CN113116907A - Medical application of cycloastragenol - Google Patents
Medical application of cycloastragenol Download PDFInfo
- Publication number
- CN113116907A CN113116907A CN202011510492.0A CN202011510492A CN113116907A CN 113116907 A CN113116907 A CN 113116907A CN 202011510492 A CN202011510492 A CN 202011510492A CN 113116907 A CN113116907 A CN 113116907A
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- Prior art keywords
- cycloastragenol
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- obstructive pulmonary
- chronic obstructive
- pulmonary disease
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to application of cycloastragenol, namely application of the cycloastragenol in preparing a medicine for treating chronic obstructive pulmonary disease. Animal experiments show that the traditional Chinese medicine composition has a remarkable prevention and treatment effect on chronic obstructive pulmonary disease and can be used for treating chronic obstructive pulmonary disease in a stable phase or an acute exacerbation phase. The cycloastragenol is a natural traditional Chinese medicine monomer extracted from traditional Chinese medicine astragalus, has high safety and low toxic and side effects, and is suitable for long-term medication treatment of chronic obstructive pulmonary disease.
Description
Technical Field
The invention belongs to the field of medicines, relates to a medical application of cycloastragenol, and particularly relates to an application of cycloastragenol in preparing a medicine for preventing or treating chronic obstructive pulmonary disease.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a chronic bronchitis and/or emphysema characterized by airflow obstruction that can further progress to the common chronic diseases of cor pulmonale and respiratory failure. The disease is related to abnormal inflammatory reaction of harmful gas or harmful particles, the disability rate and the fatality rate are high, and the worldwide incidence rate of over 40 years old is up to 9-10%. The exact cause of chronic obstructive pulmonary disease is unknown, and it is thought that factors involved in the development of chronic bronchitis and obstructive emphysema may contribute to the onset of chronic obstructive pulmonary disease. Risk factors that have been found can be broadly divided into two categories, external (i.e., environmental factors) and internal (i.e., individual predisposition factors). External factors include smoking, inhalation of dust and chemicals, air pollution, respiratory infections and other factors. Endogenous factors include genetic factors, increased airway responsiveness, individuals with lung development or poor growth during pregnancy, neonatal, infant or childhood due to a variety of causes.
In the onset of chronic obstructive pulmonary disease, the stationary phase and the acute exacerbation phase alternate. The acute exacerbation stage of chronic obstructive pulmonary disease refers to symptoms such as cough, expectoration, short breath and/or exacerbation of asthma, and increased sputum with purulent or mucopurulent accompanied by fever in a short period of time during the course of the disease.
At present, the medicines clinically used for treating the chronic obstructive pulmonary disease comprise bronchodilators, commonly used short-acting beta 2 adrenergic receptor agonists are salbutamol and terbutaline, and commonly used long-acting beta 2 adrenergic receptor agonists comprise salmeterol and formoterol, and in addition, anticholinergic medicines and theophylline medicines. Bronchodilators can ameliorate symptoms of chronic obstructive pulmonary disease, stabilize lung function, but have no therapeutic effect on inflammatory symptoms of the lung. Drugs aiming at the causes of chronic obstructive pulmonary disease have anti-inflammatory drugs, such as glucocorticoid, and currently, budesonide, beclomethasone dipropionate, triamcinolone acetonide, fluticasone propionate, flunisolide, mometasone furoate, ciclesonide and the like are commonly used clinically, and are combined with bronchodilators to treat chronic obstructive pulmonary disease and bronchial asthma by inhalation, but the effect is not as good as that of treating asthma. Therefore, development of new therapeutic drugs is becoming a necessity.
The radix astragali is dried root of Astragalus membranaceus (Fisch.) Bge. of Leguminosae, Astragalus membranaceus (Astragalus membranaceus) Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Astragalus membranaceus) (Fisch.) Bge. Astragalus root, as a traditional Chinese medicine, has the effects of invigorating qi and raising yang, benefiting wei and defensive qi and consolidating superficial resistance, expelling toxin and promoting granulation, inducing diuresis and relieving swelling, and has been used for enhancing the immunity of the organism all the time. The chemical components of astragalus root mainly comprise saponins, flavonoids, polysaccharides and the like, and the research on the pharmacological action of astragalus root has been greatly advanced in recent years, particularly in the aspects of immunoregulation, heart protection, blood sugar reduction, liver protection and the like.
