TW202000197A - Novel uses of Pipoxolan and its pharmaceutical preparations - Google Patents

Abstract

Novel uses of Pipoxolan HCl and its pharmaceutical preparations are disclosed. Pipoxolan is useful therapeutic drugs for pathological conditions caused by coronary artery spasm which reduce myocardial blood flow, and lead to myocardial ischemia, the symptoms including: chest pain, chest tightness, arrhythmia, stenocardia, angina pectoris, myocardial infarction, and sudden death...clinical syndromes. The pharmaceutical preparations which contain Pipoxolan HCl can cure and prevent those symptoms.

Description

Pipoxolan's novel use and pharmaceutical preparation based on this novel use

The present invention relates to a novel use of Pipoxolan and a pharmaceutical preparation based on the novel use, especially Pipoxolan to treat pathological symptoms caused by coronary artery spasm.

Pipoxolan (皮普苏兰) (Pipoxolan HCl), the chemical name is: 5,5-diphenyl-2-(2-piperidin-1-ylethyl)-1,3-dioxolan-4- One hydrochloride) is a compound with anti-spasmodic effect synthesized by Pailer et al. in 1968, which is a 1,3-dioxolane derivative.

Since 1968, Pipoxolan has been used clinically to relieve smooth muscle spasm in the digestive tract, urinary tract, and reproductive system. It is used to treat dysmenorrhea, bilateral urinary tract stones, gallstones, chronic gastritis, Postpartum contractions, urinary tract stones, hydronephrosis, and renal colic. Since previous pharmaceutical and clinical studies have not found it to have an anti-coronary artery spasm effect, Pipoxolan has not been used clinically for cardiovascular diseases in the past fifty years.

Coronary artery spasm refers to a group of clinical syndromes caused by transient contraction of the subepithelial conduction artery caused by various reasons, causing partial or complete occlusion of blood vessels, leading to myocardial ischemia. Myocardial ischemia caused by coronary artery spasm can cause clinical syndromes including chest pain, chest tightness, arrhythmia, angina, myocardial infarction, and sudden death. Coronary artery spasm is the basic cause of various cardiac ischemic diseases, including variant angina pectoris, unstable angina pectoris, acute myocardial infarction, and sudden death. Coronary artery spasm tends to occur in coronary arteries with atherosclerosis, and occasionally in superficial "normal" coronary arteries. Any one or more of its branches can be affected. Coronary artery spasm is the basic cause of various cardiac ischemic diseases, including variant angina pectoris, unstable angina pectoris, acute myocardial infarction, and sudden death. Coronary artery spasm tends to occur in coronary arteries with atherosclerosis, and occasionally in superficial "normal" coronary arteries. Any one or more of its branches can be affected.

The mechanism of coronary artery spasm can be divided into two aspects: neural mechanism and humoral mechanism.

(1) Neural mechanism:

Central nervous and autonomic nerve activities play an important role in the occurrence of coronary spasm. There are two kinds of adrenergic receptors, α and β on the coronary artery. When the α receptor is activated, it causes the coronary artery to contract, and when the β receptor is activated, it causes the coronary artery to relax. Sympathetic nerves can activate α and β receptors simultaneously. However, under normal circumstances, the sympathetic nerves dominate the coronary artery. When under psychological stress (such as excessive excitement, tension, anxiety, panic, grief) or cold stimulation, vigorous exercise, sympathetic nerves can be overexcited, which can induce coronary artery spasm. Smoking, high blood pressure, high cholesterol, lack of exercise, poor diet, obesity, alcohol and diabetes, lack of sleep, mood, smoking, psychological stress can also increase the incidence of coronary artery spasm.

When the vagus nerve is excited, the acetylcholine released by the preganglionic fibers can also release the norepinephrine of the sympathetic nerves. The sympathetic nerves are overexcited, and the local hypersensitivity of the coronary arteries can induce coronary artery spasm. Acting on alpha receptors can induce coronary artery spasm. When β-receptor blockers, the sympathetic nerve is blocked by the vasodilator effect of β-receptor, and the vasoconstrictor effect of α-receptor is relatively enhanced, which also easily causes coronary artery spasm. Alpha adrenaline, such as norepinephrine, can directly excite alpha receptors and induce coronary artery spasm. The vagus nerve can also cause coronary artery spasm through the activation of muscarinic receptors. One-time heavy smoking or alcoholism can cause central and sympathetic, parasympathetic dysfunction, thereby inducing coronary artery spasm. Coronary artery angiography can also cause coronary spasm during coronary angiography. Long-term smoking and drinking can increase the incidence of coronary atherosclerosis and increase the prone factors of coronary spasm.

