CN114832111A - Pharmaceutical composition for preventing and/or treating hypertension - Google Patents
Pharmaceutical composition for preventing and/or treating hypertension Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition for preventing and treating hypertension, and belongs to the field of medicines. The active ingredients of the pharmaceutical composition comprise ginkgo terpene lactones and angiotensin converting enzyme inhibitor and/or angiotensin II receptor blocker. The invention also discloses application of the pharmaceutical composition in preparing a medicament for treating and preventing hypertension. The active ingredients of the pharmaceutical composition disclosed by the invention, namely the ginkgolide, the angiotensin converting enzyme inhibitor and the angiotensin II receptor blocker, have good synergistic effect, and can be used for preventing and treating hypertension, especially simple diastolic hypertension or systolic-diastolic hypertension.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition containing ginkgolide and a renin-angiotensin system inhibitor, and pharmaceutical application and combined application of the pharmaceutical composition.
Background
Hypertension is a common chronic disease, is also the most main risk factor of cardiovascular and cerebrovascular diseases, is characterized by the increase of systolic pressure and/or diastolic pressure (the systolic pressure SBP is more than or equal to 140mmHg, the diastolic pressure DBP is more than or equal to 90mmHg), and is a group of clinical symptoms which can be accompanied with the functional damage of organs such as heart, brain, kidney and the like.
Hypertension is divided into three subtypes, including Isolated Systolic Hypertension (ISH): SBP is more than or equal to 140mmHg, and DBP is less than 90 mmHg; isolated Diastolic Hypertension (IDH): SBP is less than 140mmHg and DBP is more than or equal to 90 mmHg; systolic-diastolic two-phase hypertension: SBP is more than or equal to 140mmHg and DBP is more than or equal to 90 mmHg. Franklin et al showed that elevated diastolic blood pressure is the strongest risk factor for coronary heart disease in people under 50 years of age.
The result of a cooperative research on the stroke of east and coronary heart disease brought into 12 million China and Japanese shows that: people with a DBP > 110mmHg are 13 times more at risk of stroke than people with a DBP < 80mmHg, with a DBP reduction of 5mmHg, a 46% reduction in the incidence of hemorrhagic stroke and a 39% reduction in the incidence of ischemic stroke (ref: Eastern stoke and coronary heart disease social research group. blood pressure, cholestol, and stroke in Eastern Asia [ J ]. Lancet, 1998, 352 (9143): 1801-7).
Another prospective observation study, including 42 million, demonstrated: DBP has a clear linear correlation with stroke, even if the DBP is in a normal range, the numerical value of the DBP has a clear positive correlation with the stroke, the stroke incidence rate of the population with the DBP of 90mmHg is obviously higher than that of the population with the DBP of 70mmHg, the stroke incidence rate is increased by 46 percent and the coronary heart disease incidence rate is increased by 19 percent when the DBP is increased by 7.5 mmHg. It can be seen that the harm caused by IDH is not small (ref: Bots ML, Witteman JC, Hofman A, et al. Low Diascolic image compression and adhesion in detail subjects. the rotterdam study [ J ]. Arch Intren Med, 1996, 156(8): 843-8).
However, the high diastolic pressure of hypertension is a difficult problem in clinical treatment. Generally, for patients with diastolic blood pressure below 95mmHg, non-drug treatment may be used, primarily to improve lifestyle, including relaxation of mood, maintaining a pleasant mood; the daily work and rest rule, attention and rest are combined; the diet should be light; moderate movement is necessary. If the above-mentioned contents can be made, it is possible to regulate the function of autonomic nerves, reduce sympathetic excitability, improve vascular responsiveness, and promote peripheral vasodilation to lower blood pressure, particularly diastolic blood pressure. For patients with diastolic blood pressure greater than 95mmHg, especially those already presenting symptoms of hypertension, medication should be initiated. However, there is no unified opinion about the treatment of diastolic hypertension and no special medicine for lowering diastolic pressure. Most drug trials for treating diastolic hypertension intervene with only one drug (or one regimen) (ref: Pu Piao et al. diastolic hypertension. Zhonghua J. hypertension. 2014 7: 686 689, vol. 22, 7).
In view of the above, there is a need to develop or explore drugs or pharmaceutical compositions for lowering diastolic pressure.
Antihypertensive drugs are drugs that lower blood pressure and alleviate target organ damage, and are classified into 5 classes according to the mechanism of action, namely diuretic antihypertensive drugs, sympathetic inhibitory drugs, renin-angiotensin system inhibitory drugs, calcium antagonists, and vasodilators. The inhibitor of renin-angiotensin system can inhibit ACE activity, reduce ATII production, dilate blood vessel, relieve or reverse cardiovascular constitution, and exert its effect of effectively reducing blood pressure.
Inhibitors of the renin-angiotensin system include 3 classes: (1) angiotensin Converting Enzyme Inhibitor (ACEI): such as perindopril (long acting), captopril (short acting), etc. (2) Angiotensin ii receptor blockers: such as losartan, candesartan, and the like. (3) Renin inhibitors: such as remicade, and the like. Among them, angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers are the most commonly used hypotensive drugs at present, but these two hypotensive drugs have good effect on systolic blood pressure and limited effect on diastolic blood pressure.