Cycloastragenol (CAG) is a triterpenoid saponin compound separated from astragalus and has the following chemical structural formula:
chinese patent CN103880910A discloses a preparation method of cycloastragenol and application thereof in preparing anticancer adjuvant therapy medicines. Chinese patent CN101116667A discloses that cycloastragenol can effectively treat and prevent the diseases caused by abnormal immunity. The literature reports that the cycloastragenol has the anti-aging effect (Caojinling, Liwenlan, Weilingyu and the like, the anti-aging effect of the cycloastragenol on D-galactose-induced aging mice, China journal of experimental prescriptions, 2012, 18 (19): 208-211). The results of the study on the influence of continuous gavage of cycloastragenol on the activity of P450 enzyme of rat liver show that the cycloastragenol has obvious inhibition effect on CYP3A4 sub-enzyme and has obvious induction effect on CYP2E1 sub-enzyme (Weibahong, leaf tranquilizer, Xuebajuan and the like, the influence of continuous gavage of cycloastragenol on the activity of P450 enzyme of rat liver, China New medicine journal, 2014, 23 (4): 476 + 479).
However, no report on the anti-chronic obstructive pulmonary disease activity of cycloastragenol is found so far.
Disclosure of Invention
The applicant of the present invention has long devoted to the research on the pharmacological activity of cycloastragenol, and the present inventors have surprisingly found through a large number of pharmacological experimental studies that cycloastragenol has significant activity in the preparation of drugs for preventing or treating chronic obstructive pulmonary disease.
In the onset of chronic obstructive pulmonary disease, the stationary phase and the acute exacerbation phase alternate. Chronic obstructive pulmonary disease treatment in stationary phase mainly depends on inhalational hormone to control inflammatory response, but inhalational hormone has inevitable defects in aspects of inhibiting body immunity and increasing infection risk. In the acute exacerbation phase, patients experience dyspnea, cough and/or sputum aggravation obviously on the basis of the original symptoms, the lung function deterioration is accelerated, and serious complications and even death are caused. Therefore, prevention of acute exacerbations, and augmentation of the steady-phase effective intervention are critical to improving the prognosis of patients with chronic obstructive pulmonary disease.
Treatment of chronic obstructive pulmonary disease is not fixed and is graded primarily according to the severity of the patient's condition. To date, there is no specific radical cure for chronic obstructive pulmonary disease. In addition, chronic obstructive pulmonary disease requires long-term treatment, and therefore, the safety of therapeutic drugs is particularly important.
One of the purposes of the present application is to provide a new application of cycloastragenol, namely, an application of cycloastragenol in preparing a medicament for preventing or treating chronic obstructive pulmonary disease.
The research of the inventor finds that the cycloastragenol has a remarkable treatment effect on chronic obstructive pulmonary disease.
Further, cycloastragenol can be used for treating chronic obstructive pulmonary disease in the stable phase.
Further, cycloastragenol can be used for treating chronic obstructive pulmonary disease in acute exacerbation stage.
Experiments in embodiment 10 of the invention show that the cycloastragenol can improve the general state of rats with chronic obstructive pulmonary disease, increase the weight of the rats and improve the pulmonary function of the rats.
Experiments in example 11 of the invention show that the bioavailability of cycloastragenol is high, and that the cycloastragenol has obvious technical advantages in the aspect of pharmacy.
In addition, the cycloastragenol is a natural traditional Chinese medicine monomer extracted from traditional Chinese medicine astragalus, has low toxic and side effects on human bodies, can remarkably improve the medication safety and medication compliance of patients, is suitable for long-term treatment medication of patients with chronic obstructive pulmonary disease, and has great significance.
In the medical application, the cycloastragenol can be prepared into a proper pharmaceutical dosage form for oral administration or injection administration, and the applicable object can be a human or other homothermal animals. Preferably, the cycloastragenol can be prepared into a suitable pharmaceutical dosage form for subcutaneous injection or intramuscular injection. When the target is human, the amount of cycloastragenol is preferably 0.001 to 50 mg/kg-d, more preferably 0.01 to 10 mg/kg-d. The time and frequency of administration of the agent for preventing or treating chronic obstructive pulmonary disease of the present invention are determined according to the specific diagnosis result of the disease and are within the skill of those skilled in the art. For example, it will be apparent to those skilled in the art that a therapeutic regimen for preventing or treating chronic obstructive pulmonary disease in rats is applied to humans using a drug whose effective human dose can be converted to an effective rat dose of the drug.
