CN109381476B - Weight-losing pharmaceutical composition - Google Patents
Weight-losing pharmaceutical composition Download PDFInfo
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- CN109381476B CN109381476B CN201811417188.4A CN201811417188A CN109381476B CN 109381476 B CN109381476 B CN 109381476B CN 201811417188 A CN201811417188 A CN 201811417188A CN 109381476 B CN109381476 B CN 109381476B
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
A weight-losing pharmaceutical composition belongs to the technical field of medicines. The invention aims to provide a weight-losing pharmaceutical composition which can not only lose weight, but also reduce adverse reactions. The active ingredients prepared by the invention comprise: cordycepin and 3' -deoxyinosine. The weight-losing tea disclosed by the invention is combined with the theory of western medicine and pharmacology, is reasonably proportioned, can effectively lose weight, can reduce adverse reactions, and is high in quality and low in price.
Description
Technical Field
The invention belongs to the technical field of medicines.
Background
The obesity refers to a state that the body weight is excessively increased due to excessive fat accumulation in the body and causes pathology, physiological changes or latency of the human body, when the intake of heat in the human body is higher than the consumption amount, the body weight is excessively increased, and the body state is overstaffed, the obesity evaluation standard is that the obesity degree is = (actual body weight-standard body weight) ÷ standard body weight × 100%, the actually measured body weight is more than the standard body weight by 20%, and the fat percentage is more than 30%, so the obesity refers to the state that the body fat accumulation is excessive.
The main diet drugs currently in clinical use and under study are central appetite suppressants, digestive absorption blockers, metabolic promoters, obesity gene products and other drugs for treating obesity, which all have more or less side effects.
Disclosure of Invention
The invention aims to provide a weight-losing pharmaceutical composition which can not only lose weight, but also reduce adverse reactions.
The weight ratio of the effective components prepared by the invention is as follows: cordycepin 3' -deoxyinosine = 2: 1.
The invention relates to an application of a pharmaceutical composition in preparing a weight-reducing medicine.
The invention relates to an application of a weight-losing pharmaceutical composition in preparing a medicament for preventing and treating obesity-related cardiovascular and cerebrovascular diseases.
The weight-losing pharmaceutical composition is applied to the preparation of medicines for preventing and treating obesity-related impaired glucose tolerance, diabetes, fatty liver, cirrhosis, cholelithiasis, pancreatitis, fundus hemorrhage, blindness, claudication and hyperuricemia.
The weight-losing tea disclosed by the invention is combined with the theory of western medicine and pharmacology, is reasonably proportioned, can effectively lose weight, can reduce adverse reactions, and is high in quality and low in price.
Drawings
FIG. 1 is a fluorescence microscope for detecting fat droplets in adipocytes;
figure 2 is a fat titer analysis.
Detailed Description
The weight ratio of the effective components prepared by the invention is as follows: cordycepin 3' -deoxyinosine = 2: 1.
Cordycepin, 3 '-deoxyadenosine (3' -deoxyadenosine), is a purine alkaloid prepared from Cordyceps militaris (L.) LinkCordyceps militaris) The nucleoside substance obtained by chemical separation has a structural formula shown in general formula (I); 3'-deoxyinosine (3' -deoxyinosine) is a product of deamination of cordycepin by adenosine deaminase, and has a molecular formula of C10H12N4O4Molecular weight is 252.227, and the structural formula is shown as general formula (II):
the invention relates to application of a weight-losing pharmaceutical composition in preparing weight-losing medicines.
The invention relates to an application of a weight-losing pharmaceutical composition in preparing a medicament for preventing and treating obesity-related cardiovascular and cerebrovascular diseases.
The weight-losing pharmaceutical composition is applied to the preparation of medicines for preventing and treating obesity-related impaired glucose tolerance, diabetes, fatty liver, cirrhosis, cholelithiasis, pancreatitis, fundus hemorrhage, blindness, claudication and hyperuricemia.
