Compound antihypertensive medicinal composition and application thereof
阅读说明：本技术 一种复方降压药物组合物及其应用 (Compound antihypertensive medicinal composition and application thereof ) 是由 徐希平 陈光亮 白洁 于多 李锦良 田敏卿 陈亚宁 于 2020-05-08 设计创作，主要内容包括：本发明提供一种治疗难治性高血压的药物组合物,该药物组合物由2.5～10mg氨氯地平、1～2.5mg吲达帕胺和2.5～10mg阿米洛利组成。本发明的药物组合物针对难治性高血压患者,尤其是低肾素难治性高血压患者提供一种有效的降压药物。本发明全新的复方降压制剂组方合理,在一定比例范围内不仅起到协同降压效果,还减少了药物的不良反应,提高了患者的顺应性,易于被患者接受。(The invention provides a pharmaceutical composition for treating refractory hypertension, which consists of 2.5-10 mg of amlodipine, 1-2.5 mg of indapamide and 2.5-10 mg of amiloride. The pharmaceutical composition provided by the invention provides an effective antihypertensive drug for patients with refractory hypertension, especially patients with low renin refractory hypertension. The brand new compound antihypertensive preparation has reasonable formula, not only has synergistic antihypertensive effect in a certain proportion range, but also reduces adverse reaction of the medicine, improves the compliance of patients and is easy to be accepted by the patients.)
1. A pharmaceutical composition for treating refractory hypertension comprises the following components:
(1) 2.5-10 mg amlodipine
(2) 1-2.5 mg of indapamide;
(3) 2.5-10 mg amiloride.
2. The pharmaceutical composition according to claim 1, wherein amlodipine is contained in an amount of 5 to 10mg, indapamide is contained in an amount of 1.5 to 2.5mg, and amiloride is contained in an amount of 5 to 7.5 mg.
3. Pharmaceutical composition according to claim 2, characterized in that it consists of 5mg of amlodipine, 1.5mg of indapamide, 5mg of amiloride.
4. Pharmaceutical composition according to claim 2, characterized in that it consists of 5mg of amlodipine, 2.5mg of indapamide, 5mg of amiloride.
5. Pharmaceutical composition according to claim 2, characterized in that it consists of 10mg of amlodipine, 1.5mg of indapamide, 5mg of amiloride.
6. Pharmaceutical composition according to claim 2, characterized in that it consists of 10mg of amlodipine, 2.5mg of indapamide, 5mg of amiloride.
7. Pharmaceutical composition according to claim 2, characterized in that it consists of 10mg of amlodipine, 2.5mg of indapamide, 7.5mg of amiloride.
8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated with pharmaceutically acceptable carriers into oral dosage forms such as tablet, sustained release tablet, chewable tablet, soft capsule, hard capsule, powder, and granule.
9. Use of the pharmaceutical composition of claim 1 in the manufacture of a medicament for the treatment of refractory hypertension.
10. Use according to claim 9, characterized in that said refractory hypertension is a low renin-type refractory hypertension.
Technical Field
The invention provides a brand-new antihypertensive drug composition, which consists of amlodipine, indapamide and amiloride. Belongs to the field of pharmacy.
Background
On the basis of improving the life style, 3 reasonable and sufficient blood pressure reducing medicines (including diuretics) are jointly applied to treat the hypertension which is not up to the standard after a certain time (more than or equal to 1 month) or the blood pressure can be effectively controlled only by taking more than or equal to 4 blood pressure reducing medicines, so the hypertension is called refractory hypertension (Chinese experts in diagnosis and treatment of refractory hypertension, China journal of hypertension, 2013, 21(4), 321-doped 326). Risk factors for Refractory Hypertension (RH) include race, body mass index, age, chronic kidney disease, diabetes, and the like. The etiology and pathophysiological mechanisms of RH are multifaceted. There are basic etiologies, as well as central and local neurohumoral mechanisms. High salt intake, obesity, and hypofunction of carotid baroreflex are the basic reasons for the difficulty in controlling blood pressure in hypertensive patients. On this basis, activation of the renin-angiotensin-aldosterone system (RAAS) in circulation and tissues and excessive increase in sympathetic nervous activity of central or local tissues (especially kidneys) initiate inflammatory factors, oxidative stress processes and contribute to the development and progression of atherosclerosis and atherosclerosis, exacerbating abnormalities in vascular structure and function, thereby making it difficult to control elevated blood pressure.