In the medical application, the cycloastragenol can be prepared into a proper pharmaceutical preparation according to the condition of animals and the application part so as to facilitate the application of the medicine, for example, the cycloastragenol can be developed into an oral preparation, a sublingual buccal preparation or an injection preparation so as to facilitate the application of patients, wherein the oral preparation can be a tablet, a capsule or a microemulsion preparation, and is preferably a tablet; the sublingual buccal preparation is a pharmaceutical preparation which contains cycloastragenol and is suitable for sublingual administration, and is preferably a sublingual tablet; the injection preparation can be injection, injection microsphere and the like, and is preferably injection. When cycloastragenol is prepared into injection, the pharmaceutically acceptable carrier can be water for injection, sodium chloride, sodium citrate, citric acid, glycerol, ethanol, propylene glycol, etc. The above-mentioned cycloastragenol injection can also be added with appropriate additives according to the nature of the medicine, such as osmotic pressure regulator, pH regulator, solubilizer, therapeutic oxygen agent, bacteriostatic agent, emulsifier, suspending agent, etc., wherein the solubilizer is any one or two of polyethylene glycol 400 and tween-80.
The preparation method of the pharmaceutical preparation can be prepared by adopting the conventional preparation method for preparing the dosage form by the technical personnel in the field. In the medicinal preparation, each preparation unit contains 0.001-50 mg of cycloastragenol.
Compared with the prior art, the invention has the advantages that:
1. the cycloastragenol has obvious effect of preventing or treating chronic obstructive pulmonary disease. Experiments in embodiment 10 of the invention show that the cycloastragenol can improve the general state of rats with chronic obstructive pulmonary disease, increase the weight of the rats and improve the pulmonary function of the rats. Experiments in example 11 of the invention show that the bioavailability of cycloastragenol is obviously higher than that of astragaloside IV, which shows that cycloastragenol has obvious technical advantages in the aspect of pharmacy.
2. The cycloastragenol is a natural traditional Chinese medicine monomer extracted from traditional Chinese medicine astragalus, has low toxic and side effects on human bodies, can remarkably improve the medication safety and medication compliance of patients, and further greatly improves the treatment effect and life quality of patients with chronic obstructive pulmonary diseases.
Detailed Description
The present invention will be further described below by way of specific embodiments, but the scope of application of the present invention is not limited to the following examples. Alterations and/or combinations of features of the invention will be apparent to those skilled in the art from the disclosure, spirit and/or scope of the invention, and are intended to be encompassed by the invention.
Example 1 Cycloastragenol injection
The preparation process comprises the following steps: mixing propylene glycol and ethanol, adding cycloastragenol, stirring for dissolving, adding 0.9% sodium chloride solution, stirring, adding 0.5% needle activated carbon, stirring, and removing carbon.
Example 2 Cycloastragenol injection
The preparation process comprises the following steps: adding cycloastragenol into PEG-400, stirring to dissolve, adding 0.9% sodium chloride solution to 10L, stirring, adding 0.5% active carbon for injection, stirring, and removing carbon.
Example 3 Cycloastragenol injection
The preparation process comprises the following steps: mixing ethanol and tween-80, adding cycloastragenol, stirring for dissolving, adding water for injection to 10L, stirring, adding 0.5% injectable active carbon, stirring, and removing carbon.
Example 4 Cycloastragenol injection
Cycloastragenol 0.01g
Ethanol 3.3L
Adding water for injection to 10L
The preparation process comprises the following steps: adding ethanol into cycloastragenol, stirring for dissolving, adding water for injection to 10L, stirring, adding 0.5% injectable active carbon, stirring, and removing carbon.
EXAMPLE 5 Cycloastragenol tablet
The preparation process comprises mixing cycloastragenol and adjuvants including microcrystalline cellulose and sodium carboxymethyl starch, adding appropriate amount of starch slurry to make soft mass, sieving with 16 mesh sieve, and granulating. Drying wet granules at 60 deg.C, sieving dry granules with 20 mesh sieve, grading, sieving to obtain fine powder, mixing with magnesium stearate, mixing with dry granules, and tabletting to obtain tablet of about 200 mg.
