CN110787157A - Use of diacerein for relaxing pre-contracted tracheal smooth muscle and treating asthma - Google Patents
Use of diacerein for relaxing pre-contracted tracheal smooth muscle and treating asthma Download PDFInfo
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- CN110787157A CN110787157A CN201911181633.6A CN201911181633A CN110787157A CN 110787157 A CN110787157 A CN 110787157A CN 201911181633 A CN201911181633 A CN 201911181633A CN 110787157 A CN110787157 A CN 110787157A
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Abstract
The invention relates to application of Diacerein (Diacerein) in relaxing pre-contracted tracheal smooth muscle and preparing a medicine for treating asthma, belonging to the field of medicines. Through the detection of the tension of isolated tracheal ring muscles of experimental mice, the diacerein disclosed by the invention is found to have a high-efficiency effect of relaxing tracheal smooth muscles, particularly can relax the pre-contraction of airway smooth muscles induced by high potassium and the pre-contraction of airway smooth muscles induced by acetylcholine, and is expected to be applied to relieving the symptoms of airway obstruction when asthma patients attack.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of Diacerein (Diacerein) in relaxing pre-contracted tracheal smooth muscle and treating asthma, which can be used for developing a new medicine for preventing or treating asthma.
Background
Asthma is a serious chronic respiratory disease and also an allergic disease with abnormal immune function, and is a worldwide problem. However, the disease has high incidence rate, long course of disease and easy recurrence, and is a serious public health problem. In recent years, with the intensive research on subjects such as genetics, immunology, cytology, biology, molecular biology and the like, the research on the pathogenesis of bronchial asthma has not progressed, and a new step is marked for the prevention and treatment of asthma. However, the pathogenesis of asthma is very complex, and some mechanisms are not clear, so that the disease cannot be completely cured clinically at present, and only proper medicines can be used for effectively controlling the disease and relieving symptoms.
Asthma attacks are generally characterized by several features: 1. airway Hyperresponsiveness (AHR), a condition that is extremely dangerous because it is closely linked to a decline in lung function. 2. Reversible airflow is limited, breathing is extremely difficult and wheezing, and severe cases are airway spasm, cough and the like. 3. Airway Remodeling (air remodelling), the occurrence of which is based on chronic inflammation of the airways. Airway remodeling is also an extremely dangerous condition, as long as the airway is slightly irritated, it is easily blocked, resulting in difficulty in breathing and, in severe cases, life threatening. Therefore, it is of great importance to develop new drugs for treating asthma by studying small molecule compounds that relax pre-contracted airway smooth muscle.
Diacerein, formula C19H12O8Are important inhibitors of osteoarthritis IL-1. Diacerein is also called diacetyl dihydro anthracene carboxylic acid, 1, 8-diacetyl-3-carboxyl anthraquinone, Daiselin, and ambudin, etc., is a new Interleukin (IL) -1 inhibitor, has a chemical name of diacetyl rhein, and belongs to anthraquinone compounds. The product can induce chondrogenesis, has effects of relieving pain, resisting inflammation and relieving fever, can also significantly improve joint function of osteoarthritis patients, delay disease course, relieve pain, improve life quality of patients, has good safety, and can be used for treating Osteoarthritis (OA) to exert antibacterial effect.
The research on the aspect of treating asthma by expanding airway smooth muscle with diacerein has no relevant report at home and abroad at present.
Disclosure of Invention
In view of the above, the present invention aims to provide the use of diacerein in relaxing pre-contracted smooth muscle of the pre-trachea and in preparing a medicament for treating asthma.
In order to achieve the above objects, the present invention provides, in one aspect, the use of diacerein for the preparation of a medicament for the relaxation of pre-contracted airway smooth muscle.
In one aspect, the diacerein is present in the patient in an amount of 0.7-1.4 mg/kg/d; preferably 1.4 mg/kg/d.
In one aspect, the diacerein is present in an amount of 5.56% to 8.33% by weight of the medicament; preferably 8.33 wt%.
In one aspect, the medicament further comprises sugar powder; preferably glucose powder.
In one aspect, the powdered sugar is present in the patient in an amount of 20-40 mg/kg/d; preferably 30 mg/kg/d.
In one aspect, the sugar powder is present in the medicament in an amount of 5.56% to 8.33% by weight; preferably 8.33 wt%.
