CN109364069B - Application of checkerboard alkali in preparing medicine for treating allergic diseases - Google Patents
Application of checkerboard alkali in preparing medicine for treating allergic diseases Download PDFInfo
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- CN109364069B CN109364069B CN201811321618.2A CN201811321618A CN109364069B CN 109364069 B CN109364069 B CN 109364069B CN 201811321618 A CN201811321618 A CN 201811321618A CN 109364069 B CN109364069 B CN 109364069B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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Abstract
The invention belongs to the field of medicines, and particularly relates to application of checkerboard alkali in preparation of medicines for treating allergic diseases. The study shows that the checkerboard alkali has certain improvement effect on vascular permeability increase caused by histamine and anaphylactic shock caused by allergen. The administration route is preferably oral administration or intravenous injection administration.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of checkerboard alkali in preparation of medicines for treating allergic diseases.
Background
Allergic diseases, also known as allergic diseases, are physical symptoms caused by allergic allergies. Such diseases are usually caused by the contact of the human body with antigenic substances, resulting in physiological dysfunction or tissue damage due to excessive immune response. The allergen, which is the antigen substance of allergic diseases, is very extensive, and plant pollen, dust mites, fungal spores, drugs and the like may enter the body to induce acute or chronic allergic diseases. Such as allergic rhinitis, allergic asthma, urticaria, eczema, angioneurotic edema, allergic gastritis, drug eruption, etc. Wherein, some allergic diseases such as drug allergy and the like have quick onset, have serious influence on key systems such as respiration, cardiovascular and the like, and are easy to cause anaphylactic shock symptoms.
The cytological pathogenesis of allergic diseases is that after entering into the body, antigen is combined with IgE attached to mast cells and basophils, so that the cells release bioactive substances to cause pathological changes such as smooth muscle contraction, increase of vascular permeability and the like. Such biologically active substances include histamine, bradykinin, leukotrienes, prostaglandins, and the like.
The drugs for allergic diseases mainly include:
(1) histamine receptor antagonists: it can be used for inhibiting binding of histamine to its receptor, and inhibiting biological activity of histamine by inhibiting binding of histamine to receptor. The medicine belongs to nonspecific abnormal antiallergic medicine, and mainly comprises diphenhydramine, promethazine, chlorphenamine and the like. The medicine has strong central nerve inhibition effect, so the application is limited. The second generation antihistamine medicine includes terfenadine, loratadine, astemizole, etc., and part of the second generation antihistamine medicine has obvious cardiotoxicity. Third generation histamine drugs such as fexofenadine, levocetirizine, etc. have been on the market today.
(2) The anaphylactic reaction medium releases the drug in an obstructing way: by stabilizing the cell membrane of the mast cell, the cell is prevented from releasing allergic reaction mediators such as histamine, bradykinin, leukotriene and the like due to the combination of antigen and IgE. The medicine mainly comprises cromolyn sodium, ketotifen and the like.
(3) Leukotriene receptor antagonists: the medicine is mainly used for inhibiting symptoms caused by the release of leukotriene, and the medicine mainly comprises Montelukast, zafirstest and the like.
(4) Drugs that inhibit immune responses: the allergic symptoms are inhibited by inhibiting antigen-antibody reaction, and the medicines mainly comprise glucocorticoid, immunosuppressant and the like.
(5) Drugs that decrease vascular permeability: calcium can reduce the permeability of capillary vessels and cell membranes, so that calcium-containing drugs can be used for reducing vascular permeability and inhibiting allergy-induced increase in vascular permeability.
There are certain differences in the treatment methods for different allergic diseases. For example, anaphylactic shock is a severe allergic reaction with acute morbidity and high mortality rates, resulting in life-threatening respiratory failure. Patients often have the symptoms of plasma extravasation, insufficient blood volume, respiratory failure and the like, so that emergency injection of adrenalin is mostly adopted to prevent the release of allergic medium and improve blood pressure; co-injecting antihistamine drugs; oxygen uptake, etc. The non-acute allergic diseases are usually treated by oral medicines.