EXAMPLE 6 Cycloastragenol tablet
The preparation process comprises the following steps: the components are dried, crushed, sieved, pretreated, mixed uniformly and directly tabletted to obtain the tablet.
EXAMPLE 7 Cycloastragenol tablet
The preparation process comprises the following steps: drying the main drug and each auxiliary material component, crushing, sieving and pretreating, uniformly mixing the main drug, lactose and sodium carboxymethylcellulose, preparing a soft material from the uniformly mixed material by taking pure water as an adhesive, sieving with a 20-mesh sieve, granulating, drying at 60 ℃ to prepare dry granules, adding magnesium stearate into the dry granules, mixing and tabletting to obtain the tablet.
Example 8 Cycloastragenol microemulsion concentrate
The preparation process comprises the following steps: weighing medium-chain fatty glyceride, polyoxyethylene castor oil EL-40, 1, 2-propylene glycol and absolute ethyl alcohol according to the prescription amount, mixing, uniformly stirring, adding cycloastragenol for dissolving, or performing ultrasonic treatment to accelerate dissolving to obtain a clear concentrated solution, namely a cycloastragenol microemulsion concentrate. The microemulsion concentrate can be further diluted for injection or oral administration.
Example 9 Cycloastragenol microemulsion concentrate
The preparation process comprises the following steps: weighing PEG-2-stearate, Tween-20, 1-hexanol and PEG3350 according to the prescription amount, mixing, stirring uniformly, adding cycloastragenol for dissolving, or performing ultrasonic treatment to accelerate dissolving to obtain a clear concentrated solution, namely the cycloastragenol microemulsion concentrate. The microemulsion concentrate can be further diluted according to the requirement of administration for injection administration or oral administration of patients.
Example 10 Experimental study of the drug Effect of Cycloastragenol on chronic obstructive pulmonary disease rats
1.1 establishment of Chronic obstructive pulmonary disease rat model
Smoking box
The self-made cigarette box is sealed by a paper box, the volume of the box is 48L (60cm multiplied by 40cm multiplied by 20cm), the box body is divided into an upper layer and a lower layer, the middle of the box body is separated by a small-aperture iron net, a rat is placed on the upper layer, a lighted cigarette is placed on the lower layer, meanwhile, ventilation holes with the diameter of 3cm are respectively arranged on the front side and the rear side of the upper layer of box body, and a cigarette placing hole with the diameter of 6cm is arranged on the.
Molding die
40 Wistar male mice were randomly divided into 5 groups: normal control group, model control group, cycloastragenol low dose group, cycloastragenol high dose group, and astragaloside IV group. On days 1 and 14, except for a control group, carrying out intraperitoneal injection anesthesia on rats in other groups by using 10% chloral hydrate solution (3-4mL/kg), exposing a trachea after anesthesia, quickly injecting 200ul LPS (lipopolysaccharide) (1mg/mL) into the trachea by using a 1mL injector, quickly vertically rotating the rats for 10-20s after completion to uniformly distribute the LPS solution in two lungs, and smearing a small amount of sodium penicillin at an incision and suturing to avoid infection; and (3) performing the treatment on days 2-13 and days 15-28, except for the normal control group, placing the rats in a self-made smoking box to continuously smoke cigarette smoke, wherein the number of cigarettes is 12 per time, 30min per time and 2 times per day, and the interval is 2 hours, and placing a proper amount of allochroic silica gel drying agent at the bottom of the box in order to reduce the influence of water vapor generated by cigarette combustion on the rats.
1.2 modes of administration
1g of cycloastragenol, grinding, preparing a suspension solution of 10mg/mL by using 0.5% CMC-Na (sodium carboxymethyl cellulose), and performing gavage administration for 1 time every day from the 1 st day for 28 days continuously.
The following doses were administered to each group of animals:
cycloastragenol low dose group: 1mg/kg cycloastragenol;
cycloastragenol high dose group: 10mg/kg cycloastragenol;
astragaloside group: 10mg/kg astragaloside IV;
the medicines are all suspended by 0.5 percent of sodium carboxymethyl cellulose.
Normal control group: equal volume of sodium carboxymethylcellulose;
model control group: equal volume of sodium carboxymethylcellulose.
