CN113730413A - Application of terazosin in preparation of medicines for reducing blood vessel hardness - Google Patents
Application of terazosin in preparation of medicines for reducing blood vessel hardness Download PDFInfo
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- CN113730413A CN113730413A CN202111196648.7A CN202111196648A CN113730413A CN 113730413 A CN113730413 A CN 113730413A CN 202111196648 A CN202111196648 A CN 202111196648A CN 113730413 A CN113730413 A CN 113730413A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention discloses an application of terazosin in preparing a medicine for reducing blood vessel hardness, wherein the terazosin also comprises a medicinal salt formed by active ingredients of the terazosin or a solvate thereof, the terazosin can be administrated through the digestive tract according to the daily dose of 0.1-1 mg of the active ingredients of the terazosin, and the administration concentration of the terazosin is far lower than the conventional dose at present. The invention has the following beneficial effects: animal tests and clinical studies show that terazosin can reduce the vascular pulse wave conduction velocity, and animal tests and cell tests show that terazosin can effectively reduce the vascular hardness, thus developing a medicament capable of interfering in vascular degenerative change at early stage for clinical practice. The invention can greatly reduce the dosage of the medicine, save the medicine cost and reduce the medical burden of patients. Meanwhile, the invention can limit the adverse side effect of terazosin to an extremely low level.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a new pharmaceutical application of terazosin, and particularly relates to an application of terazosin in preparing a medicine for reducing vascular hardness.
Background
Terazosin (Terazosin) is commonly used in hospital clinical treatment in the form of its hydrochloride salt, and the marketed Terazosin tablet or capsule is mainly 1mg, 2mg and 5mg, etc. Terazosin hydrochloride can be used for treating benign prostatic hyperplasia, and also can be used for treating hypertension. They can be used alone or in combination with other antihypertensive drugs such as diuretics or alpha 1-adrenergic receptor blockers (Wilde MI, Fitton A, Sorkin EM (1993) Terazosin. A review of its pharmacological coding and pharmacological properties, and therapeutic potential in the biochemical hypertension. drugs&aging 3: 258-; achari R, Hosman B, Bonacci E, O' Dea R (2000) The correlation between a terazosin dose and a block pressure in a hyper text in journal of clinical pharmacy 40: 1166-; zusman RM (2000) The role of alpha 1-blocks in combination therapy for hypertension. International journal of clinical practice54: 36-40). Aiming at the existing clinical indications, the daily dose of terazosin for treating adult patients is mostly in the range of 1-10 mg. When terazosin is used to treat Benign Prostatic Hyperplasia (BPH), the reduction of symptoms and improvement in urine flow rate following administration of terazosin is associated with smooth muscle relaxation caused by alpha 1-adrenergic receptor blockade in the bladder neck and prostate. Terazosin is able to relieve obstruction of the bladder outlet without affecting bladder contractions due to the relatively few alpha 1-adrenergic receptors in the bladder body (wild TJ, Howe RW, Rutks IR, MacDonald R (2002) Terazosin for adjacent positive hyperplasia, the Cochrane database of systematic reviews CD 003851). In addition, terazosin lowers blood pressure by reducing total peripheral vascular resistance. The vasodilatory, blood pressure lowering action of terazosin appears to be caused primarily by alpha 1-adrenergic receptor blockade. The chemical name of terazosin is (4- (4-amino-6, 7-dimethoxyquinazolin-2-yl) piperazine-1-Yl) (tetrahydrofuran-2-yl) methanone, chemical formula C19H25N5O4The chemical structural formula is shown as the following formula I:
there is increasing evidence that age is one of the major risk factors for the development and progression of cardiovascular and cerebrovascular disease in patients, where vascular degenerative changes play a dominant role. The vascular degeneration refers to the physiological and pathological process of aging and degeneration of the function and structure of blood vessels under the combined action of other factors with the increase of age. Clinically, the vascular degeneration is mainly manifested by an increase in the hardness of blood vessels, which is manifested by an increase in the velocity of pulse wave propagation. In particular, it is to be noted that: the increase in vessel stiffness is significantly different from atherosclerosis in the mechanism of formation, which more broadly leads to structural remodeling of the vessel wall. In the absence of atherosclerosis, the increase in vascular stiffness is mainly manifested by a significant increase in intravascular Intermediate Membrane Thickness (IMT), and there is also damage and dysfunction of endothelial cells, a significant decrease in Nitric Oxide (NO) -dependent vasodilation of the blood vessels. This structural remodeling and dysfunction interact with each other and ultimately contribute to increased vascular stiffness (Zhangsmart, Zhangtai; importance is attached to the assessment and prevention of vascular aging; China J.geriatric 2020,39(8): 857-. Detailed differentiation of atherosclerosis and increased vascular stiffness is shown in Table 1 below (China medical society, aged medical society, cardiovascular group; clinical assessment of vascular aging and intervention in China experts consensus (2018); China aged medical journal 2018,37(11): 1177-1184).