In addition to the above-mentioned artificially synthesized chemical substances, some active substances present in natural plants have been found to have a definite antiallergic effect. Typically as follows:
quercetin and kaempferol in the flavonoids drugs can inhibit mast cell degranulation, thereby playing an antiallergic role and having an improvement effect on allergic asthma animal models. The matrine in the alkaloid medicine can obviously resist anaphylactic reaction induced by croton oil and carrageenan. In the quinone class of drugs, alkannin inhibits the inhibition of IgE-induced histamine release. In addition, magnolin, curcumin and the like in natural plants have been found to have an antiallergic effect.
Disclosure of Invention
In view of the above problems, it is an object of the present invention to provide a novel use of a natural active substance, in particular to provide a use of checkerboard alkali in the preparation of a medicament for the treatment of allergic diseases. The technical scheme of the invention is as follows:
use of chebularine for the preparation of a medicament for the treatment of allergic diseases. Wherein the chessboard alkaloid is named Zygadenine in English; CAS number: 545-45-9.
Preferably, the allergic disease is allergic dermatitis.
Preferably, the allergic disease is an increase in vascular permeability due to allergy.
Preferably, the allergic disease is anaphylactic shock.
Preferably, the therapeutic agent for allergic diseases is an external agent
Preferably, the therapeutic agent for allergic diseases is an oral agent.
Preferably, the therapeutic agent for allergic diseases is an intravenous injection agent.
When used for treating allergic dermatitis, the therapeutic agent for allergic diseases containing the checkerboard alkali is preferably an external agent, particularly a transdermal agent.
When used for treating vascular permeability increase caused by allergy, the therapeutic agent for allergic diseases containing the checkerboard alkali is preferably an intravenous injection agent or an oral agent.
When used for treating anaphylactic shock, the checkerboard base-containing therapeutic agent for allergic diseases is preferably an intravenous injection agent.
As for the administration dose, the administration dose of the therapeutic agent for allergic diseases containing checkerboard base is 1mg to 20 mg per day in terms of body weight of 60 kg. Can be used in combination with epinephrine for emergency treatment when used for anaphylactic shock treatment.
In another aspect of the present invention, there is provided an antiallergic agent comprising checkerboard alkali as an active ingredient.
Preferably, the anti-allergic reaction with the checkerboard alkali as the active ingredient is a medicine for external use.
Preferably, the external medicine is an external gel preparation. The external gel preparation is prepared from checkerboard alkali, carbomer 940, glycerol, triethanolamine, disodium ethylene diamine tetraacetate and distilled water.
As another preferred scheme, the anti-allergic reaction taking the checkerboard alkali as the active ingredient is an oral medicament.
Preferably, the oral drug is an oral tablet. The oral tablet is prepared from checkerboard alkali, sodium carboxymethyl starch, maltodextrin, magnesium stearate and water.
As still another preferred embodiment, the anti-allergic reaction with the checkerboard alkali as the active ingredient is an intravenous injection drug. Preferably, the intravenous injection medicament is prepared from checkerboard base, hydroxypropyl-beta-cyclodextrin, ethanol and water for injection.
Experimental research shows that the checkerboard alkali has an antiallergic effect, has a certain improvement effect on allergic diseases such as increase of vascular permeability and anaphylactic shock caused by allergy, and is expected to be used for treating the allergic diseases.
Detailed Description
The present invention is further illustrated by the following examples.
EXAMPLE 1 tessellatine gel for external use
Raw materials and auxiliary materials: 10g of checkerboard alkali, 94020 g of carbomer, 450g of glycerol, 50g of triethanolamine, 0.2g of disodium ethylene diamine tetraacetate and distilled water added to 1000 g.
Preparation: weighing 10g of checkerboard alkali and 0.2g of disodium ethylene diamine tetraacetate, adding a proper amount of distilled water for dissolving, adding 450g of glycerol for mixing, uniformly grinding, adding 94020 g of carbomer under stirring, standing overnight for full swelling, slowly adding 50g of triethanolamine under stirring to prepare gel, adding water to 1000g, and subpackaging.
