The purpose of the present invention is to provide a composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome (SIRS), which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0019] In order to achieve the purpose of the present invention, the present invention provides a pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome (SIRS), which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] In addition, the present invention provides a method for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, comprising a step of administering taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to a subject.

[0021] In addition, the present invention provides a pharmaceutical composition containing taurodeoxycholic acid or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of vasoplegic syndrome or systemic inflammatory response syndrome.

[0022] In addition, the present invention provides the use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the prevention or treatment of vasoplegic syndrome or systemic inflammatory response syndrome.

[0023] In the present invention, it was confirmed that the level of proinflammatory cytokines was stably maintained during and after cessation of cardiopulmonary bypass (CPB) in an animal model administered with the sodium salt of taurodeoxycholic acid. In addition, it was confirmed that the amount of norepinephrine required to maintain mean blood pressure after cessation of CPB in the animal model was small, and systemic vascular resistance (SVR) was maintained, confirming that taurodeoxycholic acid contributes to reducing vasoplegia. Therefore, taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be easily utilized as an active ingredient in a composition for preventing or treating systemic inflammatory response syndrome (SIRS) or cardiopulmonary bypass-induced vasoplegic syndrome, which may be induced during surgery such as CPB.

[0024] Figure 1 shows changes in plasma cytokine concentration levels in experimental animals that received intravenous injection of NuSepin® (0.2 mg / kg) and underwent cardiopulmonary bypass (CPB). TO is time point 0, immediately after anesthesia induction; T1 is time point 1, 60 minutes after the start of CPB; T2 is time point 2, 120 minutes after the start of CPB; and T3 is time point 3, 120 minutes after the cessation of CPB.

[0025] Figure 2 is a diagram showing the total norepinephrine usage and mean blood pressure (MBP) of experimental animals that were intravenously injected with NuSepin® (0.2 mg / kg) and underwent CPB over time. (A) shows the total norepinephrine usage of the control group, (B) shows the total norepinephrine usage of the NuSepin administration group, (C) shows the mean blood pressure of the control group, and (D) shows the mean blood pressure of the NuSepin administration group.

[0026] Figure 3 shows a comparison of sustained systemic vascular resistance (SVR) in experimental animals administered intravenously with NuSepin® (0.2 mg / kg) and undergoing CPB with the control group. In (A), the vertical line represents the baseline SVR-SVR value, the line on the graph represents the mean, and data points are marked with markers indicating standard deviation. In (B), the red color indicates the interval where the difference between the two groups was statistically significant (p-value <0.05) when comparing SVR at consecutive time points.

[0027] Figure 4 shows the continuous hemodynamic data for 120 minutes after CPB was discontinued in experimental animals that received intravenous injection of NuSepin® (0.2 mg / kg) and underwent CPB compared to the control group.

[0028] Hereinafter, the present invention will be described in more detail.

[0029] In the present invention, the term "prevention" means any act of inhibiting or delaying the occurrence, spread, and recurrence of a disease by administering the composition of the present invention, and the term "treatment" means any act of improving or beneficially changing the symptoms of a disease by administering the composition of the present invention.

[0030] The term "administration" in the present invention refers to providing a given substance to a patient by any suitable method. The composition of the present invention may be administered orally or parenterally via any conventional route as long as it can reach the target tissue. Furthermore, the composition may be administered by any device capable of transporting the active substance to target cells.

[0031]

[0032] The present invention provides a pharmaceutical composition for preventing or treating cardiopulmonary bypass-induced vasoplegic syndrome or systemic inflammatory response syndrome (SIRS), which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0033] In addition, the present invention provides a method for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, comprising a step of administering taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to a subject.

[0034] In addition, the present invention provides a pharmaceutical composition containing taurodeoxycholic acid or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of vasoplegic syndrome or systemic inflammatory response syndrome.

[0035] In addition, the present invention provides the use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the prevention or treatment of vasoplegic syndrome or systemic inflammatory response syndrome.

