CN112438970B - New application of milnacipran or/and pharmaceutical salt of milnacipran - Google Patents
New application of milnacipran or/and pharmaceutical salt of milnacipran Download PDFInfo
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Abstract
The invention relates to a new application of milnacipran or/and pharmaceutical salt of milnacipran, in particular to an application of milnacipran or/and pharmaceutical salt of milnacipran in preparing a medicine for preventing or/and treating intestinal ischemia reperfusion injury. Compared with the prior art, the invention has the following beneficial effects: according to the invention, milnacipran and/or the medicinal salt thereof are used for preventing and/or treating intestinal ischemia reperfusion injury for the first time, and the effect of the medicament is verified on a constructed classical intestinal ischemia reperfusion model, and verification results show that milnacipran obviously improves intestinal tissue injury induced by intestinal ischemia reperfusion of mice, improves survival rate of the mice, and has remarkable effect and small side effect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a novel application of milnacipran or/and pharmaceutical salt of milnacipran, and specifically relates to an application of milnacipran or/and pharmaceutical salt of milnacipran in preparing medicines for preventing or/and treating intestinal ischemia reperfusion injury.
Background
Milnacipran (MC) is a novel specific 5-hydroxytryptamine (5-HT) and reuptake inhibitor (SNRI) of Norepinephrine (NE), which are drugs clinically used for the treatment of depression. Milnacipran of formula C 15 H 22 N 2 O, molecular weight 246.348, has the following chemical structure:
milnacipran has anti-pain and anti-inflammatory effects in rat hyperalgesia and inflammation induced by carrageenan, and can reduce inflammatory oedema by inhibiting NO, IL-6 and MPO activity.
Intestinal ischemia reperfusion (I/R), injury is a common pathological change in surgery, is a phenomenon of aggravated injury by reperfusion of blood flow after ischemia of intestinal tissue and organs, is commonly found in perioperative period, and plays an important role in the occurrence and development of fatal diseases of severe infection and traumatic shock. Intestinal bacteria shift caused by blood flow reperfusion, intestinal I/R can cause local damage to intestinal tracts, and intestinal bacteria translocation and endotoxin outward shift caused by damage to intestinal mucosa barriers, and various free radicals generated locally enter blood and shift to tissue organs outside the intestines, so that the intestinal organs are not fully functional, even fail and die.
Intestinal ischemia reperfusion injury has high morbidity and mortality in clinical perioperative period. However, no effective drug has been developed for targeted treatment of intestinal ischemia reperfusion injury. Therefore, the exploration of an effective control strategy for intestinal ischemia reperfusion injury is a technical problem to be solved in clinic at present.
Disclosure of Invention
Based on the above, the main purpose of the invention is to provide a new application of milnacipran or/and pharmaceutical salt of milnacipran, in particular to an application of milnacipran or/and pharmaceutical salt of milnacipran in preparing a medicine for preventing or/and treating intestinal ischemia reperfusion injury.
The specific technical scheme is as follows:
use of milnacipran or/and a pharmaceutically acceptable salt of milnacipran in the manufacture of a medicament for the prevention or/and treatment of intestinal ischemia reperfusion injury.
In one embodiment, the pharmaceutically acceptable salt of milnacipran is the hydrochloride salt of milnacipran.
In one embodiment, the medicament comprises milnacipran or/and a pharmaceutically acceptable salt of milnacipran and pharmaceutically acceptable excipients.
In one embodiment, each 1kg of the medicament comprises 1mg to 1.5mg of the milnacipran or/and a pharmaceutically acceptable salt of milnacipran.
In one embodiment, the pharmaceutical dosage form is a tablet.
In one embodiment, the tablet is a coated tablet.
In one embodiment, the pharmaceutical dosage form is a capsule.
In one embodiment, the pharmaceutical dosage form is an oral liquid.
In one embodiment, the pharmaceutical dosage form is an oral granule.
In one embodiment, the pharmaceutical dosage form is an oral powder.
In one embodiment, the pharmaceutical is in the form of an injection.
In one embodiment, the injection is a freeze-dried powder injection or an emulsion for injection.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, milnacipran and/or the medicinal salt thereof are used for preventing and/or treating intestinal ischemia reperfusion injury for the first time, and the effect of the medicament is verified on a constructed classical intestinal ischemia reperfusion model, and verification results show that milnacipran obviously improves intestinal tissue injury induced by intestinal ischemia reperfusion of mice, improves survival rate of the mice, and has remarkable effect and small side effect.
