CN115624522B - Drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure and preparation method and application thereof - Google Patents

Drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure and preparation method and application thereof Download PDF

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CN115624522B
CN115624522B CN202211091892.1A CN202211091892A CN115624522B CN 115624522 B CN115624522 B CN 115624522B CN 202211091892 A CN202211091892 A CN 202211091892A CN 115624522 B CN115624522 B CN 115624522B
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ethanol
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ethanol injection
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ethyl alcohol
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王德明
范新东
沈禹辰
苏立新
王瑱冯
郑连洲
韩一峰
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Ninth Peoples Hospital Shanghai Jiaotong University School of Medicine
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Abstract

The invention provides a medicine-carrying ethanol injection capable of preventing acute increase of pulmonary arterial pressure, which comprises the following raw materials of absolute ethanol vasodilator and renin-angiotensin system antagonist, wherein the mass fraction of ethanol in the medicine-carrying ethanol injection is 90% -95%. The invention also provides a preparation method of the drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure. The drug-loaded ethanol injection capable of preventing acute increase of pulmonary artery pressure provided by the invention does not change the physicochemical property of ethanol, has the mass fraction of ethanol of 90% -95%, ensures the embolism hardening capacity of absolute ethanol, has vasodilation capacity, can offset the vascular pathological contraction caused by ethanol to a certain extent, can further inhibit the critical path of pulmonary artery increase, ensures that pulmonary artery pressure is maintained at a normal level, and reduces ethanol treatment risk and complications.

Description

Drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a medicine-carrying ethanol injection capable of preventing acute increase of pulmonary arterial pressure, and a preparation method and application thereof.
Background
Vascular malformations are congenital diseases caused by congenital malformation of blood vessels or lymphatic vessels, which are well developed in the head and face parts, and can also involve limbs and trunk. The light vascular deformity affects the appearance, brings huge life and psychological burden to the patient, and serious vascular deformity even causes organ shift, skeletal deformity and dysfunction, thereby greatly reducing the life quality of the patient. The traditional methods of treatment of vascular malformations are interventional sclerotherapy and interventional embolic therapy. The drugs used for interventional hardening or embolic therapy are called hardening agents or embolic agents and mainly include absolute ethanol, bleomycin (pingyangmycin), foam hardening agents (polidocanol, polylauryl alcohol, sodium tetradecyl sulfate), etc. The principle is that vascular endothelial cells and vascular wall structures are damaged, secondary coagulation and thrombosis are caused, thereby causing vascular atrophy fibrosis and reducing the size of a focus. Ethanol is used as a liquid hardener/embolic agent, can quickly destroy vascular endothelial cells, simultaneously denature hemoglobin, cause wide thrombosis and fibrosis in blood vessels, and promote vascular occlusion and thrombosis in lesions. The absolute ethyl alcohol has obvious effect of treating venous malformation, lymphatic malformation and arteriovenous malformation. It is cheap and easy to obtain, so it is widely used in the treatment of vascular malformations.
During the ethanol intravascular injection, a sharp rise in pulmonary arterial pressure is often observed, although it is not clear whether the ethanol-induced rise in pulmonary arterial pressure is similar to the primary/secondary pulmonary arterial pressure, but the ethanol intravascular injection-induced rise in pulmonary arterial is a more dangerous complication in ethanol embolic therapy. When large amounts of ethanol enter the cardiopulmonary circulatory system, the concentration of ethanol in the blood increases, which may cause spasticity of the pre-capillary pulmonary artery or extensive thromboembolism by microvascular generation. Although pulmonary arterial pressure increases are usually transient, if not effectively controlled, irreversible damage to cardiopulmonary function can occur, and even cardiopulmonary arrest or even death can occur.
In order to reduce the heart and lung risks caused by the intravascular injection of ethanol, the protection of organs such as heart and lung, especially pulmonary arteries, is particularly important in the ethanol injection process.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure, which is prepared by mixing absolute ethanol, vasodilator and renin-angiotensin system antagonist, wherein the physical and chemical properties of the ethanol are not changed, the mass fraction of the ethanol is 90% -95%, the embolism hardening capacity of the absolute ethanol is ensured, the ethanol-loaded ethanol injection has vasodilation capacity, can offset vascular pathological contraction caused by the ethanol to a certain extent, and can further inhibit critical pathways of pulmonary arterial increase, so that pulmonary arterial pressure is maintained at a normal level, and the ethanol treatment risk and complications are reduced.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the first aspect of the invention provides a drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure, which comprises the following raw materials of absolute ethanol, vasodilator and renin-angiotensin system antagonist, wherein the mass fraction of ethanol in the drug-loaded ethanol injection is 90% -95%.