Recent researches show that the main active ingredients in the ginkgo leaves are flavonoid compounds and ginkgo terpene lactones. The ginkgetin includes flavonol glycosides, biflavonoids, and catechin. Ginkgolides and bilobalide are collectively referred to as ginkgolides. The bilobalide comprises A, B, C, D, J, M, K, L, N, P, Q. The results of the study show that ginkgolides are diterpene lactones with a cage-like skeleton, which contains 6 oxygen-rich five-membered rings (including one spiro [4.4] -nonane, one tetrahydrofuran ring and three lactone rings), 10-12 stereocenters and a characteristic tert-butyl group. The isolated bilobalide differs in structure only in the number and position of hydroxyl groups: the bilobalide A, B, C, M is distinguished by whether the carbon at the 1, 3 and 7 positions of the molecular skeleton has a hydroxyl functional group; lactone L, K and N are obtained by removing one molecule of water from bilobalide A, B, C to obtain alkene; the structural difference between the lactone P, Q and the molecule is that the tert-butyl position is hydroxylated, and the ginkgolide compound is a novel ginkgolide compound. In addition to ginkgolides, in 1971 Major, weiges and Nakanishi et al have identified the structure of bilobalide, a compound with a similar configuration to ginkgolides, which likewise contains three lactone rings and a tert-butyl group, but has only one all-carbon ring, belonging to the sesquiterpene lactones.
The presently reported ginkgolides have the functions of antianaphylaxis, anti-inflammation, antishock, protection against ischemic injury, protection against organ transplant rejection and the like (the pharmacological action research of the ginkgolides is advanced, No. 22 and No. 3 of 1995). Xujiang Ping et al reported that ginkgolides could reduce the cerebral vascular resistance of anesthetized dogs and increase cerebral blood flow, but did not affect heart rate and blood pressure (Xujiang Ping et al. ginkgolides had an effect on cerebral blood flow of dogs. Proc. in the. Proc. of the integration of Chinese and Western medicine. 2005-01-15).
Disclosure of Invention
In order to solve the technical problems, the invention provides a pharmaceutical composition for preventing and/or treating hypertension, which comprises ginkgolide and a renin-angiotensin system inhibitor, a medical application thereof and a combined application of the ginkgolide and the renin-angiotensin system inhibitor.
The technical scheme adopted by the invention for solving the technical problems is as follows:
in one aspect, the present invention provides a pharmaceutical composition comprising a ginkgolide and an inhibitor of the renin-angiotensin system which is an angiotensin converting enzyme inhibitor and/or an angiotensin ii receptor blocker.
The ginkgolide extraction and preparation process is reported more, and can be directly prepared by referring to the methods reported in the prior documents such as ZL200610103626.0 or ZL200610103625.6, or can be prepared by combining ginkgolide monomeric compounds, or can be prepared by directly purchasing a commercially available ginkgolide injection.
The renin angiotensin converting enzyme inhibitor is selected from one or more of benazepril, perindopril, fosinopril, captopril, ramipril and cilazapril; the angiotensin II receptor blocker is selected from one or more of losartan, olmesartan medoxomil, valsartan, candesartan cilexetil, eprosartan cilexetil and irbesartan.
Preferably, the weight ratio of the ginkgolide to the renin angiotensin converting enzyme inhibitor is as follows: (5-25): (1-8) W/W; preferably, the weight ratio of the ginkgolide to the angiotensin II receptor blocker is as follows: (2-12): (1-4) W/W.
More preferably, the weight ratio of the ginkgolide to the renin angiotensin converting enzyme inhibitor is as follows: (5-25): (2-8) W/W, preferably, (8-25): (2-1) W/W, more preferably, (5-15): (1-8) W/W; the weight ratio of the ginkgolide to the angiotensin II receptor blocker is as follows: (2-12): (1-2) W/W, preferably (2-12): 1W/W.
More preferably, the angiotensin converting enzyme inhibitor is captopril, and the weight ratio of the ginkgolide to the captopril is as follows: (5-15): (2-8) W/W; or the angiotensin converting enzyme inhibitor is perindopril, and the weight ratio of the ginkgolide to the perindopril is as follows: (12.25-25) to (2-4) W/W; or the angiotensin converting enzyme inhibitor is preferably fosinopril, and the weight ratio of the ginkgolide to the fosinopril is as follows: (4-8): (1-4) W/W.
More preferably, the angiotensin ii receptor blocker is candesartan cilexetil, and the weight ratio of the ginkgolide to the candesartan cilexetil is as follows: (6-12): (1-2) W/W; or the angiotensin II receptor blocker is olmesartan medoxomil, and the weight ratio of the ginkgolide to the olmesartan medoxomil is as follows: (2-4): 1W/W.
Further, the ginkgolide comprises ginkgolide and bilobalide, wherein the weight ratio of ginkgolide to bilobalide is as follows: ginkgo diterpene lactone: bilobalide is (5-60): (5-65) W/W.
In another aspect, the present invention provides the use of the above pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of hypertension.
Preferably, the hypertension is isolated diastolic hypertension or systolic-diastolic hypertension.
In still another aspect, the present invention provides the use of the active ingredients of the above pharmaceutical composition, ginkgo terpene lactones and renin-angiotensin system inhibitors, in the preparation of a combination for the treatment and/or prevention of hypertension.
Preferably, the hypertension is isolated diastolic hypertension or systolic-diastolic hypertension.
The invention has the beneficial technical effects that:
the ginkgolide, the renin angiotensin converting enzyme inhibitor and the angiotensin II receptor blocker in the pharmaceutical composition disclosed by the invention have good synergistic effect, and the two are applied together or combined, so that the clinical blood pressure reducing effect is good, the blood pressure reduction is more stable, and the pharmaceutical composition can be used for preventing and/or treating hypertension, especially refractory diastolic hypertension.
1) The animal test results show that: the pharmaceutical composition consisting of ginkgolide and renin angiotensin converting enzyme inhibitor captopril disclosed by the invention has better antihypertensive effect on systolic pressure and diastolic pressure of SHR rats than that of the single application of the active ingredients, can be used for preventing and/or treating hypertension, and particularly can be used for preventing and/or treating simple diastolic hypertension or systolic-diastolic double-phase hypertension.