Drawings
FIG. 1 is a graph of the results of milnacipran in improving the survival rate of ischemia reperfusion in mice; the meaning of the reference symbols in fig. 1 is: the data were expressed as Log-rank (Mantel-Cox) test, with statistically significant p <0.05 for comparison with the I/R group;
FIG. 2 is a graph showing pathological results of milnacipran improvement in intestinal tissue damage induced by ischemia reperfusion in mice; FIG. 2A is a graph of HE staining for morphological changes in intestinal tissue for each group, FIG. 2B is a quantitative scoring result for intestinal tissue lesions for each group, and the scale of the graph is 100 μm; the meaning of the reference symbols in the figures is: data were analyzed using one-way ANOVA test, indicating that differences compared to group I/R had a statistical significance p <0.05.
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions, such as, for example, sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
In order to facilitate an understanding of the present application, the meaning of some terms and expressions in the text of the present invention will be explained below.
As used herein, the term "ischemia" relates to a condition that may occur in any organ or tissue that lacks an oxygen supply and/or a metabolite supply. Ischemia occurs when there is an imbalance between oxygen supply and demand due to inadequate perfusion (i.e., blood supply). The lack of oxygen supply may be caused by thrombosis, the presence of stenotic atherosclerosis, restenosis, anemia, stroke, arterial clotting, vasoconstriction and/or endothelial dysfunction of the microvascular system (Taku Su Bo syndrome).
The term "ischemia reperfusion injury" refers to an injury to an organ or tissue due to insufficient blood supply to the organ or tissue during ischemia prior to the onset of reperfusion (i.e., an ischemic injury is an injury caused by ischemia during the time between the onset of ischemia and the onset of reperfusion).
A typical and pathological manifestation of ischemic injury is the ischemic area becoming pale. In contrast, in reperfusion, non-necrotic ischemic tissue regains its physiological color.
From a biochemical point of view, ischemic injury is characterized by local and systemic changes in pH (acidification) in blood (leukocytes, preferably PBMCs) in ischemic tissue, changes in ATP concentration, increased susceptibility of platelets to activation, and enhanced inflammatory responses in both ischemic tissue localization and the blood system.
Ischemic injury may be caused, for example, by atherosclerosis, thrombosis, thromboembolism, lipid embolism, hemorrhage, stents, surgery, angioplasty, intraoperative bypass surgery, organ transplantation, total ischemia, myocardial infarction, vasoconstriction, microvascular dysfunction, and/or combinations of two or more thereof.
Ischemic injury may involve cell death of muscle cells (preferably by necrosis and/or apoptosis, more preferably by necrosis), injury due to acidification of intracellular pH caused by ischemia, and/or injury due to inflammatory reactions initiated by ischemia and further amplified during reperfusion.
During ischemia, anaerobic metabolism dominates, resulting in a decrease in cell pH. To buffer this accumulation of hydrogen ions, na + /H + The exchanger discharges excess hydrogen ions, which creates a large influx of sodium ions. Calogris (Kalogeris) et al, int Rev Cell Mol biol.2012;298:229-317, which summarize the major pathological events of ischemia and reperfusion components contributing to tissue damage. Ischemia also depletes cellular ATP, inactivating atpase (e.g., na+/k+ atpase), reducing active Ca 2+ Outflow and limiting the re-uptake of calcium by the Endoplasmic Reticulum (ER), thereby producing an intracellular calcium overload. These changes are accompanied by mitochondrial permeability transition (mitochondrial permeability transition, MPT) pore opening that dissipates mitochondrial membrane potential and further impairs ATP production. These changes and thus the extent of tissue damage vary to some extent with the magnitude of the blood supply reduction and the duration of the ischemic period.
Ischemic injury may involve the following symptoms: chest discomfort, shortness of breath, other areas of the upper body, nausea and/or anxiety.
As used herein, the term "reperfusion" relates to restoration of blood flow to ischemic tissue. Although there are clear benefits to reperfusion of blood to ischemic tissue, it is well known that reperfusion itself can lead to a series of adverse reactions that paradoxically harm tissue.