[0036] In the present invention, the taurodeoxycholic acid is a type of bile acid, is in the form of taurine-conjugated deoxycholic acid, and has a chemical structure described by the following [Chemical Formula 1], and more specifically, has a chemical structure described by the following [Chemical Formula 2]:

[0037] [Chemical Formula 1]

[0038]

[0039] [Chemical Formula 2]

[0040]

[0041] In addition, the above taurodeoxycholic acid can be used without any problem, whether it is isolated from an animal carcass, such as a cow, pig, sheep, dog, goat or rabbit, commercially available or synthetic.

[0042] In the present invention, the vasoplegic syndrome or systemic inflammatory response syndrome may occur during surgery, and examples of the surgery include, but are not limited to, cardiopulmonary bypass (CPB), cardiac surgery, cardiovascular surgery, or lumbar surgery.

[0043] In the present invention, the composition can prevent or treat a systemic inflammatory response syndrome induced by surgery by maintaining the level of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6 or IL-8, during or after surgery at the level of proinflammatory cytokines before surgery.

[0044] Additionally, the composition can prevent or treat surgically induced vasoplegic syndrome by maintaining systemic vascular resistance (SVR) during surgery.

[0045] For this purpose, the composition may be administered intravenously before surgery, wherein taurodeoxycholic acid or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 mg to 0.4 mg, 0.1 mg to 0.3 mg or 0.2 mg.

[0046] In a specific embodiment of the present invention, the inventors intravenously administered 0.2 mg / kg of a clinical formulation (Nusepin®) containing the sodium salt of taurodeoxycholic acid before performing CPB in an animal model, and measured plasma proinflammatory cytokine levels before, during, and after CPB discontinuation. As a result, the plasma cytokine concentration levels in the Nusepin administration group were generally lower than in the control group, and tended to remain unchanged during CPB. In particular, the plasma level of IL-6, a potential marker directly related to the risk of postoperative complications, was significantly reduced compared to the control group after CPB discontinuation. This confirmed that taurodeoxycholic acid or a pharmaceutically acceptable salt thereof suppresses the systemic inflammatory response syndrome induced by surgery in a non-infectious environment.

[0047] In addition, when measuring the total norepinephrine usage and systemic vascular resistance (SVR) after discontinuation of CPB in the above animal model, the total norepinephrine usage in the Nusepin administration group was significantly lower than in the control group, and the Nusepin administration group maintained the SVR without a significant difference from the baseline SVR even after discontinuation of CPB. This confirmed that taurodeoxycholic acid or a pharmaceutically acceptable salt thereof suppresses the vasoplegic syndrome that may occur during cardiac surgery or cardiovascular surgery using CPB.

[0048] Accordingly, the present inventors have confirmed that the administration of sodium salt of taurodeoxycholic acid during CPB can stably maintain the level of proinflammatory cytokines during and after CPB discontinuation, can reduce the amount of norepinephrine required to maintain mean blood pressure after CPB discontinuation, and can maintain systemic vascular resistance (SVR). Therefore, the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be easily used as an active ingredient of a pharmaceutical composition for preventing or treating systemic inflammatory response syndrome or vasoprehensis syndrome, specifically, systemic inflammatory response syndrome or vasoprehensis syndrome that can be induced by surgery such as CPB.

[0049] The taurodeoxycholic acid of the present invention includes all pharmaceutically acceptable salts, possible solvates, hydrates, racemates, or stereoisomers that can be prepared therefrom.

[0050] The taurodeoxycholic acid of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, Contains terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0051] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving the taurodeoxycholic acid of the present invention in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Alternatively, the salt can be prepared by evaporating the solvent or excess acid from the mixture to dryness, or by suction filtration of the precipitated salt.

[0052] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are pharmaceutically suitable for preparing the metal salt, and more specifically, in the case of taurodeoxycholic acid, the sodium salt is suitable for preparing. Furthermore, the corresponding silver salt is obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0053] The taurodeoxycholic acid or a pharmaceutically acceptable salt thereof of the present invention may be contained in a therapeutically effective amount and may include a pharmaceutically acceptable carrier.