2) Clinical observations suggest: the ginkgolide and an angiotensin converting enzyme inhibitor and/or an angiotensin II receptor blocker are combined or co-administered, so that the blood pressure is reduced stably, the diastolic pressure reducing effect is obvious, and the treatment effect on refractory diastolic hypertension is good.
Detailed Description
The ginkgolide monomer compound can be obtained by purchasing products sold in the market or prepared by separating and purifying by the existing method. Through inspection, all monomer compounds are consistent with the structures of corresponding reference substances, and the purity of the monomer compounds is more than 98% through HPLC detection.
The ginkgolide of the invention can be one or more of ginkgolide A, B, C, D, J, M, K, L, N, P, Q.
When the ginkgolide disclosed by the invention comprises more than two compositions, the ginkgolide can be prepared by combining corresponding monomer compounds.
The ginkgolide containing ginkgolide A, B, C and bilobalide can be prepared by directly purchasing a commercially available ginkgolide injection, or directly by a method of ZL200610103626.0 or ZL200610103625.6, or can be prepared by combining monomer compounds.
The invention selects captopril, perindopril and fosinopril as representative medicaments of the angiotensin converting enzyme inhibitor to carry out animal pharmacodynamic tests and clinical observation medication, and carries out long-term clinical observation on various angiotensin converting enzyme inhibitors such as benazepril, ramipril, cilazapril and the like.
The invention selects candesartan cilexetil and olmesartan medoxomil as the representative drugs of angiotensin II receptor blockers to carry out clinical observation and medication, and carries out long-term clinical observation on various angiotensin II receptor blockers such as losartan, valsartan, eprosartan cilexetil and irbesartan.
Captopril (captopril) is an orally active angiotensin converting enzyme inhibitor with the chemical name: 1- [ (2S) 2-methyl-3-mercapto-1-oxypropyl ] -L-proline, of the formula C9H13NO 3S. Captopril is collected in the second part of the 2010 edition of the Chinese pharmacopoeia, is one of the first choice drugs for renal parenchyma, renal vascular hypertension and congestive heart failure, and is widely used at home and abroad.
Perindopril (Perindopril) is a third-generation angiotensin converting enzyme inhibitor, has the greatest blood pressure reduction effect after 6 hours of taking, has long action duration, can dilate large and small arteries, reduces blood volume, reduces systemic vascular resistance, left ventricular filling pressure and pulmonary capillary wedge pressure, increases cardiac output and stroke volume, increases cardiac index without changing heart rate, improves exercise tolerance of patients, reduces left ventricular cardiac hypertrophy, and improves hemodynamics.
Fosinopril (Fosinopril), the first inhibitor of angiotensin converting enzyme containing phosphorus, has effects in reducing vascular resistance, reducing aldosterone secretion, increasing plasma renin, dilating artery and vein, reducing peripheral vascular resistance (afterload) and pulmonary capillary wedge pressure (preload), and improving cardiac output.
Candesartan (Candesartan Cilexetil) is an angiotensin ii AT1 receptor antagonist that antagonizes the vasoconstrictive effects of angiotensin ii by binding to vascular smooth muscle AT1 receptors, thereby reducing peripheral vascular resistance. Tests performed on hypertensive patients showed that: the product can increase the activity of plasma renin, the concentration of angiotensin I and the concentration of angiotensin II after being taken by patients for many times; the product is continuously administered for 1 time every day at 2-8 mg, so that systolic pressure and diastolic pressure are reduced, left ventricular cardiac muscle weight and peripheral vascular resistance are reduced, and no obvious influence is caused on cardiac output, ejection fraction, renal vascular resistance, renal blood flow and glomerular filtration rate; has no influence on cerebral blood flow for patients with primary hypertension with cerebrovascular disorder.
Olmesartan Medoxomi I has a better curative effect than losartan and other early-appearing sartan medicaments, is an ideal antihypertensive medicament for treating hypertension I, has a better curative effect on various types of hypertension, and has the outstanding characteristic of longer half-life period, and can effectively control blood pressure in one day, so the Olmesartan Medoxomi I is more convenient to take. Compared with other angiotensin II receptor antagonist drugs, the antihypertensive drug has the obvious advantages of small dosage, quick response, stronger and durable antihypertensive effect, low incidence of adverse reaction and the like. Olmesartan has good effects on arteriosclerosis, cardiac hypertrophy, heart failure, diabetes, nephropathy and the like.
The composition of the ginkgolide of the present invention may be, but is not limited to:
ginkgo terpene lactones 1: the weight ratio of the ginkgoditerpene lactone to the bilobalide is 60: 5. Wherein the bilobalide comprises bilobalide A, B, C at a weight ratio of 10: 5: 3.
Ginkgo terpene lactones 2: the weight ratio of the ginkgoditerpene lactone to the bilobalide is 5: 65. Wherein the ginkgolide is composed of ginkgolide A, B, C, and the weight ratio of the ginkgolide to the ginkgolide is 45:5: 35.
Ginkgo terpene lactones 3: the weight ratio of the ginkgoditerpene lactone to the bilobalide is 5: 10. Wherein the ginkgolide is composed of ginkgolide A, B, C, and the weight ratio of the ginkgolide to the ginkgolide is 10:40: 35.
Ginkgo terpene lactones 4: the weight ratio of the ginkgoditerpene lactone to the bilobalide is 15: 5. Wherein the bilobalide comprises bilobalide A, B, C at a weight ratio of 30: 10.
Ginkgolide 5: the weight ratio of the ginkgolide to the bilobalide is 60: 5. Wherein the ginkgoditerpene lactone is ginkgolide B.
