Use of oxeladin for the preparation of a medicament for the prevention or treatment of perioperative hypothermia

Abstract

The application belongs to the technical field of medicine, and discloses application of oxeladin in preparation of a medicine for preventing or treating perioperative hypothermia. The dose of the medicine ranges from 1 to 3 mg. The medicine is applied to perioperative hypothermia caused by general anesthesia. The general anesthesia includes sevoflurane and esketamine. The medicine further comprises a pharmaceutically acceptable carrier and / or excipient. It is found in the previous application that the incidence of hypothermia and chills after general anesthesia is significantly reduced in the oxeladin administration group compared with the blank control group, and the further verification is carried out through animal experiments. The achievement of the application provides an effective prevention and treatment scheme for improving perioperative hypothermia and chills in clinic.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to the application of oxalidin in the preparation of a drug for the prevention or treatment of perioperative hypothermia. Background Technology

[0002] The incidence of perioperative hypothermia is high, and its prevention and treatment urgently need improvement. Aggressive temperature control measures can reduce the incidence of postoperative complications caused by hypothermia. Although perioperative warming systems are widely used and there are expert consensus guidelines, the incidence of perioperative hypothermia still occurs frequently. In addition to external warming methods, clarifying the relevant mechanisms of perioperative hypothermia is also essential; however, the mechanisms of perioperative hypothermia are currently unclear. Therefore, elucidating the pathogenesis of hypothermia induced by general anesthesia and finding effective prevention and treatment strategies are crucial.

[0003] Perioperative hypothermia is defined as a core body temperature ≤36.0℃ in the perioperative period, with an incidence of 78.6%. The incidence of hypothermia is 56.6% within 2 hours and 100% after 2 hours. High scores in the American Society of Anesthesiologists (ASA), level 3-4 surgery, laparoscopic surgery, anesthesia duration >2 hours, unwarmed intravenous fluids and irrigation solutions, and infusions or irrigations >1000ml significantly increase the incidence of perioperative hypothermia. A decrease in core body temperature in perioperative patients can lead to numerous adverse reactions, such as increased transfusion requirements, coagulation disorders, arrhythmias, immunosuppression, and surgical site infection. Furthermore, the discomfort caused by shivering due to perioperative hypothermia is comparable to postoperative pain. Due to the limited number of reported studies, the consequences of hypothermia in animals are still uncertain. Human body temperature is strictly regulated by nerves and hormones to maintain stability; however, factors such as anesthesia and surgical exposure during the perioperative period often cause hypothermia in patients. Therefore, it is necessary to actively manage the patient's body temperature before, during, and after surgery in order to reduce the risk of perioperative hypothermia. Summary of the Invention

[0004] To overcome the problems existing in the related technologies, the present invention discloses an application of oxalidin in the preparation of a drug for the prevention or treatment of perioperative hypothermia.

[0005] The technical solution is as follows: the application of oxalidin in the preparation of a drug for the prevention or treatment of perioperative hypothermia.

[0006] Furthermore, the dosage range of the drug is 1–3 mg.

[0007] Furthermore, the drug is used in the treatment of perioperative hypothermia caused by general anesthesia.

[0008] Furthermore, the general anesthesia includes the administration of sevoflurane and esketamine.

[0009] Furthermore, the drug also includes pharmaceutically acceptable carriers and / or excipients.

[0010] Another object of the present invention is to provide an application of oxalidin in the preparation of drugs that regulate Ucp1 expression.

[0011] Another object of the present invention is to provide an application of oxalidin in the preparation of drugs that regulate the expression of IL-1β and IL-6.

[0012] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of perioperative hypothermia, wherein the active ingredient of the pharmaceutical composition is oxalidin.

[0013] Furthermore, the pharmaceutical composition also includes a pharmaceutically acceptable carrier and / or excipients.

[0014] Another object of the present invention is to provide a method for preventing or treating perioperative hypothermia, the method comprising administering oxaliplatin to a subject.