The present invention is described in further detail below:
the cordycepin and 3' -deoxyinosine composition has excellent weight-losing effect.
The pharmaceutical composition of the invention comprises: cordycepin and 3' -deoxyinosine.
Cordycepin (3 'Deoxyadenosine, 3' -Deoxyadenosine) also called Cordycepin (Cordycepin) is a nucleoside antibiotic with multiple biological activities extracted from fermentation liquor of Cordyceps militaris or Cordyceps sinensis. The cordyceps militaris, also called as cordyceps militaris, has similar bioactive components with cordyceps sinensis, mainly comprises cordycepin, cordycepic acid, cordyceps polysaccharide, ergosterol, amino acid, nucleoside substances and the like, has similar efficacy with the cordyceps sinensis, has higher cordycepin content and antioxidant activity than the cordyceps sinensis, and is the best substitute of the cordyceps sinensis. The molecular formula of cordycepin is C10H13N5O3The ultraviolet-curable resin has the relative molecular weight of 251, the melting point of 230-231 ℃, is soluble in water, hot ethanol and methanol and insoluble in benzene, ether and chloroform, and the maximum absorption wavelength under ultraviolet light is 259 nm. As early as the 70's in the 20 th century, cordycepin was found to have antibacterial, antiviral, anti-inflammatory and immunomodulatory effects. And 3'-deoxyinosine (3' -deoxyinosine) is a deaminated product of cordycepin by adenosine deaminase.
Therefore, the cordycepin and 3' -deoxyinosine composition can be used for preparing medicaments for preventing and treating obesity and obesity-related cardiovascular and cerebrovascular diseases. The cardiovascular and cerebrovascular diseases are preferably apoplexy, coronary heart disease, myocardial infarction, sudden cardiac death, hypertension, atherosclerosis and peripheral vascular diseases.
In mammals, lipid Droplets play an important role in cellular lipid homeostasis, primarily the storage of cholesterol esters for membrane and steroid hormone synthesis, or triacylglycerols, which serve as energy substrates or sources of signal-conducting lipids or precursors for membrane phospholipid synthesis, the growth and consumption of fat Droplets may occur through a variety of pathways, but both processes ultimately depend on the regulated exchange of lipid content between the fat Droplets and other organelles within the aqueous cytoplasm, because the fat Droplets are not associated with the regulated exchange of lipid content between the fat Droplets and other organelles within the aqueous cytoplasm, and thus, the lipid Droplets may be directly linked to the growth of lipid Droplets in vivo, and to the prevalence of lipid Droplets in vivo, and to the development of lipid Droplets in vivo, as well as to the development of lipid Droplets in vivo, and to the development of lipid Droplets.
The invention mainly relates to a pharmaceutical composition and has the effect of efficiently losing weight. The basic mechanism of the weight-losing effect is as follows: cordycepin has the obvious effect of degrading fat drops in white fat cells, 3' -deoxyinosine can obviously strengthen the effect of cordycepin, and the combined use of cordycepin and 3' -deoxyinosine is obviously stronger than the effect of cordycepin alone on degrading fat drops, so that the combination of cordycepin and 3' -deoxyinosine can achieve better weight-losing effect.
According to the invention, the pharmaceutical composition can be tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations and various microparticle delivery systems.
In the safety experiment, cordycepin and 3' -deoxyinosine were separately administered by gavage at 5.0 g/kg in rats. After administration, the rats were observed for two weeks continuously, and the behavior, activity, body weight, food intake, feces and death were recorded, and sacrificed after two weeks for necropsy. After the rat is administrated, the hair color is smooth, the behavior and activity are active, the body weight is increased, the food intake is normal, and the feces are normal and have no obvious difference compared with a solvent control group; and for two weeksNecropsy is carried out after sacrifice, main organs (heart, liver, spleen, lung and kidney) are not abnormally changed by naked eye observation, and have no obvious difference compared with a solvent control group, which shows that both cordycepin and 3'-deoxyinosine have no obvious toxic reaction, the maximum tolerance of rats is more than 6.25 g/kg, namely the cordycepin and the 3' -deoxyinosine are L D orally administered50Greater than 6.25 g/kg.