In addition to the symptomatic treatments, such as obstructive sleep apnea, chronic kidney disease, primary aldosteronism, cushing's syndrome, and the like, the RH therapy is not ideal, for example, many observational studies have shown that the drug treatment of most RH patients is not optimal, and a community-based study shows that half of the RH patients do not use the optimal treatment, while the patients who use the optimal treatment have a higher risk of cardiovascular disease or suffer from diabetes or chronic kidney disease (MESSERLI F H. Vasoldillatory: a common side effect of diabetes or chronic kidney disease [ J ]. CurrCardiol Rep,2002,4(6): 479-482). The usual three-drug combination regimen recommends a renin-angiotensin system inhibitor (RASI) [ Angiotensin Converting Enzyme Inhibitor (ACEI) or angiotensin receptor Antagonist (ARB) ]) + calcium antagonist + thiazide diuretic. Spirolactone (which is required to assess renal function and the risk of potentially hyperkalemic potassium) or a combination of beta, alpha beta or alpha blockers may be considered when blood pressure is still not up to standard. When the blood pressure still can not reach the standard, the central nervous system inhibiting medicines such as clonidine, reserpine and the like can be used as a fifth antihypertensive medicine of a combined scheme. For RH treatment, at present, no single antihypertensive drug or compound antihypertensive drug is approved for RH treatment at home and abroad. The RH treatment medicine is still in the development stage at present, most of the medicines in the patents for treating RH which are published in China contain traditional Chinese medicine components, the action mechanism of the traditional Chinese medicine is complex, the effect is slow under the common condition, the treatment period is longer, and the RH patients can generate greater harm if the blood pressure is in high position for a long time and are not in accordance with the treatment characteristics of the traditional Chinese medicine.
Indapamide is a diuretic by inhibiting Na at the beginning of the renal distal convoluted tubule+-Cl-Syntropy transporter, Na reduction+、Cl-And reabsorption of water, which reduces the volume of extracellular fluid by excreting excess sodium and water in the body to achieve the effect of reducing swelling. The reasons for edema include congestive heart failure, acute emphysema, nephrotic syndrome, acute and chronic nephritis, etc., and indapamide is an auxiliary drug for treating the diseases. Indapamide is mainly used for treating mild and moderate hypertension, senile hypertension complicated with heart failure and other diseases in the aspect of lowering blood pressure. Indapamide, a typical adverse reaction to diuretics, also tends to cause low blood potassium levels in patients taking the drug.
Amlodipine as calcium channel antagonist can directly relax vascular smooth muscle, expand peripheral blood vessel and reduce peripheral resistance, and can effectively treat vascular characteristics of narrowing of arterial lumen, increasing hardness, reducing aorta elasticity, reducing self-compliance and reducing elasticity expansion capability of old people.
The existing compound preparation of the calcium ion antagonist and the diuretic only contains amlodipine indapamide compound tablets (NATRIXAM) developed by Schweiya, is marketed in Europe in 2013, and is not marketed in China. The compound tablet consists of 1.5mg of indapamide and 5mg (10mg) of amlodipine, is used as a replacement therapy of single drug combination of amlodipine and indapamide, and is used for treating primary hypertension. In patent applications, some manufacturers also pay attention to the combination of a calcium ion antagonist and a diuretic, for example, chinese patent 201110187762.3 discloses a compound antihypertensive pharmaceutical composition of indapamide and levamlodipine; chinese patent 200810026058.8 discloses a blood pressure lowering drug combination of amlodipine besylate and indapamide. Amlodipine and indapamide have the side effects of edema, low blood potassium and the like while synergistically reducing blood pressure. For example, it is clear in the specification of NATRIXAM that NATRIXAM has the side effect of hypokalemia, indicating that the person with low blood potassium should use it with caution; compared with the curative effect and safety of 2-level essential hypertension treated by combining 3 antihypertensive drugs with indapamide respectively, the Chinese pharmacy 2017,28(21), 2933-2936 discloses that the blood potassium level is reduced from 4.4mmol/L to 3.8mmol/L after amlodipine is added, the difference has significance, the blood potassium level reduction is suggested to be the main adverse reaction of the amlodipine indapamide compound tablet, in addition, the combination also has the side effects of high incidence of edema, facial flushing and the like, and the application of the amlodipine indapamide compound tablet is limited.