[0015] Combining all the above technical solutions, the beneficial effects of this invention are as follows:

[0016] Previous findings of this invention revealed that the incidence of hypothermia and shivering after general anesthesia was significantly lower in the oxalidin-treated group compared to the control group, and this was further validated through animal experiments. The results of this invention provide an effective prevention and treatment strategy for improving perioperative hypothermia and shivering in clinical practice. Attached Figure Description

[0017] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this disclosure and, together with the description, serve to explain the principles of this disclosure;

[0018] Figure 1 This is a schematic diagram illustrating the inhibition of body temperature drop caused by sevoflurane inhalation general anesthesia by ocelidine, provided in an embodiment of the present invention.

[0019] Figure 2 This is a schematic diagram illustrating the inhibition of body temperature reduction caused by oseltidine under esketamine intravenous general anesthesia, provided in an embodiment of the present invention.

[0020] Figure 3 The image shows a mirror image of oxaliplatin, provided in this embodiment of the invention, which increases the expression of Ucp1 in mice.

[0021] Figure 4 The bar chart shows how oxaliplatin, as provided in this embodiment of the invention, can increase the expression of Ucp1 in mice.

[0022] Figure 5 This is a graph showing the reduction in 5IL-1β expression after administration of oxalidin infusion, as provided in an embodiment of the present invention.

[0023] Figure 6 This is a graph showing the reduction in IL-6 expression after administration of oxalidin infusion, as provided in an embodiment of the present invention. Detailed Implementation

[0024] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0025] The innovative aspect of the application of oxaliplatin in the preparation of drugs for the prevention or treatment of perioperative hypothermia provided in this invention is as follows:

[0026] Previous findings in this invention revealed a significant reduction in shivering and hypothermia after general anesthesia in patients treated with ocelidine compared to the control group. Based on this, the applicant hypothesized that ocelidine might be a potential drug for the prevention and treatment of perioperative hypothermia, with a therapeutic dose range of 1–3 mg. Currently, animal and clinical trials have not provided evidence that ocelidine has a therapeutic effect on perioperative hypothermia. Therefore, this invention designed animal experiments to verify the above analysis, providing a clinically effective treatment strategy for improving perioperative hypothermia.

[0027] Example 1: This embodiment of the invention provides an ocelidine (molecular formula: C 22 Application of H30N2O2S in the preparation of drugs for the prevention or treatment of perioperative hypothermia.

[0028] In this embodiment of the invention, the perioperative hypothermia is caused by general anesthesia.

[0029] In embodiments of the present invention, general anesthesia may include the administration of sevoflurane or esketamine.

[0030] In embodiments of the present invention, the drug further includes a pharmaceutically acceptable carrier and / or excipients.

[0031] Example 2, based on ocelidine (molecular formula: C) provided in Example 1 22 The application of H30N2O2S in the preparation of drugs for the prevention or treatment of perioperative hypothermia, and further, the application of oxalidin in the preparation of drugs that regulate Ucp1 expression.

[0032] Example 3, based on ocelidine (molecular formula: C) provided in Example 1 22 The application of H30N2O2S in the preparation of drugs for the prevention or treatment of perioperative hypothermia, and further, the application of oxalidin in the preparation of drugs for regulating the expression of IL-1β and IL-6.

[0033] Example 4, based on ocelidine (molecular formula: C) provided in Example 1 22 The application of H30N2O2S in the preparation of a medicament for the prevention or treatment of perioperative hypothermia; further, a medicament composition for the prevention or treatment of perioperative hypothermia is provided, wherein the active ingredient of the medicament composition is oxalidin.

[0034] In embodiments of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier and / or excipients.

[0035] Example 5, based on ocelidine (molecular formula: C) provided in Example 1 22 The application of H30N2O2S in the preparation of drugs for the prevention or treatment of perioperative hypothermia; further, embodiments of the present invention provide a method for the prevention or treatment of perioperative hypothermia, the method comprising administering oxalidin to a subject.

[0036] The subjects were patients in the perioperative period.