EXAMPLE 2 oral Carnitine tablets
Raw materials and auxiliary materials: 200g of checkerboard alkali, 250g of sodium carboxymethyl starch, 400g of starch, 500g of maltodextrin and 10g of magnesium stearate.
Preparation: weighing 200g of checkerboard alkali, 250g of sodium carboxymethyl starch, 400g of starch and 500g of maltodextrin, respectively grinding, and sieving with a 100-mesh sieve; weighing 10g of magnesium stearate, and sieving the magnesium stearate with a 40-mesh sieve; mixing the checkerboard alkali, the sodium carboxymethyl starch and the maltodextrin according to the prescription amount, preparing the starch into 10% starch slurry, and adding the mixture of the checkerboard alkali, the sodium carboxymethyl starch and the maltodextrin to prepare a soft material; sieving the obtained soft material with 16 mesh sieve, granulating, drying at 70 deg.C, sieving with 16 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.
EXAMPLE 3 tessellatine injection
Raw materials and auxiliary materials: 10g of checkerboard alkali, 100g of hydroxypropyl-beta-cyclodextrin, 50ml of ethanol and 2000ml of water for injection.
Preparation: weighing 10g of checkerboard alkali, and adding into 50ml of ethanol; 100g of hydroxypropyl-. beta. -cyclodextrin were weighed out and dissolved in 2000ml of water for injection. Adding the mixture of gomisin and ethanol into hydroxypropyl-beta-cyclodextrin water solution, stirring at room temperature at 100 rpm for 3 hr, filtering with microporous membrane to remove pyrogen, and packaging into 1000 injections.
Example 4 alkali checkerboard anti-Passive allergy test
1. Preparation of antiserum:
dissolving ovalbumin in normal saline. Injecting 6 male SD rats with egg albumin physiological saline solution, 5mg of egg albumin is administered to each rat, and 0.5ml of complete Freund's adjuvant is injected to each abdominal cavity; every other day, 4 times. Blood was collected 12 days after the last sensitization, centrifuged at 2000rpm for 10 minutes, and serum was separated and stored at-20 ℃. Before use, the antiserum is diluted into two concentration gradients of 1:2 and 1:8 by normal saline and is prepared as it is.
Administration and sensitization
Taking 12 male SD rats with the weight of 200-250 g, randomly dividing the male SD rats into two groups, wherein each group comprises 6 male SD rats, and carrying out continuous intragastric administration for 7 days by intragastric administration of normal saline for 1 time every day and 1.5ml each time; the treatment group adopts the mixed solution of the checkerboard alkali and the normal saline for intragastric administration, the checkerboard alkali is added into the normal saline to prepare the mixed solution containing 0.2mg of checkerboard alkali every 1.5ml, the intragastric administration is carried out for 1 time every day, 1.5ml of the mixed solution is carried out every time, and the intragastric administration is carried out continuously for 7 days. Shearing hairs at 1.5cm positions on both sides of spinal column of each group of animals 2 hours after the 5 th intragastric administration, taking 2 points on each side, and injecting antiserum into skin at intervals of 2cm for sensitization.
Wherein, 2 points on the left side are respectively injected with antiserum physiological saline solution with the ratio of 1:2 and 1: 8; the right side corresponds to 2 points and is injected with 1:2, 1:8 antiserum physiological saline solution.
Excitation
2 hours after the last administration, i.e. 48 hours after sensitization, challenge with a 0.5% solution of evans containing egg albumin, 2mL of a 0.5% solution of evans containing egg albumin, 5mg of which was administered intravenously to each rat.
Measurement method
Animals of each group were sacrificed 30 minutes after challenge, the skin at the back injection site was removed, the skin was inverted, the inside blue spots were examined and the diameter of the blue spots was measured, and the diameter of the irregular blue spots was calculated as half the sum of the major and minor diameters. The diameter of the blue spot of each rat is counted according to the concentration gradient of the injection site, namely the diameter of the blue spot at the concentration is represented by the average value of the diameters of the two injection sites under the same concentration gradient. For example, the diameter of the blue spot of each rat is averaged when the 1:2 antiserum is injected into the physiological saline injection site on the left and right sides of the back of the rat.
