CN111249443A

CN111249443A - Cyclosporine composition for treating hemolytic anemia and application thereof

Info

Publication number: CN111249443A
Application number: CN202010184904.XA
Authority: CN
Inventors: 沈万照; 黄晔; 唐静
Original assignee: Jiangsu Jiuyang Biological Pharmaceutical Co ltd
Current assignee: Jiangsu Jiuyang Biological Pharmaceutical Co ltd
Priority date: 2020-03-17
Filing date: 2020-03-17
Publication date: 2020-06-09

Abstract

The invention discloses a pharmaceutical composition for treating hemolytic anemia and application thereof, wherein active ingredients in the pharmaceutical composition consist of montelukast sodium and cyclosporine, the montelukast sodium and the cyclosporine bring obvious synergistic curative effects through different action targets in the aspect of treating hemolytic anemia, meanwhile, the side effect and adverse reaction rate of the montelukast sodium are low, and the dosage of the cyclosporine is only one fifth of the conventional dosage, so that the medication cost, the side effect and the adverse reaction rate are greatly reduced, and the medication safety and compliance of patients are improved.

Description

Cyclosporine composition for treating hemolytic anemia and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a cyclosporine composition for treating hemolytic anemia and application thereof.

Background

Hemolytic Anemia (HA) refers to a type of anemia that occurs when destruction of red blood cells is accelerated and bone marrow hematopoiesis is under-compensated. Hemolysis (haemolysis) is a process in which red blood cells are destroyed and their life is shortened. The marrow has the compensation capacity 6-8 times of the normal hematopoiesis, and when the hemolysis exceeds the compensation capacity of the marrow, the anemia caused by the hemolysis is hemolytic anemia; when hemolysis occurs and the bone marrow is able to compensate, there may be no anemia, referred to as a hemolytic state (hemolytic state). The fundamental cause of hemolytic anemia is shortened erythrocyte life, and the cause of accelerated destruction of erythrocytes can be summarized in two aspects: intrinsic defects of the red blood cells themselves and abnormalities in the external factors of the red blood cells. The former is often hereditary hemolysis, and the latter causes acquired hemolysis. Among them, the intrinsic defects of erythrocytes mainly include erythrocyte membrane defect, erythrocyte enzyme defect, globin abnormality, etc. The abnormal external factors of the red blood cells mainly comprise immune factors and non-immune factors. The clinical manifestations of hemolytic anemia are mainly related to the duration of the hemolytic process and the severity of hemolysis.

Currently, the common drug for the treatment of hemolytic anemia in humans is glucocorticoid, which acts by inhibiting phagocytosis and processing of antigens by macrophages, inhibiting the production of IL-2 by T cells. However, the index of the medicine is not fundamental, and the medicine has more adverse reactions and is easy to relapse after stopping taking the medicine. In recent years, researchers have tried to obtain satisfactory results by treating autoimmune diseases such as hemolytic anemia with immunosuppressive agents. However, patients are required to take the medicine for a long time to treat the diseases, and the existing immunosuppressants generally have the defects of strong adverse reaction and difficult long-term tolerance of the patients. Therefore, the development of novel immunosuppressive agents with high efficacy and low toxicity remains an important issue for pharmacological research.

Disclosure of Invention

The inventor unexpectedly discovers that montelukast sodium shows a certain drug effect on hemolytic anemia when clinically used. Based on the research, the invention carries out further animal experiment research on the discovery, and finds that the montelukast sodium and the cyclosporine show unexpected synergistic effect in the aspect of treating the hemolytic anemia animal model.

Therefore, the invention aims to provide a pharmaceutical composition for treating hemolytic anemia and application thereof. Specifically, the object of the present invention is achieved by:

a pharmaceutical composition for treating hemolytic anemia, wherein the active ingredients in the pharmaceutical composition consist of montelukast sodium and cyclosporine. The pharmaceutical composition of the invention solves the contradiction between serious adverse reaction which is difficult to be tolerated by patients and treatment which must be carried out for a long time caused by single administration of cyclosporine to a great extent through combined administration.

Preferably, the pharmaceutical composition for treating hemolytic anemia as described above, wherein the weight ratio of montelukast sodium to cyclosporine in the active ingredients is (0.1-0.5): 1.

further preferably, the pharmaceutical composition for treating hemolytic anemia as described above, wherein the weight ratio of montelukast sodium to cyclosporine in the active ingredients is (0.2-0.3): 1.

still further preferably, the pharmaceutical composition for treating hemolytic anemia as described above, wherein the weight ratio of montelukast sodium to cyclosporine in the active ingredients is 0.25: 1.

the pharmaceutical composition for treating hemolytic anemia can exert the drug effect after oral administration, so that the pharmaceutical composition is prepared into oral preparations, and the oral preparations comprise capsules (such as soft capsules), tablets and granules.

Further preferably, the pharmaceutical composition for treating hemolytic anemia as described above contains 1-2.5mg of montelukast sodium and 5-10mg of cyclosporin per unit formulation.

The hemolytic anemia animal model is currently accepted as an erythrocyte hematopoietic damage model induced by adopting acetylphenylhydrazine. The inventor successfully duplicates a hemolytic anemia model by injecting acetylphenylhydrazine into the abdominal cavity of a rat, treats hemolytic anemia of the rat by using different medicines, and observes curative effects through various anemia indexes of the hemolytic anemia, and finds that red blood cells, hemoglobin and hydroncypertension of the rat in each administration group are averagely increased compared with a model control group, and the difference has statistical significance (P is less than 0.05); compared with each single medicine group (MK group and CSA group), the level of erythrocytes, hemoglobin and hematocrit of rats in the MK-CSA group is obviously increased (P is less than 0.05), and the synergy of the combination of montelukast sodium and cyclosporine is shown. Accordingly, the present invention also provides a pharmaceutical use, namely: the application of montelukast sodium in preparing the medicine for treating hemolytic anemia and the application of active ingredients consisting of montelukast sodium and cyclosporine in preparing the medicine for treating hemolytic anemia.

