TW201322984A - Funny current (I<SB>f</SB>) inhibitors for use in a method of treating and preventing heart failure in feline - Google Patents

Abstract

The present invention relates to an I<SB>f</SB> blocker or a pharmaceutically acceptable salt thereof for the treatment and/ or prevention of a feline patient suffering from heart failure (HF). The invention also relates to improving the quality of life, improving the general health condition as well as a prolonging the life expectancy in feline patients suffering from heart failure and/ or heart failure due to one or more of the following etiologies HCM, DCM, RCM, UCM and / or ARVC.

Description

Trolltech current (I f ) inhibitor for the treatment and prevention of feline heart failure

The present invention relates to the field of medicine, in particular to the field of veterinary medicine. The present invention relates to the effect of a funny current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof on the treatment of heart disease, preferably heart failure (HF) associated with feline patients. The present invention further relates to improving the quality of life and general health and prolonging expectations of feline patients suffering from heart failure caused by heart failure and/or one or more of the following sources of HCM, DCM, RCM, UCM and/or ARVC life.

Feline heart failure is mainly caused by different cardiomyopathy. The most common feline cardiomyopathy (CMP) is hypertrophic cardiomyopathy (HCM), followed by restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM), and arrhythmia. Right ventricular cardiomyopathy (ARVC).

In general, cats with latent cardiomyopathy remain asymptomatic at the beginning of the disease before they are given to the veterinarian because the disease continues to develop and the ventricular diastolic and/or systolic function is severely impaired leading to heart failure.

Cats at this stage show that any clinical symptoms of mild to moderate clinical symptoms are accompanied by shortness of breath to severe respiratory distress (dyspnea), due to pulmonary edema and/or pleural effusion, requiring oxygen therapy and intravenous diuresis Agent and thoracic puncture for emergency treatment of pleural effusion.

Especially for pets, the heart rate can be accelerated by a slowing rhythm agent such as, for example, a calcium (Ca ⁺⁺ ) channel blocker, a beta-blocker, and other antiarrhythmic agents.

Known Ca ⁺⁺ channel blockers useful for this purpose are diltiazem, verapamil, amlodipine, and nifedipine.

Known beta-blockers useful for this purpose are atenolol, bisoprolol, carvedilol, esmolol, sotalol. (sotalol), metoprolol or propanolol.

Beta-blockers and calcium channel blockers are the most commonly used drugs in preclinical feline CMP. However, the use of such drugs remains controversial because neither of these drugs has demonstrated beneficial effects on disease progression or survival. In addition, atenolol has been shown to significantly reduce left atrial contraction and overall function.

Other known antiarrhythmic drugs that can be used for this purpose are adenosine, amiodarone, atropine, digoxin, isoproterenol, lidocaine. , tocainide, mexiletine, phenytoin, procainamide, propafenone, and quinidine, for example, sulfonate , gluconate. Calcium channel blockers and beta blockers can also be used as antiarrhythmic drugs.

In addition, angiotensin-converting enzyme inhibitors (ACE inhibitors), positive-shrinking agents, and anti-thrombotic drugs are often administered to cats with heart failure. ACE inhibitors can be used to reduce the activity of the renin-angiotensin-aldosterone system. A positive contraction agent is used if the heart contraction function declines. An antithrombotic agent is administered to prevent the development of a thrombus or to dissolve an already existing thrombus.

Well-known ACE inhibitors that can be used for this purpose are enalapril, ramipril, benzeppril, quinapril, perindopril. , lisinopril, imidapril, zofenopril and trandolapril.

The well-known positive shrinking agents that can be used for this purpose are pimobendan, dopamine, dobutamine, adrenaline, norepinephrine, isoproterenol, foxglove, hair. Digitalis alkaloid and theophylline.

Well-known antithrombotic drugs that can be used for this purpose are antiplatelet agents, such as clopidogrel, aspirin; anticoagulants such as heparin, warfarin, low molecular weight heparin; And thrombolytic agents, such as streptokinase, tissue plasminogen activator.

