JP4872044B2 - Cardiac remodeling inhibitor and heart failure treatment - Google Patents

Description

  The present invention relates to a therapeutic agent for heart failure. Specifically, it is a therapeutic agent for heart failure containing a cholinesterase inhibitor as an active ingredient.

  Heart failure is a condition in which the heart's pumping function declines due to chronic myocardial damage, and it is impossible to pump out blood volume that meets the oxygen demand of the major peripheral organs. The condition that caused the disorder. In the past, heart failure was thought to be a condition in which kidney function declined and water was stored in the body, and diuretics were used as therapeutic agents. As a result, cardiotonic drugs and vasodilators have been used to improve it. More recently, heart failure has been considered a neurohumoral disease, and now it has been clarified that enhanced sympathetic nerve activity and neurohumoral renin / angiotensin / aldosterone system are exacerbations of heart failure. Β-blockers, angiotensin converting enzyme inhibitors (ACE inhibitors) and the like have become the main therapeutic agents.

  By the way, the present inventors have previously found that electrical stimulation to the vagus nerve improves cardiac function in rats with heart failure after myocardial infarction, prevents cardiac remodeling, and improves long-term survival (Patent Document) 1 and Non-Patent Document 1). However, in order to apply such knowledge to clinical treatment of heart failure, it is necessary to develop a dedicated nerve stimulation device, the burden on patients accompanying implantation of the nerve stimulation device is large, and when attaching electrodes to the vagus nerve In addition, there is a possibility of damaging the nerve after a long period of time, and it is necessary to replace a stimulation device including a battery for a long-term treatment.

On the other hand, cholinesterase inhibitors suppress the degradation of acetylcholine released by nerve excitation, increase the concentration of acetylcholine at the nerve effector junction, ganglion and central nerve synapse, and indirectly inhibit the action of acetylcholine on the postsynaptic membrane. It has the effect of enhancing and sustaining, and has been conventionally used as a therapeutic agent for gastrointestinal stagnation, dysuria, myasthenia gravis, glaucoma and the like. Furthermore, in recent years, it has been found that some cholinesterase inhibitors are effective for the treatment of senile dementia such as Alzheimer's disease, and several therapeutic agents have been developed (for example, see Patent Document 2). The effectiveness of cholinesterase inhibitors for the treatment of heart failure is still unknown.
International Publication No. 2004/012814 Pamphlet Japanese Patent No. 2578475 Meihua Li, et al. "Valve Nerve Stimulation Marked Improves Long-Term Survival After Chronic Heart Failure in Rats", Circulation, 2004, 109, p. 120-124

  An object of the present invention is to provide a novel therapeutic agent for heart failure.

  Based on the knowledge obtained by electrical stimulation of the vagus nerve, the present inventors have conducted extensive studies on therapeutic agents for heart failure, and as a result, found that cholinesterase inhibitors markedly improve various symptoms of heart failure. completed.

(1) That is, this invention is a cardiac remodeling inhibitor which uses donepezil or its physiologically acceptable salt as an active ingredient.

(2) The present invention is also a therapeutic agent for heart failure including the cardiac remodeling inhibitor described in (1).

(3) The present invention is also the therapeutic agent for heart failure according to (2), wherein the heart failure is chronic heart failure.

(4) The present invention is also the therapeutic agent for heart failure according to (2) or (3), wherein the heart failure is post-myocardial infarction heart failure.

  The therapeutic agent for heart failure according to the present invention comprises reduced exercise capacity, shortness of breath during exertion and rest, shallow and fast breathing, forced breathing, nocturnal paroxysmal dyspnea, sitting breathing, respiratory alkalosis, cardiac enlargement, liver edema, lower limbs and Various types of heart failure such as systemic edema, pulmonary edema, pleural effusion, cardiac asthma, palpitation, tachycardia, atrial fibrillation, fatal arrhythmia, peripheral circulatory failure, oliguria, electrolyte abnormalities, nutritional status deterioration, sympathetic myocardial disorder Excellent cardiac function improvement effect, cardiac remodeling prevention effect, fluid retention prevention effect, improvement of general circulation, improvement of respiratory status, improvement of nutritional status, reduction of arrhythmia, suppression of abnormal increase in sympathetic nerve activity Etc.