1.3 detection of relevant index of pulmonary function in rats
On the 29 th day, 10% chloral hydrate solution is used for abdominal cavity anesthesia of a rat, then the trachea is exposed, a Y-shaped tube is inserted into the trachea, a micro-pressure sensor of a lung function tester is connected to one end of the Y-shaped tube, a flow sensor is connected to the other end of the Y-shaped tube, a pressure sensor is inserted into the esophagus of the rat at the same time, and when the esophageal pressure shows a negative value, the ventilation per minute (Ve), the expiratory peak flow rate (PEF) and the lung dynamic compliance (C) of the rat can be testedL) Airway resistance (R)L)。
2.1 results of the experiment
2.1.1 general State and weight changes
The normal control group rats are active and well-moving; the activity of the rats in the model control group is obviously reduced, the mental is lacked and obvious asthma appears; the activity of the group with low and high dose of cycloastragenol is increased, the mental state is improved, and the asthma degree is relieved.
No significant difference in body weight of rats in each group was observed at 0 d; in the 4 th week, the weight average of the cycloastragenol low-dose group and the cycloastragenol high-dose group is larger than that of the model control group, and the two administration groups and the model control group have significant difference. The above observations indicate that cycloastragenol group can improve the general state of chronic obstructive pulmonary disease rats and increase their body weight.
Compared with the astragaloside IV group, the rats with the high-dose and low-dose cycloastragaloside IV groups have better weight improvement effect.
The change in body weight of the rats in each group is shown in Table 1.
TABLE 1 weight change (g) of rats in each group
Compared with the model control group,#P<0.05，##P<0.01；
compared with the group of astragalosides IV,&P<0.05。
2.1.2 pulmonary function-related indices
Model control group ventilation per minute (Ve), peak expiratory flow rate (PEF), pulmonary dynamic compliance (C)L) All were lower than those of the control group, airway resistance (R)L) The ratio of the lung ventilation to the lung ventilation is higher than that of the control group, and the two groups have significant difference, which indicates that the ventilation of the model control group is reduced, the airway resistance is increased, and the lung function is obviously reduced.
Cycloastragenol low and high dose groups Ve, PEF, CLAre all higher than the model group, RLThe ratio of the drug to the drug is lower than that of the model control group, and the two drug administration groups and the model control group have significant difference, which shows that the cycloastragenol drug administration group can improve the lung function of rats.
Compared with the group of astragaloside IV, the indexes of the group with high dose of cycloastragaloside IV and the group with low dose of cycloastragaloside IV have better improvement effect.
The results of the lung function-related indices of the rats in each group are shown in Table 2.
TABLE 2 pulmonary function related indices of rats in each group
Compared with the model control group,#P<0.05，##P<0.01；
compared with the group of astragalosides IV,&P<0.05。
in conclusion, the cycloastragenol has the effect of preventing and/or treating chronic obstructive pulmonary disease.
EXAMPLE 11 determination of bioavailability of Cycloastragenol
1. Animal grouping and administration
60 Wistar rats (220 +/-30) g, half of male and female, provided by experimental animal center of Shandong New times pharmaceutical industry Co., Ltd, production license number: SCXK (lu) 20060019. Feeding the chickens under the conditions of 20-22 ℃ of temperature, 45-65% of relative humidity and 12h/12h of illumination/darkness, and freely eating and drinking water.
And (3) intragastric administration group: 30 healthy Wistar rats which are fasted for 12 hours and have freely drunk water are divided into 5 groups, namely an astragaloside group (astragaloside is administrated by gastric lavage) and a cycloastragaloside group (cycloastragaloside is administrated by gastric lavage). Each group was administered by single gavage at a dose of 20 mg/kg. Fasting and free drinking were carried out 12h before administration. About 300. mu.L of retroorbital venous plexus blood was collected before (0h), 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24h after administration, and heparin was anticoagulated, centrifuged at 12000rpm at 4 ℃ for 5min, plasma was separated, and stored in a low-temperature refrigerator at-20 ℃. During the experiment, water was freely drunk and the patient took food 2h after the gavage.