Current treatments for cats can temporarily alleviate the symptoms associated with diuretics to prevent further decompensation of heart failure. However, all of these treatments are only supportive and therefore extremely limited.

The use of cilobradine or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition suitable for the treatment or prevention of heart failure is known from EP 1 534 296 B1.

However, there is still a need to treat and prevent cat heart disease (specifically, cats) heart failure, and especially for cats with any pathogenic heart failure (specifically referred to as cats) to further improve rickets, quality of life and long-term Survival time.

The problem hidden in the present invention is to provide a treatable feline patient (specific Words refer to cats) drugs for heart failure. In addition, it is desirable to find a way to improve the quality of life and reduce the risk of death for feline patients (better cats), especially for those suffering from any pathogenic heart failure.

Before the present invention, the singular forms "a", "an" and "the" Thus, for example, reference to "a formulation" includes a plurality of such formulations. Unless otherwise defined, all technical and scientific terms used herein have the meaning as commonly understood by those skilled in the art. All specified ranges and values may vary from 1 to 5% unless otherwise indicated or as familiar to those skilled in the art, so the term "about" is omitted in the description. Although any methods and materials similar or equivalent to those described herein can be used to operate or test the invention, the preferred methods, devices, and materials are now discussed. In order to disclose and disclose materials, excipients, and carriers, all of the publications described herein are incorporated herein by reference. It is not to be taken as an admission that the invention is not limited by the invention.

The solution to the above technical problem can be achieved by the invention description and the embodiment in which the characteristics are represented in the request item.

The present invention relates to a fungic current (I _f ) inhibitor suitable for treating and/or preventing heart failure (HF) associated with a feline disease (preferably cat), or a medical treatment thereof Accept the salt. Furthermore, the present invention relates to a singular current (I _f ) suppression suitable for improving the quality of life and/or improving general health and/or extending life expectancy for feline patients with HF (specifically referred to as cats). Or a pharmaceutically acceptable salt thereof.

The term "heart failure" as used herein relates to a condition in which a structural or functional problem of the heart detracts from its ability to provide sufficient blood flow to meet the needs of the body, in particular any contractile condition or disease of the heart. Clinical manifestations are usually the result of changes in the cells and molecular components of the heart and the mediator that drives steady state control. Heart failure is caused by a variety of different diseases of the heart. The indications for various pathogens that can cause heart failure include the following: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), and Arrhythmogenic right ventricular cardiomyopathy (ARVC). Preferably, such cardiomyopathy is classified according to Kittleson (Kittleson, Textbook of veterinary internal medicine, edit Ettinger, Feldman, Elsevier Saunders, Philadelphia. 2005, 1082). Therefore, according to another aspect, the present invention relates to a HF suitable for treating or preventing a heart disease (preferably, one or more of the following pathogens HCM, DCM, RCM, UCM, and/or ARVC) A funky current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof. Accordingly, the present invention is also directed to a feline patient (preferred cat) suitable for use in HF caused by one or more of the following sources of HCM, DCM, RCM, UCM and/or ARVC to improve quality of life and/or An interesting current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof that improves general health and/or prolongs life expectancy. The invention also relates to the management of cat heart failure caused by HCM, UCM, RCM, DCM and/or ARVC.

Feline disease (better cat) heart disease (specifically, heart failure or The degree of heart failure caused by HCM, UCM, RCM, DCM, and ARVC is classified according to the ISACHC classification scheme. According to the present invention, the ISACHC category is adopted by the definition of the International Small Animal Cardiac Health Council (ISACHC) classification scheme:

In feline patients (specifically referred to as cats), heart failure is classified based on medical history results, physical examinations, and further examinations such as, for example, ultrasound echocardiography and chest radiographic examinations deemed necessary.

Category I A: Asymptomatic Cat

Evidence of cardiac murmur but no clinical signs and no echocardiographic evidence of cardiac structural changes.

Category I B: Asymptomatic Cat

There is evidence of heart murmur but no clinical signs, but there is no echocardiographic evidence of cardiac structural changes in the absence of enlargement of the heart.