[0054] As used herein, "effective amount" or "effective dose" refers to an amount of a compound of the present invention sufficient to delay or minimize a disease; or provide a therapeutic benefit in the treatment or management of a disease. Specifically, the taurodeoxycholic acid or pharmaceutically acceptable salt thereof of the present invention may be included in an amount of 0.1 mg to 0.4 mg, 0.1 mg to 0.3 mg, or 0.2 mg.

[0055] The pharmaceutically acceptable carrier may include, for example, a carrier for oral administration or a carrier for parenteral administration, and specifically, a carrier for parenteral administration may be used. The carrier for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. In addition, the carrier for parenteral administration may include water, suitable oils, saline solution, aqueous glucose, glycol, etc., and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Other pharmaceutically acceptable carriers may be referred to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

[0056] The pharmaceutical composition of the present invention can be administered to mammals, including humans, via any route of administration, and specifically can be administered orally or parenterally, and more specifically can be administered parenterally.

[0057] Parenteral administration methods may include, for example, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration, and specifically, intravenous administration.

[0058] The pharmaceutical composition of the present invention can be formulated as a preparation for oral administration or parenteral administration according to the administration route as described above, and specifically can be formulated as a preparation for parenteral administration, and more specifically can be formulated as a preparation for intravenous administration.

[0059] In the case of preparations for oral administration, the composition of the present invention can be formulated into powders, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. using methods known in the art. For example, oral preparations can be obtained by mixing an active ingredient with a solid excipient, grinding the mixture, adding a suitable auxiliary agent, and then processing the mixture into a granule mixture to obtain a tablet. Examples of suitable excipients may include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, and maltitol; starches including corn starch, wheat starch, rice starch, and potato starch; cellulosics including cellulose, methyl cellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; fillers such as gelatin and polyvinylpyrrolidone. Additionally, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrating agent, depending on the case. Furthermore, the pharmaceutical composition of the present invention may additionally include an anticoagulant, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, and the like.

[0060] For parenteral administration, preparations can be formulated into injections, creams, lotions, topical ointments, oils, moisturizers, gels, patches, aerosols, and nasal inhalers using methods known in the art. These formulations are described in the literature (Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour), a commonly known prescription manual for all pharmaceutical chemistry.

[0061] The total dosage of the pharmaceutical composition of the present invention may be administered to a patient as a single dose, or may be divided into multiple doses. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the symptoms of the disease. However, the dosage of the pharmaceutical composition of the present invention will be determined by a person skilled in the art by taking into consideration various factors such as the route of administration and number of treatments, as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate.

[0062] Additionally, the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent. When administered in combination with another therapeutic agent, the composition of the present invention and the other therapeutic agent may be administered simultaneously, separately, or sequentially. In this case, the other therapeutic agent may be a substance already known to have a preventive or therapeutic effect on vasoplegic syndrome or systemic inflammatory response syndrome, such as norepinephrine. When the pharmaceutical composition of the present invention is administered in combination with another therapeutic agent, the composition of the present invention and the other therapeutic agent may be formulated separately in separate containers or may be compounded together in the same dosage form.

[0063] Hereinafter, the present invention will be described in detail by examples.

[0064] However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited to the following examples.

[0065] <Example 1> Production of an animal model for cardiopulmonary bypass (CPB) and drug administration

[0066] <1-1> Animal model

[0067] Animal experiments were approved by the Korea University Institutional Animal Care and Use Committee (KUIACUC, Approval: KOREA-2022-0024-C2). To minimize hormonal fluctuations, eight male Yorkshire pigs, weighing 40.5 ± 0.76 kg and aged 11–12 weeks, were used. The pigs were supplied as "bacon pigs" from Orient Bio BP Farms in Korea and were acclimated to the Korea University animal facility for 2 weeks before the experiment. The animals were housed in individual cages (2 × 2 m), fed a maintenance diet (Purina Feeds Ltd. pig diet), and maintained in a temperature-controlled environment (23 ± 2.3°C) under a 12:12 h light / dark cycle with free access to tap water. The pigs were fasted for 24 h before surgery.

