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.

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.

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

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.

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.

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.

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

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.