JPH03169826A - Use of drug having muscarinic action for preventing and treating ventricular arrhythmia - Google Patents

Abstract

PURPOSE: To prevent and cure ventricular arrhythmia by administering a muscarinic agonist. CONSTITUTION: Ventricular arrhythmia of mammals are prevented or cured by administering a muscarinic agonist, e.g. oxotremorine, methacholine, bethanechol, pilocarpine or pharmaceutically allowable salts of them. The muscarinic agonist is especially suitable for preventing malignant ventricular arrhythmia induced by ischemic episode, increase of sympathetic activity or a combination of the both factors and effective for curing ventricular arrhythmia induced by myocardial infarction at its acute stage. If needed, usual curing agents for arrhythmia, e.g. flecainide, encainide, procainamide, lidocaine, etc., can be used at the same time.

Description

DETAILED DESCRIPTION OF THE INVENTION Malignant ventricular arrhythmia that causes fatal sudden cardiac death is
It is the number one cause of death for men aged 20 to 65 in industrialized countries.

Approximately 400,000 people die from this disease each year in the United States, although the number of people infected with this disease has been decreasing recently. This is because fatal events, rapid ventricular arrhythmias that often lead to cardiac arrest, almost always occur outside the hospital. Clearly, the only way to reduce the incidence of this disease is to take precautions.

Clinical experiments and autopsy results indicate that patients who died of sudden cardiac death mostly suffered from coronary disease. This coronary disease is sometimes asymptomatic, but often results in a previous myocardial infarction.

Acute ischemic episodes generally seem to be frequently included in the etiology of ventricular fibrillation, with a probable thrombotic basis, however in most cases fixed coronary artery occlusion is present. Not likely. This is because patients who are resuscitated after cardiac arrest outside of a hospital rarely have a myocardial infarction.

One clinical observation made after the coronal unit began to act was that
showed that autonomic nervous system imbalance is quite frequent in the first stage of myocardial infarction. Experimental studies have shown the existence of vagal and sympathetic reflexes induced by acute myocardial ischemia, and have also pointed out that the sympathetic reflex promotes the development of ventricular fibrillation in coronary artery occlusion. Sympathetic activity in the occurrence of sudden cardiac death
β-blockers have been used to reduce the mortality rate after myocardial infarction because of the known important role of myocardial infarction. Previously had a myocardial infarction 4
An overall randomized survey of more than 10,000 patients has been conducted to evaluate the effectiveness of beta-blockers. These findings showed a clear reduction in mortality among treated patients. However, the reduction rate is relatively small (20-25%), and only one life can be saved for every 100 patients. Furthermore, a significant proportion of patients cannot be treated with beta-blockers due to treatment contraindications. In other words, beta blockers! l! This is the only treatment known to have an effective effect on survival rates after myocardial infarction.

In fact, studies of conventional antiarrhythmia agents (quinidine, procainamide, and mexiletine) conducted after myocardial infarction have shown that the trend toward increased mortality among treated patients is at best modest. A very recent study (CAST), most relied upon by proponents of the hypothesis that the use of rational arrhythmia therapy reduces mortality, appeared to overcome the limitations of the study. However, these studies were stopped early due to a 2.6 times higher mortality rate observed in patients treated with flecainide and encainide compared to patients treated with Braceivo. Therefore, ventricular arrhythmia (ventricular arrhythmia) in mammals.
There is a strong need for therapeutic approaches for ventricular arrhythmias, and even more so for prophylactic approaches to ventricular arrhythmias. The inventors have discovered a new treatment method for this condition. Therefore, the first object of the present invention is to use muscarinic agonists (m-
agonist). Another object of the present invention is to use a muscarinic agonist in a method for preventing or treating ventricular arrhythmia in mammals. The use of muscarinic agonists according to the invention is particularly suitable for preventing malignant ventricular arrhythmias induced by ischemic episodes, increased sympathetic activity, or, as often occurs, a combination of these two factors. A feature of the present invention is that for certain subjects at high risk of sudden death, such as patients after myocardial infarction, dilated heart disease, or malignant ventricular arrhythmia, muscarinic agonists are can be used as a preventive measure.

Examples of muscarinic agents that can be used in the manufacture of drugs and in the prophylactic or therapeutic methods of the invention include oxotremorine, methacalin, betanchol, pilocarbin and pharmaceutically acceptable salts of these agents.

Another feature of the invention is that muscarinic agonists can be used even in the acute stage treatment of ventricular arrhythmias caused by acute myocardial infarction.

In the treatment of this condition, muscarinic agents can be administered, optionally in conjunction with "conventional" antiarrhythmic agents.

Examples of "conventional" antiarrhythmic agents that may be used include flecainide, encainide, procainamide, mexiletine, quinidine, lidocaine, probafenone, and pharmaceutically acceptable salts of these agents.

The term "concomitant administration" in the present invention refers to separate and simultaneous administration of a muscarinic agent and an antiarrhythmia agent. Individual treatment with a muscarinic agent can be initiated before or after treatment with an antiarrhythmic agent.

Pharmaceutically acceptable salts of the muscarinic agents and antiarrhythmia agents of the present invention include, for example, fi acids, especially acetic acid, brobionic acid, lactic acid, oxalic acid, tartaric acid, citric acid, fumaric acid, and cinnamic acid) or inorganic acids, especially hydrochloride, nitric acid and sulfuric acid) addition salts, and salts of inorganic and organic bases [especially alkylamines, preferably triethylamine or hydroxides of alkali metals (sodium or potassium) and alkaline earth metals (calcium or magnesium)]. It will be done. It will be appreciated that the dose of muscarinic agent that may be administered in embodiments of the present invention will depend on many factors, such as the route of administration and the medical condition to be treated. The precise dose is selected in particular according to the specific conditions of the patient being treated, so as to provide the most appropriate blood concentration.