In one aspect, in the medicine, the mass ratio of the diacerein to the powdered sugar is 1: 20-1: 30, preferably 1: 20, or the molar ratio of the two is 1: 20-1: 40, preferably 1: 30.
in one aspect, tracheal smooth muscle is relaxed after the patient receives the drug.
In one aspect, the patient is selected from a human or non-human animal; preferably a non-human animal; more preferably a mouse.
In order to achieve the above objects, another aspect of the present invention provides the use of diacerein for the preparation of a medicament for the treatment of asthma.
In another aspect, the diacerein is present in the patient in an amount of 0.7-1.4 mg/kg/d; preferably 1.4 mg/kg/d.
In another aspect, the diacerein is present in an amount of 5.56% to 8.33% by weight of the medicament; preferably 8.33 wt%.
In another aspect, the medicament further comprises powdered sugar; preferably glucose powder.
In another aspect, the powdered sugar is present in the patient in an amount of 20-40 mg/kg/d; preferably 30 mg/kg/d.
In another aspect, the powdered sugar is present in the medicament in an amount of 91.67% to 94.44% by weight; preferably 91.67 wt%.
In another aspect, in the medicament, the mass ratio of the diacerein to the glucose powder is 1: 20-1: 30, preferably 1: 20 or the molar ratio of the two is 1: 20-1: 40, preferably 1: 30.
in another aspect, asthma is inhibited after the patient receives the drug.
In another aspect, the patient is selected from a human or non-human animal; preferably a non-human animal; more preferably a mouse.
In yet another aspect, the present invention provides a pharmaceutical composition for relaxing pre-contracted tracheal smooth muscle comprising diacerein and a pharmaceutically acceptable carrier.
In yet another aspect, the diacerein is present in an amount of 5.56% to 8.33% by weight in the pharmaceutical composition; preferably 8.33 wt%.
In yet another aspect, the pharmaceutical composition further comprises a sugar powder; preferably glucose powder.
In yet another aspect, the sugar powder is present in the medicament in an amount of 91.67% to 94.44% by weight; preferably 91.67 wt%.
In still another aspect, in the pharmaceutical composition, the mass ratio of the diacerein to the powdered sugar is 1: 20-1: 30, preferably 1: 20 or the molar ratio of the two is 1: 20-1: 40, preferably 1: 30.
in yet another aspect, the pharmaceutical composition may be formulated into a pharmaceutical formulation according to conventional methods. In the formulation process, it is preferable to mix the diacerein with a pharmaceutically acceptable carrier or dilute the diacerein with a carrier. When the carrier serves as a diluent, it may be solid, semi-solid or liquid. The preparation is selected from tablet, pill, powder, capsule, suspension, emulsion, solution, aerosol, injectable solution, etc.
In yet another aspect, the present invention provides a pharmaceutical composition for treating asthma comprising diacerein and a pharmaceutically acceptable carrier.
In yet another aspect, the diacerein is present in an amount of 0.7 to 1.4 mg/kg/d; preferably 1.4 mg/kg/d.
In yet another aspect, the pharmaceutical composition further comprises a sugar powder; glucose powder is preferred.
In still another aspect, in the pharmaceutical composition, the mass ratio of the diacerein to the glucose powder is 1: 20-1: 30, preferably 1: 20 or the molar ratio of the two is 1: 20-1: 40, preferably 1: 30.
in yet another aspect, the pharmaceutical composition may be formulated into a pharmaceutical formulation according to conventional methods. In the formulation process, it is preferable to mix the diacerein with a pharmaceutically acceptable carrier or dilute the diacerein with a carrier. When the carrier serves as a diluent, it may be solid, semi-solid or liquid. The preparation is selected from tablet, pill, powder, capsule, suspension, emulsion, solution, aerosol, injectable solution, etc.
The invention has the beneficial effects that: through the detection of the tension of isolated tracheal ring muscles of experimental mice, the diacerein disclosed by the invention is found to have a high-efficiency effect of relaxing tracheal smooth muscles, particularly can relax the pre-contraction of airway smooth muscles induced by high potassium and the pre-contraction of airway smooth muscles induced by acetylcholine, and is expected to be applied to relieving the symptoms of airway obstruction when asthma patients attack. The diacerein can relax the pre-contraction of the tracheal smooth muscle caused by high potassium, and the relaxation percentage reaches 81.02 +/-1.947%; for the pre-contraction of the tracheal smooth muscle caused by ACh, the relaxation percentage reaches 98 +/-2.185%, and the mechanism that the diacerein can relax the pre-contracted tracheal smooth muscle is utilized, so that the diacerein is expected to be developed into a medicine for treating asthma.