TABLE 1
When the aorta such as aorta and carotid Artery is increased in Stiffness due to degenerative change, the peripheral muscular Artery does not have obvious change, and the energy of the pulse wave is transmitted more to microcirculation, thereby destroying microcirculation structure and affecting the perfusion of the terminal tissue and cells of the patient, which can cause the damage of organs with high-flow and low-resistance Vascular bed, such as myocardium, kidney, brain, placenta and testis (Chirinos JA, Segers P, Hughes T, Townsend R.Large-arm bed in Health and Disease: CC State-of-the-arm review. J Am Cold. 2019; 74(9) 1237 + 3. nuwak KL, Rossman MJ, Chonchol M, Seals DR.Strategie for Achiey blood vessel), and high-contraction of left heart blood pressure (71. Vat) caused by high-flow and low-resistance Vascular bed in heart, heart Disease, heart failure, pulse wave-related nephropathy, cognitive impairment, cognitive decline, incidental dementia, preeclampsia, fetal intrauterine growth retardation, testicular aging, etc. (Zhang Yu, Zhang Cheng Tai; emphasis on assessment and prevention of vascular aging; China J. geriatric J. 2020,39(8): 857-. The obvious difference between atherosclerosis and vascular degenerative stiffness of patients is that the atherosclerosis mainly causes the pathological changes of corresponding organs in local areas, such as coronary heart disease and the like.
At present, no medicine capable of directly treating or delaying blood vessel hardness increase at an early stage is clinically available, people with blood vessel hardness increase often carry out corresponding symptomatic treatment after relevant target organ damage or symptoms appear in long-term vascular degenerative disease, and at the moment, the damage of the relevant target organ is often irreversible. In order to solve the problems, medical researchers have endeavored to find medicines capable of interfering with the hardness of blood vessels of patients before the occurrence of related diseases so as to delay or relieve pathological symptoms of the patients and improve the quality of life of the patients, but satisfactory progress has not been achieved at present. Therefore, the art still expects to provide a medicament with direct blood vessel stiffness reduction for clinical use.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides the application of terazosin in preparing a medicine for reducing the vascular hardness, and develops a medicine capable of interfering in the early vascular degenerative change for clinical practice.
In order to achieve the purpose, the invention discloses an application of terazosin in the preparation of new medicines, namely an application of terazosin or a medicinal salt or a solvate thereof in the preparation of medicines for reducing vascular hardness.
Preferably, the medicinal salt is one or more of hydrochloride, phosphate, benzene sulfonate, mesylate, sulfate and nitrate of terazosin, and the hydrochloride of terazosin is usually selected.
Preferably, the solvate is a hydrate of terazosin or a pharmaceutically acceptable salt thereof.
Further, the hydrate is usually selected from a monohydrate or a dihydrate.
Still further, the solvate is terazosin hydrochloride dihydrate.
In the specific experimental study of the present invention, terazosin hydrochloride dihydrate was selected for the test, unless otherwise specified.
Preferably, the terazosin is administrated through the digestive tract in a daily dose of 0.1-1 mg of active ingredients, and is taken once or more times a day.
Furthermore, the terazosin is administrated through the digestive tract in a daily dose of 0.25-0.75 mg of active ingredients, and is taken once or two to three times a day.
Furthermore, the terazosin is administrated through the digestive tract according to the daily dose of 0.50-0.75 mg of the active ingredient, and is taken once or twice a day; the composition is taken once a day in a fixed time, and is taken twice a day in the morning and at night.
Still further, the terazosin is administered via the digestive tract in a daily dose of 0.50mg of its active ingredient, once daily, taken before bedtime.