For example, in the case of betanchol, an adult male is given a dose of approximately 20-10 On+g per dose.
se) can be administered orally, preferably 3 to 4 times per day.

Can be administered concomitantly with a muscarinic agonist of the present invention゜''
Doses for conventional "arrhythmia therapy agents" are those typically used for treatment with such agents.

For example, in the case of procainamide, for adult males, the drug should be administered for approximately 1 to 4 m at intervals of approximately 5 minutes until the arrhythmia subsides.
g doses can be administered orally or doses of about 100 mg can be administered intravenously (repeatedly available tablets).
repeatable bolus)). Lidocaine is administered at a dose of approximately 100 mg (repeated tablets) and probafenone is administered at approximately 300-800 mg per day.
can be administered intravenously.

Another object of the present invention is to provide a pharmaceutical composition (1) containing a muscarinic agonist and a pharmaceutical composition (1) of an arrhythmia therapeutic agent in divided containers.
2) It is an object of the present invention to provide a kit for treating the acute stage of ventricular arrhythmia.

The muscarinic agents and antiarrhythmia agents to be used in embodiments of the present invention can be administered in the form of various pharmaceutical compositions known in the art.

However, parasensory nerve stimulants are generally potentially dangerous when administered intravenously, and it is therefore preferable to administer these agents orally or subcutaneously.

Pharmaceutical compositions of the invention suitable for oral administration may be in the form of capsules, dragees or tablets, in the form of granules or powders, as solutions or suspensions in aqueous or non-aqueous liquids, each containing a predetermined amount of the active ingredient. or in the form of an oil-in-water or water-in-oil emulsion.

Solutions or suspensions for subcutaneous administration may be prepared in a pharmaceutically acceptable receptor or carrier such as sterile water, olive oil, ethyl oleate, glycols (e.g. propylene glycol).
and active commandments.

Suppositories can include a pharmaceutically acceptable carrier (eg, turmeric, polyethylene glycol, or lecithin) and an active ingredient.

The following examples illustrate the invention in a non-limiting manner.

Malignant ventricular arrhythmia was induced in anesthetized cats by combining short-term occlusion of the postfrontal descending coronary artery with electrical stimulation of the left stellate ganglion.

Because arrhythmias are easy to reproduce, internal controls (internal
It was possible to evaluate with a single intervention using the control method. Grading was performed based on the degree of arrhythmia. No arrhythmia = 0 1-10 premature ventricular contractions = 1 11-50 premature ventricular contractions = 2 Ventricular tachycardia = 3 Ventricular fibrillation = 4 2.5 μg/kg in 7 animals e. v. Obstruction and irritation after administering oxotremorine sesquifumarate?
The experiment was conducted as a control. The average arrhythmia degree of all animals ranged from 3.1+0.7 to 0.6+0.8 (p・0.0004
＞ has been reduced to ＞. Even when the heart rate did not change due to atrial stimulation, the arrhythmia degree continued to decrease (from 6, 3.2 + 0.8 to 1,7
+1.5, p:0. 017).

Group X 1 Previous frontal stabilization myocardial infarction (Withpr
EVIOUS FRONT STABILIZED M
yocardium infarct) The circumflex coronary artery was occluded for 2 minutes in conscious dogs. This started in the last minute of the rotating bed stress test.

This method is of great clinical importance as it relates to factors that play a known role in the occurrence of sudden cardiac death in humans. Because the animals continue to reproduce the ventricular fibrillation that occurred during this study for several months, an internal control analysis is still possible in this case. The ventricular fibrillation induction test was repeated in 6 dogs by injecting methacholine at 0.5 μs/kg/min.

Medication prevented ventricular fibrillation in three of the six dogs.

The study was repeated with at least three dogs receiving 10 μs 7 kg of oxotremorine as a slow bolus. This treatment prevented fatal arrhythmias in two of the three dogs.

K Masukai Danichi Capsules (100mg) Betancol 100s+g Lactose 248mg Cornstarch 50mg stearic acid Magnesium Total 400mg Encapsulated with hard gelatin film. Mitatekin 1 suppository (100g) Betankor o. tog lecithin cocoa butter total 0.14. L sword h 2. OOg

Claims (7)

[Claims] (1) Use of a muscarinic agonist in the manufacture of a drug for preventing or treating ventricular arrhythmia in mammals. (2) The use according to claim 1, wherein the ventricular arrhythmia is malignant. (3) The use according to claim 1, characterized in that the ventricular arrhythmia is in an acute phase. (4) Oxotremorine, methacholine, betancol,
4. Use according to any one of claims 1 to 3, characterized in that the active agent is chosen among pilocarpine or a pharmaceutically acceptable salt thereof. (5) The use according to any one of claims 1 to 4, wherein the muscarinic agent is used in combination with an antiarrhythmia agent. (6) The antiarrhythmia agent is selected from flecainide, encainide, quinidine, procainamide, mexiletine, lidocaine, propafenone, or pharmaceutically acceptable salts of these drugs.
Uses as described in. (7) Ventricular arrhythmia during the acute stage, characterized in that it consists of a pharmaceutical composition (1) containing a muscarinic agonist and a pharmaceutical composition (2) containing an antiarrhythmic agent in separate containers. treatment kit.