CN111494394A

CN111494394A - Application of calcitriol in pharmaceutical composition for treating or preventing altitude diseases

Info

Publication number: CN111494394A
Application number: CN202010249820.XA
Authority: CN
Inventors: 施建飞; 钱建
Original assignee: Nantong Huashan Pharmacy Co ltd
Current assignee: Nantong Huashan Pharmacy Co ltd
Priority date: 2020-04-01
Filing date: 2020-04-01
Publication date: 2020-08-07

Abstract

The invention discloses application of calcitriol in a pharmaceutical composition for treating or preventing altitude diseases, wherein the altitude diseases refer to acute and chronic altitude diseases generated in altitude environment with altitude of more than 3000 m. The calcitriol medicament prepared by the invention comprises a pharmaceutically acceptable excipient or carrier, and the dosage form mainly comprises an intestinal or parenteral composition. The preparation forms mainly comprise liquid preparations, granules, tablets, electuary, capsules, dripping pills or injections. The invention can obviously reduce the inflammatory reaction induced by the plateau environment and the damage of the brain and the lung by inhibiting the activation of a brain and lung NF kB signal channel by using calcitriol, has obvious prevention and treatment effects on the plateau disease, and has the advantages of quick response, obvious effect, convenient use and the like. Because calcitriol is clinically used for treating osteoporosis, the clinical popularization risk of the invention is low.

Description

Application of calcitriol in pharmaceutical composition for treating or preventing altitude diseases

Technical Field

The invention relates to the field of biological medicines, in particular to application of calcitriol in a pharmaceutical composition for treating or preventing altitude diseases.

Background

The altitude sickness refers to a syndrome caused by the insufficient or maladjusted adaptability to low-pressure and low-oxygen environments when people enter a plateau from a plain (above 3000 meters), and is also called as mountain sickness. Hypoxia caused by high altitude hypoxia environment is the cause of the disease. Upper respiratory tract infection, fatigue, cold, mental stress, hunger, pregnancy, etc. are the causative factors of the disease, and are classified into mild (or benign) and severe (or malignant) according to their severity. Mild immediate response or acute altitude response; heavy duty is divided into: acute altitude disease of brain type (also known as altitude coma or altitude cerebral edema), acute altitude disease of lung type (also known as altitude pulmonary edema), and mixed type (i.e. the comprehensive manifestations of lung type and brain type). Common clinical manifestations of altitude sickness include headache, dizziness, palpitation, shortness of breath, nausea, vomiting, fatigue, insomnia, dim eyesight, lethargy, numbness of limbs, cyanosis of lips and fingers, and increased heart rate, while other symptoms and signs are different depending on the type. If not properly treated, the altitude disorder can progress to cerebral edema or pulmonary edema, and even death. At present, medicines or related health care products for preventing and treating altitude sickness are rhodiola rosea, plateau disease, American ginseng, salvia miltiorrhiza pills, Bai Bei Ning and the like. However, these drugs and foods have disadvantages such as slow onset of action and many side effects. The inventor finds that the calcitriol has a remarkable curative effect on treating or preventing the altitude diseases for the first time.

Animal studies indicate that plateau exposure can cause the NF kappa B signal pathway to be activated, thereby causing the levels of proinflammatory factors such as serum TNF- α, I L-1 β, I L-6 and the like to be obviously increased.

Calcitriol is vitamin D3, is metabolized into 1, 25-dihydroxyl metabolite with strongest activity in resisting rickets by liver and kidney hydroxylase, and can promote absorption of intestinal calcium. Calcitriol can be rapidly absorbed by small intestine after being orally taken, and is one of the clinical medicines for treating osteoporosis. The prevention and treatment effects of calcitriol on altitude diseases are not reported in research and application.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide application of calcitriol in preventing and treating altitude diseases, wherein the altitude diseases are acute and chronic altitude diseases generated in an altitude environment.

The technical scheme is as follows: the application of calcitriol in a pharmaceutical composition for treating or preventing altitude diseases is characterized in that: calcitriol is combined with a pharmaceutical excipient or carrier and applied to the treatment or prevention of the altitude sickness; the molecular formula of the calcitriol is C₂₇H₄₄O₃The molecular structural formula is:

furthermore, the altitude disease is a mixed disease which is caused by high altitude cerebral edema, high altitude pulmonary edema or abnormal symptoms of the brain and the lung under high altitude environment.

Furthermore, the plateau environment is above an altitude of 3000m and has low-pressure and anoxic conditions.

Furthermore, the pharmaceutical excipients are selected from one or the combination of more than two of solvents, emulsifiers, plasticizers, disintegrants, fillers, binders, sweeteners or lubricants.