The ginkgolide monomer compounds can be obtained by purchasing commercially available products or prepared by separating and purifying by the existing method.
The Angiotensin Converting Enzyme Inhibitor (ACEI) comprises an angiotensin converting enzyme inhibitor and an active metabolite or a pharmaceutically acceptable salt thereof. Benazepril, perindopril, fosinopril, captopril, ramipril, cilazapril and active metabolites thereof or pharmaceutically acceptable salts thereof are preferred.
The angiotensin II receptor blocker comprises an angiotensin II receptor blocker and an active metabolite or a pharmaceutically acceptable salt thereof. Preferred are losartan, olmesartan medoxomil, valsartan, candesartan cilexetil, eprosartan, irbesartan and active metabolites thereof or pharmaceutically acceptable salts thereof.
The smoothness index is a new index reflecting the stability of the medicine for reducing the blood pressure, and the higher the SI value is, the smaller the blood pressure fluctuation is, the more stable the blood pressure reduction is (the reference document: Shenqiang, Wenwjun. Valsartan/Hydroxyazin combination treatment primary old people hypertension clinical curative effect observation. clinical medicine 2003, 23 (12): 49).
Smoothing Index (SI) calculation: the mean of the hourly blood pressure changes in 24h, daytime and nighttime were divided by the corresponding standard deviation.
The dosage form of the pharmaceutical composition of the invention includes, but is not limited to, common tablets, double-layer tablets, multilayer tablets, sustained-release tablets, single-chamber controlled-release tablets, double-chamber controlled-release tablets, micro-emulsion controlled-release tablets, sublingual tablets, orally disintegrating tablets, dispersible tablets, enteric-coated tablets, granules, pills, enteric-coated capsules, delayed-release tablets, timed/positioned release tablets, common capsules, sustained-release capsules, controlled-release capsules, capsules containing pellets or small tablets, pH-dependent capsules containing pellets or small tablets, oral liquid, films or patches.
The pharmaceutical composition can be a compound preparation and can also be a preparation suitable for combined medication.
The pharmaceutical compositions of the present invention may alternatively be used in a "combination kit".
The "combination kit" may be a box-shaped container containing the pharmaceutical composition in various dosage forms, and further may contain instructions for administration. The combined medicine box is more suitable for individual medicine.
It is understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., test examples) may be combined with each other to constitute new or preferred technical solutions. To those skilled in the art, in light of the teachings of the present invention, many changes can be made in the specific embodiments and applications illustrated herein without departing from the scope of the invention. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The advantageous effects of the present invention will be specifically described below by way of test examples and clinical observation examples.
Test example the hypotensive effect of a composition comprising ginkgo terpene lactones and captopril on hypertensive rats
1. Experimental Material
1.1 Experimental animals: WKY rats (male, normal rats); SHR rats (male, hypertensive rats). All provided by Weitonglihua.
1.2 Experimental drugs: ginkgolide 1 to ginkgolide 5 (the composition is shown in the detailed description, and ginkgolide A, ginkgolide B, ginkgolide C and bilobalide are provided by pharmaceutical corporation of Kyokuyu pharmaceutical Co., Ltd. and the content is 5mg/mL based on the content of ginkgolide), perindopril (Cantonese Pididi pharmaceutical industry) and captopril (Changzhou pharmaceutical industry).
1.3 Experimental instruments: BP-6A full-automatic noninvasive blood pressure tester (Chengdutai alliance science and technology Co., Ltd.).
1.4 Experimental methods: the rats in each experimental group are continuously orally administrated with the corresponding medicine for 7 days (administration is carried out 1 time per day), the tail artery systolic pressure and the diastolic pressure of the rats before administration and 7 days after continuous administration are measured by a tail artery pressure measurement method, an average value is taken as a blood pressure value, the blood pressure change value of each group is calculated, and the systolic pressure and the diastolic pressure are simultaneously compared to evaluate the blood pressure reducing effect of the medicine, wherein the blood pressure change value is the blood pressure before administration-the blood pressure after administration.
1.5 Experimental groups
The following drugs and drug combinations were prepared as solutions in 1% DMSO as solvent, at a volume of 10mL/kg rat body weight. Negative control and blank control groups were gavaged with vehicle (1% DMSO).
Negative control group: WKY rats were given only 1% DMSO in a volume calculated as 10mL/kg rat weight.
Blank control group: SHR rats were given only 1% DMSO in a volume calculated as 10mL/kg rat weight.
Captopril control group: SHR rat, captopril 8 mg/kg/d.
Composition 1: ginkgolide 15 mg/kg/d.
Composition 2: 15 mg/kg/d of ginkgolide and 8mg/kg/d of captopril, and the ratio is 5: 8.
Composition 3: ginkgolide 230 mg/kg/d.
Composition 4: 230 mg/kg/d of ginkgolide and 8mg/kg/d of captopril in a ratio of 15: 4.
Composition 5: the ginkgolide content is 320 mg/kg/d.
Composition 6: 320 mg/kg/d of ginkgolide and 8mg/kg/d of captopril in a ratio of 5: 2.
Composition 7: the ginkgolide content is 410 mg/kg/d.
Composition 8: 410 mg/kg/d of ginkgolide and 8mg/kg/d of captopril in a ratio of 5: 4.
Composition 9: ginkgolide 55 mg/kg/d.
Composition 10: 55 mg/kg/d of ginkgolide, 8mg/kg/d of captopril and a ratio of 5: 8.
1.6 statistical treatment
The analysis is carried out by adopting SPSS15.0 statistical software, and the data adopt the mean value plus or minus standard deviation:
and (4) showing. Statistical analysis and processing were performed using the t-test with P < 0.05 as the criterion for significance of differences.
