阅读说明：本技术 抗生素呋喃妥因（Nitrofurantoi）可作为新型抗心律失常药物 (Antibiotic nitrofurantoin (nitrofuratoi) can be used as novel antiarrhythmic drug ) 是由 吴博威 刘清华 贺培凤 卢学春 于琦 郝亚楠 吕艳华 于 2018-08-20 设计创作，主要内容包括：本发明公开了呋喃妥因在制备治疗心律失常药物中的应用。本发明首次发现呋喃妥因能够有效的作为I<Sub>K1</Sub>特异性激动剂,其具有和zacopride相类似的效果,可以作为制备抗心律失常作用的药物,因而提供了一条有效、安全治疗的新途径。(The invention discloses application of nitrofurantoin in preparing a medicament for treating arrhythmia. The invention discovers that nitrofurantoin can be effectively used as I for the first time K1 The specific agonist has similar effect to zacopride, and can be used for preparing medicaments with anti-arrhythmia effect, thereby providing a new way for effective and safe treatment.)

1. Application of nitrofurantoin in preparing medicine for treating arrhythmia is disclosed.

2. The use of claim 1, wherein: the medicine is capsule, microcapsule, liposome, granule, injection, tablet, or oral liquid.

3. The use of claim 1, wherein: the dose of the nitrofurantoin is 0.018-1.8 mg/kg.

4. The use of claim 1, wherein the nitrofurantoin is used in combination with a sodium channel blocker, an β receptor blocker, a potassium channel blocker, a calcium channel blocker.

Technical Field

The invention relates to a cardiovascular disease medicament, in particular to application of nitrofurantoin in preparing a medicament for treating arrhythmia.

Background

Arrhythmia refers to the abnormality of heart beat frequency and rhythm, and serious arrhythmia is one of the main causes of death of patients with cardiovascular diseases. The mechanism for forming severe arrhythmia is complex and often not single, but at the very least, there is a change in the functional activity of myocardial ion channels, and thus the change in ion current affects the occurrence and morphology of action potential. Those drugs that are able to change the action potential may thus have an arrhythmogenic risk or an antiarrhythmic effect.

The current antiarrhythmic drugs applied clinically are almost all various ion channel blockers, the main targets of the antiarrhythmic drugs act on Na, Kv and Ca ion channels, and the drugs for treating the tachyarrhythmia are divided into four types according to the action of the drugs on the ion channels and receptors:

class I: sodium channel blockers

Ⅰ_a: moderate intensity (moderate blockade of sodium channels), quinidine, procainamide

Ⅰ_b: mild blockade of sodium channels, lidocaine, phenytoin sodium, mexiletine, tocainide

Ⅰ_c: severe blockade of sodium channels, propafenone, flecainide

The medicine can block sodium channel, change the conduction of unidirectional tissue area and eliminate reentry.

β receptor blockers, such as propranolol, which cause reduced 4-phase depolarizing current and reduced autonomy.

Class III: the action potential time course prolonging medicine (potassium channel blocking medicine) such as amiodarone can inhibit Kv channel, reduce the outflow of repolarization 3-phase potassium ions, obviously prolong the action potential time course, prolong the effective refractory period and eliminate the reentry.

And IV: calcium channel blockers, such as verapamil and diltiazem, block calcium channels, reduce the influx of action potential 4-phase calcium ions, reduce the autonomy of slow-reacting cells, and can be used to treat supraventricular arrhythmias.

The four main treatments for tachyarrhythmia

At present, any antiarrhythmic drug has certain arrhythmogenic effect. Class i drugs can induce reentry by blocking sodium channels and slowing conduction; class iii drugs induce long QT syndrome by prolonging the time course of action potential. This has attracted attention and it is urgent to find new and safer treatments. After the middle of the nineties, great progress is made in treating various kinds of arrhythmia by cardiac catheter interventional technology, and a new direction for treating arrhythmia is developed. However, interventional therapy has a range of indications, and therefore, for most patients with cardiac arrhythmias, drug therapy is still the primary method of treatment or an essential component. Since class i drugs can induce reentry by blocking sodium channels and slowing conduction; in recent years, research on antiarrhythmic drugs has shifted from class i antiarrhythmic drugs to class iii antiarrhythmic drugs. The class III antiarrhythmic drugs play a role in prolonging Action Potential Duration (APD) and Effective Refractory Period (ERP), effectively prevent and treat atrial flutter, atrial fibrillation and ventricular fibrillation by inhibiting turn-back excitation, basically do not affect conduction, and have no obvious influence on hemodynamics.

The causes of arrhythmia caused by antiarrhythmic drugs are manifold, and many scholars think that a new thought should be developed to search for new drugs.

The Inward rectifier potassium channel (IK 1) load current is the most dominant background outward current of the myocardium and is involved in the maintenance of Resting Potential (RP) and repolarization at the end of myocardial Action Potential (AP) 3 (fig. 1). Regulation I_K1The stability of resting membrane potential and action potential repolarization of cardiac muscle are influenced, so that the excitability of cardiac muscle and the occurrence of arrhythmia are deeply influenced.

