CN109172578B - Application of piperaquine phosphate in preparing medicine for treating lipid metabolism disorder and hyperlipidemia - Google Patents
Application of piperaquine phosphate in preparing medicine for treating lipid metabolism disorder and hyperlipidemia Download PDFInfo
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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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
- A61P1/16—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
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention relates to the field of pharmacy, in particular to application of piperaquine phosphate in preparing a medicament for treating lipid metabolism disorder and hyperlipidemia. The piperaquine phosphate has the effects of obviously reducing the TC and TG levels of serum, has obvious lipid-lowering effect, can obviously reduce weight, has no obvious toxic or side effect, can be used for showing that the piperaquine phosphate has good treatment effect on hyperlipidemia, and can be applied to the preparation of the medicament for treating the hyperlipidemia.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to application of piperaquine phosphate in preparing a medicament for treating lipid metabolism disorder and hyperlipidemia.
Background
Hyperlipidemia is a disease caused by the disturbance of systemic fat metabolism and caused by the imbalance of one or more lipid structures in blood plasma, namely, the condition refers to the condition that Total Cholesterol (TC) or Triglyceride (TG) in blood is too high or high density lipoprotein cholesterol (HDL-C) is too low, and the modern medicine is called as dyslipidemia.
The national survey result of 2012 shows that the overall prevalence rate of dyslipidemia of adults in China is as high as 40.40%. The increase of the serum cholesterol level of the population leads to about 920 ten thousand of cardiovascular disease events in China during the period from 2010 to 2030. The hypercholesterolemia prevalence rate of children and teenagers in China is also obviously increased, which indicates that adult dyslipidemia and related disease burden in China will be continuously increased.
Hyperlipidemia is an important risk factor for cardiovascular and cerebrovascular diseases, and the up-to-standard blood lipid is regarded as a core strategy for preventing and treating cardiovascular diseases. The main approaches to reach the blood lipid level include exercise, lifestyle changes, weight control and the use of lipid-lowering drugs. A considerable part of patients with dyslipidemia need treatment of lipid-lowering drugs clinically, the treatment drugs mainly comprise two categories of fibrates and statins, the clinical curative effect is obvious, but the side effect is obvious, the side effects such as rhabdomyolysis and liver injury can occur, and rebound easily occurs after drug withdrawal.
Due to the limitations of current hyperlipidemia therapeutic drugs, therapeutic approaches and targets remain under investigation.
The piperaquine phosphate is an oral long-acting anti-malarial drug, is mainly used for preventing and treating malaria, has good prevention and treatment effects on malignant malaria and vivax malaria, but has not been reported for treating hyperlipidemia.
Disclosure of Invention
The invention aims to provide a new application of piperaquine phosphate, namely an application of the piperaquine phosphate in preparing a medicament for treating lipid metabolism disorder.
Further elaborating the application of piperaquine phosphate in preparing the medicament for treating hyperlipemia. Wherein, the hyperlipemia includes dyslipidemia caused by triglyceride and/or total cholesterol rise, and any one of coronary heart disease, atherosclerosis, diabetes, pancreatitis, fatty liver and myocardial infarction caused by the dyslipidemia.
Further, the piperaquine phosphate is a solid preparation, a semi-solid preparation or a liquid preparation. And when it is a liquid preparation, the concentration of the drug which can exert a therapeutic effect is 1.88 mg/mL-1Above, or between 1.88 mg/mL-1-7.52mg·mL-1In the meantime.
Animal tests show that piperaquine phosphate has good effect on treating lipid metabolism disorder. Animal experiments show that the piperaquine phosphate can effectively reduce the weight of a mouse, reduce triglyceride and total cholesterol in the mouse and has small toxic and side effects, thereby indicating that the piperaquine phosphate has great application prospect in preparing the medicine for treating hyperlipidemia.
Therefore, the beneficial effects of the invention are as follows:
the invention explores the application of piperaquine phosphate, develops new application of the piperaquine phosphate in the drugs for treating lipid metabolism disorder, particularly in the preparation of hyperlipidemia drugs, and remarkably reduces the content of total cholesterol and triglyceride. Has good treatment effect on dyslipidemia caused by total cholesterol and/or triglyceride and diseases such as coronary heart disease, atherosclerosis, diabetes, pancreatitis, fatty liver, myocardial infarction and the like caused by the dyslipidemia.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments will be briefly described below.