(2) Body fluid mechanism:

A. Platelets and prostaglandins: In platelets, arachidonic acid is mainly converted into thromboxane A2, into unstable vasoconstrictors and platelet aggregates; in the blood vessel wall, arachidonic acid is converted into prostacyclin , Into unstable vasodilators and anti-aggregates. The balance between prostacyclin and thromboxane A2 regulates the blood coagulation state. When coronary atherosclerosis or other lesions damage vascular endothelial cells, it is easy to cause blood stasis, platelet aggregation, and increase the release of thromboxane A2. At the same time, due to the damage of vascular endothelial cells, the intimal synthesis of prostacyclin is reduced. The increase of thromboxane A2 and the decrease of prostacyclin can induce coronary artery spasm. Vascular spasm further aggravates blood stasis and platelet aggregation, thereby generating more thromboxane A2, forming a vicious circle. At the same time, the aggregated platelets also release adenosine diphosphate and serotonin, which aggravates the contraction of blood vessels. Coronary artery spasm may be the result of multiple factors. Coronary artery spasm can also be induced when using beta-blockers or epinephrine. In severe concentric lesions, the smooth muscles of the tube wall were atrophy, and the plaque stiffness was irreversible, and no spasm occurred. This shows that coronary artery spasm is the result of a combination of factors.

B. Endothelin (ET): Endothelin (ET) is a strong vasoconstrictor substance synthesized by vascular endothelial cells. The underlying coronary artery disease leads to chronic myocardial ischemia, which increases the ET synthesized and released by vascular endothelial cells, and increases the density of ET receptors on coronary artery smooth muscle, thereby inducing vasospasm. A vicious circle is formed between myocardial ischemia, increased ET secretion, and coronary artery spasm. Recent studies have shown that in addition to the strong vasoconstriction effect, ET can also enhance the contraction of norepinephrine and serotonin on coronary arteries. In addition, coronary artery spasm and thrombosis are induced by disrupting the balance of prostacyclin and thromboxane A2 in the coronary arteries. In terms of humoral mechanism, between thromboxane (TXA2) and prostaglandin (PGI2), and between endothelin (EDCF) and endothelium-derived relaxing factor (EDRF), the local balance is an important factor in regulating the caliber of blood vessels. When coronary atherosclerosis, the number of platelets in the narrowed blood vessels increases. Due to the shedding of endothelium, platelets adhere to and aggregate, releasing TXA2 and serotonin. In addition, the synthesis of PGI2 in the wall of the atherosclerosis decreases, which has a strong vasoconstrictor effect. TXA2 increased and PGI2 with vasodilatory effect decreased, the two lost balance, causing coronary artery spasm. At the same time, the EDRF synthesis of the diseased blood vessel wall is reduced, and the production of EDCF with obvious vasoconstriction is increased, which also easily induces coronary artery spasm.

From the above factors, it can be inferred that coronary artery spasm and vascular stenosis caused by coronary artery endothelial cell proliferation are mutually causal and coexist. Studies have shown that the effects of Ca, H+ and Mg, as well as smoking and drinking, can cause central and autonomic dysfunction, thereby inducing coronary spasm. Of course, the narrowed coronary artery must be semilunar or eccentric, and its contralateral tube wall still has the ability to contract. The effects of Ca+2, H+ and Mg+2 in the blood can cause coronary artery spasm. Increased estrogen levels can also induce coronary artery spasm.