1.7 test results
TABLE 1 Effect of compositions on systolic blood pressure in SHR rats
When comparing the compositions 2, 4, 6, 8 and 10 with the captopril alone group, i.e. the captopril control group, and the compositions 1, 3, 5 and 7 with the ginkgolide alone, respectively, the reduction of the systolic blood pressure of rats after 7 days of the administration of the ginkgolide and captopril simultaneously was found to be greater than the effect of the two administration alone.
The test results show that: ginkgo terpene lactones: when the weight ratio of captopril is (5-15) to (2-8), the captopril has better effect of reducing systolic pressure than that of the ginkgolide or captopril which is independently applied, and the captopril and the ginkgolide have a synergistic effect. The relative large systolic blood pressure change values before and after the administration of drug group 4, drug group 6 and drug group 8 indicate that the ratio of ginkgolides: when the weight ratio of captopril is (5-15) to (2-4), the effect of contracting and reducing the pressure is better.
TABLE 2 Effect of the compositions on the diastolic pressure in SHR rats
When the compositions 2, 4, 6, 8 and 10 were compared with the captopril alone, i.e., the captopril control group, and the ginkgolides alone, i.e., the compositions 1, 3, 5 and 7, respectively, it was found that the reduction of the diastolic blood pressure of rats was greater than that of the two compositions when they were administered alone 7 days after the administration of the ginkgolides and captopril simultaneously.
The above test results illustrate that: in the case of ginkgo terpene lactones: when the weight ratio of captopril is (5-15): (2-8), the antihypertensive drug has better diastolic pressure lowering effect than that obtained by singly applying ginkgolide or captopril, and the two have synergistic effect. The relative maximum diastolic pressure change values before and after administration of drug group 4, 6, and 8 indicated that ginkgolides: when the weight ratio of captopril is (5-15) to (2-4), the diastolic pressure lowering effect is better.
And (3) knotting:
when the composition consisting of the ginkgolide and the renin-angiotensin system inhibitor disclosed by the invention is applied, particularly the composition consisting of the ginkgolide and the renin angiotensin converting enzyme inhibitor captopril is obviously reduced in systolic pressure and diastolic pressure of an SHR rat compared with the composition which is singly applied by the ginkgolide or the captopril; the ginkgolide and the renin angiotensin converting enzyme inhibitor in the pharmaceutical composition disclosed by the invention have good synergistic effect, so that the pharmaceutical composition has good antihypertensive effect and can be used for preventing and/or treating hypertension.
The diastolic blood pressure of SHR rats is significantly reduced by administering the composition consisting of ginkgolide and an inhibitor of the renin-angiotensin system, especially the composition consisting of ginkgolide and the renin angiotensin converting enzyme inhibitor captopril, as disclosed in the present invention, compared to administration of ginkgolide or captopril alone. Therefore, the pharmaceutical composition disclosed by the invention can be particularly used for preventing and/or treating simple diastolic hypertension or systolic-diastolic hypertension.
Clinical efficacy Observation example 1
The inclusion criteria of cases were: according to the diagnostic standard that the essential hypertension accords with the Chinese hypertension prevention and treatment guideline of 2005, the systolic pressure is more than or equal to 140mmHg and the diastolic pressure is more than or equal to 95 mmHg; or the diastolic pressure is more than or equal to 95 mmHg. The medicine can be used for eliminating secondary hypertension, hypertension complicated with target organ damage, serious liver and kidney dysfunction, bilateral renal artery stenosis, gout, pregnant women, lactating women, allergic constitution or patients allergic to various medicines.
General data: 126 men and 54 women in 180 patients; the age was 40-58 years, with the mean (51. + -.1) years, and no treatment was given before the group. 180 patients were divided into 2 groups of 90 patients according to the random number table method. The clinical data of two groups of patients are compared, and the difference is not statistically significant (P is more than 0.05).
The treatment method comprises the following steps:
in the treatment group, oral administration of one tablet of Jatropha-Perindopril (Schuyagi pharmaceutical Co., Ltd., approved document: national Standard 5320H4300, commercial specification 4 mg/tablet) was performed in the morning. The ginkgolide injection (Chengdouyu, approval document: national standard Z20110035, 2 mL/piece of commercial specification, each piece containing 10mg of terpene lactone) is intravenously instilled, 5 pieces (10mL) are added once, the medicine is slowly added into 250mL of 0.9% sodium chloride injection for dilution before use, the intravenous drip is slowly instilled, 1 time a day, the dripping speed is strictly controlled during the use, and the dripping speed is not higher than 40-60 drops per minute. Treatment cycle, 14 days.
For the control group, perindopril in 4mg tablets were taken orally, one tablet per day, in the morning. Treatment cycle, 14 days.
Monitoring dynamic blood pressure: the dynamic blood pressure monitor is adopted to measure the dynamic blood pressure. And (3) measuring date: 08: 00-09: 00 at the current day to 08: 00-09: 00 at the 2 nd day. The daytime time is 06: 00-22: 00, and the nighttime time is 22: 00-06: 00. The daytime measurement interval time is 30min, the nighttime measurement interval time is 1h, and the effective measurement times are not less than 90% of the required measurement times of 24 hours.
The main observation indexes are as follows: before and after treatment, 24h mean systolic pressure and diastolic pressure, daytime mean systolic pressure and diastolic pressure, and nighttime mean systolic pressure and diastolic pressure.
Smoothing Index (SI) calculation: the mean of the hourly blood pressure changes in 24h, daytime and nighttime were divided by the corresponding standard deviation.