Further, the administration mode of the calcitriol after being prepared into the medicament is as follows: oral administration or injection administration, and the pharmaceutical composition is administered into the body by oral, intravenous or intraperitoneal routes.

Further, the calcitriol can be prepared into a dosage form of an intestinal or parenteral combined medicament, wherein the dosage form is one or a combination of more than two of a liquid preparation, a granule, a tablet, a medicinal granule, a capsule, a sustained-release agent, a dropping pill or an injection.

Furthermore, the calcitriol can inhibit the activation of an organism NF kappa B signal channel induced by a plateau environment, remarkably relieve inflammatory reaction, prevent cerebral edema and pulmonary edema, improve neurobehavioral symptoms and have obvious prevention and treatment effects on the plateau disease.

Has the advantages that: compared with the prior art, the calcitriol is used for inhibiting the activation of NF kappa B signal channels in the brain and the lung, so that the inflammatory response induced by the plateau environment can be obviously relieved, the injury to the brain and the lung is relieved, the effect of preventing and treating the altitude disease is obvious, and the calcitriol has the advantages of quick response, obvious effect, convenience in use and the like. Because calcitriol is clinically used for treating osteoporosis, the clinical popularization risk of the invention is low.

Drawings

FIG. 1 is a graph showing the effect on the release of the pro-inflammatory factors TNF- α and I L-6 in rat serum induced by a high altitude hypoxic environment following prophylactic administration of calcitriol;

FIG. 2 is a graph showing the effect of calcitriol prophylactic administration on NF-. kappa.B signaling pathway activation (p-p65 protein level) induced in the brain and lung of rats by high altitude hypoxic environment;

FIG. 3 is a graph showing the effect of calcitriol on cerebral edema in rats induced by high altitude hypoxic conditions following therapeutic administration.

Detailed Description

The Calcitriol used in the present invention is known by the English name Calcitriol, and the CAS number is: 32222-06-3, molecular formula: c₂₇H₄₄O₃The molecular weight is: 416.64, available from Sigma, under product designation d 1530. Reagents used in the examples of the present invention are available from sales companies unless otherwise noted. The preparation solvent of calcitriol is 10% of DMSO dissolved medicine, 40% of

polyethylene glycol

200 and 50% of double distilled water.

Example 1: effect of calcitriol prophylactic administration on release of proinflammatory factors from plateau-exposed rat serum

Male Sprague-Dawley rats weighing 200 ± 10g, purchased from the laboratory animal center of the university of southeast university, were kept under constant conditions (temperature 20 ± 2 ℃, humidity 40-60%, light/dark cycle 12h) and fed with standard feed and water before the experiment, rats were kept in the laboratory for 2 weeks to acclimate, 40 rats were randomly divided into two groups, 20 rats in each group were individually model group (administered with solvent), calcitriol (0.1 μ g/kg) + solvent (calcitriol group), and administered with the corresponding drugs by intraperitoneal injection, rats were placed in a low pressure oxygen chamber, the oxygen chamber pressure was adjusted to 380mmHg, a 5500 m plateau environment was simulated, food and water were added to the animals every day for 1 hour and the corresponding drug treatment was administered, another 20 rats were kept in the same room in normal environment, as a control group, after 3 days, rats were taken, serum levels of proinflammatory factors TNF- α, proinflammatory factors L-1 and I56-396 in the serum of the rats were measured with E ISA E L ISA, and the serum levels of the rats were significantly reduced by the experimental results of the high altitude factor treatment with serum of the rats, such as shown in the experimental figure, 3-596.

Example 2: effect of calcitriol prophylactic administration on activation of NF kappa B signaling pathway in brain and lung of plateau-exposed rat

Male Sprague-Dawley rats, weighing 200. + -.10 g, were purchased from the laboratory animal center of university of Nantong. Animals were kept under constant conditions (temperature 20. + -. 2 ℃ C., humidity 40-60%, light/dark cycle 12h) fed with standard feed and water. Prior to the experiment, rats were housed in the laboratory for 2 weeks to acclimate. The 6 rats were randomly divided into two groups of 3 rats each, which were a model group (administered with solvent), calcitriol (0.1 μ g/kg) + solvent (calcitriol group), and the corresponding drugs were administered by intraperitoneal injection, respectively. Rats were placed in a hypoxic chamber, the pressure of which was adjusted to 380mmHg, simulating a 5500 m plateau environment, and the hypoxic chamber was opened for 1 hour a day in order to add food and water to the animals and to administer the corresponding medication. The other 3 rats were kept in the normal environment in the same room as a control group. After 3 days, rat brain cortex tissue and lung tissue are taken, protein is extracted, and phosphorylation level of NF kappa B subunit p65 (p-p65) is detected by a Westernblotting technology. The experimental results are shown in figure 2, when rats are treated in plateau hypoxic environment for 3 days, the NF- κ B signal pathway in the cerebral cortex and lung tissue is obviously activated, which is shown as the increase of p-p65 level. When calcitriol is used for preventive administration, the activation of NF kappa B signal pathways in the cerebral cortex and the lung of rats induced by the plateau hypoxic environment is obviously inhibited, and is expressed as the reduction of the level of p-p 65.