[0037] It is understood that the pharmaceutical compositions of the present invention can also be administered alone as a single composition or in a dosage form different from the main active ingredient, along with other therapeutic compounds. A portion of the main ingredient may be administered concurrently with other therapeutic compounds, while other doses may be administered alone. During treatment, the dosage of the pharmaceutical compositions of the present invention can be adjusted according to the severity of symptoms, the frequency of relapses, and the physiological response to the treatment regimen.

[0038] "Pharmaceutically acceptable carrier" refers to a carrier used for the administration of therapeutic agents, including various excipients and diluents. This term refers to pharmaceutical carriers that are not essential active ingredients themselves and do not cause excessive toxicity after administration. Suitable carriers are well known to those skilled in the art. Pharmaceutically acceptable carriers in compositions may contain liquids such as water, saline, or buffer solutions. Additionally, these carriers may contain auxiliary substances such as fillers, lubricants, flow aids, wetting agents or emulsifiers, pH buffers, etc. The carriers may also contain cell transfection reagents.

[0039] Pharmaceutically acceptable carriers can be one or more, including but not limited to diluents such as lactose, sodium chloride, glucose, urea, starch, and water; binders such as starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, alginate and alginates, xanthan gum, hydroxypropylcellulose, and hydroxypropyl methylcellulose; surfactants such as polyethylene oxide sorbitan fatty acid esters, sodium lauryl sulfate, glyceryl monostearate, and hexadecyl alcohol; humectants such as glycerin and starch; and adsorbents such as starch, lactose, bentonite, silica gel, kaolin, and soap binders. Soil, etc.; lubricants such as zinc stearate, glyceryl monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearate fumarate, polyoxyethylene monostearate, monolauric sucrose, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium dodecyl sulfate, etc.; fillers such as mannitol (granular or powdered), xylitol, sorbitol, maltose, erythrose, microcrystalline cellulose, polysaccharides, coupled sugars, glucose, lactose, sucrose, dextrin, starch, sodium alginate, kelp polysaccharide powder, agar powder, calcium carbonate and sodium bicarbonate, etc.; disintegrants such as crosylvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl methyl, crosylcarboxymethyl cellulose sodium, soybean polysaccharides, etc.

[0040] The pharmaceutical composition of the present invention may also include additives such as stabilizers, bactericides, buffers, isotonic agents, chelating agents, pH control agents, and surfactants.

[0041] In the above embodiments, the descriptions of each embodiment have different focuses. For parts that are not described in detail or recorded in a certain embodiment, please refer to the relevant descriptions of other embodiments.

[0042] To further illustrate the effects of the embodiments of the present invention, the following experiments were conducted.

[0043] (1) Experimental Groups:

[0044] Twenty-four adult male C57BL / 6J mice, weighing 20–25 g, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. They were randomly divided into four groups (n = 6) using a random number table.

[0045] (1.1) Sevoflurane + normal saline group (Sevo + NS group): 2.5% sevoflurane was inhaled via endotracheal tube, followed by continuous intraperitoneal infusion of 0.2 ml / kg normal saline. -1 ·h -1 Total time: 60 minutes;

[0046] (1.2) Sevoflurane + Ocelidine group (Sevo+OL group): 2.5% sevoflurane was inhaled via endotracheal tube, followed by continuous intraperitoneal infusion of 0.2 mg·kg ocelidine. -1 ·h -1 Total time: 60 minutes;

[0047] (1.3) Esketamine + Saline Group (EK + NS Group): Esketamine was administered intraperitoneally at a dose of 100 mg / kg, followed by continuous intraperitoneal infusion of 0.2 ml / kg of normal saline. -1 ·h -1 Total time: 60 minutes;

[0048] (1.4) Esketamine + Ocelidine group (EK+OL group): Esketamine 100 mg / kg was injected intraperitoneally, followed by continuous intraperitoneal infusion of Ocelidine 0.2 mg / kg. -1 ·h -1 The total duration is 60 minutes.