Classification of syndromes caused by coronary spasm

1. Variant angina: Coronary angiography confirmed that the main cause of variant angina is coronary artery spasm. There are two types of variant angina pectoris: one type occurs on the basis of coronary atherosclerosis, mostly males, the ST segment elevation during the attack is mostly in the anterior and lateral leads, ischemic is accompanied by ventricular premature beats, short-ventricular Tachycardia or ventricular fibrillation can develop into myocardial infarction. The other type occurs in normal coronary arteries, often in the right coronary arteries, mostly in women under 50 years of age. The ST segment elevation is mostly located in the inferior lead, which may be accompanied by sinus bradycardia and atrioventricular block, and heart failure and myocardial infarction generally do not occur. Many patients with coronary artery spasm do not necessarily develop angina pectoris clinically, but almost all patients with variant angina pectoris have coronary artery spasm.

2. Labor angina: angina pectoris that occurs during exercise. Coronary angiography confirmed the presence of coronary spasm during this type of attack. Myocardial oxygen consumption increases during labor, myocardial oxygen supply and demand are unbalanced, and vasospasm further aggravates myocardial ischemia, causing angina. Coronary angiography also found that part of the patients with angina pectoris had coronary arteries completely open, and angina pectoris was all caused by coronary artery spasm. During this type of angina pectoris, the ST segment is elevated, and the ST segment varies greatly with different exercise levels.

3. Unstable angina: This type of angina pectoris is associated with the rapid progression of atherosclerotic lesions. But there are also factors of coronary artery spasm. People with normal coronary arteries can also become unstable due to repeated seizures.

4. Acute myocardial infarction: Some people found coronary atherosclerosis with coronary artery spasm within 6 hours of symptoms by coronary angiography, and others found coronary angiography in a group of patients with myocardial infarction, 35% of the wall penetration Myocardial infarction, the blood vessels that dominate the infarct area are unobstructed. It shows that coronary atherosclerosis is prone to vasospasm, and the spasm changes the lumen from partial blockage to complete blockage, resulting in myocardial infarction. Normal coronary arteries cause myocardial infarction due to continuous spasm and continuous ischemia of the myocardium. In addition, continuous coronary spasm causes blood stasis and vascular intima damage, promotes platelet aggregation and plaque formation, and eventually forms thrombosis, causing myocardial infarction.

5. Sudden death: Normal coronary artery and those with coronary atherosclerotic stenosis can cause sudden death due to coronary artery spasm. The mechanism is fatal arrhythmia, such as ventricular fibrillation, severe atrioventricular block, and ventricular arrhythmia. The occurrence of ST segment elevation is caused by coronary artery spasm caused by myocardial ischemia; the occurrence of T wave inversion is caused by the release of coronary artery spasm, and blood flow reperfusion is caused by unstable ECG. It can be seen that coronary artery spasm is not a benign process. Coronary artery spasm can cause a decrease in myocardial blood flow and cause myocardial ischemia, which can cause clinical syndromes including chest pain, chest tightness, arrhythmia, angina, myocardial infarction, and sudden death. In pharmacology, the sublingual mouth contains Nitroglycerin (Nitroglycerin) 0.6-1.2mg, Nifedipine (Nifedipine) 10mg, can relieve the symptoms caused by coronary artery spasm.

At present, most of the coronary spasm clinically use Nifedipine preparations and structural derivative preparations, such as Felodipine, Nimodipine, etc. as therapeutic drugs, because Nifedipine is a calcium ion blocker, which can increase the supply of blood and oxygen to the heart 量, Therefore, it can be used to prevent and relieve angina pectoris and chronic angina pectoris.

However, this kind of structural derivative preparation has the disadvantages of dizziness, headache, flushing, nausea, stomach upset, terminal edema, palpitations, headache, flushing of the face, edema of the feet, lethargy, etc., and the agent cannot be combined with grapefruit Take.

In order to find a medicine with lower side effects, the present invention finds an old medicine with anti-coronary coronary artery spasm effect and less side effects from the other common clinical medicines on the market, as a substitute for clinical use.

Pipoxolan (Pipsulan) is a calcium antagonist. It is clinically found in the present invention that it has the effect of alleviating various diseases caused by coronary artery spasm. It can be used as a treatment and prevention of the symptoms caused by coronary artery spasm. Disadvantages of Nifedipine and other drugs.

The disclosure content of this specification proposes the novel use of Pipoxolan (Pipsulan), which is based on Pipoxolan (Pipsulan) is a calcium antagonist, which can pass low calcium to the cell membrane through the calcium channel to enter the cell, because of this The medicine is a calcium ion blocker. It should be able to relax coronary arteries pharmacologically, increase blood flow to the heart muscle, increase blood and oxygen supply to the heart, and relieve symptoms caused by coronary artery spasm.