And (3) evaluating the curative effect: the hypertension curative effect is based on the clinical research guiding principle of the Chinese medicine. The effect is shown: the diastolic pressure is reduced by more than 10mmHg and is reduced to a normal range; diastolic blood pressure has not decreased to normal but to 20mmHg or more. The method has the following advantages: the diastolic blood pressure drops by less than 10mmHg, but to normal or by (10-19) mmHg but not within the normal range; or the systolic blood pressure drops by more than 30 mmHg. And (4) invalidation: the above standard is not met. Evaluation standard of blood pressure reduction stability: SI is more than 1.
And (4) observing results:
TABLE 3 comparison of the two groups of clinical effects
As shown by the clinical observations in table 3: the total effective rate of the treatment group is higher than that of the control group, and the difference of the data of the two groups has statistical significance (P is less than 0.05). The combination of the ginkgolide injection and the perindopril tablets has good effect of reducing blood pressure and is superior to the single perindopril tablet.
TABLE 4 two sets of blood pressure SI comparisons
As shown by the clinical observations in table 4: compared with perindopril tablets alone, the combination of the ginkgolide injection and the perindopril tablets has generally increased SI value, and the difference of the two groups of data has statistical significance (P is less than 0.05). The blood pressure fluctuation of the treatment group is small, and the blood pressure reduction is more stable.
Unless otherwise stated, the ginkgolides of clinical observation examples 2 to 4 are sustained-release agents containing pharmaceutically acceptable carriers and prepared by a conventional method in the field of pharmaceutical preparations (for example, refer to "pharmaceutical excipients are used in preparation" and "pharmacy").
Clinical efficacy Observation example 2
The inclusion criteria of cases were: according to the diagnostic standard that the essential hypertension meets the Chinese hypertension prevention and treatment guideline of 2005, the systolic pressure is less than 140mmHg and the diastolic pressure is more than or equal to 95 mmHg. The medicine can be used for eliminating secondary hypertension, hypertension complicated with target organ damage, serious liver and kidney dysfunction, bilateral renal artery stenosis, gout, pregnant women, lactating women, allergic constitution or patients allergic to various medicines.
General data: 57 men and 43 women out of 100 patients; the age was 35-41 years, with the mean (39. + -.1) years, and no treatment was given before the group. 50 patients were divided into 2 groups of 50 patients according to the random number table method. The clinical data of two groups of patients are compared, and the difference is not statistically significant (P is more than 0.05).
The treatment method comprises the following steps:
in the treatment group, fosinopril sodium tablets (Shanghai Shi Guibao pharmaceutical Co., Ltd., China, approved document: national drug Standard H19980197, commercial specification of 10 mg/tablet) were orally taken in the morning in 1/2 tablets per day. The ginkgolide 2 (the weight ratio of the ginkgolide to the bilobalide is 5: 65; and the ginkgolide consists of ginkgolide A, B, C, the weight ratio of the ginkgolide to the bilobalide is 45:5:35) composition is orally taken twice a day, and 20mg (calculated according to the content of the ginkgolide) is taken once. Treatment cycle, 14 days.
In the control group, fosinopril sodium tablets (Shanghai Shigui pharmaceutical Co., Ltd., China America, approval document: national drug Standard H19980197, commercial Specification 10 mg/tablet) were orally administered in 1/2 tablets per day in the morning. Treatment cycle, 14 days.
Monitoring dynamic blood pressure: the dynamic blood pressure monitor is adopted to measure the dynamic blood pressure. And (3) measuring date: 08: 00-09: 00 at the current day to 08: 00-09: 00 at the 2 nd day. The daytime time is 06: 00-22: 00, and the nighttime time is 22: 00-06: 00. The daytime measurement interval time is 30min, the nighttime measurement interval time is 1h, and the effective measurement times are not less than 90% of the required measurement times of 24 hours.
The main observation indexes are as follows: before and after treatment, 24h mean systolic pressure and diastolic pressure, daytime mean systolic pressure and diastolic pressure, and nighttime mean systolic pressure and diastolic pressure. Smoothing Index (SI) calculation: the mean of the hourly blood pressure changes in 24h, daytime and nighttime were divided by the corresponding standard deviation.
And (3) evaluating the curative effect: the hypertension curative effect is based on the clinical research guiding principle of the Chinese medicine. The effect is shown: the diastolic pressure is reduced by more than 10mmHg and is reduced to a normal range; diastolic blood pressure has not decreased to normal but to 20mmHg or more. The method has the following advantages: the diastolic blood pressure drops below 10mmHg, but to normal or to (10-19) mmHg but not within the normal range. And (4) invalidation: the above standard is not met. Evaluation standard of blood pressure reduction stability: SI is more than 1.
TABLE 5 comparison of the two groups of clinical effects
As shown by the clinical observations in table 5: the total effective rate of the treatment group is higher than that of the control group, and the difference of the data of the two groups has statistical significance (P is less than 0.05). The combination of the ginkgolide and the fosinopril sodium tablet has good diastolic blood pressure reducing effect and is superior to the fosinopril sodium tablet which is singly used.
TABLE 6 comparison of two blood pressures SI
As shown by the clinical observations in table 6: compared with fosinopril sodium tablets singly used, the ginkgolide composition and fosinopril sodium tablets are combined, the SI value is generally increased, and the difference of the two groups of data has statistical significance (P is less than 0.05). The blood pressure fluctuation of the treatment group is small, and the blood pressure reduction is more stable.
Clinical efficacy Observation example 3
The inclusion criteria of cases were: according to the diagnostic standard that the essential hypertension meets the Chinese hypertension prevention and treatment guideline of 2005, the systolic pressure is less than 140mmHg and the diastolic pressure is more than or equal to 95 mmHg. The medicine can be used for eliminating secondary hypertension, hypertension complicated with target organ damage, serious liver and kidney dysfunction, bilateral renal artery stenosis, gout, pregnant women, lactating women, allergic constitution or patients allergic to various medicines.