[0049] (2) Rectal temperature monitoring: Rectal temperature was monitored immediately after anesthesia. The rectal temperature was measured 5 min before anesthesia (-5 min), immediately after the righting reflex disappeared in mice (0 min), and 5, 10, 15, 20, and 60 min after the start of infusion. These were the core temperatures. The laboratory temperature was 22℃.

[0050] (3) ELISA: Mice were sacrificed and plasma was collected after the last temperature test. The expression of IL-1β and IL-6 in plasma was detected by ELISA. The levels of IL-1β and IL-6 were determined according to the instructions of the manufacturer using the IL-1β assay kit (Wuhan Saive Biotechnology Co., Ltd.) and the IL-6 assay kit (Wuhan Saive Biotechnology Co., Ltd.).

[0051] (4) Western blot: Mice were sacrificed after the last body temperature test, and hypothalamic tissue was collected. The expression of uncoupling protein 1 (Ucp1) in the hypothalamus was detected by Western blot. Hypothalamic tissue was added to pre-cooled tissue protein lysis buffer, sonicated to form a homogenate, and centrifuged at 4°C for 5 min at 12,000 rpm (10 cm radius). The supernatant obtained was the total protein of the hypothalamic tissue. The total protein was denatured at 95°C for 5 min. Separation was performed by 10% SDS-PAGE electrophoresis. The sample volume was 10 μL. The protein was transferred to a PVDF membrane, blocked with 5% skim milk powder at room temperature for 2 h, and washed. Primary antibodies were added: rabbit anti-mouse Ucp1 antibody and rabbit anti-mouse GAPDH antibody (both 1:1000, Abcam, UK). Incubate overnight at 4℃, wash 5 times with TBST for 5 min each time, add goat anti-rabbit secondary antibody (dilution 1:5000, Abcam, UK) and incubate at room temperature for 2 h, wash 5 times with TBST for 5 min each time, expose with luminescent reagent in a dark room, and scan for imaging. ImageJ image analysis software was used to analyze the band gray values, and the ratio of the Ucp1 band gray value to the GAPDH band gray value reflected the expression level of the target protein.

[0052] (5) Statistical analysis: SPSS 22.0 statistical software was used for analysis. Quantitative data were expressed as mean ± standard deviation. One-way ANOVA was used for comparison between groups. P < 0.05 was considered statistically significant.

[0053] Experimental results:

[0054] (1) Perioperative hypothermia caused by general anesthesia:

[0055] Compared to 5 minutes before anesthesia, both sevoflurane inhalation general anesthesia and esketamine intravenous general anesthesia resulted in a decrease in body temperature. Starting 5 minutes after general anesthesia, the temperature remained relatively stable until approximately 20 minutes post-anesthesia. There was no statistically significant difference in body temperature between 60 minutes and 20 minutes post-anesthesia. This indicates that the body temperature decreased most rapidly and reached a relatively low level 20 minutes after general anesthesia. Figure 1 , Figure 2 );

[0056] (2) Oxyphenidyl inhibits the hypothermia induced by sevoflurane inhalation general anesthesia:

[0057] The results are as follows Figure 1As shown, 5 minutes after sevoflurane general anesthesia combined with oxalidin infusion (Sevo+OL), the body temperature increased by 0.2℃ compared to sevoflurane anesthesia alone (Sevo+NS); 10 minutes after sevoflurane general anesthesia combined with oxalidin infusion (Sevo+OL), the body temperature increased by 0.36℃ compared to sevoflurane anesthesia alone (Sevo+NS); 15 minutes after sevoflurane general anesthesia combined with oxalidin infusion (Sevo+OL), the body temperature increased by 0.42℃ compared to sevoflurane anesthesia alone (Sevo+NS); 20 minutes after sevoflurane general anesthesia combined with oxalidin infusion (Sevo+OL), the body temperature increased by 0.47℃ compared to sevoflurane anesthesia alone (Sevo+NS); and 60 minutes after sevoflurane general anesthesia combined with oxalidin infusion (Sevo+OL), the body temperature increased by 0.45℃ compared to sevoflurane anesthesia alone (Sevo+NS). The specific data on the process by which oxalidin inhibits the decrease in body temperature caused by sevoflurane inhalation general anesthesia are shown in Table 1.