In a particular clinical study of the invention, terazosin is clinically observed in daily doses of its active ingredient (e.g. 0.25mg, 0.5mg, 0.75mg and 1mg) unless otherwise specified. The effective dose of terazosin for human body can be adjusted according to various factors such as human body weight, age, disease state and the like, the daily dose of terazosin for adult administration in the invention is 0.1-1 mg, and the dose in the range is equivalent to the dose used in the specific experimental study of the invention, but is greatly lower than the conventional dose of terazosin in clinical use at present. Also, terazosin may be administered by various routes, such as orally, by injection, transdermally, and the like. Oral administration is optimal as a drug for early intervention of vascular stiffness and is the same as its existing route of administration. The choice of the dosage form of the drug is easy, given the determined route of administration.
As one of the verification schemes, the effect judgment of the blood vessel hardness reducing medicine is to clinically evaluate the hardening degree of blood vessels by measuring the pulse wave conduction velocity.
As the second verification scheme, the effect judgment of the blood vessel hardness reducing medicine is to evaluate the hardening degree of blood vessels by measuring the pulse wave conduction velocity on an animal model.
As a third verification scheme, the effect judgment of the medicine for reducing the vascular hardness is to evaluate the aging degree of vascular tissues by detecting beta-galactosidase activity in an experiment.
The invention has the beneficial effects that: cell experiments, animal experiments and clinical researches on the currently clinically common medicament terazosin show that the small dose of terazosin can effectively reduce the blood vessel hardness, thereby providing important technical support for early treatment or prevention of diseases related to vascular sclerosis. The experimental and clinical research results of the invention also prove that the terazosin with the dosage range of 0.1-1 mg has good speed reduction effect in the aspect of reducing the vascular pulse wave conduction speed. More remarkably, the speed reduction effect of using 0.50-0.75 mg of terazosin is superior to that of using 0.25mg and 1mg of terazosin. Optimally, the speed reduction effect of 0.50mg of terazosin is equivalent to that of 0.75mg of terazosin, and compared with the conventional dosage of 2-5 mg of terazosin, the terazosin can greatly reduce the dosage, save the dosage cost and reduce the medical burden of patients. Meanwhile, because the dose of terazosin used in human body is extremely low, the adverse side effect related to terazosin is basically avoided.
Drawings
FIG. 1 is a line graph of 0.25-1 mg terazosin in reducing pulse wave velocity of an observed subject in clinical studies;
FIG. 2 is a bar graph of 0.25-1 mg terazosin in clinical studies to reduce the difference in pulse wave velocity of subjects under observation;
FIG. 3 is a bar graph of terazosin in an animal model to reduce the pulse wave velocity of the experimental animal;
FIG. 4 is a bar graph of the effect of terazosin on reducing the activity of beta-galactosidase in vascular tissue of experimental animals;
FIG. 5 is a schematic view showing the staining of terazosin after improving the state of elastic fibers in the vascular tissue of an experimental animal;
Detailed Description
The present invention will be described in further detail below with reference to the drawings, examples and experimental examples. Of course, the scope of protection of the invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit of the invention. The present invention has been described generally and/or specifically with respect to materials used in experiments and test methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is described herein in as detail as possible. The following examples further illustrate the invention without limiting it. Any equivalent changes in form only, but not in material, made in accordance with the present inventive concept should be considered as within the scope of the present invention.
In the experiments described below, the terazosin used was the hydrochloride dihydrate thereof, unless otherwise specified. It is well known that the salts of different forms and/or solvates thereof generally only affect the physicochemical properties of the drug, such as solubility, etc., but not the biological activity of the drug, and therefore it is expected that the free base of terazosin and other forms of salts thereof, such as sulfate, phosphate, etc., whose biological properties in the experiments described below would exhibit equivalent results to terazosin hydrochloride dihydrate, etc.
Example 1
The terazosin hydrochloride tablet or capsule is 0.50mg (calculated by active ingredients), is orally taken through the digestive tract and is taken before sleep once a day, the treatment course is 12-52 weeks, and the terazosin hydrochloride tablet or capsule is used for reducing the blood vessel hardness and preventing and treating the increase of the blood vessel hardness caused by the vascular degenerative change. The end-of-treatment period determined the follow-up treatment regimen based on the physical examination data.
Example 2
The terazosin hydrochloride tablet or capsule is 0.75mg (calculated by active ingredients), is orally taken through the digestive tract and is taken before sleep once a day, the treatment course is 12-52 weeks, and the terazosin hydrochloride tablet or capsule is used for reducing the blood vessel hardness and preventing and treating the increase of the blood vessel hardness caused by the vascular degenerative change. The end-of-treatment period determined the follow-up treatment regimen based on the physical examination data.