  The therapeutic agent for heart failure of the present invention comprises a cholinesterase inhibitor as an active ingredient.

  The cholinesterase inhibitor used in the present invention is not particularly limited as long as it has an action of inhibiting cholinesterase and suppressing the degradation of acetylcholine, and various existing cholinesterase inhibitors can be used. . Cholinesterase inhibitors generally have muscarinic activity and nicotine-like activity, or are classified into brain migration (lipid-soluble) and brain non-migration (water-soluble). In the invention, any of them can be used.

  Specific examples of the cholinesterase inhibitor used in the present invention include donepezil: 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine: see Japanese Patent No. 2578475. ), Tacrine (9-amino-1,2,3,4-tetrahydroacridine: refer to Japanese Patent Publication No. 6-055725), rivastigmine ((S) -N-ethyl-3-[(1-dimethyl) Amino) ethyl] -N-methyl-phenyl-carbamate: see Japanese Patent No. 2625478), galantamine: (4aS, 6R, 8aS) -3-methoxy-11-methyl-4a, 5,9,10,11 12-Hexahydro-6H- [1] benzofuro [3a, 3 -Ef] [2] Benzazepine-6-ol: Refer to Japanese Patent Publication No. 8-000778), pyridostigmine (3-hydroxy-1-methylpyridinium dimethylcarbamate), neostigmine (Nostigmine: N- [3- (dimethyl) Carbamoyloxyphenyl) -N, N, N-trimethylammonium) or the like or a physiologically acceptable salt thereof. Among these, donepezil or a physiologically acceptable salt thereof is particularly preferably used. These cholinesterase inhibitors can be produced by a known production method described in each document.

  Although the mechanism of action of the therapeutic agent for heart failure of the present invention is not necessarily clear, cholinesterase inhibitors can reduce heart rate and decrease myocardial oxygen consumption, suppress the sympathetic nerve by acting on the center and suppress the parasympathetic nerve. It can be considered to be activated, to improve the circadian fluctuation of the autonomic nerve in the center, to suppress cardiomyocyte death, to enhance angiogenesis in the myocardium.

  The therapeutic agent for heart failure of the present invention includes one or more cholinesterase inhibitors alone, or tablets, pills, powders, powders, granules, syrups, solutions, suspensions, emulsions, capsules, etc. Can be administered orally to the patient. Further, it can be administered as an injection intravenously, intramuscularly, intradermally, subcutaneously, intraperitoneally, intraarterially, intrathecally, or the like. Furthermore, it may be administered into the rectum as a suppository, or can be implanted with a pellet. It can be administered as a spray, an inhalant, etc., or can be administered transdermally as an external preparation such as an ointment, cream, powder or liquid coating agent, patch. Among the above-mentioned, a preferable formulation form, administration form, and the like are appropriately selected by a doctor according to the patient's age, sex, constitution, symptoms, treatment timing, and the like.

  When the preparation is made into a solid preparation such as a tablet, pill, powder, powder, granule, etc., the cholinesterase inhibitor is added to an appropriate additive according to a conventional method such as lactose, sucrose, mannitol, corn starch. , Synthetic or natural gums, excipients such as crystalline cellulose, starch, cellulose derivatives, gum arabic, gelatin, polyvinylpyrrolidone and other binders, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, corn starch, alginic acid It can be produced by appropriately mixing with disintegrants such as sodium, lubricants such as talc, magnesium stearate, sodium stearate, fillers or diluents such as calcium carbonate, sodium carbonate, calcium phosphate and sodium phosphate. . Tablets and the like may be coated with sugar coating, gelatin, enteric coating, film coating, etc. using an appropriate coating base as necessary.