FIG. 1 is a graph of the change in body weight of ob/ob mice before and after administration in the mouse experiment of example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Piperaquine phosphate (Pipeqaquinephophate, 1, 3-bis- [4- (7-chloroalanin-4) -piperaquine-1 ] -propane tetraphosphate tetrahydrate, the chemical structural formula is as follows:
Further, the preparation method of piperaquine phosphate is also prepared by the prior art, for example, the preparation method can be prepared by the patent with the application number of CN200810237162.1, or other preparation methods.
The piperaquine phosphate used in the embodiment of the invention is the existing piperaquine phosphate, and can be directly obtained by purchasing.
Further, the piperaquine phosphate used in the embodiments of the present invention is a solid formulation, a semi-solid formulation, or a liquid formulation. The solid preparation can be tablets, granules, powder and the like, the semisolid preparation can be ointments, gels and the like, and the liquid preparation can be oral liquid, injection or other liquid preparations.
Further, when piperaquine phosphate is in a liquid preparation, or when piperaquine phosphate in a solid preparation is dispersed or dissolved in water, the drug concentration of piperaquine phosphate is 1.88 mg/mL-1Above, or between 1.88 mg/mL-1-7.52mg·mL-1And then a good effect can be achieved.
Example 1
The present example will illustrate the new use of piperaquine phosphate in the pharmaceutical field by using animal experiments and results of the piperaquine phosphate in the treatment of lipid metabolism disorder, especially hyperlipidemia.
1. Material
1.1 test drugs
Piperaquine phosphate, production unit: chongqing southwest pharmaceutical two-plant, Limited liability company; batch number: y180504; the preparation formulation is as follows: dissolving the powder in purified water to obtain 1.88 mg/mL-1、3.76mg·mL-1And 7.52 mg. multidot.mL-1The concentration of the concentrated medicinal liquid is 1.88 mg/mL for low dose, medium dose and high dose groups-1、3.76mg·mL-1And 7.52 mg. multidot.mL-1。
1.2 Experimental animals
The ob/ob mouse is a leptin gene knockout mouse, can induce animal obesity and obesity-related high TC and high TG blood diseases even if being eaten by ordinary diet, and is a stable hyperlipemia animal model.
Male SPF grade ob/ob mice of 10 weeks old are adopted, the weight is 39.62 g-49.25 g, and the male SPF grade ob/ob mice are provided by Nanjing university-Nanjing biological hospital research institute; animal production license number: SCXK (threo) 2015-0001; animal certification number: 32002100005227, respectively; raising in the laboratory barrier environment quarantine room of the new southern drug safety evaluation center, wherein the laboratory animal uses license number: SYXK (Yue) 2013-; animal experiment facility use certificate number: 11400700314649. animal breeding environment: the temperature and humidity are recorded by a DSR-TTLA temperature and humidity monitoring system, the room temperature is 20.0-22.6 ℃, the relative humidity is 50.7-65.7%, and the feed is fed by adopting standard feed and purified water.
1.3 Main Experimental instruments
Japanese 7080 full-automatic biochemical analyzer (HITACHI group); an ADVIA2120i full-automatic animal blood analyzer (SIEMENS corporation); the model is as follows: one hundredth electronic balance of Shuangjie JJ500Y (Shuangjie testing instruments factory, Normal City).
1.4 Main test reagents
Cholesterol (CHOL) kit (lot: ZCAUGQ009), Triglyceride (TG) kit (lot: ZCIUULQ 008), supplied by Shanghai Pierce Biotech Ltd.
2 method of experiment
2.1 animal grouping and administration
Selecting 32 male SPF grade ob/ob mice qualified for adaptive breeding, randomly dividing into 4 groups, which are respectively a solvent control group and a piperaquine phosphate low-dose group (18.8mg kg)-1·d-10.25-fold clinical dose), and medium dose group (37.6 mg. kg)-1·d-10.5 times the clinical dose) and high dose group (75.2 mg. kg)-1·d-1Corresponding to the clinical dosage), the mice of each administration group are subjected to intragastric administration, and the vehicle control group is administered with purified water of the same volume for 4 weeks 1 time a day. Fasting for 12 hours at the end of week 4, collecting blood in orbit, centrifuging, and separating serum; with CO2Mice were sacrificed by (dry ice) asphyxiation of cervical dislocation and subjected to systematic necropsy.
2.2 detection of indicators
2.2.1 weight observations: the mice were weighed 1 time per day before and after dosing, with the dosing data expressed as mean ± standard deviation(s), analyzed using SPSS19.0 statistical software, in line with normal distribution test and homogeneity of variance test, for multiple comparisons (LSD) between groups, and in line with normal distribution and variance, for Kruskal-Wallis rank sum test. The results of the measurements are shown in Table 1 and FIG. 1.