Disclosure of Invention
The invention aims to provide a more effective and safer antihypertensive drug composition for refractory hypertension, in particular low-renin refractory hypertension.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pharmaceutical composition for treating refractory hypertension comprises the following components:
(1) 2.5-10 mg of amlodipine;
(2) 1-2.5 mg of indapamide;
(3) 2.5-10 mg of amiloride;
(4) a pharmaceutically acceptable carrier.
In the pharmaceutical composition provided by the invention, amlodipine can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The amlodipine provided by the invention is used as a pharmaceutical ingredient, and the existing forms of salts, esters, active metabolites or medicinal precursors of the amlodipine are also within the protection scope of the application. In the present invention, the pharmaceutical dosage of amlodipine is selected from 2.5 to 10mg, preferably 5 to 10 mg. The medicinal dosage of the existing forms of the salts, esters, active metabolites or medicinal precursors of amlodipine and the like can be correspondingly converted.
In the pharmaceutical composition provided by the invention, indapamide can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The indapamide provided by the invention is used as a medicinal ingredient, and the existing forms of salts, esters, active metabolites or medicinal precursors of the indapamide and the like are also within the protection range of the application. In the invention, the medicinal dosage of the indapamide is selected from 1-2.5 mg, preferably 1.5-2.5 mg. The medicinal dosage of the existing forms of the salts, esters, active metabolites or medicinal precursors of the indapamide and the like can be correspondingly converted.
In the pharmaceutical composition provided by the invention, amiloride may exist in the form of salts, esters, active metabolites or pharmaceutically acceptable precursors. The amiloride provided by the invention is used as a pharmaceutical ingredient, and the existing forms of the salts, esters, active metabolites or medicinal precursors of the amiloride are also within the protection scope of the application. In the present invention, the pharmaceutical dosage of amiloride is selected from 2.5 to 10mg, preferably 5 to 7.5 mg. The pharmaceutical dosage of the salt, ester, active metabolite or precursor of amiloride may be converted accordingly.
In the present invention, the pharmaceutically acceptable dose of the active ingredient of the composition means a dose range in which the active ingredient of the composition exerts its pharmacological effect when combined with other active ingredients in the composition. The preferred dosage is the preferred dosage of the active ingredients of the composition, and the preferred dosage has better efficacy than the pharmaceutical dosage. Generally, the pharmaceutical dosage of the active ingredient of the composition will include an optimal dose or range of optimal doses that will produce the maximum effect of the composition, which optimal dose or range of optimal doses will benefit the patient even more.
Preferably, the pharmaceutical composition provided by the invention comprises 5mg of amlodipine, 1.5mg of indapamide and 5mg of amiloride.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 5mg of amlodipine, 2.5mg of indapamide and 5mg of amiloride.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 10mg of amlodipine, 1.5mg of indapamide and 5mg of amiloride.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 10mg of amlodipine, 2.5mg of indapamide and 5mg of amiloride.
As another preferred embodiment, the present invention provides a pharmaceutical composition consisting of 10mg of amlodipine, 2.5mg of indapamide, and 7.5mg of amiloride.
The pharmaceutical composition also contains pharmaceutically acceptable carriers, can be prepared into common oral preparations, including common tablets, common capsules, sustained-release tablets, controlled-release tablets, granules and the like, and when the pharmaceutical composition is prepared into tablets, the pharmaceutically acceptable carriers comprise excipients and adjuvants which are helpful for preparing active compounds into pharmaceutical preparations, such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite and the like, and belong to the common knowledge in the field.