  When this preparation is a liquid preparation such as an injection, inhalant, spray, lotion, syrup, solution, suspension, emulsion, etc., the compound having the cholinesterase inhibitory action is purified water, phosphate buffer Suitable buffer solution such as liquid, physiological salt solution such as physiological saline, Ringer's solution, lock solution, vegetable oil such as cocoa butter, sesame oil, olive oil, mineral oil, higher alcohol, higher fatty acid, organic solvent such as ethanol, etc. Dissolve, and emulsifiers such as cholesterol, suspending agents such as gum arabic, dispersion aids, wetting agents, polyoxyethylene hydrogenated castor oil-based, polyethylene glycol-based surfactants, sodium phosphate, etc. if necessary Solubilizers, stabilizers such as sugar, sugar alcohol, albumin, preservatives such as paraben, isotonic agents such as sodium chloride, glucose, glycerin, buffering agents, As a sterilized aqueous solution, non-aqueous solution, suspension, liposome, emulsion, etc. by appropriately adding a soothing agent, adsorption inhibitor, moisturizer, antioxidant, colorant, sweetener, flavor, fragrance, etc. Can be adjusted. At this time, the injection preferably has a physiological pH, preferably in the range of 6-8.

  To make this preparation semi-solid preparations such as lotions, creams, ointments, etc., the compounds having the cholinesterase inhibitory action are fats, fatty oils, lanolin, petrolatum, paraffin, wax, plasters, resins, plastics, glycols. , Higher alcohol, glycerin, water, emulsifier, suspending agent, etc.

  The content of the cholinesterase inhibitor contained in the therapeutic agent for heart failure of the present invention varies depending on the administration form, severity, target dose, etc., but generally, the content is 1 for the total weight of the preparation. -50% by weight, preferably 2-10% by weight.

  The dosage of the therapeutic agent for heart failure of the present invention varies depending on the drug to be administered, age, weight and symptoms of the patient, intended dosage form and method, therapeutic effect, treatment period, etc., and the exact amount is determined by a doctor. In general, for adults, the daily dose of the cholinesterase inhibitor is 2 to 500 mg for oral administration and 0.25 to 10 mg for intravenous administration once or Divide into several doses.

Confirmation of heart failure treatment effect in rat post-myocardial infarction heart failure model

The efficacy of the therapeutic agent for heart failure of the present invention was confirmed by a pharmacological test using a rat heart failure model after heart infarction in rats.
(A) Test

Donepezil hydrochloride was used as a cholinesterase inhibitor. A myocardial infarction was created by ligating the left coronary artery of an 8-week-old rat and used as a heart failure model. A telemeter for blood pressure and pulse measurement was implanted 1 week after the operation. Two weeks after myocardial infarction, rats were randomly divided into 2 groups, and donepezil hydrochloride was dissolved in the drinking water of the donepezil administration group so that the oral dose was 4.8 mg per kg body weight. After 6 weeks of administration, the hemodynamics, heart weight, plasma norepinephrine concentration, etc. of the group administered with or without donepezil hydrochloride were measured to confirm the effect of treating heart failure.
(B) Results (1) Infarct size

FIG. 1 is a diagram showing the size of myocardial infarction in a prepared rat. As is clear from FIG. 1, there was no significant difference in the size of myocardial infarction created between the non-administration group and the administration group.
(2) 24-hour average heart rate

FIG. 2 is a graph showing changes in 24-hour average heart rate of rats after treatment. As is apparent from FIG. 2 of healthy rats, a decrease in heart rate was not significantly observed in the non-administered group, whereas a significant decrease in heart rate was observed in the administered group.
(3) 24-hour mean blood pressure

FIG. 3 is a graph showing changes in 24-hour mean blood pressure of rats after treatment. As is clear from FIG. 3, no significant difference was observed in blood pressure between the non-administered group and the administered group.
(4) Weight

FIG. 4 is a diagram showing the weight of the rat after treatment. As is clear from FIG. 4, no significant difference in body weight was observed between the non-administered group and the administered group.
(5) Right atrial pressure