General data: 61 men and 39 women out of 100 patients; the age was 35-45 years, with the mean (40. + -.1) years, and no treatment was given before the group. 50 patients were divided into 2 groups of 50 patients according to the random number table method. The clinical data of two groups of patients are compared, and the difference is not statistically significant (P is more than 0.05).
The treatment method comprises the following steps:
in the treatment group, oral candesartan cilexetil tablets (Shanxi Huangcheng Xiangfu pharmaceutical Co., Ltd., approved document: national Standard H20080183, 10 mg/tablet of commercial specification) are taken in the morning of 1/2 tablets per day. Orally administering the composition of ginkgolide 3 (the weight ratio of ginkgolide to bilobalide is 5: 10. the ginkgolide is composed of ginkgolide A, B, C, the weight ratio of ginkgolide to bilobalide is 10:40:35) three times a day, 30mg (based on the content of ginkgolide) is taken once. Treatment cycle, 14 days.
In the control group, tablets of candesartan cilexetil (Shanxi Huangcheng Xiangfu pharmaceutical Co., Ltd., approved article No.: national Standard H20080183, commercial Specification 10 mg/tablet) were orally administered at 1/2 tablets per day in the morning. Treatment cycle, 14 days.
Monitoring dynamic blood pressure: the dynamic blood pressure monitor is adopted to measure the dynamic blood pressure. And (3) measuring date: 08: 00-09: 00 at the current day to 08: 00-09: 00 at the 2 nd day. The daytime time is 06: 00-22: 00, and the nighttime time is 22: 00-06: 00. The daytime measurement interval time is 30min, the nighttime measurement interval time is 1h, and the effective measurement times are not less than 90% of the required measurement times of 24 hours.
The main observation indexes are as follows: before and after treatment, 24h mean systolic pressure and diastolic pressure, daytime mean systolic pressure and diastolic pressure, and nighttime mean systolic pressure and diastolic pressure. Smoothing Index (SI) calculation: the mean of the hourly blood pressure changes in 24h, daytime and nighttime were divided by the corresponding standard deviation.
And (3) evaluating the curative effect: the hypertension curative effect is based on the clinical research guiding principle of the Chinese medicine. The effect is shown: the diastolic pressure is reduced by more than 10mmHg and is reduced to a normal range; diastolic blood pressure has not decreased to normal but to 20mmHg or more. The method has the following advantages: the diastolic blood pressure drops below 10mmHg, but to normal or to (10-19) mmHg but not within the normal range. And (4) invalidation: the above standard is not met. Evaluation standard of blood pressure reduction stability: SI is more than 1.
TABLE 7 comparison of the clinical effects of the two groups
As shown by the clinical observations in table 7: the total effective rate of the treatment group is higher than that of the control group, and the difference of the data of the two groups has statistical significance (P is less than 0.05). The combined use of the ginkgolide and the candesartan cilexetil tablet has good diastolic blood pressure reducing effect and is superior to the candesartan cilexetil tablet used alone.
TABLE 8 two sets of blood pressure SI comparisons
As shown by the clinical observations in table 8: compared with the candesartan cilexetil tablet used alone, the ginkgolide composition and the candesartan cilexetil tablet used together have the advantages that the SI value is generally increased, and the difference of two groups of data has statistical significance (P is less than 0.05). The blood pressure fluctuation of the treatment group is small, and the blood pressure reduction is more stable.
Clinical efficacy Observation example 4
The inclusion criteria of cases were: according to the diagnostic standard that the essential hypertension meets the Chinese hypertension prevention and treatment guideline of 2005, the systolic pressure is more than or equal to 140mmHg and the diastolic pressure is more than or equal to 95 mmHg. The medicine can be used for eliminating secondary hypertension, hypertension complicated with target organ damage, serious liver and kidney dysfunction, bilateral renal artery stenosis, gout, pregnant women, lactating women, allergic constitution or patients with various drug allergies.
General data: 119 men and 61 women in 180 patients; the age was 45-65 years, the mean (59. + -. 1) years, and no treatment was given before the group. 180 patients were divided into 2 groups of 90 patients according to the random number table method. The clinical data of two groups of patients are compared, and the difference is not statistically significant (P is more than 0.05).
The treatment method comprises the following steps:
in the treatment group, olmesartan medoxomil tablets (Aometan) (first Sanjia Co., Ltd., approved article No.: national drug Standard YBH06992006, product specification 20 mg/tablet) were orally taken 1 tablet per day in the morning. Orally administering 20mg (based on the ginkgolide content) of the ginkgolide 4 composition (the weight ratio of ginkgolide to bilobalide is 15:5, wherein the ginkgolide is composed of ginkgolide A, B, C, and the weight ratio of the ginkgolide to the bilobalide is 30:10:10) twice a day. Treatment cycle, 14 days.
In the control group, 20mg of olmesartan medoxomil tablet (aotan) was orally taken one tablet per day in the morning. Treatment cycle, 14 days.
Monitoring dynamic blood pressure: the dynamic blood pressure monitor is adopted to measure the dynamic blood pressure. And (3) measuring date: 08: 00-09: 00 at the current day to 08: 00-09: 00 at the 2 nd day. The daytime time is 06: 00-22: 00, and the nighttime time is 22: 00-06: 00. The daytime measurement interval time is 30min, the nighttime measurement interval time is 1h, and the effective measurement times are not less than 90% of the required measurement times of 24 hours.
The main observation indexes are as follows: before and after treatment, 24h mean systolic pressure and diastolic pressure, daytime mean systolic pressure and diastolic pressure, and nighttime mean systolic pressure and diastolic pressure. Smoothing Index (SI) calculation: the mean of hourly blood pressure changes over 24h, day and night were divided by the corresponding standard deviation.