Preferably, the mass fraction of the vasodilator in the drug-loaded ethanol injection is 2.5% -5%; the mass fraction of the renin-angiotensin system antagonist is 2.5% -5%.
Preferably, the ethanol injection for carrying medicine further comprises one or more medicines for treating vascular malformations.
Preferably, the vasodilator is selected from a drug that relaxes vascular smooth muscle, a calcium channel antagonist, an alpha receptor blocker or a herbal mixture.
Preferably, the renin-angiotensin system antagonist is selected from the group consisting of an angiotensin converting enzyme antagonist, an angiotensin II receptor antagonist or an angiotensin receptor enkephalinase antagonist.
The second aspect of the invention provides a method for preparing a drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure, comprising the following steps:
Firstly, mixing a vasodilator with absolute ethyl alcohol, stirring until the vasodilator is completely dissolved, and regulating the mass fraction of the vasodilator to be 2.5% -5%, so as to prepare an absolute ethyl alcohol-vasodilator mixed solution, wherein the mass fraction of the ethyl alcohol in the absolute ethyl alcohol-vasodilator mixed solution is 95% -97.5%;
And step two, further adding the renin-angiotensin system antagonist into the absolute ethyl alcohol-vasodilator mixed solution, stirring until the renin-angiotensin system antagonist is completely dissolved, and regulating the mass fraction of the renin-angiotensin system antagonist to be 2.5% -5%, so as to prepare the medicine-carrying ethanol injection, wherein the mass fraction of ethanol in the medicine-carrying ethanol injection is 90% -95%.
In a preferred embodiment of the invention, the preparation method further comprises the steps of: adding one or more drugs for treating vascular malformation into the ethanol injection.
The using method comprises the following steps: the drug-carrying ethanol injection disclosed by the invention is stable in liquid property and can be directly administered by injection. Under Digital Subtraction Angiography (DSA), a catheter is cannulated via femoral artery puncture, the catheter tip is delivered to the lesion, and then injection therapy is performed through the catheter.
The third aspect of the invention provides an application of the drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure in preparing a vascular malformation embolism treatment medicament.
The drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure provided by the invention has the following beneficial effects:
1. The drug-loaded ethanol injection provided by the invention maintains the embolism capability of absolute ethanol, has the capability of promoting vasodilation by adding a vasodilator, counteracts the pathological vasoconstriction caused by ethanol to a certain extent, maintains the pulmonary artery pressure at a normal level, and reduces the risk and complications of ethanol treatment.
2. The drug-loaded ethanol injection combines the effects of the absolute ethanol physical embolic agent and the renin-angiotensin system antagonist, can further inhibit the critical path of pulmonary artery increase while the vasodilation drug plays a role, and can maintain the pulmonary artery pressure at a normal level, so that a patient can receive ethanol treatment more safely.
Drawings
Fig. 1 is an effect of saline, absolute ethanol, ethanol-losartan mixed solution on systolic pressure, diastolic pressure and mean pulmonary artery pressure of swine (P <0.05; =p <0.01; =p < 0.001); in the graph, A is the influence of physiological saline on the systolic pressure of the pulmonary artery of the pig; b is the influence of absolute ethyl alcohol on the systolic pressure of the pulmonary artery of the pig; c is the influence of the ethanol-losartan mixed solution on the pulmonary artery systolic pressure of the pigs; d is the influence of normal saline on the diastolic blood pressure of pigs; e is the influence of absolute ethyl alcohol on the diastolic blood pressure of pigs; f is the influence of the ethanol-losartan mixed solution on the diastolic blood pressure of pigs; g is the influence of normal saline on the average pulmonary artery pressure of pigs; h is the effect of absolute ethanol on mean pulmonary arterial pressure in pigs; and I is the influence of the ethanol-losartan mixed solution on the average pulmonary artery pressure of pigs.