FIG. 5 is a diagram showing the right atrial pressure of the treated rat. From FIG. 5, the administration group showed significantly lower right atrial pressure than the non-administration group.
(6) Left ventricular end-diastolic pressure

FIG. 6 is a graph showing the left ventricular end-diastolic pressure of rats after treatment. From FIG. 6, the administration group showed significantly lower left ventricular end-diastolic pressure than the non-administration group.
(7) Left ventricular maximum pressure change rate (LV + dP / dt _max )

FIG. 7 is a graph showing the left ventricular maximum pressure change rate (LV + dP / dt _max ) of rats after treatment. From FIG. 7, the administration group had a significantly greater left ventricular maximum pressure change rate than the non-administration group.
(8) Cardiac output coefficient

FIG. 8 is a diagram showing the cardiac output coefficient of the rat after treatment. From FIG. 8, the administration group had a significantly higher cardiac output coefficient than the non-administration group.
(9) Ventricular weight

FIG. 9 is a diagram showing the ventricular weight of the rat after treatment. From FIG. 9, the ventricular weight was significantly smaller in the administration group than in the non-administration group.
(10) Plasma norepinephrine concentration

FIG. 10 is a graph showing the plasma norepinephrine concentration in rats after treatment. From FIG. 10, it was found that the plasma norepinephrine concentration in the administration group was significantly lower than that in the non-administration group.
(11) Intracardiac thrombus complication rate

  FIG. 11 is a graph showing the intracardiac thrombosis rate in rats after treatment. From FIG. 11, it was found that the administration group had a significantly lower intracardiac thrombosis rate than the non-administration group.

  Based on the above, in the post-myocardial infarction heart failure model, compared to the non-administration group, the group treated with donepezil hydrochloride had no effect on food intake, activity, or their circadian rhythm. It was found to improve cardiac function, prevent cardiac remodeling, and correct abnormal increases in sympathetic nerve activity.

  The therapeutic agent for heart failure according to the present invention comprises reduced exercise capacity, shortness of breath during exertion and rest, shallow and fast breathing, forced breathing, nocturnal paroxysmal dyspnea, sitting breathing, respiratory alkalosis, cardiac enlargement, liver edema, lower limbs and Various types of heart failure such as systemic edema, pulmonary edema, pleural effusion, cardiac asthma, palpitation, tachycardia, atrial fibrillation, fatal arrhythmia, peripheral circulatory failure, oliguria, electrolyte abnormalities, nutritional status deterioration, sympathetic myocardial disorder Excellent cardiac function improvement effect, cardiac remodeling prevention effect, fluid retention prevention effect, improvement of general circulation, improvement of respiratory status, improvement of nutritional status, reduction of arrhythmia, suppression of abnormal increase in sympathetic nerve activity Etc.

It is a figure which shows the size of the produced myocardial infarction of the rat. It is a figure which shows the change of the 24-hour average heart rate of the rat after a process. It is a figure which shows the change of the 24-hour average blood pressure of the rat after a process. It is a figure which shows the body weight of the rat after a process. It is a figure which shows the right atrial pressure of the rat after a process. It is a figure which shows the left ventricular end-diastolic pressure of the rat after a process. It is a figure which shows the left ventricular maximum pressure change rate of the rat after a process. It is a figure which shows the cardiac output coefficient of the rat after a process. It is a figure which shows the ventricular weight of the rat after a process. It is a figure which shows the plasma norepinephrine density | concentration of the rat after a process. It is a figure which shows the intracardiac thrombus complication rate of the rat after a process.

Claims (4)

A cardiac remodeling inhibitor comprising donepezil or a physiologically acceptable salt thereof as an active ingredient. A therapeutic agent for heart failure comprising the cardiac remodeling inhibitor of claim 1 . The therapeutic agent for heart failure according to claim 2 , wherein the heart failure is chronic heart failure. The therapeutic agent for heart failure according to claim 2 or 3 , wherein the heart failure is post-myocardial infarction heart failure.

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