Example 3: effect of therapeutic administration of calcitriol on cerebral edema in plateau-exposed rats

Male Sprague-Dawley rats weighing 200 ± 10g, purchased from the centre of the university of southeast university animals were kept under constant conditions (temperature 20 ± 2 ℃, humidity 40-60%, light/dark cycle 12h), fed with standard feed and water, before the experiment, 16 rats were kept in the laboratory for 2 weeks to acclimate, the rats were first placed in a low pressure oxygen chamber, the pressure of the oxygen chamber was adjusted to 380mmHg, a 5500 m plateau environment was simulated, the low pressure hypoxia chamber was opened every day for 1 hour to add food and water, after 3 days of rat hypoxia treatment, 16 rats were randomly divided into two groups of 8 rats each, each group was a model group (administered with solvent), calcitriol (0.1 μ g/kg) + solvent (calcitriol group), and the corresponding drugs were administered by intraperitoneal injection, another 8 rats were kept in the same room with normal environment, after 3 days of drug treatment, the rats were decapitated, the brains were weighed (dry weight) were placed in a vacuum chamber, the rats were dried under vacuum, and the rats were then treated with a significant increase in brain edema after the environment, the rat moisture content was calculated as a water content after 3 days of altitude treatment, the rat was calculated as a significant increase in the normal brain edema-rat-induced brain edema-induced by a rat moisture content-induced significant increase in-induced by-induced brain-induced by-induced cerebral hypoxia treatment.

The invention can obviously reduce the inflammatory reaction induced by the plateau environment and the damage of the brain and the lung by inhibiting the activation of a brain and lung NF kB signal channel by using calcitriol, has obvious prevention and treatment effects on the plateau disease, and has the advantages of quick response, obvious effect, convenient use and the like. Because calcitriol is clinically used for treating osteoporosis, the clinical popularization risk of the invention is low.

While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. The application of calcitriol in a pharmaceutical composition for treating or preventing altitude diseases is characterized in that: calcitriol is combined with a pharmaceutical excipient or carrier and applied to the treatment or prevention of the altitude sickness; the molecular formula of the calcitriol is C₂₇H₄₄O₃The molecular structural formula is:

2. calcitriol according to claim 1 for use in a pharmaceutical composition for the treatment or prevention of altitude disorders characterized in that: the altitude sickness is a mixed type disease which is generated in a high altitude environment and has high altitude cerebral edema, high altitude pulmonary edema or abnormal symptoms of the brain and the lung.

3. Calcitriol according to claim 2 for use in a pharmaceutical composition for the treatment or prevention of altitude disorders characterized in that: the plateau environment is above the altitude of 3000m and has the conditions of low pressure and oxygen deficiency.

4. Calcitriol according to claim 1 for use in a pharmaceutical composition for the treatment or prevention of altitude disorders characterized in that: the medicinal auxiliary materials are selected from one or the combination of more than two of solvent, emulsifier, plasticizer, disintegrant, filler, adhesive, sweetener or lubricant.

5. Use of calcitriol according to any of claims 1 to 4 for the preparation of a pharmaceutical composition for the treatment or prevention of altitude disorders characterized in that: the administration mode of the calcitriol after being prepared into the medicament is as follows: oral administration or injection administration, and the pharmaceutical composition is administered into the body by oral, intravenous or intraperitoneal routes.

6. Calcitriol according to claim 1 for use in a pharmaceutical composition for the treatment or prevention of altitude disorders characterized in that: the calcitriol can be prepared into intestinal or parenteral combination preparations, and the preparation form is one or the combination of more than two of liquid preparations, granules, tablets, granules, capsules, sustained-release agents, dropping pills or injections.

7. Calcitriol according to claim 1 for use in a pharmaceutical composition for the treatment or prevention of altitude disorders characterized in that: the calcitriol can inhibit the activation of an organism NF kappa B signal channel induced by a plateau environment, remarkably relieve inflammatory reaction, prevent cerebral edema and pulmonary edema, improve neuroethological symptoms and have obvious prevention and treatment effects on plateau diseases.