The pharmaceutical composition provided by the invention aims at patients with refractory hypertension, particularly low renin type refractory hypertension, and provides a more effective and safer antihypertensive pharmaceutical composition. The medicinal effective components of the pharmaceutical composition provided by the invention are amlodipine, indapamide and amiloride, and the composition has the advantages of rapid blood pressure reduction and obvious curative effect in treating refractory hypertension, and is particularly suitable for patients with low renin type refractory hypertension. Firstly, after amlodipine, indapamide and amiloride are combined, the drug effect of treating refractory hypertension is obvious, and the drug effect can be exerted by non-single drug or combination of two drugs. And secondly, amiloride serving as a potassium-retention diuretic can relieve the hypokalemia side effect of long-term application of indapamide and is beneficial to reducing lower limb edema caused by retention of amlodipine and sodium hydrate, and the amiloride, the amiloride and the amiloride reduce the adverse reaction of single medicine while realizing synergistic interaction, so that the amiloride and the amiloride are a very beneficial combination. Thirdly, the inventor finds the optimal dosage proportion of the amlodipine, the indapamide and the amiloride in the aspects of synergy and side effect reduction by screening the dosages of the amlodipine, the indapamide and the amiloride. The pharmaceutical composition provided by the invention is used for treating refractory hypertension, especially low-renin refractory hypertension, and has the advantages of rapid blood pressure reduction, small blood pressure fluctuation, obvious curative effect, few side effects, especially side effects such as blood potassium metabolic disturbance and edema caused by medicines, high patient compliance and obvious increase of standard reaching rate of blood pressure reduction.
It is to be understood that the amount of drug provided herein is not a limitation of the present invention, but is preferred herein, and that the drug is generally within the range of the amount that produces an effective therapeutic effect in the affected individual. The subject to be affected is an independent living body suffering from a disease, and in the present invention, a living body refers to a human being. It should be understood that in the prior art, the pharmaceutical content or range of pharmaceutical content for human can be converted with mammals, such as rat, mouse, etc., to obtain the pharmaceutical content or range of content suitable for the corresponding animal.
The present invention is further described with reference to the following detailed description, which is not intended to be limiting, but rather is intended to cover all equivalent art-recognized alternatives falling within the scope of the invention.
Detailed Description
Example 1-example 6 preparation of amlodipine/indapamide/amiloride capsules (1000 capsules)
Table 1 composition ratio
Proportioning composition
Example 1
Example 2
Example 3
Example 4
Example 5
Example 6
Amlodipine (I) salt
2.5g
5g
5g
10g
10g
10g
Indapamide
1g
2.5g
2.5g
2.5g
2.5g
2.5g
Amiloride of Amiroli
2.5g
5g
7.5g
2.5g
5g
7.5g
MCC(PH102)
106g
99.6g
97.1g
95.1g
92.6g
90.1g
Anhydrous calcium hydrogen phosphate
30g
30g
30g
30g
30g
30g
Sodium starch glycolate
2g
2g
2g
2g
2g
2g
10% Povidone K30 ethanol solution
Proper amount of
Proper amount of
Proper amount of
Proper amount of
Proper amount of
Proper amount of
Magnesium stearate
2g
2g
2g
2g
2g
2g
The preparation process comprises the following steps:
1) weighing amlodipine, indapamide and amiloride according to a prescription, and respectively sieving with a 80-mesh sieve for later use; 2) mixing amlodipine, indapamide and amiloride with microcrystalline cellulose and carboxymethyl starch sodium, and sieving; 3) adding anhydrous calcium hydrogen phosphate into the mixture obtained in the step 2), and uniformly mixing; 4) making into soft mass with appropriate amount of 10% polyvidone ethanol solution, granulating, drying, and grading. 5) Mixing the granules with water content of about 3% with magnesium stearate, and encapsulating.
Example 7-example 12 preparation of amlodipine, indapamide and amiloride tablets (1000 tablets)
Table 2 composition ratio
Formulation composition
Example 7
Example 8
Example 9
Example 10
Example 11
Example 12
Amlodipine (I) salt
5g
5g
5g
10g
10g
10g
Indapamide
2.5g
2.5g
2.5g
2.5g
2.5g
2.5g
Amiloride of Amiroli
2.5g
5g
7.5
5g
7.5g
10g
Pregelatinized starch
30g
30g
30g
30g
30g
30g g
Microcrystalline cellulose
149g
147.5g
174g
144.5g
143g
141.5
Sodium starch glycolate
4g
4g
4g
4g
4g
4g
10% Povidone K-30
Proper amount of
Proper amount of
Proper amount of
Proper amount of
Proper amount of
Proper amount of
Magnesium stearate
2g
2g
2g
2g
2g
2g
The preparation process comprises the following steps:
mixing amlodipine, indapamide and amiloride, adding carboxymethyl starch sodium and pregelatinized starch, sieving, adding microcrystalline cellulose, mixing, adding appropriate amount of 10% polyvidone ethanol solution to obtain soft mass, granulating, drying, grading, mixing with appropriate amount of magnesium stearate, and tabletting to obtain 1000 tablets.