Category II: Mild to moderate heart failure

Ultrasound cardiographic evidence of CMP and mild to moderate heart failure: evidence of mild to moderate clinical symptoms of heart failure (ie, shortness of breath/shortness of breath, mild respiratory distress/dyspnea). Here, treatment is required (i.e., using a diuretic as described herein, such as furosemide) to control clinical symptoms, but may also be treated at home.

Category III A: Late heart failure, but still available for outpatient treatment.

Ultrasound cardiographic evidence for CMP and advanced heart failure: clinical symptoms become apparent immediately, such as respiratory distress (dyspnea) or insufficient perfusion at rest . Outpatient care is feasible; no hospitalization is required.

Category III B: Advanced heart failure requiring hospitalization

Ultrasound cardiographic evidence from CMP suggests that late clinical signs of heart failure require hospital treatment (ie, iv (intravenous) administration of furosemide, supplemental oxygen).

Thus, an example thereof is that, for example, a cat belonging to category III A or B, in particular, compared to an untreated cat, has improved in health or symptoms sufficient to achieve a better ISACH such as either category II or category IA or category IB. category. This is also valid for cats classified as Category II according to the ISACH scheme, especially when compared to untreated cats, whose symptoms are improved to be classified as Category IA or Category IB.

According to another aspect of the invention, a cat suffering from a heart disease can also be scored on a 4th scale, following ISACHC with a score of 1, 2 or 3:

1 point: Heart disease without clinical signs (auscultation, ultrasound cardiogram and radiography).

2 points: The clinical signs of heart failure are significant and negatively affect the quality of life. Typical signs include difficulty breathing/breathing, lung congestion, weakness/sleepiness, anorexia, and exercise without endurance.

3 points: Immediate clinical signs of advanced heart failure. These clinical signs include shortness of breath, severe ascites/pulmonary congestion, severe exercise without endurance, or insufficient perfusion at rest.

4 points: Severe cases: sudden death of the individual, suffering from cardiogenic shock or acute hind limb paralysis / paralysis. Forced hospitalization.

Thus, as an example, especially in comparison to untreated cats, for example, the improvement in the health and/or symptoms of cats belonging to scores 3 or 4 is such that they achieve a better ISACHC score value, such as 2 or 3 points, respectively.

The term "quality of life" as used herein also refers to a preference for better quality of life (QoL) when treated with Trolltech current (I _f ) inhibitors, particularly for the cats in the cilostatin-treated group versus the placebo-treated group. . For the purposes of the present invention, it is specifically stated by its owner, such as Freeman LM, Rush JE, Oyama MA. Development and Evaluation of a Quality of Life Questionnaire for Cats with Cardiac Disease. J Vet Intern Med 2010 ;24:674) to assess the quality of life of cats. Use the following grading system to measure changes (specifically, improvement in quality of life): 0 (no/no change), 1 (very small/very small), 2 (less/less), 3 (medium change) / some), 4 points (large/multiple changes) and 5 points (very large/many). The assessment further includes assessments of developments and/or changes in dyspnea, fatigue/fatigue, fainting/fainting, eating habits, drinking habits, general behavior, behavior regarding the use of a drainage cassette, psychology, and hospitalization.

The quality of life of a cat can also be assessed daily by its owner. The following grading systems were used to measure changes: 1 (better), 2 (same), and 3 (worse). The assessment involves the overall feeling of including all impressions of the male/female owner.

Thus, a method for improving the quality and quality of life described herein is specifically directed to improving one of the grading systems described above. An example of the present invention relates to improvement in the quality of life of feline patients after administration as described herein, in particular from 3 or 4 to 2 or 3, respectively, compared to untreated cats.

In addition, the ease of administration also affects the quality of life of the animal in need of such treatment, as the treatment can be successful only if it is possible to administer a pharmaceutical composition to treat a feline (preferably cat) heart disease as described herein. Therefore, it is possible to further evaluate the convenience of administration, whether it can be most easily administered most of the time, difficult administration, or often fail to include inhibitors containing Trolltech current (I _f ) inhibitors (specifically, cilostatin) and other The pharmaceutical composition of the agent and/or vehicle. In addition, the owner should be asked whether to use the syringe to deliver the drug directly to the mouth for most of the time or to use a small amount of food to administer the drug.