[0058] Table 1

[0059]

[0060] (3) Ocelidine inhibits the hypothermia caused by esketamine intravenous general anesthesia:

[0061] The results are as follows Figure 2 As shown, 5 minutes after esketamine intravenous general anesthesia combined with oxalidin infusion (EK+OL), the body temperature increased by 0.23℃ compared to esketamine anesthesia alone (EK+NS); 10 minutes after esketamine intravenous general anesthesia combined with oxalidin infusion (EK+OL), the body temperature increased by 0.38℃ compared to esketamine anesthesia alone (EK+NS); 15 minutes after esketamine intravenous general anesthesia combined with oxalidin infusion (EK+OL), the body temperature increased by 0.38℃ compared to esketamine anesthesia alone (EK+NS); At 1 minute, the body temperature was 0.48°C higher than that of esketamine anesthesia alone (EK+NS); 20 minutes after esketamine intravenous general anesthesia combined with oxalidin infusion (EK+OL), the body temperature was 0.55°C higher than that of esketamine anesthesia alone (EK+NS); 60 minutes after esketamine intravenous general anesthesia combined with oxalidin infusion (EK+OL), the body temperature was 0.55°C higher than that of esketamine anesthesia alone (EK+NS).

[0062] Rectal temperature monitoring showed that oxaliplatin significantly improved body temperature caused by general anesthesia. Remimazolam 0.2 mg / kg was administered via continuous intraperitoneal infusion. -1 ·h -1 It can effectively reduce the hypothermia caused by general anesthesia. Data on the process by which oxaliplatin inhibits the hypothermia induced by esketamine intravenous general anesthesia are shown in Table 2.

[0063] Table 2

[0064]

[0065] (4) Analysis of the molecular mechanism by which oxaliplatin improves the reduction of body temperature after general anesthesia.

[0066] like Figures 3-4 As shown, ocelidine can increase the expression of Ucp1 in mice, suggesting that ocelidine may promote fat thermogenesis by increasing Ucp1 expression. Furthermore, as... Figure 5 The graph shows a decrease in 5IL-1β expression after administration of oxalidin infusion, and Figure 6 The graph showing the decrease in IL-6 expression after ocelidine infusion indicates that the expression of 5IL-1β and IL-6 decreased after ocelidine infusion, suggesting that ocelidine may improve systemic hypothermia by reducing systemic inflammatory response.

[0067] The data on how ocelidine can increase the expression of Ucp1 in mice are shown in Table 3;

[0068] Table 3

[0069]

[0070]

[0071] The data on the reduction in 5IL-1β expression after administration of oxalidin infusion are shown in Table 4.

[0072] Table 4

[0073] 462 136 394 129 436 182 387 118 398 173 412 167 410 189 438 151 453 199 376 192 471 154 358 143

[0074] Table 5 shows the data on the reduction of IL-6 expression after administration of oxalidin infusion.

[0075] Table 5

[0076] 379 112 352 76 361 153 321 93 352 140 313 105 331 136 309 113 317 125 277 117 308 109 293 139

[0077] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions and improvements made by those skilled in the art within the scope of the technology disclosed in the present invention and within the spirit and principles of the present invention should be covered within the scope of protection of the present invention.

Claims

1. The use of ocelidine in the preparation of a medicament for the prevention or treatment of perioperative hypothermia, characterized in that, The application is the use of drugs in the perioperative hypothermia caused by general anesthesia; The general anesthesia included the administration of sevoflurane and esketamine.

2. The application according to claim 1, characterized in that, The dosage range of the drug is 1 to 3 mg.

3. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable carriers and / or excipients.

4. The use of ocelidine in the preparation of a drug for treating perioperative hypothermia caused by general anesthesia by regulating Ucp1 expression.

5. The use of ocelidine in the preparation of a drug for treating perioperative hypothermia caused by general anesthesia by regulating IL-1β and IL-6 expression.

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