Compared with the prior art, the active ingredients in the pharmaceutical composition provided by the invention consist of montelukast sodium and low-dose cyclosporin, the montelukast sodium and the cyclosporin bring obvious synergistic curative effects through different action targets in the aspect of treating hemolytic anemia, meanwhile, the side effects and adverse reaction rate of the montelukast sodium are low, and the dose of the cyclosporin is only one fifth of the dose of the conventional dose, so that the administration cost, the side effects and the adverse reaction rate are greatly reduced, and the administration safety and compliance of patients are improved.

Detailed Description

The present invention will be further described with reference to specific embodiments, and the technical effects of the present invention will become more apparent as the description proceeds. It should be understood that the illustrated embodiments are exemplary only, and are not intended to limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit of the invention, and it is intended to cover all such changes and modifications as fall within the scope of the invention.

Example 1 efficacy test of montelukast sodium in combination with cyclosporin on hemolytic anemia model rats

50 Wistar rats with the weight of 180-220 g. Feeding conditions are as follows: the room temperature is 20-25 ℃, the relative humidity is 38% -41%, artificial illumination is carried out, the light and the shade are 12 hours respectively, solid common feed and tap water are supplied, drinking water can be freely taken, and good ventilation is realized; the indoor sanitation is cleaned for 2 times every day, and no obvious ammonia odor exists in the room.

50 rats were randomly divided into five groups as follows: normal control group, model control group, MK group, CSA group, MK-CSA group, 10 rats in each group, male and female. After the rats are adaptively fed for one week, except for the normal control group, the other groups are respectively injected with 0.2g/kg of 2 percent acetophenylhydrazine normal saline solution in the abdominal cavity on the first day and the fourth day, and the normal control group is replaced by the normal control group through the normal saline solution in the abdominal cavity. After the molding is successful, the administration is started on the same day, the MK group is infused with the montelukast sodium 0.9mg/kg, the CSA group is infused with the ciclosporin 8mg/kg, the MK-CSA group is infused with the montelukast sodium 0.5mg/kg and the ciclosporin 2mg/kg, the administration is continuously carried out for 7 days, and meanwhile, the normal control group and the model control group are infused with the normal saline. 24 hours after the last administration, the heart was sampled and examined for red blood cells, hemoglobin, and hematocrit. The results of the measurements of the respective indices are shown in Table 1 after mathematical statistics.

The test results in table 1 show that the rat erythrocytes, hemoglobin and hematocrit of the model group are significantly reduced (P is less than 0.05) compared with the normal control group, which indicates that the hemolytic anemia model is successfully prepared. Compared with the model control group, the red blood cells, the hemoglobin and the hydrops of the red blood cells of the rats in each administration group are averagely increased, and the difference has statistical significance (P is less than 0.05). In particular, the levels of erythrocytes, hemoglobin and hematocrit were significantly increased (P < 0.05) in rats of the MK-CSA group compared to each of the monotherapies (MK group, CSA group), and showed a synergistic effect of montelukast sodium in combination with cyclosporine.

TABLE 1 comparison of the level of erythrocytes, hemoglobin and hematocrit in rats of each group

Note that compared with the model control group, # P < 0.05, compared with the MK-CSA group, # P < 0.05, compared with the CSA group, ￥ P < 0.05.

In addition, the body mass of the rats was weighed before and after the test, and the general state of the rats was observed, and the results showed that: the constitution of the CSA group is obviously reduced, and rats all show listlessness, fatigue, easy fright, slow movement, group contraction of bow and waist, pale lips, eyelids and auricles, easy depilation, little fluffy and luster; more water, less food intake, dry and dark stool. The body constitution of the rats in other groups is increased, the mental state is better recovered, the rats are strengthened by spirit, the movement is quick, the eyes are bright and are bright, the fresh pink color is formed, the nose and the lips are clean and moist and are light pink, the tail is round and pink, the back and the waist are flat and straight, the fur is glossy and dense, and the excrement is yellow and soft.

Claims

1. A pharmaceutical composition for treating hemolytic anemia, comprising: the active ingredients in the pharmaceutical composition consist of montelukast sodium and cyclosporine.

2. The pharmaceutical composition for the treatment of hemolytic anemia according to claim 1, wherein: the weight ratio of montelukast sodium to cyclosporine in the active ingredients is (0.1-0.5): 1.

3. the pharmaceutical composition for the treatment of hemolytic anemia according to claim 2, wherein: the weight ratio of montelukast sodium to cyclosporine in the active ingredients is (0.2-0.3): 1.

4. the pharmaceutical composition for the treatment of hemolytic anemia according to claim 3, wherein: the weight ratio of montelukast sodium to cyclosporine in the active ingredients is 0.25: 1.

5. the pharmaceutical composition for the treatment of hemolytic anemia according to any one of claims 1-4, wherein: the pharmaceutical composition is an oral preparation, and the oral preparation comprises capsules, tablets and granules.

6. The pharmaceutical composition for the treatment of hemolytic anemia according to claim 5, wherein: each unit preparation contains 1-2.5mg of montelukast sodium and 5-10mg of cyclosporine.

7. Application of montelukast sodium in preparing a medicament for treating hemolytic anemia.

8. Use of an active ingredient consisting of montelukast sodium and cyclosporine for the preparation of a medicament for the treatment of hemolytic anemia.