Table 1 effect of piperaquine phosphate on body weight of ob/ob mice (g,
)
note:*compared with the solvent control group, P is less than 0.05,**compared with the solvent control group, P is less than 0.01,***p is less than 0.001 compared with the vehicle control group.
As can be seen from Table 1 and FIG. 1, the body weight of the mice in the low dose group after piperaquine phosphate administration at day 18 (D18) and the body weight of the mice in the medium dose group at day 15 (D15) and day 3 (D3) are both significantly lower than those in the vehicle control group, the differences are significant (P is less than 0.05), and particularly, the body weight of the mice in the high dose group is significantly reduced and the dose-effect relationship is significant.
2.2.2 general case observations: the mental state, the physical signs, the behavior activity, the gland secretion, the respiration, the feces and the death of the mice are observed and recorded every day, and if the abnormality exists, the mice are recorded independently.
According to the observation of the vehicle control group, the low, medium and high dose groups, the mice have good general conditions of eyes, ears, mouths, noses and the like from the beginning to the end of administration, have no abnormal secretion, have no abnormal gait and furs, have no convulsion, have no phenomenon of loose stool and the like; the mouse has no abnormality in spirit, appearance, respiration, behavior and autonomic activity.
2.2.3 measurement of serum Total Cholesterol (TC) and Triglyceride (TG) levels in mice before and after administration: and detecting by using a full-automatic biochemical analyzer. The results of the tests are shown in tables 2 and 3.
TABLE 2 ob/ob mice pre-dose TC and TG levels
TABLE 3 TC and TG levels following administration of ob/ob mice
Note:*p is less than 0.05 compared with the vehicle control group
As can be seen from tables 2 and 3, the differences between the levels of serum TC and TG in ob/ob mice of each dose group before administration and the vehicle control group are significant (P > 0.05).
After the administration (4 weeks), the serum TC and TG levels of the ob/ob mouse in the piperaquine phosphate high-dose group are obviously reduced, and compared with a solvent control group, the differences have significance (P is less than 0.05), so that the piperaquine phosphate high-dose group is equivalent to the clinically used dose and has better effect of reducing the serum TC and TG levels of the ob/ob mouse.
2.2.4 systematic Caesarean
The appearance and the nutritional status of the whole body of the mouse, the luster, the density and the absence of hair removal of the quilt are observed by naked eyes; whether the skin has rash, hemorrhage, wound, scar, whether the eye, ear, mouth, nose, anus and external genitalia have secretion, excrement, exudate and mucosal hemorrhage, whether the body has swelling, fracture and the like; the presence or absence of abnormalities in each tissue and organ was visually observed.
According to the observation that the administration is finished, the mice of each dose group are bright and dense in hair without depilation. The gross morphology observation shows that no obvious abnormality is found in the gross observation of the examined tissue and organ.
In conclusion, the piperaquine phosphate has the effects of obviously reducing the TC and TG levels of serum, has obvious lipid-lowering effect, can obviously reduce weight, has no obvious toxic or side effect, can be used for further showing that the piperaquine phosphate has a good treatment effect on hyperlipidemia, can be applied to the preparation of the medicament for treating the hyperlipidemia, and expands the application range of the piperaquine phosphate.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (8)
1. Application of piperaquine phosphate in preparing medicine for treating hyperlipemia is provided.
2. The use according to claim 1, wherein the hyperlipidemia is dyslipidemia due to elevation of triglycerides.
3. The use according to claim 1, wherein the hyperlipidemia is dyslipidemia due to elevated total cholesterol.
4. The use according to claim 1, wherein the hyperlipidemia is dyslipidemia with elevated triglycerides and total cholesterol.
5. The use according to claim 1, wherein the medicament is a solid, semi-solid or liquid formulation.
6. The use of claim 5, wherein the solid preparation is any one of a tablet, a granule or a powder injection.
7. The use of claim 5, wherein when the medicament is in a liquid formulation, the concentration of piperaquine phosphate in the medicament is 1.88 mg-mL-1The above.
8. The use of claim 7, wherein when the medicament is a liquid formulation, the concentration of piperaquine phosphate in the medicament is 1.88 mg-mL-1-7.52mg·mL-1。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811395108.XA CN109172578B (en) | 2018-11-21 | 2018-11-21 | Application of piperaquine phosphate in preparing medicine for treating lipid metabolism disorder and hyperlipidemia |
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