Drawings
FIG. 1 is a graph of the pre-contraction of airway smooth muscle induced by the relaxation of high potassium by diacerein;
FIG. 2 is a graph showing the control group's inability to relax high potassium induced airway smooth muscle under the same experimental conditions as in FIG. 1;
FIG. 3 is a graph of the pre-contraction of the airway smooth muscle induced by diacerein relaxation of acetylcholine;
FIG. 4 is a graph showing the failure of the control group to relax acetylcholine-induced airway smooth muscle under the same experimental conditions as in FIG. 3.
Detailed Description
The present invention is explained below with reference to examples, which are merely illustrative of the present invention. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention.
The test materials used in the following test methods are readily available from commercial companies unless otherwise specified.
Example 1:
1. experimental animals:
purchased from the centers for disease prevention and control in Hubei province (Wuhan, China), healthy sexually mature male BALB/c mice, SPF grade, with an average age of 6-8 weeks. The most suitable environment for raising the mice is as follows: the light-dark cycle is carried out for 12 hours (8:00-20:00), the room temperature is kept at 20-25 ℃, and the humidity is kept at 50-60%.
2. Experiment consumptive material and instrument and equipment:
microscope (IX71) (olympus); dissecting mirror (XTL-2300) (Shanghai precision instruments Co.); stereoscopic microscopes (SZM) (wuhan esteee scientific instruments ltd); ultra pure water systems (icopu); biological function experiment system (BL-420S) (Chengdutai Union technologies, Inc.); HV-4 type isolated tissue organ constant temperature perfusion system (Chengtai Union science and technology Co., Ltd.); tension transducer (JH-2 type) (Beijing, China, research institute of aerospace medical engineering); a circulating water type vacuum pump (SHZ-D (III)) (Shiwa instruments, Inc., Oken City);
acetylcholine (ACh) (shanghai source leaf biotechnology limited); diacerein (pharmacia); HEPES (national group chemical Co., Ltd.); magnesium chloride (MgCl)2) (chemical agents of the national drug group Co., Ltd.); sodium chloride (NaCl) (national drug group chemical agents limited); potassium chloride (KCl) (chemical agents ltd, national drug group); calcium chloride CaCl2(chemical agents of the national drug group Co., Ltd.); Tris-HCl (national institute)Pharmaceutical group chemical agents limited); hydrochloric acid (HCl) (chemical agents ltd, national drug group); glucose (Glucose) (national group chemical agents limited); sodium bicarbonate (NaHCO)3) (national group chemical Co., Ltd.); magnesium chloride hexahydrate (national group chemical Co., Ltd.).
3. In vitro isolation of mouse trachea:
adult male BALB/C mice sacrificed by cervical dislocation were pinned to the mouth and extremities on a dissecting plate, sprayed with 75% (v/v) alcohol, the chest was cut open to expose the heart and lung tissue, after heart was removed, a whole section of tissue from the laryngeal prominence to the lung was removed, and the removed tissue was immediately soaked in PSS solution (NaCl 135mM, KCl 5mM, MgCl)21mM,CaCl22mM HEPES (4-hydroxyethylpiperazineethanesulfonic acid) 10mM glucose 10mM pH 7.4), and then transferred to a gel plate for further trimming (the trimming is to remove tissues except the main gas). The connective tissue around the trachea and the residual blood in the lumen were carefully removed under a stereomicroscope with a Venus scissors.
4. The tension detection method of the mouse airway smooth muscle comprises the following steps:
the mouse trachea was cut into a trachea loop of about 5mm length and connected to a hook, the tension transducer was carefully engaged and placed in a 37 ℃ constant temperature water bath containing 6mL of PSS solution and continuously aerated with oxygen, the preload was adjusted to 300mg, and equilibration was initiated. During the equilibration period, the solution was changed 1 time every 15min, and 4 times in total. After the balance is finished, using 80mM high potassium solution or 100 mu M acetylcholine (ACh) solution for pre-stimulation, after the tissue activity is fully stimulated, changing the solution (the purpose of changing the solution is to elute the high potassium or ACh in the solution for pre-stimulation, the solution for changing the solution is still PSS), eluting until the solution returns to the baseline, and starting the test after 30min, wherein the specific steps are as follows: when the trachea is trimmed and hung on a biological function experiment system machine for ACh or high potassium stimulation, diacerein is added to observe whether the contraction of the tracheal smooth muscle can be relaxed. In addition, we also performed control experiments, specifically: when the trachea was trimmed and hung on a biofunctional test system machine for ACh or high potassium stimulation, PSS of the same volume (1.1mL) as diacerein was added to observe whether the contraction of the tracheal smooth muscle could be relaxed.