As used herein, the term "reperfusion injury" refers to an injury to an organ or tissue that results when blood supply returns to the organ or tissue after an ischemic period. Thus, reperfusion injury is an injury that is caused during the time between the start of reperfusion and the end of reperfusion (typically, a substantial portion of the injury will be caused during the first few minutes of reperfusion). The underlying mechanism of reperfusion injury is complex, multifactorial, and involves (1) the reintroduction of molecular oxygen upon blood flow remodeling to promote the production of reactive oxygen species (reactiveoxygen species, ROS), (2) calcium overload, (3) the opening of MPT pores, (4) endothelial dysfunction, (5) the appearance of a pre-thrombotic phenotype, and (6) a significant inflammatory response. The lack of oxygen and nutrients in the blood during the ischemia period creates a situation in which the recovery of circulation leads to inflammation and oxidative damage by inducing oxidative stress rather than restoring normal function. Oxidative stress associated with reperfusion may cause damage to the affected tissue or organ. The biochemistry of reperfusion injury is characterized by oxygen depletion during an ischemic event followed by reoxygenation during reperfusion with concomitant production of active oxygen. The damage that occurs with reperfusion is the result of interactions between substances accumulated during ischemia and substances delivered upon reperfusion. The basis of these events is oxidative stress, which is defined as an imbalance between oxygen radicals and endogenous scavenging systems. The result is cell damage and death, which is initially localized, but eventually becomes systemic if the inflammatory response is not examined.
Reperfusion injury is primarily characterized by oxygen bursts and inflammatory response reperfusion injury and consequent tissue damage may occur after revascularization of infarcted (ischemic) tissue. This is associated with an impaired mitochondrial membrane potential, further with the progression of apoptosis, reperfusion-related arrhythmias, cardiac arrest and an overall increase in infarct size caused by ischemia. Thus, the final infarct size (tissue damage) depends on the ischemic damage (tissue damage caused by itself during ischemia) and to a lesser extent on the tissue damage caused by reperfusion.
Reperfusion injury may be caused, for example, by a mechanical event, or by one or more surgical procedures or other therapeutic interventions that restore blood flow to a tissue or organ that has undergone reduced blood flow supply. Such surgical procedures include, for example, coronary artery bypass grafting, coronary angioplasty, and organ grafting. In particular embodiments, reperfusion injury results from treatment of an ischemic process resulting from rupture/erosion of an atherosclerotic plaque and superimposition with a thrombus, thromboembolism, lipid embolism, hemorrhage, stent, surgery, angioplasty, end of a bypass during surgery, organ transplantation, total ischemia, vasoconstriction or microvascular dysfunction, or a combination thereof.
Reperfusion injury may involve oxidative damage, and injury and/or cardiomyocyte death due to an inflammatory response that, although weaker, becomes evident upon reperfusion, that is initiated during ischemia. Preferably, reperfusion injury involves oxidative damage, injury due to inflammatory response and cardiomyocyte death. More preferably, reperfusion injury involves oxidative damage, injury due to inflammatory reactions, and cardiomyocyte death, rather than by intracellular pH acidification.
Reperfusion injury may involve symptoms of palpitations, acute respiratory distress, fatigue, and/or edema.
The embodiment of the invention relates to application of milnacipran or/and pharmaceutical salt of milnacipran in preparation of medicines for preventing or/and treating intestinal ischemia reperfusion injury.
According to the embodiment of the invention, milnacipran and/or the medicinal salt thereof are used for preventing and/or treating intestinal ischemia reperfusion injury, and the effect of the medicament is verified on a constructed classical intestinal ischemia reperfusion model, and the verification result shows that the milnacipran obviously improves intestinal tissue injury induced by intestinal ischemia reperfusion of a mouse, improves the survival rate of the mouse, and has remarkable effect and small side effect.
Preferably, the pharmaceutically acceptable salt of milnacipran is the hydrochloride salt of milnacipran.
Preferably, the medicament comprises milnacipran or/and pharmaceutical salt of milnacipran and pharmaceutically acceptable auxiliary materials.
Preferably, each 1kg of the medicine contains 1mg to 1.5mg of the milnacipran or/and the pharmaceutical salt of the milnacipran.