[0068] <1-2> Anesthesia

[0069] The anesthetics used were Rompun® (xylazine, 1 mg / kg, Dechra; USA) and Zoletil® (zolazepam / tiletamine, 7 mg / kg, Virbac; New Zealand), which were injected intramuscularly. The animals were intubated with an endotracheal tube (Portex®, inner diameter 6 mm, Smith-Medical, USA) with a standard cuff, and the cuff was inflated with 15 ml of air. The correct placement of the endotracheal tube was confirmed by chest expansion, bilateral chest auscultation, air leaks around the cuff, and end-tidal CO2 detection by capnography. Anesthesia was maintained with isoflurane at an end-tidal concentration of 1.5%. The fresh gas flow was maintained at 4 L / min with an FiO2 of 0.5. The tidal volume and respiratory rate were set at 8 ml / kg and 15 breaths / min, respectively. The animals were placed in the supine position with their necks extended on the operating table and monitored using a standard anesthesia monitor including electrocardiogram, pulse oximetry, and noninvasive blood pressure. To monitor central venous pressure (CVP), a 3-lm central venous catheter (Arrowg+ard Blue Plus® Teleflex, North Carolina, USA) was inserted into the femoral vein, and 5 ml kg lactate solution (Ringer's lactate solution) was administered during anesthesia. -1 h -1was administered. An arterial catheter was inserted into the femoral artery to monitor arterial blood pressure (ABP). All hemodynamic data, including ABP, CVP, stroke volume (SV), stroke volume variance (SVV), and cardiac output (CO), were monitored using an EV1000® (Edwards Lifesciences, Irvine, USA) equipped with a FloTrac sensor. All drugs were administered using an Agilia® infusion pump (Fresenius Kabi, Bad Homburg, Germany). All vital signs observed using an anesthesia monitoring device were recorded as continuous waveforms using a vital recorder (VitalDB; Seoul, Korea).

[0070] When cardiopulmonary bypass (CPB) was discontinued, norepinephrine was continuously infused to maintain the mean blood pressure above 60 mmHg, and normal saline was used to maintain stroke volume variation (SVV) below 15.

[0071] <1-3> Drug administration

[0072] After induction of anesthesia and placement of an intravenous line, pigs were randomly assigned to a control or experimental group using a coin toss. The control group received 10 ml of saline intravenously, and the experimental group received 10 ml of NuSepin® (0.2 mg / kg) intravenously. NuSepin® is an injectable clinical preparation containing sodium taurodeoxycholate (TDCA) provided by Chaperone Co., Ltd. After injection, the pigs were prepared for surgery, and cannulation was performed to initiate CPR.

[0073] <1-4> CPB

[0074] In general, the CPB time is less than 2 hours for experienced operators performing heart valve surgery. Therefore, the CPB time was set to 2 hours considering the clinical situation. Before starting CPB, the tidal volume was adjusted to achieve normal breathing with oxygen in air (FiO20.5) and controlled by blood gas analysis to maintain normal arterial carbon dioxide tension. The experiment was conducted using a standard CPB technique (2.4 l / min / m) with moderate hypothermia (nasopharyngeal temperature 32-34°C), roller pump, and heparin (300 IU / kg) administration. 2 ) was performed and the activated clotting time was maintained above 400 seconds. The circuit was primed with Ringer's lactated solution, albumin, and mannitol, and the cannulation strategy was the standard Bicaval technique venous drainage (32 and 40 Fr, Medtronics, Minenesota, USA) back to the distal ascending aorta (16 Fr, Medtronics, Minenesota, USA). After stopping CPB (rectal temperature 36.5-37°C), the anticoagulant activity was reversed by administering protamine sulfate:heparin at a ratio of 1 mg:100 IU. The CPB withdrawal protocol was as follows: the venous line was partially clamped, and the preload of the venous drainage device was gradually increased. As preload increased, the arterial waveform was observed along with the ejection, and venous drainage was gradually reduced to maintain the normal arterial pressure. CPB was stopped when the pump flow rate was less than 10%.