The experimental results are as follows:
(1) diacerein inhibits acetylcholine-induced airway smooth muscle contraction
Adding 100 mu M of ACh into the solution in which the tracheal rings are positioned, stimulating the tracheal rings of mice to shrink by the ACh, adding diacerein into the solution in which the tracheas are positioned according to the concentration gradient of 0.01-3.16 mg/mL after the contraction value is stable, and gradually relaxing the tracheas to a baseline; as shown in figure 1, the isolated mouse trachea ring is stably and continuously pre-contracted in 100 mu M solution, and the contracted trachea ring tension is gradually reduced after the diacerein is added, and gradually returns to the level before the contraction along with the increase of the diacerein concentration. The diacerein can completely relax acetylcholine to cause airway smooth muscle contraction, and the effect of the drug is dose-dependent. As can be seen from FIG. 2, in 100. mu.M ACh solution, as time goes by, PSS of equal volume (1.1mL) with diacerein did not relax the contraction of the tracheal smooth muscle.
(2) Diacerein inhibits airway smooth muscle contraction caused by high potassium (80mM K +)
80mM KCl solution was added to the solution in which the tracheal rings were placed, K+Stimulation of VDLCCs channel opening to promote extracellular Ca2+Internal flow of intracellular Ca2+The tracheal rings of the mice contract when the concentration is increased, diacerein is added into the solution of the tracheal rings according to the concentration gradient of 0.01 mg/mL-3.16 mg/mL after the contraction value is stable, and the contracted trachea gradually relaxes; as shown in FIG. 3, the trachea of the isolated mice was surrounded by high potassium (80mM K)+) Stable and continuous pre-contraction occurs in the solution, the tracheal ring tension which contracts gradually decreases after diacerein is added, and the tracheal ring tension gradually returns to the level before the contraction along with the increase of the concentration of the diacerein. The diacerein can completely relax high potassium to cause the contraction of airway smooth muscle, and the effect of the medicine is dose-dependent. As can be seen from FIG. 4, potassium is high at 120. mu.M (80mM K)+) In solution, PSS of equal volume (1.1mL) with diacerein did not relax the contraction of the tracheal smooth muscle with increasing time.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (10)
1. Use of diacerein for the preparation of a medicament for the relaxation of pre-contracted tracheal smooth muscle.
2. Use of diacerein for the preparation of a medicament for the treatment of asthma.
3. A pharmaceutical composition for treating diastolic pre-systolic tracheal smooth muscle comprising diacerein and a pharmaceutically acceptable carrier.
4. The pharmaceutical composition according to claim 3, wherein the diacerein is present in an amount of 5.56% to 8.33% by weight of the pharmaceutical composition.
5. The pharmaceutical composition of claim 4, wherein the diacerein is present in an amount of 8.33% by weight of the pharmaceutical composition.
6. A pharmaceutical composition according to claim 4, further comprising sugar powder, preferably glucose powder.
7. A pharmaceutical composition for treating asthma comprising diacerein and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition according to claim 7, wherein the diacerein is present in an amount of 5.56% to 8.33% by weight of the pharmaceutical composition.
9. The pharmaceutical composition of claim 8, wherein the diacerein is present in an amount of 8.33% by weight of the pharmaceutical composition.
10. Pharmaceutical composition according to claim 8, further comprising sugar powder, preferably glucose powder.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102202673A (en) * | 2008-10-28 | 2011-09-28 | Twi生物技术有限公司 | Pharmaceutical compositions containing diacerein |
| CN108349867A (en) * | 2015-08-17 | 2018-07-31 | 安成生物科技股份有限公司 | Diacerein or its analog for inhibiting the expression of ASC, the expression of NLRP3 and/or the formation of NLRP3 inflammatory complex |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102202673A (en) * | 2008-10-28 | 2011-09-28 | Twi生物技术有限公司 | Pharmaceutical compositions containing diacerein |
| CN108349867A (en) * | 2015-08-17 | 2018-07-31 | 安成生物科技股份有限公司 | Diacerein or its analog for inhibiting the expression of ASC, the expression of NLRP3 and/or the formation of NLRP3 inflammatory complex |
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