It will be appreciated that the medicament of the embodiments of the present invention may be formulated with different pharmaceutically acceptable excipients to produce suitable clinical dosage forms including, but not limited to, the following: tablets (including but not limited to coated tablets), capsules, oral liquids, oral granules, oral powders, injections (including but not limited to lyophilized powder injection or emulsion for injection). Such pharmaceutically acceptable excipients include, but are not limited to, diluents, wetting agents, binders, disintegrants, lubricants, color and flavor modulators, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, topical analgesics, pH modifying agents, isotonic or isotonic agents and the like. Further: diluents such as starches, sucrose, celluloses, inorganic salts and the like; wetting agents such as water, ethanol, and the like; binders such as starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol, and the like; disintegrants such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium dicarboxymethyl cellulose, crospovidone, surfactants, running disintegrants, etc.; lubricants such as talc, calcium stearate, magnesium lauryl sulfate, silica gel micropowder, polyethylene glycol, etc.; color, flavor, taste, and smell modifiers such as coloring matter, perfume, sweetener, mucilage, and corrigent, specifically such as fuchsin and xylitol; solvents such as water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, ethyl acetate, etc.; solubilizers such as tweens, sellers, polyoxyethylene fatty alcohol ethers, soaps, sulphates, sulphonates and the like; cosolvents such as organic acids (e.g., citric acid) and salts thereof, amides and amines, inorganic salts, polyethylene glycol, povidone, glycerin, and the like; emulsifying agents such as span, tween, herba Euphorbiae Helioscopiae, benzyl, glycerin fatty acid ester, higher fatty acid salt, sulfate, sulfonate, acacia, tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, hydroxide, silica, bentonite, etc.; suspending agents such as glycerin, syrup, acacia, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, thixotrope and the like; antioxidants such as sulfite, metabisulfite, bisulfite, ascorbic acid, gallic acid, esters thereof, and the like; metal complexing agents such as disodium edetate, polycarboxylic acid compounds, and the like; inert gases such as nitrogen, carbon dioxide, and the like; preservatives, such as nipagins, organic acids and salts thereof (e.g., sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols, volatile oils, and the like; local analgesics such as benzyl alcohol, chlorobutanol, lidocaine, procaine and the like; pH adjusting agents such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetate, citric acid, citrate, etc.; isotonic or isotonic agents, such as glucose, sodium chloride, sodium citrate, sorbitol, xylitol, and the like. It will be appreciated that the diluents described in the examples of the present invention may also be referred to as fillers, which may also function the same in pharmaceutical formulations; the water in the embodiment of the invention is water meeting the requirements of medicaments, such as water for injection, purified water and the like, and the oil is oil for injection; the preservative provided by the embodiment of the invention can also be called an antibacterial agent, and plays roles in inhibiting the growth of microorganisms, prolonging the shelf life and the like in the preparation; the lubricant of the embodiment of the invention contains a glidant, an anti-sticking agent and the like; the sugar in the embodiment of the invention can be powdered sugar or syrup, and the type of the sugar is not limited to glucose; perfumes according to embodiments of the present invention include, but are not limited to, fragrances.
It will be appreciated that the medicaments according to the embodiments of the present invention may be formulated in different dosage forms based on different excipients, and accordingly, the mode of administration may also be varied.
Example 1: milnacipran can improve survival rate of ischemia reperfusion injury of mice
1 Experimental materials
1.1 laboratory animals
80 male C57BL/6J mice with the age of 6 weeks to 8 weeks are selected in the experiment, the weight is 18g to 22g, the mice are purchased in the animal center of the south hospital, the raising place is the SPF-class animal experiment department of the south hospital of the university of south medical science, the operation involved in the animal raising process is approved by the ethical committee, and the requirements of animal ethics are met.
1.2 reagents and instruments
Milnacipran (MedChemExpress, USA); isoflurane (ravode life technologies limited); microvascular arterial clip (north american biotech limited); sterile silk (Ningbo medical needle limited); normal saline (Shijizhuang four-medicine limited); phosphate buffered saline (phosphate buffer saline, PBS) pH7.4 buffer (Gibco).
2 experimental methods and results
2.1 animal experiments
(1) Establishment of a mouse superior mesenteric artery I/R model (an animal model of intestinal ischemia reperfusion is a model of perioperative intestinal injury constructed by classical superior mesenteric artery occlusion):
preoperatively fasted for 12 hours, free drinking water, isoflurane inhalation into anesthetized mice, and the superior mesenteric artery was occluded with a non-invasive microvascular arterial clip, blocking blood flow.