Example 13: the amlodipine/indapamide/amiloride compound preparation has the effect on lowering blood pressure and blood potassium of a DOCA-salt hypertensive rat.
Preparing an animal model: 200 and 220g of male SD rats fed with common daily ration feed, detecting the basic blood pressure 7 days after quarantine, randomly selecting 16 rats for a false operation, and continuously feeding with the common feed until the experiment is finished. Other rats are subjected to model building, pentobarbital sodium anesthesia, dorsal fixation, abdominal hair shearing, conventional disinfection, left abdominal cavity incision, left renal arteriovenous ligation, left renal removal, layer-by-layer suture, intraperitoneal injection of 10 ten thousand units/mouse of penicillin sodium 1 time per day for 2 days continuously, right abdominal subcutaneous implantation of DOCA silicone tube (100 mg/mouse), suture (Gushuna et al, establishment of a DOCA-salt hypertension rat model, Chinese pharmacology report 2010; 26 (6): 832-supplement 835). The animals were fed with 1% saline at the same time. The operation of anesthetizing, incising the abdominal cavity and finding out the left kidney of a sham-operated rat is the same as that of a model group, but ligation and left kidney removal are not carried out, penicillin is directly sprayed into the rat and then sutured, a silica gel tube without medicinal powder is embedded into the right abdominal part, and penicillin anti-infection injection and normal drinking are carried out after 2 days. Blood pressure measurement was performed 4 weeks after molding, and molding was successful when the blood pressure stabilized at 140mmHg or more.
Grouping and administration: the rats successfully modeled are divided into a model group and an administration group according to the blood pressure condition, 13-14 rats in each group are randomly divided, 14 rats with larger rejection deviation of the sham operation are reserved as a sham operation control group, the administration volume is 1ml/100g of body weight, and the administration is carried out continuously for 12 weeks.
Detection indexes are as follows: (1) detecting the serum Renin (REN) and Aldosterone (ALD) levels of rats after grouping and before administration; (2) blood pressure measurement before and 4 weeks, 12 weeks; (3) and (4) measuring the blood potassium level.
The statistical method comprises the following steps:
1. test data toAnd (4) showing. Comparison between groups by t test, P<0.05 statistically significant difference, P<0.01 had a very significant statistical difference.
2. And analyzing the experimental result by adopting a golden mean Q value method, and evaluating whether the coordination and synergism action exists between the medicine combinations.
Q-value method for equal distribution of Jinzheng, Zhang laugh, equiprobability and curve and Q5 e-New method for estimating combined effect of medication, Shanghai second college of medicine, 1981]Also called probability addition method, according to the pharmacological action of two drugs combined together and the pharmacological action of two drugs singly in the dose-effect curve region, the following formula is used to calculate Q ═ EA+B/(EA+EB-EA×EB) In the formula, the numerator represents the 'measured merging effect', the denominator represents the 'expected merging effect', and Q is the ratio of the two. Q value<At 0.85, the combination of the two drugs is considered as antagonistic action, and at 0.85<Q value<1.15 is considered to be an additive effect, Q value>1.15 is considered to be synergistic. In order to satisfy the analysis of pharmacological action relationship, the blood pressure value is converted into the effect which can visually reflect the strength of the pharmacological action, and the formula is calculated: ei＝(1-Pi/PModel set)×100％，PiIs the blood pressure value, P, of each groupModel setBlood pressure values for the model group.
As a result:
(1) model rat serum Aldosterone (ALD) and Renin (REN) levels
The model of hypertension caused by DOCA-high salt intake has lower serum renin and aldosterone levels (P <0.01) in rats compared with the sham operation group. See table 3.