Example 3
1mg (calculated by active ingredients) of terazosin hydrochloride tablets or capsules is orally taken through the digestive tract and taken before sleep once a day, and the treatment course is 12-52 weeks, so that the terazosin hydrochloride tablets or capsules are used for reducing the blood vessel hardness and treating the increase of the blood vessel hardness caused by the blood vessel degenerative change. The end-of-treatment period determined the follow-up treatment regimen based on the physical examination data.
Example 4
The terazosin hydrochloride tablet or capsule is 0.25mg (calculated by active ingredients), is orally taken through the digestive tract and is taken before sleep once a day, and the treatment course is 12-52 weeks, so that the terazosin hydrochloride tablet or capsule is used for preventing the increase of the hardness of blood vessels caused by the degenerative change of the blood vessels.
In order to confirm the excellent efficacy of terazosin in the application of drugs for reducing vascular stiffness, the results obtained in various pharmacological basic studies are further described below:
experimental example 1
Clinical effect of terazosin on reducing vascular stiffness
Clinically, the population taking terazosin 0.25mg, 0.5mg, 0.75mg and 1mg every day is collected, the pulse wave conduction velocity before and during taking is measured on the left side and the right side, and the detection result is recorded. As shown in fig. 1: compared with the pulse wave velocity before taking, the pulse wave velocity is obviously reduced after taking terazosin (the difference is statistically significant by adopting the statistical analysis of paired t test, and p is less than 0.01); two points connected in fig. 1 are results of measuring Pulse Wave Velocity (PWV) on the left and right sides of the body before and after the same person takes terazosin, respectively, and the ordinate is PWV. In the process of natural aging, the conduction speed of the blood vessel pulse wave of the human body is increased year by year. As shown in fig. 2: in the aspect of reducing the blood vessel pulse wave conduction velocity, the effect of using 0.5mg and 0.75mg of terazosin is better than the effect of using 0.25mg and 1mg of terazosin, which shows that terazosin still has excellent effect of reducing blood vessel hardness under the condition that the conventional dose of terazosin is far lower than 2-5 mg. However, in the experimental study, all the observed subjects did not have the side effects related to terazosin, such as weakness, palpitation, nausea, orthostatic hypotension, etc.
Experimental example 2
Effect of terazosin in reducing blood vessel stiffness in mouse model of vascular progeria
APOE-/-mice were fed a high-fat diet and an arteriosclerosis model was established to simulate the premature aging of blood vessels. After 8 weeks of high fat diet feeding, the mice were subjected to arterial pulse wave velocity measurement and statistical analysis of the experimental results. Each group of experiments used 10 mice, and the experiments were repeated three times. The statistical method is a one-way ANOVA analysis, and the statistical result is shown in fig. 3: the arterial Pulse Wave Velocity (PWV) of mice was significantly increased after high fat feeding (HFD) compared to normal diet (CTRL) mice (PWV is the ordinate in the figure); the arterial pulse wave velocity of mice fed with high fat and given with a small dose of terazosin (HFD + lowTZ) of 0.05mg/Kg is obviously reduced; similarly, the arterial pulse wave velocity of mice fed with high fat and given with a large dose of terazosin (HFD + highTZ) of 0.5mg/Kg is also obviously reduced; there was a significant difference in vascular stiffness (p <0.05, indicated by x in the figure) between high fat-fed + terazosin-treated mice and mice fed solely high fat.