After the intestinal ischemia lasts for 60min, the arterial clamp is loosened to restore blood supply, the intestinal reperfusion is carried out, and after no bleeding in the abdominal cavity is checked, the peritoneum, the muscle and the skin are sutured layer by using sterile silk threads.
After interruption and during reperfusion, 0.5ml of warm normal saline at 37 ℃ is subcutaneously injected for liquid resuscitation, and survival and perfusion time of mice are observed and recorded.
(2) Experimental grouping:
80C 57BL/6 mice were randomly split into Sham, intestinal I/R (I/R), intestinal I/R+milnacipran (I/R+MC) and intestinal I/R+PBS solution (I/R+PBS) from 6 weeks to 8 weeks.
1) Sham surgery group (Sham): only open the abdomen, separate the superior mesenteric artery but not pinch it;
2) Intestinal group I/R (I/R): establishing an intestinal I/R model;
3) Intestinal group I/R + milnacipran (I/R + MC): after 1.25mg/kg of milnacipran was administered intraperitoneally for 1h pretreatment, an intestinal I/R model was established.
4) Intestinal group I/R + PBS solution (I/R + PBS): after 1h pretreatment with PBS solution for intraperitoneal injection, an intestinal I/R model was established.
2.2 survival statistics
The time points of death of the mice in the above groups were observed and recorded, and survival time of each group of mice was counted separately.
2.3 experimental results
Results referring to fig. 1, fig. 1 is a graph of results of milnacipran improving survival rate of ischemia reperfusion in mice intestine; the meaning of the reference symbols in fig. 1 is: the data were expressed as Log-rank (Mantel-Cox) test, with statistically significant p <0.05 compared to the I/R group. Figure 1 shows that treatment with milnacipran significantly increases the time to 60min reperfusion survival in mice and increases survival in mice.
Example 2: milnacipran slows down ischemia reperfusion-induced intestinal tissue pathological damage of mouse intestine
1 Experimental materials
1.1 laboratory animals
32 male C57BL/6J mice with the age of 6 weeks to 8 weeks are selected in the experiment, the weight is 18g to 22g, the mice are purchased in the animal center of the south hospital, the raising place is the SPF-class animal experiment department of the south hospital of the university of south medical science, the operation involved in the animal raising process is approved by the ethical committee, and the requirements of animal ethics are met.
1.2 reagents and instruments
Milnacipran (MedChemExpress, USA); isoflurane (ravode life technologies limited); microvascular arterial clip (north american biotech limited); sterile silk (Ningbo medical needle limited); normal saline (Shijizhuang four-medicine limited); phosphate buffered saline (phosphate buffer saline, PBS) ph7.4 buffer (Gibco); hematoxylin-eosin staining (Beijing Lei Gen Biol); absolute ethanol (Guangdong Guanghua technology Co., ltd.); xylene (Guangdong Guanghua technology Co., ltd.); paraffin wax (lycra); 4% paraformaldehyde (Beijing Soy Bao technology Co., ltd.); neutral gums (Solarbio); full-automatic fluorescence microscope (olympus).
2 experimental methods and results
2.1 animal experiments:
(1) Establishment of a mouse superior mesenteric artery I/R model (an animal model of intestinal ischemia reperfusion is a model of perioperative intestinal injury constructed by classical superior mesenteric artery occlusion):
preoperatively fasted for 12 hours, free drinking water, isoflurane inhalation into anesthetized mice, and the superior mesenteric artery was occluded with a non-invasive microvascular arterial clip, blocking blood flow.
After the intestinal ischemia lasts for 60min, the arterial clamp is loosened to restore blood supply, the intestinal reperfusion is carried out, and after no bleeding in the abdominal cavity is checked, the peritoneum, the muscle and the skin are sutured layer by using sterile silk threads.
After blocking and during reperfusion, 0.5ml of warm physiological saline at 37 ℃ is injected subcutaneously to carry out liquid resuscitation, and after 2 hours of perfusion, the intestinal tissue of the mice is taken for examination.
(2) Experimental grouping:
32C 57BL/6 mice were randomly split into Sham, intestinal I/R (I/R), intestinal I/R+milnacipran (I/R+MC) and intestinal I/R+PBS solution (I/R+PBS) from 6 weeks to 8 weeks.