Table 3: rat Pre-dose ALD and REN levels
Note: compared with the group of the pseudo-operation,#P<0.05，##P<0.01
(2) influence of amlodipine/indapamide/amiloride compound preparation on rat blood pressure
Compared with the sham operation group, the blood pressure of the model group is obviously increased at 4 weeks and 12 weeks. Compared with the model group, the amlodipine/indapamide/amiloride compound medicine can obviously reduce the blood pressure of rats. Except for the lowest dose group (0.5+0.25+0.25) mg/kg, the combination of the amlodipine/indapamide/amiloride compound medicines can further remarkably reduce the blood pressure compared with the amlodipine + indapamide, amlodipine + amiloride, indapamide or an amiloride control group, and the average value of the blood pressure is lower than 140 mmHg. Therefore, the amlodipine, the indapamide and the amiloride have a synergistic effect on the blood pressure reducing effect, and the blood pressure reducing effect of the amiloride in the composition is not further increased when the dose of the amiloride is more than 0.5 mg/kg. Amlodipine + amiloride + hydrochlorothiazide, amlodipine + indapamide + spironolactone also have a blood pressure lowering effect, but the blood pressure lowering effect of the amlodipine/indapamide/amiloride compound drugs (0.5+0.25+0.5, 1+0.25+0.5, 1+0.25+0.75) group is stronger than that of the amlodipine + amiloride + hydrochlorothiazide, amlodipine + indapamide + spironolactone, and the amlodipine/indapamide/amiloride compound drugs (1+0.25+0.5, 1+0.25+0.75) group significantly lower than that of amlodipine + amiloride + hydrochlorothiazide, amlodipine + indapamide + spironolactone, showing a statistical difference, indicating that the group of drugs has a more significant blood pressure lowering effect than amlodipine + amiloride + hydrochlorothiazide, amlodipine + indapamide + spironolactone. See table 4.
Table 4: influence of amlodipine/indapamide/amiloride compound preparation on rat blood pressure (n＝13-14)
Compared with the group of the pseudo-operation,#P<0.05，##P<0.01; comparison with model group*P<0.05，**P<0.01; compared with the corresponding amlodipine + indapamide group or amlodipine + amiloride group,&P<0.05; compared with the amiloride group or the indapamide group at the corresponding dose,△P<0.05,△△P<0.01; with amlodipine + amiloride + hydrochlorothiazide or amlodipine + indapamide + spironolactoneThe ratio of the ester group to the total amount of the ester,$P<0.05。
as shown in table 5 and table 6, compared with the two bigeminal and single drugs at the same dose, the Q values of the amlodipine/indapamide/amiloride (0.5+0.25+0.25) groups are 1.149 and 1.143, and the Q values of the amlodipine/indapamide/amiloride combination drug groups influencing the systolic blood pressure of the DOCA salt hypertensive rats at 4 weeks and 12 weeks are all more than 1.15, which indicates that the three components of the pharmaceutical composition of the invention have synergistic effect with each other except that the low dose shows partial synergistic effect, and indicates that the three drugs are reasonably compatible and can enhance the antihypertensive effect of the drugs on the DOCA salt hypertensive rats.
Table 5: q value analysis of amlodipine/indapamide/amiloride compound preparation on influence on blood pressure of rats for 4 weeks
Table 6: q value analysis of amlodipine/indapamide/amiloride compound preparation on influence on blood pressure of rats for 12 weeks
(3) Amlodipine and indapamide amiloride compound preparation for influencing rat blood potassium level
After 12 weeks of administration, the amlodipine indapamide group and the indapamide group had lower blood potassium levels (P <0.05) compared to the model and sham group; the potassium sparing diuretic amiloride alone and amlodipine + amiloride group showed elevated blood potassium levels (P < 0.05). Comparison of amlodipine + indapamide and amiloride with different doses of the combination shows that the combination of amlodipine + indapamide + amiloride (0.5+0.25+0.5), (1+0.25+0.5) and (1+0.25+0.75) mg/kg has the best effect of balancing blood potassium. The amlodipine, the amiloride, the hydrochlorothiazide, the amlodipine, the indapamide and the spironolactone have the function of slightly increasing the blood potassium. See table 7.