Group for intravenous administration: 30 healthy Wistar rats which are fasted for 12 hours and have freely drunk water are divided into 5 groups, namely an astragaloside group (astragaloside is given by injection) and a cycloastragaloside group (cycloastragaloside is given by injection). The tail of each group was administered by intravenous injection at a dose of 3 mg/kg. About 300. mu.L of retroorbital venous plexus blood was collected before (0h), after 0.033, 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24h administration, respectively, anticoagulated with heparin, centrifuged at 12000rpm at 4 ℃ for 5min, plasma was isolated, and stored in a low-temperature refrigerator at-20 ℃. During the experiment, food and water were taken freely.
2. Plasma sample assay
All treated plasma samples were subjected to UPLC-MS/MS quantitative analysis to determine plasma drug concentrations.
3. Calculation of bioavailability
The measured blood concentration-time data was compiled by DAS software (Drug and staticiscs, chinese society for mathematics and pharmacology, sun rui, etc.) to calculate pharmacokinetic parameters. And (4) calculating the absolute bioavailability of the cycloastragenol according to a formula, wherein t is the sampling time of the final actually measured medicine concentration.
4. Absolute bioavailability of cycloastragenol
TABLE 3 bioavailability of cycloastragenol
As can be seen from the above table, the bioavailability of cycloastragenol is obviously higher than that of astragaloside, which shows that the cycloastragenol has obvious technical advantages in the aspect of pharmacy.
The inventor carries out repeated administration toxicity experiments and reproductive development toxicity experiments of the cycloastragenol, and the result shows that the cycloastragenol has no obvious toxicity to SD rats after being orally administered for 70 days.
Example 12 repeated toxicity test of cycloastragenol in rats
Cycloastragenol is a known telomerase activator, and the literature reports that a mitochondrial enzyme activator may have a potential carcinogenic risk, and this experiment is aimed at investigating the toxicity of repeated administration of cycloastragenol.
The test result shows that under the test condition, the SD rat continuously injects 10mg/kg/d of cycloastragenol intravenously on 0-20 th day of pregnancy, and the cycloastragenol does not cause maternal toxicity of the rat.
1. Animal grouping and administration
After the quarantine period is finished, all the quarantine qualified animals enter the test. Weighing the animal body weight, randomly grouping according to the body weight, and dividing the animals into a solvent control group and a test object group, wherein each group contains at least 50 animals, and the animals are half female and half male.
Each animal was given a unique number to identify the individual. Identification between groups by using animal cages, wherein the test object group adopts red cages, and the solvent control group adopts blue cages.
According to the results of preliminary experiments on the prior pharmacokinetics, the dose is set to be the lowest dose of the maximum exposure dose, i.e. 10 mg/kg/d. The vehicle control group was given an equal volume of vehicle control.
The administration route is as follows: the injection is administered 1 time per day. The administration of the drug is started after the male rats are grouped, and the drug administration is continued for 70 days; the administration was started 2 weeks after the grouping of female rats and continued for 70 days.
The weight was weighed 1 time per week and administered by injection according to the latest weight.
2. Observation and inspection
2.1 general observations
At least 1 observation is made each day, including but not limited to animal fur, mental state, activity, secretions, etc.
2.2 body weight
Surviving animals were weighed at least 1 time per week.
2.3 anatomical examination
2.3.1 Male mouse dissection examination
10 rats were randomly selected and subjected to routine blood, biochemical blood, and bone marrow smear examination, and a whole set of organs were harvested for histopathological examination.
2.3.2 dissection of female mice
10 rats were randomly selected and subjected to routine blood, biochemical blood, and bone marrow smear examination, and a whole set of organs were harvested for histopathological examination.
3. Test results
3.1 animal death and dying
During administration, 3 and 5 animals died or moribund in the vehicle control group and the cycloastragenol group, respectively, some of the animals had some or all of the following symptoms as seen by autopsy: white foam in nasal cavity, damaged esophagus, tracheal hemorrhage, pleural effusion and lung enlargement; microscopic examination shows that the alveolar cavity is filled with homogeneous white serous fluid and/or alveolar cells are degenerated and destroyed; the chest had the symptoms of lump or suppuration observed in combination with the animal signs.
3.2 general State
Cycloastragenol does not cause abnormal changes in the general state of animals.
During the test period, except dead and moribund animals, other animals generally have good state, normal self-activity and good mental state, and no toxicity symptoms related to the test article are seen.
TABLE 4 Effect of repeated injectable administration of Cycloastragenol on general signs in Male rats
TABLE 5 Effect of repeated administration of Cycloastragenol on general signs in female rats
3.3 body weight
Cycloastragenol did not cause abnormal changes in rat body weight.