Detailed Description
The invention relates to a drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure, and a preparation method and application thereof.
The first aspect of the invention provides a drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure, which comprises the following raw materials of absolute ethanol, vasodilator and renin-angiotensin system antagonist, wherein the mass fraction of ethanol in the drug-loaded ethanol injection is 90% -95%.
The reason for the elevated pulmonary artery pressure is that ethanol, after reaching the pulmonary artery capillary bed with blood circulation, acts directly on pulmonary artery smooth muscle cells and causes transient precharacterizing cramps, which in turn leads to elevated pulmonary artery pressure, increased right post-cardiac load, decreased right cardiac output and even severe heart-lung failure.
The mass fraction of the ethanol in the drug-loaded ethanol injection is 90% -95%, the embolism efficiency of the ethanol is not changed, firstly, the ethanol is mixed with a vasodilator to achieve the purpose of dilating pulmonary arteries, the acute pulmonary arterial pressure increase caused by the ethanol is reduced, secondly, the pulmonary arterial pressure increase is related to the activation of a renin-angiotensin system, and the key pathway capable of inhibiting the increase of the pulmonary arteries can be inhibited by adding the renin-angiotensin antagonist, so that the pulmonary arterial pressure is maintained at a normal level in the embolism hardening treatment process.
In some preferred embodiments of the invention, the mass fraction of vasodilator in the drug-loaded ethanol injection is 2.5% -5%; the mass fraction of the renin-angiotensin system antagonist is 2.5% -5%.
In some preferred embodiments of the present invention, the drug-loaded ethanol injection further comprises one or more of drugs for treating vascular malformations. Further, the drugs for treating vascular malformations comprise polydiol, polidocanol, bleomycin, pingyangmycin and the like.
Vasodilators promote muscle relaxation, thereby increasing the vessel diameter size of the vessel to allow vasodilation, and may also directly affect the action of vascular smooth muscle or interfere with vasodilation of the nerve signal that governs vasoconstriction.
In some preferred embodiments of the invention, the vasodilator is selected from a drug that relaxes vascular smooth muscle, a calcium channel antagonist, an alpha receptor blocker, or a herbal mixture. In some more preferred embodiments of the present invention, the vasodilator smooth muscle drug is selected from one or more of nitroglycerin and sodium nitroprusside. In some more preferred embodiments of the present invention, the calcium channel antagonist is selected from one or more of nifedipine and amlodipine. In some more preferred embodiments of the present invention, the alpha receptor blocker is selected from one or more of phentolamine and prazosin. In some preferred embodiments of the present invention, the Chinese medicinal mixture is selected from one or more of Saviae Miltiorrhizae radix, thrombi, folium Ginkgo, rhizoma Ligustici Chuanxiong sweet, and DANSHONG.
The renin-angiotensin system (Renin-Angiotensin System, RAS) has important physiological functions in body water-salt metabolism and blood pressure maintenance, and excessive activation of RAS can lead to hypertension. Renin, an enzyme, acts by acting on angiotensinogen to form the decapeptidyl-angiotensin i. Under the action of Angiotensin Converting Enzyme (ACE), angiotensin i is rapidly converted to octapeptide angiotensin II. Angiotensin II acts to raise blood pressure through a number of mechanisms, including raising total peripheral resistance.
In some preferred embodiments of the invention, the renin-angiotensin system antagonist is selected from the group consisting of an angiotensin converting enzyme antagonist, an angiotensin II receptor antagonist or an angiotensin receptor enkephalinase antagonist. In some more preferred embodiments of the present invention, the angiotensin converting enzyme antagonist is selected from one or more of enalapril, cilazapril, quinapril, ramipril, benazepril, perindopril, spiropril, fosinopril, captopril. In some more preferred embodiments of the present invention, the angiotensin II receptor antagonist is selected from one or more of candesartan, valsartan, losartan. In some more preferred embodiments of the invention, the angiotensin receptor enkephalinase antagonist is Sha Kuba% of the sodium valsartan.
In a preferred embodiment of the present invention, the vasodilator is nitroglycerin and the renin-angiotensin system antagonist is losartan.
In a preferred embodiment of the present invention, nifedipine is selected as the vasodilator and captopril is selected as the renin-angiotensin system antagonist.