[0075] <Example 2> Blood sample collection

[0076] Blood samples of the animal model of <Example 1> were collected immediately after anesthesia induction in the animal model (time point 0, T0), 1 hour after the start of CPB (time point 1, T1), 2 hours after the start of CPB (time point 2, T2), and 2 hours after the cessation of CPB (time point 3, T3). Considering that most cardiac surgeries are completed within 2 hours after CPB, blood samples were collected up to 2 hours after the end of CPB, and the pigs were euthanized using potassium after sampling. All samples were collected from the cannulated femoral artery, anticoagulated with ethylene diamine tetra-acetic acid, immediately cooled to 4°C, centrifuged within 10 minutes, and stored at -80°C until analysis. To assess the levels of proinflammatory cytokine release, serum levels of TNF-α, IL-1β, IL-6, and IL-8 were measured using commercially available enzyme-linked immunosorbent assays (ELISAs) according to the manufacturer's procedures.

[0077] <Example 3> Statistical analysis

[0078] The chi-square test was used to compare categorical data. Nonparametric data were analyzed using the Mann-Whitney test. All values ​​are expressed as mean ± standard deviation (SD) and compared based on the distribution of variables. The Mann-Whitney U test and the Kruskal-Wallis test were used to compare the levels of TNF-α, IL-1β, IL-6, and IL-8. Norepinephrine dose and systemic vascular resistance (SVR) between the two groups were compared by summing the integrals under the dose curves. Statistical analyses were performed using IBM SPSS Statistics 22.0 (IBM Corp. Armonk, NY, USA). Hemodynamic data were analyzed using a general linear mixed model followed by the Tukey-Kramer correction. A p-value <0.05 was considered statistically significant.

[0079] <Experimental Example 1> Characteristics of an animal model undergoing cardiopulmonary bypass (CPB)

[0080] The animal model characteristics of <Example 1> above, baseline hemodynamic values, and baseline cytokine levels were measured. Baseline hemodynamic values ​​were measured every 10 minutes from the completion of arteriovenous cannulation until the start of surgery.

[0081] As a result, as shown in Table 1, there were no significant differences in characteristic data, pre-CPB time (time from immediately after anesthesia to the start of CPB), CPB time, baseline hemodynamic values, or baseline cytokine levels between the Nusepin administration group and the control group.

[0082] Nusepin Group (n=4) Control Group (n=4) pvalue Age (weeks) 11.5±0.4 11.6±0.3 0.69 Weight (kg) 40.6±0.4 40.7±0.4 0.89 PreCPB time (min) 80.5±5.3 81.8±4.3 0.69 CPB time (min) 120±0 120±01 Baseline hemodynamic values ​​SBP (mmHg) 99±6 105±5 0.53 MBP (mmHg) 72±5 76±5 0.53 DBP (mmHg) 58±5 61±5 0.80 HR (bpm) 95±15 100±20 0.64 CO (L / min) 5.6±0.5 6.5±0.3 0.11 SV (ml) 52.8±8.9 61.7±8.7 0.63 CVP (mmHg) 15.8±4.5 13.4±1.9 0.63 SVR (mmHg*sec / ml) 768.5±68.4 830.7±46.6 0.63 Baseline level of cytokines TNF-α (pg / ml) 94.1±15.6 102.2±20.3 0.34 IL-1β (pg / ml) 122.5±9.6 133.1±9.7 0.49 IL-6 (pg / ml) 75.8±3.4 86.4±11.9 0.34 IL-8 (pg / ml) 21.0±8.1 23.8±11.4 0.34* SBP: Systolic blood pressure, MBP: Mean blood pressure, DBP: Diastolic blood pressure, HR: Heart rate, CO: Cardiac output, SV: Stroke volume, CVP: Central venous pressure, SVR: Systemic vascular resistance

[0083] <Experimental Example 2> Analysis of Plasma Cytokine Levels in an Animal Model Subjected to Cardiopulmonary Bypass (CPB)