During the administration period, the body weight of the male rats in the cycloastragenol group steadily increases, and has no difference compared with the vehicle control group (p > 0.05); the body weight of female rats in the cycloastragenol group is steadily increased, wherein the body weight of the female rats on the 26 th day and the 47 th day of the administration has significant difference (p is less than or equal to 0.05) compared with the vehicle control group, and the body weight of the female rats at other time points during the administration has no difference (p is more than 0.05) compared with the vehicle control group. Although the weight gain difference has statistical significance, the weight gain difference does not have dose-effect relationship and aging relationship, and is considered as normal fluctuation of data and has no toxicological significance.
TABLE 6 Effect of repeated administration of cycloastragenol on body weight in male rats
TABLE 7 Effect of repeated administration of cycloastragenol on female rat body weight
Note: statistical significance (p ≦ 0.05) compared to vehicle control group.
3.4 hematology
The cycloastragenol group had the following changes in hematology compared to the vehicle control group:
cycloastragenol group: the PDW, MPV and P-LCR of the male mouse are reduced; the RDW-SD and RDW-CV of pregnant mice are increased, the PDW and MPV are reduced, and the differences are statistically different (p is less than or equal to 0.05).
The indexes of the cycloastragenol group male mice PDW, MPV and P-LCR, pregnant mice RDW-SD, RDW-CV, PDW and MPV have statistical significance, but the change range is more than 10 percent, and the index change of individual animals has no obvious internal correlation and is considered as normal fluctuation of data.
TABLE 8 influence of Cycloastragenol administration by injection on the hematology of male rats
Note: statistical significance (p ≦ 0.05) compared to vehicle control group.
TABLE 9 Effect of Cycloastragenol injection on hematology of pregnant females
Note: statistical significance (p ≦ 0.05) compared to vehicle control group.
3.5 blood biochemistry
Compared with the vehicle control group, the blood biochemistry of the cycloastragenol group has the following changes:
cycloastragenol group: the AST, CK-MB, CK and LDH of the male rat are reduced, and the gamma-GT is increased; pregnant mice have decreased T-Bil-V, increased LDL-C, HDL-C, TC, UREA, Glu-G, all of which are statistically different (p is less than or equal to 0.05).
The indexes of the cycloastragenol group of male mice AST, CK-MB, CK, LDH, gamma-GT, pregnant mice-Bil-V, LDL-C, HDL-C, TC, UREA and Glu-G are different, but the index change of individual animals has no obvious internal association, and is considered as normal fluctuation of data and not as the toxic effect of the test sample.
TABLE 10 Effect of Cycloastragenol injection on the biochemistry of male rat blood
Note: statistical significance (p ≦ 0.05) compared to vehicle control group.
TABLE 11 Effect of Cycloastragenol injection on the biochemistry of the blood of female mice
Note: statistical significance (p ≦ 0.05) compared to vehicle control group.
Under the condition of the experiment, the SD rat repeatedly injects for 70 days to give the cycloastragenol to find no abnormal change of the animals, and the maximum non-effect dose (NOEL) is higher than 10 mg/kg/d.
Example 13 toxicity test of reproductive development in rat Cycloastragenol
The test result shows that under the test condition, the SD rat continuously injects and gives 10mg/kg/d of the cycloastragenol on the 0 th day to the 20 th day of pregnancy, the cycloastragenol does not cause the embryo-fetus development toxicity of the rat, and the intravenous injection dosage of the astragaloside IV is 1.0mg/kg, so that certain embryo toxicity exists. Compared with astragaloside IV, the cycloastragaloside provided by the invention has higher safety.
1. Animal grouping and administration
After the quarantine period is finished, all the quarantine qualified animals enter the test. Weighing the animal body weight, randomly grouping according to the body weight, and dividing the animals into a solvent control group and a test object group, wherein each group contains at least 50 animals, and the animals are half female and half male.
Each animal was given a unique number to identify the individual. Identification between groups by using animal cages, wherein the test object group adopts red cages, and the solvent control group adopts blue cages.
According to the results of preliminary experiments of early pharmacokinetics, the dosage is set as the lowest dosage of the maximum exposure dosage, and the cycloastragenol is injected intravenously at 10 mg/kg/d. The vehicle control group was given an equal volume of vehicle control. The dose of astragaloside IV is 1.0 mg/kg/d.