In a preferred embodiment of the invention, the vasodilator is phentolamine and the renin-angiotensin system antagonist is valsartan.
In a preferred embodiment of the present invention, the vasodilator is ginkgo leaf extract and the renin-angiotensin system antagonist is losartan.
In the medicine-carrying ethanol injection provided by the invention, the absolute ethanol is liquid ethanol, and the mass fraction of the ethanol in the medicine-carrying ethanol injection is 90% -95%.
The second aspect of the invention provides a method for preparing a drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure, comprising the following steps:
Firstly, mixing a vasodilator with absolute ethyl alcohol, stirring until the vasodilator is completely dissolved, and regulating the mass fraction of the vasodilator to be 2.5% -5%, so as to prepare an absolute ethyl alcohol-vasodilator mixed solution, wherein the mass fraction of the ethyl alcohol in the absolute ethyl alcohol-vasodilator mixed solution is 95% -97.5%;
And step two, further adding the renin-angiotensin system antagonist into the absolute ethyl alcohol-vasodilator mixed solution, stirring until the renin-angiotensin system antagonist is completely dissolved, and regulating the mass fraction of the renin-angiotensin system antagonist to be 2.5% -5%, so as to prepare the medicine-carrying ethanol injection, wherein the mass fraction of ethanol in the medicine-carrying ethanol injection is 90% -95%.
In a preferred embodiment of the invention, the preparation method further comprises the steps of: adding one or more drugs for treating vascular malformation into the ethanol injection. The medicine for treating vascular malformations comprises polydiol, polidocanol, bleomycin, pingyangmycin and the like.
The preparation method of the drug-loaded ethanol injection is not particularly limited to temperature and pressure, and can be prepared under normal temperature and normal pressure conditions.
The stirring mode in the preparation method of the drug-loaded ethanol injection is not particularly limited, and can be mechanical stirring, magnetic stirring and the like.
The ethanol injection for carrying the medicine accords with various regulations related to injection items of Chinese pharmacopoeia 2020 edition, and is sterile and bacterial endotoxin: the endotoxin content per 1mg was less than 1.0EU.
The third aspect of the invention provides an application of the drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure in preparing a vascular malformation embolism treatment medicament.
Vascular malformations, also known as vascular malformations, are classified by blood flow velocity and lumen type into Capillary Malformations (CM), lymphatic Malformations (LM), venous Malformations (VM) of low blood flow velocity; arterial Malformations (AM), arteriovenous fistulae (AVF) and arteriovenous malformations (AVM) of high blood flow rates, wherein diagnosis and treatment of AVM are difficult problems in medical practice. The absolute ethyl alcohol can denature the contacted hemoglobin and directly destroy the abnormal vascular endothelial cells serving as the recurrence source of the AVM due to the dehydration and the denudation, thereby achieving the effect of curing the AVM. The absolute ethyl alcohol has the characteristics of easy availability, easy storage and relatively low cost, can be fully dispersed in abnormal blood vessel groups as a liquid embolic agent, can generate long-acting embolic effect after being injected in the blood vessel, and can not generate foreign body rejection reaction after being removed by metabolism in the body, thereby providing guarantee for wide application of the absolute ethyl alcohol as the embolic agent in the treatment of AVM.
Common complications of absolute ethanol embolism therapy AVM include local and systemic symptoms or lesions. Local symptoms include pain, vasospasm, tissue edema, skin ulcers, skin or mucosal blisters, nerve damage, muscle or cartilage necrosis, adjacent organ damage, and the like; examples of systemic symptoms include nausea, vomiting, coma, bronchospasm, pulmonary hypertension, pulmonary arterial embolism, pleural effusion, hematocrit reduction, transient hemoglobinuria, acute renal failure, respiratory depression, hypoglycemia, rhabdomyolysis, arrhythmia, cerebral apoplexy, deep vein thrombosis, behavior modification, and the like.
The drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure provided by the invention has the advantages that the preparation condition is mild, the preparation can be carried out at normal temperature and normal pressure, the obtained mixture is uniform and stable, and suspension or layering phenomenon can not occur.