The pharmaceutical compositions of the present invention may be prepared according to methods known in the art. For this purpose, the active ingredient may, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants in a suitable administration form or dosage form for human administration.
The pharmaceutical compositions of the present invention may be administered in unit dosage form, either enterally or parenterally, for example orally, intramuscularly, subcutaneously, nasally, oromucosally, dermally, peritoneally or rectally, and the like.
The route of administration of the pharmaceutical composition of the present invention may be administration by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.
The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.
In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of vectors are as follows: diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc., wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dry starch, alginates, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid esters, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of vectors are as follows: diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, and the like; binding agents, such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.
For making the administration unit into a suppository, various carriers well known in the art can be widely used. Examples of vectors are as follows: such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, and the like.
To encapsulate the administration units, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. Or making into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection.
For example, the composition of the present invention is formulated into an injectable preparation, such as a solution, a suspension solution, an emulsion, a lyophilized powder, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, PH adjusters and the like may also be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparations, if desired.
The optimal weight ratio of cordycepin to 3' -deoxyinosine in the pharmaceutical composition provided by the invention is as follows: cordycepin 3' -deoxyinosine = 2:1, the dosage of the composition for treating obesity is determined according to the age, physical state and disease condition of patients, the recommended dosage is 2:1 with better effect and 1:1 with better effect according to the weight ratio, and the administration frequency is once a day.
The dose of the pharmaceutical composition of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administrations, etc., and thus the therapeutic dose of the present invention can be widely varied. The treatment days of the present invention are completed with appropriate adjustments to achieve the desired therapeutically effective amount of the actual effective amount of drug contained in the final formulation of the pharmaceutical composition of the present invention.
The following examples are intended to further illustrate the invention but are not intended to limit the invention in any way
First, test of weight loss mechanism
Example 1: mechanism research of interaction between cordycepin and 3' -deoxyinosine and fat cells in vitro
1 Material
[ Experimental animals ] SD rat, male, weight 180 ~ 200g, by the national people's liberation military medical science institute experimental animals center, the experimental animals use license number: SCXK 2015-0001.
[ test product ] Cordycepin (purchased from Sigma-Aldrich, 500 mg/bottle, 99% pure).
[ feed ] basal feed, purchased from Nantong Telofibroth feed science and technology Limited basic feed formulation: 20% of flour, 10% of rice flour, 20% of corn, 20% of bean flour, 25% of bran, 2% of bone meal and 2% of fish meal. And (3) high-fat feed formula: 83.6 percent of basal diet, 15 percent of fat, 1.2 percent of cholesterol and 0.2 percent of bile salt. High-fat feed D12494: purchased from Research diets, usa (RodentDiet with 60% kcal% fat).
[ drug ] Cordycepin: purchased from Sigma-Aldrich, 500 mg/bottle. 3' -deoxyinosine (available from NEScientific Natick Innovation Center, 25 mg/bottle, 99% pure).
Method of producing a composite material
[ modeling and observation ] SD rats were fed with high-fat diet continuously for four weeks without a limited supply, and an obesity model was constructed. Mature adipocytes were post-killed and extracted, stained for fat droplets with BODIPY, and fat droplet content was measured by ImageJ software.
Data analysis data are expressed as mean values with standard deviation and data analysis is performed by using a t test.
Results
The results show that the fat drop content is significantly reduced after the treatment with cordycepin (administration dose is 50 mg/kg) compared with the model group (P = 0.0022<0.01); the fat drop content is reduced after the treatment of 3' -deoxyinosine (the administration dosage is 50 mg/kg), but the effect is not obvious and the difference is not obvious (P = 0.0529>0.05); after being treated by cordycepin + 3' -deoxyinosine composition (the administration dosage is 12.5 mg/kg + 6.25 mg/kg), the fat drop content is extremely reduced (P = 0.0002<0.01); the cordycepin and 3'-deoxyinosine composition had a more significant effect of degrading fat droplets than the cordycepin and 3' -deoxyinosine single-treated groups ((ii))PThe values are respectively:P compared with cordycepin = 0.008< 0.01;P Comparison with 3' -deoxyinosine = 0.0013 < 0.01). See figures 1 and 2.