Vehicle control group (1: 1 propylene glycol-ethanol diluted with 0.85% saline 1/4).
The administration route is as follows: the administration was given by tail vein injection 1 time per day. The administration of the drug is started after the male rats are grouped, and the drug is continuously administered for 10 weeks until the mating is finished and dissected; the administration was started 2 weeks after the grouping of female rats and continued until day 15 of pregnancy.
The weight was weighed 1 time per week and administered by injection according to the latest weight.
2. Observation and inspection
2.1 test methods: standard teratogenicity tests in rats (national institute of medicine and drug, New drugs (Western medicine) preclinical research guidelines compilation (pharmacy, pharmacology, toxicology) [ s ].1993 ], Yimu spring, Chendazofu, Caitoi, et al, Rapid staining of fetal rat bones [ J ]. J.J.J.J.Laboratory labor and health occupational disease, 1985, 3 (1): 130-132.).
2.2 observation indexes: animals were sacrificed one day prior to delivery (GD20) and maternal pregnancy weight changes, corpus luteum number, viable fetal rate, dead fetal rate, absorbed fetal rate, fetal length, body weight and placental weight, fetal appearance and visceral abnormalities, and skeletal development were observed.
3. Test results
3.1 in the experiment, the conditions of the live embryo rate, the dead embryo rate and the absorbed embryo rate are observed, and the comparison difference between the live embryo rate and the dead embryo rate of the SD rat at the dose of 1.0mg/kg of astragaloside IV and a control group is found to have statistical significance, which is represented as the reduction of the live embryo rate and the increase of the dead embryo rate, and shows that the SD rat has certain embryo toxicity at the dose of 1.0 mg/kg.
Compared with the astragaloside IV group, the cycloastragaloside group has increased live fetus rate and decreased dead fetus rate. The group of cycloastragenol is not different from the control group and has statistical significance. Cycloastragenol does not exhibit embryotoxicity even at a dose of 10 mg/kg.
TABLE 12 Effect of Astragaloside IV and Cycloastragenol on pregnant and fetal rats
P is less than or equal to 0.05 compared with the vehicle control group; compared with the group of astragalosides IV,&p≤0.05。
3.2 Astragaloside IV has no fetal toxicity to fetal rat at the dosage of 1.0 mg/kg. Cycloastragenol has no fetal toxicity to fetal rats under the dosage of 10 mg/kg.
TABLE 13 Effect of Astragaloside IV and Cycloastragenol on the growth and development of fetal counts (x. + -. s)
Compared with the group of astragalosides IV,&p≤0.05。
3.3 Astragaloside IV has no obvious influence on the development of fetal rats under the dosage of 1.0 mg/kg. . The cycloastragenol has no obvious influence on the development of fetal rats under the dosage of 10 mg/kg.
TABLE 14 Effect of Astragaloside IV and Cycloastragenol on skeletal development of fetal rats
4. Discussion of the related Art
Under the experimental condition, 10mg/kg/d of cycloastragenol is continuously injected into SD rats from 0 day to 20 days of pregnancy, the cycloastragenol does not cause maternal toxicity and embryo-fetus development toxicity of the rats, and the intravenous injection dose of 1.0mg/kg/d of astragaloside IV shows certain embryo toxicity.
Claims (7)
1. Use of cycloastragenol in preparing medicine for treating chronic obstructive pulmonary disease is provided.
2. Use according to claim 1, wherein the cycloastragenol is formulated as one or more of an oral, sublingual or injectable formulation.
3. Use according to claim 2, characterized in that the oral formulation is one or more of a tablet, capsule or microemulsion formulation thereof.
4. The use according to claim 2, wherein the injectable formulation is one or both of an injectable solution or injectable microspheres thereof.
5. The use according to any one of claims 1 to 4, wherein the medicament is for the treatment of chronic bronchitis in an amount of from 0.001 mg/kg-d to 50 mg/kg-d.
6. The use according to claim 5, wherein the medicament is administered in an amount of 0.01 mg/kg-d to 10 mg/kg-d in the treatment of chronic bronchitis.
7. The use according to claim 1, wherein the content of cycloastragenol in each formulation unit is 0.001mg to 50 mg.
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