And (3) evaluating the curative effect: the hypertension curative effect is based on the clinical research guiding principle of the Chinese medicine. The effect is shown: the diastolic pressure is reduced by more than 10mmHg and is reduced to a normal range; diastolic blood pressure has not decreased to normal but to 20mmHg or more. The method has the following advantages: the diastolic blood pressure drops by less than 10mmHg, but to normal or by (10-19) mmHg but not within the normal range; or the systolic blood pressure drops by more than 30 mmHg. And (4) invalidation: the above standard is not met. Evaluation standard of blood pressure reduction stability: SI is more than 1.
TABLE 9 comparison of the two groups of clinical effects
As shown by the clinical observations in table 9: the total effect of the treatment group is higher than that of the control group, and the difference of the data of the two groups has statistical significance (P is less than 0.05). The combination of the ginkgolide composition and the olmesartan medoxomil tablet has excellent antihypertensive effect, and is superior to the olmesartan medoxomil tablet singly.
TABLE 10 two sets of blood pressure SI comparisons
As shown by the clinical observations in table 10: compared with the olmesartan medoxomil tablet singly used, the ginkgolide composition and the olmesartan medoxomil tablet are combined, the SI value is generally increased, and the difference of two groups of data has statistical significance (P is less than 0.05). The blood pressure fluctuation of the treatment group is small, and the blood pressure reduction is more stable.
On the basis of the above clinical observation example, the inventors further observed and found that: the ginkgo terpene lactones are combined with one or more of other renin angiotensin converting enzyme inhibitors such as benazepril, ramipril and cilazapril, so that the blood pressure fluctuation is small, the blood pressure is reduced stably, and the clinical diastolic blood pressure reducing effect is good; the ginkgolide is combined with other angiotensin II receptor blockers such as losartan, valsartan, eprosartan and irbesartan, so that the ginkgolide has a stable blood pressure reducing effect, and a good treatment effect on refractory diastolic hypertension is clinically found.
And (4) conclusion:
the ginkgolide and the angiotensin converting enzyme inhibitor and/or the angiotensin II receptor blocker in the pharmaceutical composition disclosed by the invention have good synergistic effect, and the two are applied together or combined, so that the clinical blood pressure reducing effect is good, the blood pressure reduction is more stable, and the pharmaceutical composition has positive clinical guidance and reference significance for preventing and/or treating hypertension. The inventor is excited, and the clinical observation shows that the two medicines are applied together or combined, the effect of reducing diastolic blood pressure is obvious, and the treatment effect on refractory diastolic hypertension is good.
Claims (9)
1. A pharmaceutical composition for preventing and/or treating hypertension, which is characterized in that: comprises ginkgo terpene lactones and an inhibitor of the renin-angiotensin system, said inhibitor of the renin-angiotensin system being an angiotensin converting enzyme inhibitor and/or an angiotensin II receptor blocker;
the renin angiotensin converting enzyme inhibitor is selected from one or more of benazepril, perindopril, fosinopril, captopril, ramipril and cilazapril;
the angiotensin II receptor blocker is selected from one or more of losartan, olmesartan medoxomil, valsartan, candesartan cilexetil, eprosartan cilexetil and irbesartan.
2. The pharmaceutical composition of claim 1, wherein the weight ratio of the ginkgolide to the renin angiotensin converting enzyme inhibitor is: (5-25): (1-8) W/W; the weight ratio of the ginkgolide to the angiotensin II receptor blocker is as follows: (2-12): (1-4) W/W.
3. The pharmaceutical composition of claim 2, wherein the weight ratio of the ginkgolide to the renin angiotensin converting enzyme inhibitor is: (5-25): (2-8) W/W, preferably (8-25): (2-1) W/W, and more preferably (5-15): (1-8) W/W; the weight ratio of the ginkgolide to the angiotensin II receptor blocker is as follows: (2-12): (1-2) W/W, preferably (2-12): 1W/W.
4. The pharmaceutical composition of claim 3, wherein the angiotensin converting enzyme inhibitor is captopril, and the weight ratio of the ginkgolide to the captopril is: (5-15): (2-8) W/W; or the angiotensin converting enzyme inhibitor is perindopril, and the weight ratio of the ginkgolide to the perindopril is as follows: (12.25-25) to (2-4) W/W; or the angiotensin converting enzyme inhibitor is preferably fosinopril, and the weight ratio of the ginkgolide to the fosinopril is as follows: (4-8): (1-4) W/W.
5. The pharmaceutical composition of claim 3, wherein the angiotensin II receptor blocker is candesartan cilexetil, and the weight ratio of ginkgolide to candesartan cilexetil is: (6-12): (1-2) W/W; or the angiotensin II receptor blocker is olmesartan medoxomil, and the weight ratio of the ginkgolide to the olmesartan medoxomil is as follows: (2-4): 1W/W.
6. The pharmaceutical composition of any one of claims 1 to 5, wherein the ginkgolides comprise ginkgoditerpenes and bilobalide, wherein the weight ratio of the ginkgolides to the bilobalide is as follows: ginkgo diterpene lactone: bilobalide is (5-60): (5-65) W/W.
7. Use of the pharmaceutical composition of any one of claims 1 to 6 for the preparation of a medicament for the treatment and/or prevention of hypertension.
8. Use according to claim 7, wherein the hypertension is isolated diastolic hypertension or systolic-diastolic hypertension.
9. Use of the active ingredients of the pharmaceutical composition according to any one of claims 1 to 6, namely ginkgolides and inhibitors of the renin-angiotensin system for the preparation of a combination for the treatment and/or prevention of hypertension; preferably, the hypertension is isolated diastolic hypertension or systolic-diastolic hypertension.
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