Conclusion
The mechanism of the in vitro interaction of the cordycepin and 3' -deoxyinosine composition with the fat cells is realized by degrading fat drops in the fat cells, and the effect of the cordycepin and 3' -deoxyinosine composition on degrading the fat drops is obviously stronger than the effect of cordycepin or 3' -deoxyinosine on degrading the fat drops respectively and independently.
Second, drug efficacy test
Example 2: effect of independent administration of cordycepin and 3' -deoxyinosine on weight change of obese model rats
1 materials and methods
[ Experimental animals ] SD rat, male, weight 180 ~ 200g, by the national people's liberation military medical science institute experimental animals center, the experimental animals use license number: SCXK 2015-0001.
[ test product ] Cordycepin (purchased from Sigma-Aldrich, 500 mg/bottle, 99% pure).
[ feed ] basal feed purchased from Nantong Telofuran feed science and technology Limited, basal feed formulation: 20% of flour, 10% of rice flour, 20% of corn, 20% of bean flour, 25% of bran, 2% of bone meal and 2% of fish meal; and (3) high-fat feed formula: 83.6% basal diet, 15% fat, 1.2% cholesterol, 0.2% bile salts; high-fat feed D12494: purchased from Research diets, usa (RodentDiet, 60% kcal% fat).
[ medicine ] Cordycepin, purchased from Sigma-Aldrich company, with a specification of 500 mg/bottle and a purity of 99%; 3' -deoxyinosine: purchased from NE Scientific Natick Innovation Center, 25 mg/bottle, 99% pure.
Method of producing a composite material
Grouping and administration rats were randomly divided into eight groups by body weight: the kit comprises a normal control group, an obesity model group, a cordycepin high-dose group (50 mg/kg), a cordycepin medium-dose group (25 mg/kg), a cordycepin low-dose group (12.5 mg/kg), a 3' -deoxyinosine high-dose group (50 mg/kg), a 3' -deoxyinosine medium-dose group (25 mg/kg) and a 3' -deoxyinosine low-dose group (12.5 mg/kg), wherein 10 cordycepin low-dose groups are provided, and the mortality rate is not high. The normal control group was given ordinary diet, and the other groups were given high-fat diet, all in an unlimited amount for four weeks. After the modeling is successful, each group of rats is fed with 200g of feed every day, a blank group is fed with blank feed, a model group and a dosing group are fed with high-fat feed, each dosing group is intragastrically administered once every day, the dosing volume is 0.5 ml/100 g of body weight, and the dosing is continuously carried out for 4 weeks. The blank and model groups were given daily equal volumes of saline.
[ evaluation of drug Effect ] after 4 weeks of administration, rats of each group were weighed (g)
Data analysis data are expressed as mean values with standard deviation and data analysis is performed by using a t test.
Results
1. Compared with the weight (365 +/-3.2 g) of a normal control group rat, the weight (468 +/-2.6 g) of the model group rat is remarkably improved, which indicates that the experimental obesity model is successfully modeled.
2. After administration, the weight of the rats in cordycepin (50 mg/kg) and cordycepin (25 mg/kg) administration groups was significantly reduced compared with the weight of the rats in model group (P<0.05), while the weight of the rats in the group administered with the lowest concentration of cordycepin (12.5 mg/kg) is not significantly reduced (P>0.05), which shows that the independent administration of cordycepin with concentration higher than a certain concentration has the effect of remarkably reducing the body weight of rats; 3-deoxyinosine (12.5 mg/kg, 25mg/kg, 50 mg/kg) at the tested concentrations alone had no significant effect on reducing the body weight of rats. The results are shown in Table 2.