Experimental example 3
Effect of terazosin on dry prognosis of vascular tissues in mouse model of vascular progeria
And (3) taking the thoracic aorta-abdominal aorta segment of the model mouse with the premature vascular failure in the experimental example 2, carrying out beta-galactosidase (beta-Gal) staining and EVG staining, and carrying out statistical analysis on the experimental result. Each group of experiments used 6 mice and the experiments were repeated three times. The statistical method is one-way ANOVA analysis, and the statistical results are shown in fig. 4 and 5. As shown in fig. 4: vascular galactosidase staining was clearly positive in mice after high fat feeding (HFD) compared to normal diet (CTRL) mice; the vascular galactosidase staining positive rate of mice fed with high fat and given with a small oral dose of terazosin (HFD + lowTZ) of 0.05mg/Kg is obviously reduced; similarly, the vascular galactosidase staining positive rate of mice fed with high fat and given with oral large dose of terazosin (HFD + highTZ) of 0.5mg/Kg is also obviously reduced; there was a significant difference in the positive rate of galactosidase staining between blood vessels from mice treated with high fat plus terazosin and those from mice fed with only high fat (p <0.05, indicated by x in the figure). As shown in fig. 5: the black-stained parts represent collagen fibers in the blood vessels of the mice. EVG staining of mice after high fat feeding (HFD) showed changes in elastic fiber disorganization, disorganization of breaks, and rigidity of walking compared to normal diet (CTRL) mice; while mice treated with high-fat feeding plus a small dose of terazosin (HFD + lowTZ) were effective in alleviating collagen fiber deterioration; also, high-fat fed + high dose terazosin (HFD + highTZ) -treated mice were also effective in alleviating collagen fiber deterioration.
In conclusion, by means of the technical scheme, the new application of terazosin or analogues thereof in the aspect of medicines for reducing the blood vessel hardness can be determined, the new application not only provides a new selection scheme for medical researchers in clinical treatment, but also can greatly reduce the medicine dosage, save the medicine cost, reduce the medical burden of patients and limit the adverse side effect of the terazosin to an extremely low level compared with the 2-5 mg conventional dose of terazosin clinically used at present.
The above description is only exemplary of the present invention and should not be taken as limiting the invention, as any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (12)
1. An application of terazosin or its medicinal salt or its solvate in preparing the medicines for decreasing the hardness of blood vessel is disclosed.
2. Use of terazosin according to claim 1 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the medicinal salt is one or more of hydrochloride, phosphate, benzene sulfonate, methanesulfonate, sulfate and nitrate of terazosin.
3. Use of terazosin according to claim 1 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the solvate is a hydrate of terazosin or a pharmaceutically acceptable salt thereof.
4. Use of terazosin according to claim 3 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the hydrate is a monohydrate or a dihydrate.
5. Use of terazosin according to claim 3 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the solvate is terazosin hydrochloride dihydrate.
6. Use of terazosin according to any of claims 1-5 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the terazosin is administered via the digestive tract in a daily dose of 0.1-1 mg of its active ingredient, once or more times a day.
7. Use of terazosin according to claim 6 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the terazosin is administered via the digestive tract in a daily dose of 0.25-0.75 mg of its active ingredient, once or two to three times a day.
8. Use of terazosin according to claim 6 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the terazosin is administrated through the digestive tract in a daily dose of 0.50-0.75 mg of active ingredients, and is taken once or twice a day; the composition is taken once a day in a fixed time, and is taken twice a day in the morning and at night.
9. Use of terazosin according to claim 6 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the terazosin is administered via the digestive tract in a daily dose of 0.50mg of its active ingredient, once a day, before bedtime.
10. Use of terazosin according to claim 1 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the effect evaluation of the blood vessel hardness reducing medicine is to clinically evaluate the hardening degree of the blood vessel tissue by measuring the pulse wave conduction velocity.
11. Use of terazosin according to claim 1 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the effect evaluation of the blood vessel hardness reducing medicine is to evaluate the hardening degree of blood vessels by measuring the pulse wave conduction speed on an animal model.
12. Use of terazosin according to claim 1 for the preparation of a medicament for reducing vascular stiffness, characterized in that: the evaluation of the effect of the blood vessel hardness reducing drug is to evaluate the aging degree of the blood vessel tissue by detecting the activity of beta-galactosidase in the experiment.
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| ""第七届血管老化高峰论坛"", pages 6, Retrieved from the Internet <URL:https://www.tjh.com.cn/contents/605/31368.html> * |
| ERNESTO L. SCHIFFRIN: ""Circulatory therapeutics: use of antihypertensive agents and their effects on the vasculature"", 《J. CELL. MOL. MED.》, vol. 14, no. 5, pages 1018 - 1029 * |
| JOEL A. STROM等: ""Acute hemodynamic effects of terazosin in hypertensive and normotensive patients"", 《AMERICAN HEART JOURNAL》, vol. 122, no. 3, pages 892 - 900 * |
| 中国临床试验注册中心: ""评估特拉唑嗪降低血管硬度的前瞻性、多中心、观察性临床研究"", pages 1 - 4, Retrieved from the Internet <URL:https://www.chictr.org.cn/showproj.html?proj=65228> * |
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