Results
The results of the blue spot diameter measurement of each group of rats are shown in Table 1.
TABLE 1 blue spot diameter of rats in each group
The diameters of 12 blue spots of a model group rat under a 1:2 concentration gradient are 1.21 +/-0.07 cm; the diameter of 12 blue spots in the model group rat 1:8 concentration gradient is 0.62 + -0.04 cm. All 24 injection sites in this group had visible blue spots.
Of the 12 injection sites in the rats of the treatment group under a 1:8 concentration gradient, 2 were found without visible blue spots. The diameter of 12 blue spots under the concentration gradient of 1:2 of the rats in the treatment group is 0.67 plus or minus 0.10 cm, and the diameter of 12 blue spots under the concentration gradient of 1:8 is 0.21 plus or minus 0.08 cm.
The diameter of the blue spot under the two concentration gradients of the treatment group is obviously smaller than that of the model group (p is less than 0.01), which indicates that the transgastrolavage administration of the checkerboard alkali has obvious inhibition effect on the passive allergy of rats under the experimental dose and the administration duration. In view of the basic principle of passive allergy experiments, namely that the antigen induces anaphylaxis, so that histamine and other mediators are released, the vascular permeability is increased, and the evans leak into tissues, so that the skin generates blue spots. Therefore, the chessyline administration through gastric lavage has inhibitory effect on increase of vascular permeability caused by allergy.
Since the basic pathological mechanism of anaphylactic shock is that the allergen triggers mast cells to release mediators such as histamine, the permeability of blood vessels is increased, blood rapidly permeates to extravascular tissues, and hypovolemia, edema and bronchospasm are caused. Therefore, it is reasonable to speculate that the effect of the checkerboard alkali on inhibiting the increase of vascular permeability caused by allergy can be used for treating anaphylactic shock.
Example 5 below the effect of chelerythrine on the intervention of anaphylactic shock was preliminarily examined using guinea pigs.
Example 5 Effect study of the intervention of checkerboard alkali on anaphylactic shock
Guinea pigs, 20, weighing 250-350 g, were randomized into 2 groups of 10 animals each.
Each guinea pig was sensitized by subcutaneous injection of 0.1ml of calf serum, and 15 days after sensitization, the heart was challenged by injection of 1.0ml of calf serum.
Intravenous injection was performed immediately after challenge. The normal saline solution is injected into each model group by 0.5ml, the chessboard alkaloid normal saline solution is injected into the treatment group by 0.5ml, and the chessboard alkaloid is administered by 0.1 mg.
After dosing, the time to death of the guinea pigs in each group was observed and compared between groups. The time to death was calculated after completion of challenge, i.e. cardiac injection of calf serum. The statistical results of the death time of each group of animals are shown in Table 2.
TABLE 2 Guinea pig mortality statistics for each group
The results show that the death time of animals in the treatment group is 60% of the death time of the animals in the treatment group, and the death time of the animals in the model group is 10% of the death time of the animals in the model group, wherein the death time of the animals exceeds 10 min. Wherein the shortest death time of the model group is less than 4 minutes, and the longest death time exceeds 12 minutes and is less than 13 minutes. The treatment group had a minimum death time of more than 6 minutes and a maximum death time of more than 15 minutes and less than 16 minutes. Two groups of differences were statistically significant (P < 0.05). The result shows that the single intravenous injection of the checkerboard alkali has the tendency of delaying the death time of anaphylactic shock guinea pigs.
Claims (5)
1. Use of chebularine for the preparation of a medicament for the treatment of allergic diseases.
2. Use according to claim 1, characterized in that the allergic disease is an increase in capillary permeability caused by allergy.
3. Use according to claim 1, characterized in that the allergic disease is anaphylactic shock.
4. Use according to any one of claims 1 to 3, wherein the therapeutic agent for allergic diseases is an oral agent.
5. Use according to any one of claims 1 to 3, wherein the therapeutic agent for allergic diseases is an intravenous agent.
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