The application method of the drug-loaded ethanol injection comprises the following steps: the drug-carrying ethanol injection disclosed by the invention is stable in liquid property and can be directly administered by injection. Under Digital Subtraction Angiography (DSA), a catheter is cannulated via femoral artery puncture, the catheter tip is delivered to the lesion, and then injection therapy is performed through the catheter.
The drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure provided by the invention can not change the embolism efficiency of absolute ethanol in the drug-loaded ethanol injection, and compared with pure injection of absolute ethanol, the drug-loaded ethanol injection has the advantages that the acute increase of pulmonary arterial pressure is effectively inhibited, and the safety is higher.
The animal experiment result shows that the medicine-carrying ethanol injection provided by the invention is applied to vascular malformation embolism treatment, can effectively inhibit acute pulmonary arterial pressure increase caused by absolute ethanol in the injection process, reduces ethanol treatment risk and complications, and has an effect obviously superior to that of an absolute ethanol-vasodilator mixed solution and an absolute ethanol-renin-angiotensin system antagonist mixed solution.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, materials used in the embodiments, any methods, devices, and materials of the prior art similar or equivalent to those described in the embodiments of the present invention may be used to practice the present invention according to the knowledge of one skilled in the art and the description of the present invention.
Example 1
A medicine-carrying ethanol injection (anhydrous ethanol-nitroglycerin-losartan mixed solution) capable of preventing acute increase of pulmonary arterial pressure is prepared from anhydrous ethanol, nitroglycerin and losartan, wherein the mass fractions of the anhydrous ethanol, the nitroglycerin and the losartan are 95%, 2.5% and 2.5% respectively at 25 ℃.
A preparation method of a drug-loaded ethanol injection (absolute ethanol-nitroglycerin-losartan mixed solution) capable of preventing acute increase of pulmonary arterial pressure comprises the following steps: adding 2.5g of losartan raw material powder into 95g of absolute ethyl alcohol, stirring and mixing uniformly until the mixture is completely dissolved to obtain an absolute ethyl alcohol-losartan mixed solution, adding 2.5g of nitroglycerin raw material powder into the absolute ethyl alcohol-losartan mixed solution, stirring and mixing uniformly until the mixture is completely dissolved, and enabling the mass fraction of the ethanol to reach 95% to form the absolute ethyl alcohol-nitroglycerin-losartan mixed solution.
Example 2
A medicine-carrying ethanol injection (anhydrous ethanol-nifedipine-captopril mixed solution) capable of preventing acute increase of pulmonary arterial pressure is prepared from anhydrous ethanol, nifedipine and captopril, wherein the mass fractions of the anhydrous ethanol, nifedipine and captopril are 95%, 2.5% and 2.5% respectively at 25 ℃.
A preparation method of a drug-loaded ethanol injection (absolute ethanol-nifedipine-captopril mixed solution) capable of preventing acute increase of pulmonary arterial pressure comprises the following steps: adding 2.5g of captopril powder into 95g of absolute ethyl alcohol, stirring and uniformly mixing until the mixture is completely dissolved to obtain an absolute ethyl alcohol-captopril mixed solution, adding 2.5g of nifedipine raw material powder into the absolute ethyl alcohol-captopril mixed solution, stirring and uniformly mixing until the mixture is completely dissolved, and enabling the mass fraction of the ethyl alcohol to reach 95% to form the absolute ethyl alcohol-nifedipine-captopril mixed solution.
Example 3
A medicine-carrying ethanol injection (anhydrous ethanol-phentolamine-valsartan mixed solution) capable of preventing acute increase of pulmonary arterial pressure is prepared from anhydrous ethanol, phentolamine and valsartan, wherein the mass fractions of the anhydrous ethanol, the phentolamine and the valsartan are 95%, 2.5% and 2.5% respectively at 25 ℃.
A preparation method of a drug-loaded ethanol injection (anhydrous ethanol-phentolamine-valsartan mixed solution) capable of preventing acute increase of pulmonary arterial pressure comprises the following steps: adding 2.5g of valsartan powder into 95g of absolute ethyl alcohol, stirring and mixing uniformly until the mixture is completely dissolved to obtain an absolute ethyl alcohol-valsartan mixed solution, adding 2.5g of phentolamine raw material powder into the absolute ethyl alcohol-val Sha Tanli mixed solution, stirring and mixing uniformly until the mixture is completely dissolved, and enabling the mass fraction of the ethyl alcohol to reach 95% to form the absolute ethyl alcohol-phentolamine-valsartan mixed solution.