1) Sham surgery group (Sham): only open the abdomen, separate the superior mesenteric artery but not pinch it;
2) Intestinal group I/R (I/R): establishing an intestinal I/R model;
3) Intestinal group I/R + milnacipran (I/R + MC): after 1.25mg/kg of milnacipran was administered intraperitoneally for 1h pretreatment, an intestinal I/R model was established.
4) Intestinal group I/R + PBS solution (I/R + PBS): after 1h pretreatment of injecting PBS solution into the abdominal cavity, establishing an intestinal I/R model;
2.2 detection of pathological changes in intestinal tissue
Taking intestinal tissues of the mice in each group, putting fresh intestinal tissues into 4% paraformaldehyde for soaking and fixing for 24 hours, dehydrating, embedding, slicing, then carrying out hematoxylin-eosin staining, sealing with neutral gum, observing pathological morphological changes of the intestinal tissues under a full-automatic fluorescence microscope, and grading and scoring intestinal mucosa injuries by using a modified Chiu's method.
2.3 experimental results
Referring to fig. 2, fig. 2A is a graph of HE staining for morphological changes of intestinal tissue for each group, fig. 2B is a quantitative scoring result for intestinal tissue lesions for each group, and the scale of the graph is 100 μm; the meaning of the reference symbols in the figures is: data were analyzed using one-way ANOVA test, indicating that differences compared to group I/R had a statistical significance p <0.05. Fig. 2A and 2B show that the results of HE staining and scoring of intestinal tissue showed that the intestinal villi at the top of the I/R model group was shed and telangiectasia and that the lesions were significantly improved in the intestinal tissue of mice after milnacipran treatment. The above data demonstrate that milnacipran is able to slow down the pathomorphological changes and apoptosis of intestinal tissue in mice with ischemia reperfusion.
In conclusion, the milnacipran and/or the medicinal salt thereof are used for preventing and/or treating the intestinal ischemia reperfusion injury, and the effect of the medicament is verified on a constructed classical intestinal ischemia reperfusion model, and the verification result shows that the milnacipran obviously improves the intestinal tissue injury induced by the intestinal ischemia reperfusion of a mouse, improves the survival rate of the mouse and has a certain relieving effect on inflammatory response. Has remarkable effect and small side effect.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. Use of milnacipran or/and a pharmaceutically acceptable salt of milnacipran in the manufacture of a medicament for the prevention or/and treatment of intestinal ischemia reperfusion injury.
2. The use according to claim 1, wherein the pharmaceutically acceptable salt of milnacipran is the hydrochloride salt of milnacipran.
3. The use according to claim 1 or 2, wherein the medicament comprises milnacipran or/and a pharmaceutically acceptable salt of milnacipran and pharmaceutically acceptable excipients.
4. Use according to claim 1 or 2, characterized in that 1mg to 1.5mg of said milnacipran or/and a pharmaceutically acceptable salt of milnacipran is contained per 1kg of said medicament.
5. The use according to claim 1 or 2, wherein the pharmaceutical dosage form is a tablet.
6. The use according to claim 5, wherein the tablet is a coated tablet.
7. The use according to claim 1 or 2, wherein the medicament is in the form of a capsule, an oral liquid or an oral granule.
8. The use according to claim 1 or 2, wherein the pharmaceutical dosage form is an oral powder.
9. The use according to claim 1 or 2, wherein the medicament is in the form of an injection.
10. The use according to claim 9, wherein the injection is a lyophilized powder for injection or an emulsion for injection.
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|---|---|---|---|---|
| CN105813638A (en) * | 2013-10-15 | 2016-07-27 | 格兰马克药品股份有限公司 | Pharmaceutical composition comprising a TRPA1 antagonist and an analgesic agent |
Non-Patent Citations (2)
| Title |
|---|
| Bantsiele, Guy-Bernard et al. .Behavioral effects of four antidepressants on an ischemic rat model of emotional disturbances .《Behavioural brain research》.2009,第201卷(第2期),第265-271页. * |
| 蔡茜茜,徐旭仲.度洛西汀对大鼠心肌缺血再灌注心律失常的影响及机制.《医学研究杂志》.2018,第47卷(第47期),第19-23页. * |
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