Table 7: amlodipine and indapamide amiloride compoundEffect of the formulation on rat blood Potassium levels (n＝13-14)
The above experimental study shows that: the combination of amlodipine, indapamide and amiloride has obvious synergistic and balanced blood potassium effects in the conditions of 5-10mg of amlodipine, 0.25mg of indapamide and 5-7.5 mg of amiloride (the daily dosage of adults is converted by rats according to body surface area), and the composition is the optimal dosage ratio for synergism and attenuation.
Example 14: clinical test of amlodipine, indapamide and amiloride on blood pressure reduction curative effect and safety of low-renin refractory hypertension patients
Test method
Subject meets all of the following criteria, and no one specified by the exclusion criteria can be enrolled: (1) the sex is not limited, and the age is 40-75 years old; (2) 3 or more than 3 enough antihypertensive drugs are reasonably used for more than one month, and the sitting blood pressure (average value of 3 measurements) meets the following standard: the diastolic pressure is more than or equal to 90mmHg or the systolic pressure is more than or equal to 140mmHg, and the diastolic pressure is less than 110mmHg and the systolic pressure is less than 180 mmHg; (3) plasma Renin Activity (PRA) < 0.65 ng/mL/h; (4) voluntarily attend and sign an informed consent.
The exclusion criteria were met with any of the following.
(1) Pregnant and lactating women; (2) patients with allergic history of the components in the medicine; (3) those with definite allergic constitution; (4) white coat hypertension; (5) poor compliance; (6) known to suffer from serious medical conditions; (7) the presence of significant laboratory or physical abnormalities, at the discretion of the investigator, may indicate the presence of a serious disease in the patient, or, at the discretion of the investigator, may affect the observation and evaluation of the therapeutic efficacy or adverse events of the drug, and is not suitable for the investigator.
The subjects were randomly divided into a test group and a control group, each group of the blood pressure lowering treatment protocol was as follows, the blood pressure of the patients was measured at the 4 th and 8 th week days, respectively, and the achievement rate of each group was calculated by taking the systolic and diastolic blood pressure to reach the standards (SBP <140mmHg, DBP <90mmHg), and the safety index included the occurrence of hypokalemia, edema, etc.
The antihypertensive treatment scheme comprises the following steps:
control group: the original antihypertensive drug combination scheme (3 or more than 3 drug treatments) is continued;
test groups: the original antihypertensive combination drug is stopped, and 5-10mg of amlodipine, 1.5mg of indapamide and 5mg of amiloride are used instead.
(II) test results:
a total of 160 patients with low renin-type hypertension entered the study and completed 8 weeks of hypotensive therapy.
The control group of hypertension patients continue to be treated by the original scheme (3 or more than 3 antihypertensive drug combinations) for 4 weeks and 8 weeks, and 0 person and 3 persons respectively reach the blood pressure standard; however, the patients in the experimental group stopped the original regimen, received the combination of amlodipine, indapamide and amiloride, and had blood pressure reaching the standard of 12 persons and 57 persons after 4 weeks and 8 weeks of treatment, respectively, as shown in Table 8.
Table 8: influence of amlodipine indapamide amiloride blood pressure reduction scheme on standard reaching rate of blood pressure and adverse reaction incidence rate of patients
Note: p compared to control group<0.01，#P>0.05。
In the aspect of adverse reactions, patients in the control group have 5 cases of lower limb mild edema, 3 cases of facial flushing, and 9 cases of hypokalemia with hypodynamia; patients in amlodipine + indapamide + amiloride group showed 4 cases of mild edema of lower limbs, 5 cases of hypokalemia, and 6 cases of facial flushing. The adverse event occurrence rate difference between the two groups is not obvious, and the adverse reactions of the two groups are slight, so that the medicine can be tolerated and the treatment is not influenced.
From the research results, the aim of accurate medication is achieved through renin typing, namely, selecting a low-renin hypertension patient, the experiment group is provided with a new treatment drug combination of amlodipine, indapamide and amiloride, the three drugs are synergistic, the diuresis is enhanced, and a stronger blood volume reducing effect is obtained, so that the standard reaching rate of the blood pressure is obviously improved, and the drug combination is clinically recommended to be used for the low-renin difficult-to-treat hypertension.