Example 4
A medicated ethanol injection (anhydrous ethanol-folium Ginkgo extract-losartan mixed solution) for preventing acute pulmonary arterial hypertension is prepared from anhydrous ethanol, folium Ginkgo extract (G832683,500 g, shanghai Michelia Biochemical technology Co., ltd.) and losartan, wherein the mass fractions of the anhydrous ethanol, the folium Ginkgo extract and the losartan are 95%, 2.5% and 2.5% respectively at 25deg.C.
A preparation method of a drug-loaded ethanol injection (an absolute ethanol-ginkgo leaf extract-losartan medoxomil mixed solution) capable of preventing acute increase of pulmonary arterial pressure comprises the following steps: adding 2.5g of losartan powder into 95g of absolute ethyl alcohol, stirring and mixing until the powder is completely dissolved to obtain an absolute ethyl alcohol-losartan mixed solution, adding 2.5g of ginkgo leaf extract raw material powder into the absolute ethyl alcohol-losartan mixed solution, stirring and mixing until the powder is completely dissolved, and enabling the mass fraction of the ethanol to reach 95% to form the absolute ethyl alcohol-ginkgo leaf extract-losartan mixed solution.
Experimental data
1. Influence of the Anhydrous ethanol-losartan mixture on pulmonary artery pressure
1.1, Anhydrous ethanol-losartan mixture
The anhydrous ethanol-losartan mixed solution is prepared from the anhydrous ethanol and losartan, and the mass fractions of the anhydrous ethanol and the losartan are 95% and 5% respectively at 25 ℃.
1.2 Preparation of the Anhydrous ethanol-losartan mixture
The preparation method of the anhydrous ethanol-losartan mixed solution comprises the following steps: and adding 5g of losartan raw material powder into 95g of absolute ethyl alcohol, stirring and uniformly mixing until the powder is completely dissolved, and enabling the mass fraction of the ethyl alcohol to reach 95% to form an absolute ethyl alcohol-losartan mixed solution.
1.3, Experimental methods
32 Pigs were selected and divided into four groups: physiological saline group, losartan group, absolute ethanol group and ethanol-losartan solution group, 8 each. The normal saline, the absolute ethyl alcohol and the absolute ethyl alcohol-losartan mixed solution are respectively used for intravenous administration, and the injection is continuously carried out for 5 times, wherein the interval between each time is ten minutes, and the injection dose is not more than 0.1mL/kg body weight. The losartan group experimental pigs were orally administered once daily for three days at a weight of 10mg/kg three days before monitoring pulmonary arterial pressure.
1.4, Analysis of results
As shown in fig. 1a, D, G, in physiological conditions, the systolic pulmonary artery pressure (sapap), diastolic pressure (dPAP), and mean pulmonary artery pressure (mPAP) of the domestic pigs were not affected by losartan administration. As shown in fig. 1B, E and H, the systolic pressure, the diastolic pressure and the mean pulmonary artery pressure of the home pig pulmonary artery in the absolute ethanol group are all significantly increased, and the systolic pressure, the diastolic pressure and the mean pulmonary artery pressure of the home pig pulmonary artery in the ethanol-losartan solution group are not significantly increased. As shown in fig. 1C, F, I, losartan is capable of partially inhibiting elevated pulmonary arterial pressure compared to physiological levels of pulmonary arterial pressure of domestic pigs.
2. Influence of absolute ethanol-nitroglycerin-losartan mixed solution on pulmonary artery pressure
2.1 Sources of each medicament
Absolute ethyl alcohol: commercially available (Shanghai Ala Biochemical technologies Co., ltd., E111963, 500 mL).
Absolute ethanol-losartan mixed solution: the same as 1.1.
Absolute ethanol-nitroglycerin mixed solution: is prepared from absolute ethyl alcohol and nitroglycerin, wherein the mass fractions of the absolute ethyl alcohol and the nitroglycerin are 95% and 5% respectively at 25 ℃; the preparation method comprises the following steps: adding 5g of nitroglycerin raw material powder into 95g of absolute ethyl alcohol, stirring and uniformly mixing until the mixture is completely dissolved, and enabling the mass fraction of the ethyl alcohol to reach 95%, thus forming an absolute ethyl alcohol-nitroglycerin mixed solution.