[0084] Several factors contribute to the systemic inflammatory response, including the interaction of blood with the CPB device surface, surgical trauma, endotoxemia, blood loss, and ischemia-reperfusion injury. In the context of CPB circuit-blood contact, the classical complement pathway can be activated through C1 activation by FXIIa, whereas the alternative complement pathway has been shown to be dominantly involved in the formation of the terminal membrane attack complex (C5b-9), as well as the production of anaphylatoxins such as C3a and C5a. Neutrophil activation induced by anaphylatoxins and kallikrein leads to the release of lytic enzymes such as elastase and reactive oxygen species. Both of these factors can cause tissue damage and organ dysfunction. During CPB, both complement activation and neutrophil activation contribute to increased cytokine levels. IL-1, IL-6, IL-8, and tumor necrosis factor (TNF) are proinflammatory cytokines that are expressed at high levels in response to tissue damage and endotoxin attack. These cytokines play a key role in the development of the systemic inflammatory response syndrome after CPB. Among these cytokines, IL-6 has been suggested as a potential marker directly related to the risk of postoperative complications.

[0085] Accordingly, changes in plasma cytokine concentrations at various time points, before CPB (T0), 60 minutes after CPB application (T1), 120 minutes after CPB application (T2), and 120 minutes after CPB discontinuation (T3), were measured in the animal model of the above <Example 1> and are shown in Fig. 1 and Table 2. Fig. 1 shows changes in plasma cytokine concentrations, and Table 2 shows the magnitude of changes in plasma cytokine levels compared to baseline cytokine levels.

[0086] Nusepin group [measured value] Control group [measured value] pvalueTNF-αT0 100.00 [94.1±15.5] 100.00 [102.2±20.3]T1 103.36±23.09 [96.4±24.6] 224.89±149.19 [212.4±94.1] 0.114T2 100.49±12.94 [94.3±19.9] 198.53±99.35 [193.3±68.6] 0.114T3 100.74±11.25 [93.9±12.6] 132.12±46.87 [129.6±25.6] 0.343IL-1βT0 100.00 [122.5±9.6] 100.00 [133.1±9.7]T1 96.88±6.10 [118.4±6.9] 112.11±18.78 [148.5±21.4] 0.200T2 104.61±14.57 [127.6±15.3] 110.02±11.26 [146.1±13.0] 0.486T3 99.53±4.17 [121.8±8.6] 113.50±13.83 [151.1±21.1] 0.057IL-6T0 100.00 [75.8±3.4] 100.00 [83.4±11.9]T1 115.86±8.73 [87.7±5.4] 114.21±8.41 [94.9±11.8] 0.886T2 143.16±15.65 [108.2±8.3] 144.65±17.09 [120.0±16.7] 0.886T3 144.00±9.03 [109.2±7.9] 201.40±50.70 [166.2±39.1] 0.057IL-8T0 100.00 [18.1±0.9] 100.00 [23.9±11.5]T1 106.60±4.34 [19.3±1.3] 117.02±27.22 [25.6±9.1] 0.686T2 107.39±5.29 [19.5±1.5] 116.76±16.78 [26.8±12.0] 0.688T3 104.48±0.96 [19.0±0.8] 125.15±41.74 [26.7±9.2] 0.343

[0087] As a result, as shown in Fig. 1 and Table 2, overall, the plasma cytokine concentration levels tended to be lower in the Nusepin administration group and tended to remain unchanged during CPB. In particular, the plasma TNF-α concentration was 30% lower in the Nusepin administration group at time points T1 and T2 (p = 0.057). In addition, the plasma IL-6 level decreased sharply in the Nusepin administration group compared to the control group at time point T3. On the other hand, IL-8, which is recognized as a proinflammatory cytokine associated with tissue damage in the area affected by infection, did not show a significant difference between the Nusepin administration group and the control group. These results indicate that TDCA suppresses the systemic inflammatory response syndrome induced during surgery in a non-infectious environment.

[0088] <Experimental Example 3> Analysis of norepinephrine usage in an animal model undergoing cardiopulmonary bypass (CPB).