Conclusion
The cordycepin is administered by intragastric administration alone, and has effect in reducing weight of rat induced by high fat feed; the single intragastric administration of 3' -deoxyinosine has no weight reduction effect on the obese rats induced by high-fat feed.
TABLE 2 Effect of cordycepin administration treatment on weight change (mean + -SD) in obese rats
Note: 1. compared with blank control group“*” P<0.05，“**” P<0.01，“***” P<0.001; 2. compared with model group“△” P<0.05，“△△” P<0.01，“△△△” P<0.001; 3.3' -deoxyinosine was compared with the cordycepin administration group“#” P<0.05，“##” P<0.01，“###” P<0.001。
Example 3: effect of cordycepin and 3' -deoxyinosine composition administration on weight change of obese model rats
1 materials and methods
[ Experimental animals ] SD rat, male, weight 180 ~ 200g, by the national people's liberation military medical science institute experimental animals center, the experimental animals use license number: SCXK 2015-0001.
[ test article ]3' -deoxyinosine (available from NE Scientific Natick Innovation Center, 25 mg/bottle, 99% purity). Cordycepin (purchased from Sigma-Aldrich, 500 mg/bottle, 99% purity)
[ feed ] basal feed, purchased from Nantong Telofuran feed science and technology Co. The basic feed formula comprises: 20% of flour, 10% of rice flour, 20% of corn, 20% of bean flour, 25% of bran, 2% of bone meal and 2% of fish meal. High-fat feed: is prepared from 2% cholesterol, 10% lard, 0.2% methyl thiouracil and 87.8% basic mouse feed.
[ drug ] Cordycepin: purchased from Sigma-Aldrich, 500 mg/bottle. 3' -deoxyinosine (available from NEScientific Natick Innovation Center, 25 mg/bottle, 99% pure).
Method of producing a composite material
Grouping and administration rats were randomly divided into five groups by body weight: a normal control group, a model group, a cordycepin (12.5 mg/kg) + 3'-deoxyinosine (6.25 mg/kg) group, a cordycepin (6.25 mg/kg) + 3' -deoxyinosine (3.125 mg/kg) group, 10 of each group. The normal control group was given ordinary diet, and the other groups were given high-fat diet, all in an unlimited amount for four weeks. After the modeling is successful, each group of rats is fed with 200g of feed every day, a blank group is fed with blank feed, a model group and a dosing group are fed with high-fat feed, each dosing group is intragastrically administered once every day, the dosing volume is 0.5 ml/100 g of body weight, and the dosing is continuously carried out for 4 weeks. The blank and model groups were given daily equal volumes of saline.
[ evaluation of drug Effect ] after 4 weeks of administration, rats of each group were weighed (g)
Data analysis data are expressed as mean values with standard deviation and data analysis is performed by using a t test.
Results
1. Compared with the weight of the normal control group rat, the weight of the model group rat is remarkably improved, which indicates that the experimental obese rat model is successfully modeled.
2. After administration, the body weight measurements were as follows: compared with the weight of rats in the obesity model group, the weight of rats in the cordycepin (12.5 mg/kg) + 3' -deoxyinosine (6.25 mg/kg) group is remarkably reduced by 15.3% ((P<0.001); the weight of rats with cordycepin (6.25 mg/kg) + 3' -deoxyinosine (6.25 mg/kg) groups is reduced by 10.5% ((P<0.01); the weight of rats in the cordycepin (6.25 mg/kg) + 3' -deoxyinosine (3.125 mg/kg) group is obviously reduced by 8.7% ((P<0.05). The results are shown in Table 3.