Absolute ethanol-nitroglycerin-losartan mixed solution: as in example 1.
2.2 Experimental methods
The 32 pigs are selected and divided into four groups according to different injected medicaments: an absolute ethyl alcohol group (I), an absolute ethyl alcohol-losartan mixed solution group (II), an absolute ethyl alcohol-nitroglycerin mixed solution group (III) and an absolute ethyl alcohol-nitroglycerin-losartan mixed solution group (IV), wherein 8 absolute ethyl alcohol-nitroglycerin-losartan mixed solution groups are arranged in each group. The absolute ethyl alcohol, the absolute ethyl alcohol-losartan mixed solution and the absolute ethyl alcohol-nitroglycerin mixed solution are respectively used for intravenous administration, and the dosage of each injection is not more than 0.1mL/kg body weight. Changes in pulmonary artery systolic pressure were recorded before and after injection.
2.3 Analysis of results
The changes in pulmonary artery systolic pressure for each group are shown in table 1 below:
Table 1 influence of groups on pulmonary systolic pressure of domestic pigs
When nitroglycerin (vasodilator) and losartan (renin-angiotensin system antagonist) were used together, the increase in acute pulmonary arterial pressure due to absolute ethanol was significantly inhibited (P < 0.0001), and the effect was superior to that of losartan (p= 0.0221) or nitroglycerin (p= 0.0366) alone.
From the experimental results, the medicine-carrying ethanol injection capable of preventing acute pulmonary arterial pressure increase can effectively inhibit acute pulmonary arterial pressure increase caused by absolute ethanol in the injection process by mixing and combining the vasodilator, the renin-angiotensin system antagonist and the absolute ethanol.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.

Claims (5)

1. A drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure is characterized by comprising the following raw materials of absolute ethanol, vasodilator and renin-angiotensin system antagonist, wherein the mass fraction of ethanol in the drug-loaded ethanol injection is 90% -95%; the mass fraction of the vasodilator in the ethanol injection for carrying the medicine is 2.5% -5%; the mass fraction of the renin-angiotensin system antagonist is 2.5% -5%; the vasodilator is a drug for dilating vascular smooth muscle; the renin-angiotensin system antagonist is an angiotensin ii receptor antagonist;
the medicine for dilating vascular smooth muscle is nitroglycerin;
the angiotensin II receptor antagonist is losartan.
2. The drug-loaded ethanol injection as claimed in claim 1, wherein the drug-loaded ethanol injection further comprises one or more drugs for treating vascular malformations.
3. A method for preparing a drug-loaded ethanol injection capable of preventing acute increase of pulmonary arterial pressure according to claim 1 or 2, comprising the following steps:
Firstly, mixing a vasodilator with absolute ethyl alcohol, and stirring until the vasodilator and the absolute ethyl alcohol are completely dissolved to prepare an absolute ethyl alcohol-vasodilator mixed solution, wherein the mass fraction of the ethyl alcohol in the absolute ethyl alcohol-vasodilator mixed solution is 95% -97.5%;
And step two, further adding the renin-angiotensin system antagonist into the absolute ethyl alcohol-vasodilator mixed solution, stirring until the renin-angiotensin system antagonist is completely dissolved, and regulating the mass fraction of the renin-angiotensin system antagonist to be 2.5% -5%, so as to prepare the medicine-carrying ethanol injection, wherein the mass fraction of ethanol in the medicine-carrying ethanol injection is 90% -95%.
4. A method of preparing as claimed in claim 3, further comprising the steps of: adding one or more drugs for treating vascular malformation into the ethanol injection.
5. Use of the drug-loaded ethanol injection according to any one of claims 1-2 or the drug-loaded ethanol injection capable of preventing acute increases in pulmonary arterial pressure prepared by the preparation method according to any one of claims 3-4 in the preparation of a vascular malformation embolism sclerosis treatment medicament.
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硝苯地平与卡托普利单用及联合应用对低氧性肺动脉高压的作用;吴为群等;医药卫生科技;第17卷(第1期);第59-61页摘要、讨论部分 *

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