The disclosure content of this specification proposes the novel use of Pipoxolan (pipsulan), which can relieve coronary artery spasm, and proves that Pipoxolan (pipsulan) can reduce the pathological symptoms caused by coronary spasm of the heart, to treat and prevent the appearance of a body including Chest pain, chest tightness, arrhythmia, angina, myocardial infarction, sudden death and other clinical syndromes. Therefore, according to the novel mechanism disclosed by the present invention, Pipoxolan can be used for the prevention and treatment of pathological symptoms caused by coronary artery spasm.

Another aspect of the present invention is to provide a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms. The pharmaceutical preparation contains an effective amount of Pipoxolan ( Pipsulan); and a pharmaceutically acceptable adjuvant, which contains one or more of the following adjuvants: excipients, solvents, emulsifiers, suspending agents, decomposing agents, binding agents, stabilizers, preservatives, absorption Delayer or liposome.

Another embodiment of the present invention provides a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms. The pharmaceutical preparation contains an effective amount of Pipoxolan (HP Pusulan), and made into pharmaceutical preparations that can accelerate, delay absorption and metabolism using pharmaceutical technology.

Another embodiment of the present invention provides a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by pathological symptoms of myocardial ischemia. The pharmaceutical preparation includes: an effective amount of Pipoxolan (HP (Pusulan); and a pharmaceutical preparation that has a similar pharmacological effect to Pipoxolan (Pipsulan).

Another embodiment of the present invention provides a pharmaceutical preparation containing Pipoxolan (Pipsulan) ingredient for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms. The pharmaceutical preparation includes: an effective amount of Pipoxolan ( Pipsulan); and a compound preparation that has the same pharmacological effect as Pipoxolan (Pipsulan).

Another embodiment of the present invention provides a pharmaceutical preparation containing Pipoxolan (Pipsulan) ingredient for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms. The pharmaceutical preparation includes: an effective amount of Pipoxolan ( Pipsulan); and a compound preparation that is synergistic with Pipoxolan (Sipneran).

The following merely illustrates the possible implementation forms of the present invention with examples, but it is not intended to limit the scope of the invention to be protected, and will be described first.

The novel use of Pipoxolan (Pipsulan) of the present invention is based on Pipoxolan (Pipsulan) is a calcium antagonist, which can enter the cell through the cell membrane through the calcium channel through the calcium channel, because the drug is Calcium ion blockers can pharmacologically relax coronary arteries, increase blood flow to the heart muscle, increase blood and oxygen supply to the heart, and relieve symptoms caused by coronary artery spasm.

In order to prove whether Pipoxolan (Pipsulan) can theoretically relieve coronary artery spasm and reduce myocardial ischemia, and can be used to prevent and relieve angina pectoris and angina pectoris, a small-scale clinical trial has been specifically carried out. Pipsulan) 10mg/tab medicine is given to patients who have been diagnosed with coronary artery spasm and have had chest pain, chest tightness, arrhythmia, angina pectoris, etc. When the patient has the above symptoms, other drugs are not used Next, two tablets containing Pipoxolan (Pipsulan) 10mg/tab. are contained under the tongue to dissolve it completely, and then slowly swallowed after five minutes. Within 15~30 minutes, depending on the disappearance of the symptoms, it can be used as a criterion for evaluating whether it is effective.

The results of clinical trials to relieve the symptoms of coronary artery spasm are as follows:

Pipoxolan relieves the symptoms caused by coronary artery spasm. The clinical effective rate is as high as 80.6%.

In order to further confirm its effect of preventing the occurrence of coronary spasm symptoms, 37 patients with excellent clinical efficacy were selected, continue to be given drugs containing Pipoxolan 10mg/tab., take one orally every morning, noon and night, and count one The number of people who reappeared the above symptoms within a month was used as a criterion to evaluate the effectiveness of preventing coronary artery spasm symptoms.

The test results to prevent the occurrence of coronary spasm symptoms are as follows:

After taking Pipoxolan every day, the number of people who still have the above symptoms within a month has decreased by an average of 91.9%.