Conclusion
The cordycepin and 3' -deoxyinosine composition can obviously reduce the weight of rats after being administrated for treatment; as shown in the results of example 2, 3'-deoxyinosine alone did not have a significant weight loss effect in rats, while the dose of cordycepin (administration dose ≦ 12.5 mg/kg), which originally failed to reduce the weight of rats when administered alone, exhibited a significant weight loss effect in rats in the composition due to the addition of 3' -deoxyinosine. These results indicate that cordycepin alone, above a certain concentration, has a weight-reducing effect; the weight-losing effect of the 3' -deoxyinosine is not obvious when the single drug is taken; the 3'-deoxyinosine has the function of obviously enhancing the weight-losing effect of the cordycepin, so that the weight-losing effect of the cordycepin and 3' -deoxyinosine composition is optimal.
TABLE 3 Effect of cordycepin and 3' -deoxyinosine combination treatment on obese hyperlipidemic model rats (mean + -SD)
Note: 1. compared with blank control group“*” P<0.05，“**” P<0.01，“***” P<0.001; 2. compared with model group“△” P<0.05，“△△” P<0.01，“△△△” P<0.01。
Third, safety experiment
Example 4: cordycepin + 3' -deoxyinosine composition acute toxicity test
Materials and methods
[ Experimental animals ] SD rat, weight 180 ~ 220 g, half each sex, by the experimental animals center of China people's liberation military medical science institute, the use of the license number of experimental animals: SCXK 2015-0001.
[ test article ]3' -deoxyinosine (available from NE Scientific Natick Innovation Center, 25 mg/bottle, 99% purity). Cordycepin (purchased from Sigma-Aldrich, 500 mg/bottle, 99% purity)
[ test method ] 40 SD rats with body weight of 180-200 g and half of male and female are selected. The group was divided randomly into 2 groups of 20, i.e., cordycepin + 3' -deoxyinosine group and solvent control group, and administered 12 hours after fasting (without water). In the cordycepin + 3'-deoxyinosine group, the 3' -deoxyinosine with 12.5 percent is administrated to the mice by intragastric administration of 0.5 ml/100 g once, and the administration dose is 6.25 g/kg; the solvent control group was given an equal amount of distilled water. After administration, the rats were observed for two weeks continuously, and the behavior, activity, body weight, food intake, feces and death were recorded, and sacrificed after two weeks for necropsy.
Results
After the cordycepin + 3' -deoxyinosine composition is administrated for two weeks, the rat has smooth hair color, behavioral activity, weight increase, ingestion and normal feces, and has no obvious difference compared with a solvent control group; and no death and other abnormal conditions occurred within two weeks. Necropsy was performed after two groups (cordycepin + 3'-deoxyinosine composition group and solvent control group) died at the same time, and no abnormal change was observed in the main organs (heart, liver, spleen, lung and kidney) by naked eye, and there was no obvious difference between the cordycepin + 3' -deoxyinosine composition group and the solvent control group. The results are shown in Table 4.
Conclusion
The maximum tolerance test result of one-time oral administration of the cordycepin + 3' -deoxyinosine composition group shows that no obvious toxic reaction exists after 20 rats are administered, and no death occurs within two weeks, so that the maximum tolerance of the one-time oral administration of the cordycepin + 3' -deoxyinosine composition group is more than 6.25 g/kg, namely L D of the oral administration of the cordycepin + 3' -deoxyinosine group50Greater than 6.25 g/kg.
TABLE 4 experimental results of maximum tolerance of cordycepin + 3' -deoxyinosine group orally administered rats
Claims (4)
1. A weight-losing pharmaceutical composition is characterized in that: the weight ratio of the prepared effective components is as follows: cordycepin 3' -deoxyinosine = 2: 1.
2. The use of the weight-loss pharmaceutical composition of claim 1 in the preparation of a weight-loss medicament.
3. The use of the weight-loss pharmaceutical composition of claim 1 in the preparation of a medicament for the prevention and treatment of obesity-related cardiovascular and cerebrovascular diseases.
4. Use of the weight-loss pharmaceutical composition according to claim 1 for the preparation of a medicament for the prevention and treatment of obesity-related impaired glucose tolerance, diabetes, fatty liver, cirrhosis, cholelithiasis, pancreatitis, fundus hemorrhage, blindness, claudication, hyperuricemia.
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