[0089] In the animal model of <Example 1> above, the total amount of norepinephrine administered over time after CPB was discontinued was confirmed. Norepinephrine was administered starting 30 minutes after CPB was removed, and the average pressure was maintained at 60 mmHg or higher in the control and Nusepin administration groups. Thereafter, norepinephrine was continuously infused into the animals until the end of the experiment. Figures 2 (A) and (C) respectively show the total amount of norepinephrine and the average blood pressure of the control group, and Figures 2 (B) and (D) respectively show the total amount of norepinephrine and the average blood pressure of the Nusepin administration group.

[0090] As a result, as shown in Figure 2, it was confirmed that the total amount of norepinephrine used in the control group significantly increased 60 minutes after CPB discontinuation. The average total amount of norepinephrine used 120 minutes after CPB discontinuation was 273 mcg and 2.5 mcg in the control and Nusepin administration groups, respectively.

[0091] The above results show that TDCA suppresses vascular paralysis by maintaining blood pressure during cardiac surgery using CPB.

[0092] <Experimental Example 4> Analysis of systemic vascular resistance in an animal model undergoing cardiopulmonary bypass (CPB).

[0093] Systemic vascular resistance (SVR) is a major determinant of blood pressure. Therefore, in the animal model of <Example 1>, systemic vascular resistance (SVR) was measured over time after cessation of CPB.

[0094] As a result, as shown in Figure 3, the Nusepin administration group maintained SVR without significant difference from the baseline SVR even after CPB discontinuation. In contrast, the control group showed a large difference between the baseline SVR and the SVR, with a large fluctuation range up to 60 minutes after CPB discontinuation. In addition, the baseline SVR-SVR value immediately after CPB discontinuation was measured to be statistically lower in the Nusepin administration group.

[0095] Meanwhile, as shown in Figure 4, no differences were found between groups in any hemodynamic parameters, including blood pressure, cardiac output, stroke volume, stroke volume change, and central venous pressure.

[0096] The above results show that vascular paralysis is suppressed by maintaining SVR with TDCA during cardiac surgery using CPB.

[0097] In the present invention, it was confirmed that the sodium salt of taurodeoxycholic acid inhibits the release of proinflammatory cytokines induced by cardiopulmonary bypass (CPB) and inhibits vascular paralysis induced by CPB. Therefore, taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be easily used as an effective ingredient of a composition for preventing or treating vascular paralysis syndrome or systemic inflammatory response syndrome that may be induced during surgery such as CPB.

Claims

1. A pharmaceutical composition for preventing or treating cardiopulmonary bypass-induced vasoplegic syndrome or systemic inflammatory response syndrome (SIRS), comprising taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

2. In the first paragraph, the taurodeoxycholic acid is a compound represented by the following [chemical formula 2], a pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome: [Chemical Formula 2] .

3. A pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, wherein the pharmaceutically acceptable salt in paragraph 1 is a sodium salt.

4. A pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome in claim 1, wherein the vasoplegic syndrome or systemic inflammatory response syndrome occurs during surgery.

5. A pharmaceutical composition for preventing or treating vascular paralysis syndrome or systemic inflammatory response syndrome, wherein the surgery in paragraph 4 is cardiopulmonary bypass (CPB), cardiac surgery, cardiovascular surgery or lumbar surgery.

6. A pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, wherein the composition is administered intravenously before surgery in the fourth paragraph.

7. A pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, wherein the composition comprises 0.1 mg to 0.4 mg of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in the 6th paragraph.

8. A pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, wherein the composition maintains the level of proinflammatory cytokines during or after surgery at the level of proinflammatory cytokines before surgery.

9. A pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, wherein the proinflammatory cytokine in paragraph 8 is at least one selected from the group consisting of TNF-α, IL-1β, IL-6, and IL-8.

10. A pharmaceutical composition for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, wherein the composition maintains systemic vascular resistance (SVR) during surgery.

11. A method for preventing or treating vasoplegic syndrome or systemic inflammatory response syndrome, comprising a step of administering taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to a subject.

12. A pharmaceutical composition containing taurodeoxycholic acid or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of vasoplegic syndrome or systemic inflammatory response syndrome.

13. Use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the prevention or treatment of vasoplegic syndrome or systemic inflammatory response syndrome.

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