Although the number of patients participating in this clinical trial is not very large, the clinical effective rate is as high as 80.6%, and after taking Pipoxolan (pipsulan), the number of people who reappeared the symptoms within one month decreased by an average of 91.9%. The data analysis of the item is sufficient to prove that Pipoxolan (Pipsulan) has the effect of alleviating and preventing various diseases caused by coronary artery spasm.

According to the above clinical data, one aspect of the present invention relates to the use of Pipoxolan (pipoxolan), which is used to treat and prevent chest pain, chest tightness, arrhythmia caused by coronary artery spasm, stenosis and infarction, Clinical syndromes such as angina, myocardial infarction and sudden death.

According to an embodiment of the present invention, there is provided a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms. The pharmaceutical preparation comprises: an effective amount of Pipoxolan ( Pipsulan); and one or more of the following adjuvants: excipients, solvents, emulsifiers, suspending agents, disintegrating agents, binding agents, stabilizers, preservatives, absorption delaying agents or liposomes.

According to another embodiment of the present invention, there is provided a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms. The pharmaceutical preparation contains an effective amount of Pipoxolan ( Pipsulan), and made into pharmaceutical preparations that can accelerate, delay absorption and metabolism using pharmaceutical technology.

According to another embodiment of the present invention, there is provided a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation comprises: an effective amount of Pipoxolan (Pipsulan); and a compound preparation that is similar to Pipoxolan (Pipsulan) and has similar pharmacological effects.

According to another embodiment of the present invention, there is provided a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation comprises: an effective amount of Pipoxolan (Pipsulan); and a compound preparation made from a pharmaceutical ingredient that has the same pharmacological effect as Pipoxolan (Pipsulan).

According to another embodiment of the present invention, there is provided a pharmaceutical preparation containing Pipoxolan (Pipsulan) component for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation comprises: an effective amount of Pipoxolan (Pipsulan); and a compound preparation made from a pharmaceutical ingredient that has a synergistic effect with Pipoxolan (Pipsulan).

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Claims (7)

A use of Pipoxolan (Pipsulan), which is used to prepare a myocardial ischemia caused by stenosis and infarction of the heart due to coronary artery spasm, resulting in a myocardial blood flow and insufficient supply of nutrients and oxygen, a pathology Symptomatic treatment and preventive medicine. The use of Pipoxolan as claimed in claim 1, wherein the myocardial ischemia caused by stenosis and infarction of the heart due to coronary artery spasm, the pathological symptoms caused include chest pain, chest tightness, arrhythmia, angina pectoris, Clinical syndromes such as myocardial infarction and sudden death; pharmaceutical preparations containing Pipoxola can treat and prevent the above symptoms. A pharmaceutical preparation containing Pipoxolan (Pipsulan) ingredients for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation contains: an effective amount of Pipoxolan (Pipsulan); and a pharmaceutical An acceptable adjuvant, which contains one or more of the following adjuvants: excipients, solvents, emulsifiers, suspending agents, disintegrating agents, binding agents, stabilizers, preservatives, absorption delaying agents or liposomes. A pharmaceutical preparation containing Pipoxolan (Pipsulan) ingredients for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation contains an effective amount of Pipoxolan (Pipsulan), and pharmaceutical technology Made into pharmaceutical preparations that can accelerate, delay absorption and metabolism. A pharmaceutical preparation containing Pipoxolan (Pipsulan) ingredients for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation contains: an effective amount of Pipoxolan (Pipsulan); and a pharmaceutical It is a compound preparation made of pharmaceutical ingredients with similar pharmacological effects to Pipoxolan. A pharmaceutical preparation containing Pipoxolan (Pipsulan) ingredients for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation contains: an effective amount of Pipoxolan (Pipsulan); and a pharmaceutical It is a compound preparation made of pharmaceutical ingredients that have the same pharmacological effects as Pipoxolan. A pharmaceutical preparation containing Pipoxolan (Pipsulan) ingredients for the treatment and prevention of coronary artery spasm caused by myocardial ischemic pathological symptoms, the pharmaceutical preparation contains: an effective amount of Pipoxolan (Pipsulan); and a pharmaceutical It is a compound preparation made of pharmaceutical ingredients that have synergistic effects with Pipoxolan.