I_K1The drug is a new target of the anti-arrhythmia drug. However, none of the current antiarrhythmic drugs in clinical use is I_K1As a main target. The reason for this comes from two aspects: one is that to date there is no highly selective I_K1A blocker or an agonist. Lack of necessary pharmacological tools greatly limits I_K1Study of relationship to arrhythmia; secondly, although many experimental studies confirm that I is blocked_K1Can effectively inhibit reentry arrhythmia, but block I_K1The risks involved are also obvious. Theoretically, I_K1The inhibition will depolarize the membrane and increase the excitability and autonomy of the cellHigh, easy to delay the occurrence of triggering activities such as depolarization (DAD); i is_K1The inhibition of the membrane increases the membrane resistance, amplifies the membrane potential fluctuation caused by transmembrane current, and causes the instability of the membrane potential; inhibition of I_K1It also prolongs action potential time course (APD), leading to long QT syndrome. Numerous studies have demonstrated that_K1The acquired or absent function of (a) is involved in the development of arrhythmia and pathological remodeling. But has been due to lack of high selectivity I_K1Blockers or agonists, and methods for altering myocardial I using transgenics or gene knock-outs_K1Expression, far from physiological state, makes the relevant studies extremely restrictive. In 2012, Wu Bo Wei professor topic group reported a I for the first time_K1The selective agonist, zacopride, by agonism I_K1Can increase the negative value of resting potential (hyperpolarization) and slightly shorten the action potential time course (Liu QH, Li XL, Xu YW, Lin YY, Cao JM, Wu BW. A Novel Discovery of I)_K1Channel Agonist: Zacopride Selectively Enhances I_K1Current and pressesTriggered Arrhythmias in the rat J Cardiovasc Pharmacol, 2012, 59(1): 37-48.). But has no significant effect on other major ion channels or exchangers affecting action potential, such as Ito, ICa-L, INa/Ca, Iump, IK (guinea pig) and the like. Using this tool medicine, I_K1The role in cardiac arrhythmias is gradually elucidated. The subject group firstly proves moderate agitation I on an acute myocardial ischemia model and a chronic arrhythmia model after myocardial infarction of rats_K1The channel has inhibitory effect on ischemic arrhythmia.

Ischemic arrhythmias are the more common and more dangerous arrhythmias in the clinic. Various types of myocardial ischemia can induce arrhythmia, mainly ventricular arrhythmia, which is the main reason for early death of patients with myocardial infarction; in people who survive an acute myocardial infarction, more than 50% still die from fatal ventricular arrhythmias. Cardiac arrhythmias arising during myocardial ischemia and myocardial infarction have also been demonstrated with I_K1Is concerned with the decline. The study shows that the myocardium I of the rat chronic animal myocardial infarction model_K1The reduction is 20%; and chronic myocardial infarction rabbit non-infarct zone ventricular myocyte I_K1Is also obviously reduced; pinto et al demonstrated that the reduction in subendocardial Purkinje fiber resting potential in the ischemic area of the dog myocardium was due to I_K1The result is reduced. Kiesecker et al in human cardiomyocytes demonstrate that endothelin can significantly inhibit I_K1This effect is an important mechanism of endothelin-induced ischemic arrhythmia. Myocardial ischemia time I_K1The down regulation and/or the function weakening reduce the conductance of the resting potassium, so that the resting potential (negative value) is reduced, the excitation conduction is slowed down, and the reentry is easy to form; decreased potassium conductance also causes instability of membrane potential and increased abnormal autonomic activity, which are important causes of cardiac arrhythmias occurring during myocardial ischemia (both acute and chronic).

However, until now, only zacopride I has been used_K1Specific agonists are publicly reported. Establishment of the stimulated myocardium I_K1The theoretical relationship with antiarrhythmic is still weak, and a new I needs to be found urgently_K1A specific agonist. We have now found a drug which has a similar effect to zacopride.

Disclosure of Invention

At present, any antiarrhythmic drug has certain arrhythmogenic effect, but the drug, as an IK1 agonist, may have antiarrhythmic effect and can become a new way for effective and safe treatment. In view of the above, the present inventors have found that nitrofurantoin can be effectively used as I through extensive studies on zacopride and a drug relocation platform based on omics big data_K1A specific agonist having a similar effect to zacopride. Further research results show that the action characteristics of nitrofurantoin (nitrofuratoi) on action potential accord with the characteristics of an IK1 agonist, so that a novel medicine can be expected to be developed.

Therefore, the invention provides the application of the nitrofurantoin in preparing the medicine for treating arrhythmia.

Wherein the medicine is capsule, microcapsule, liposome, granule, injection, tablet, or oral liquid.

Preferably, the dose of the nitrofurantoin is 0.018-1.8 mg/kg.

Further, nitrofurantoin is used in combination with a sodium channel blocker, an β receptor blocker, a potassium channel blocker, and a calcium channel blocker.

The invention discovers for the first time that the nitrofurantoin can be effectively used as an IK1 specific agonist, has the similar effect with zacopride, and can be used for preparing medicaments with the effect of resisting arrhythmia, thereby providing a new way for effective and safe treatment.

Drawings

Figure 1 is involved in the formation of ion channels and corresponding phases of myocardial Action Potentials (AP).

FIG. 2 shows that Nitrofurantoi (nitrofuratoi) increases resting potential and shortens action potential time course.

Detailed Description

The invention is further illustrated below with reference to specific embodiments.