In addition, in particular, the veterinarian evaluates the activity of the feline (specifically, the cat), laziness or depression to assess the behavior of the feline (specifically, the cat). Assessment of overall control of heart disease also includes, for example, poor, poor, good or excellent.

The term "improving general health status" as used herein relates to clinical findings, laboratory test results, ultrasound cardiogram assessment, ECG, X-ray parameters, blood pressure measurements, doses administered, and cat behavior. Therefore, in order to assess the improvement in general health status of feline patients, it is preferred to perform at least two examinations, in particular, before and after administration as described herein. For example, if the specific words are compared to untreated cats, the results of clinical examination, laboratory test results, ultrasound cardiogram assessment, ECG, X-ray parameters, dose of drug administered, and behavior of the cat are shown in this article. When the benefits of administration are described, the general health status of feline patients is improved.

For cats with heart failure, the term "extended" is used in the description of Trolltech current (I _f ) inhibitors (specifically, cilostatin) over placebo (specifically, untreated group). "Life expectancy" also relates to and includes "long-term survival time" or "heart disease mortality or rickets reduction rate" as used herein, meaning that the cats have a longer period of time after they have regularly accepted the administration methods described herein. Life expectancy.

A further implication of heart disease mortality is spontaneous death during the study, although it is known to have latent heart disease but it can be determined that there are no other clinical causes. The risk of heart disease is further defined as an event in which heart disease progression requires rescue treatment. Provide rescue treatment to cats in the case of heart disease. In addition, cardiac rickets are defined as cardiac disease progression with clinical symptoms worsening (eg, worsening respiratory signs) when one of the following criteria is met: cats need diuretic therapy at doses above the upper dose limit of 10 mg/kg/day (preferably furosemide) to control clinical symptoms of heart failure (eg, dyspnea); cats deteriorate due to clinical symptoms (eg, dyspnea, lethargy) and ultrasound echocardiographic parameters worsen than baseline estimates (eg, FS Significantly reduced, left atrial size expansion) or creatinine blood concentration > 440 μmol / L (> 5.0 mg / dl) or clinically significant imbalance of electrolyte development (ie, hypokaliaemia, blood salt deficiency ( Hyponatriaemia)) worsening and requiring other treatments such as angiotensin-converting enzyme inhibitors, Ca-channel blockers, beta-blockers, nitroglycerin, diuretics other than furosemide or other anti-heart rhythms Incomplete drug; cats have a thromboembolic event; cats have more than two recurrences of acute congestive heart failure (ISACHC class IIIB), but need hospitalization for oxygen therapy and / or iv (intravenous) with diuretics ; Cats need to accept more than 2 times of repeated thoracentesis. The assessment of H0 and HA was based on the following hypothesis: the H0-cilostatin treatment group was not superior to the placebo control group; the HA-cillodine treatment group was superior to the placebo control group. An example of the present invention relates to prolonging the life expectancy of a feline patient, whether the life of the cat is prolonged or whether the evaluation result meets the requirements of the HA standard mentioned above or the like in comparison with the untreated cat. begging.

"Trolltech Current (I _f ) Inhibitors" (also known as "I _f channel blockers") are herein related to I _f inhibitors, including their pharmaceutically acceptable salts, which selectively block cardiac conduction tissue. Hyperpolarization activates the cyclic nucleotide gated channel (HCN), which is responsible for the transmembrane current (referred to as the channel of I _f ). It is postulated that the I _f channel blocker produces a specific slowing of the heartbeat effect by blocking this current. The HCN channel is widely distributed in the nervous system and the eye, which regulates the current called I _h . The effects of zatebradine and cilostatin on this I _h channel have also been explored (with respect to zalidine: Neuroscience, vol. 59(2), pp. 363-373, 1994, and on West Loridine: British Journal of Pharma-cology, Vol. 125, pp. 741-750, 1998). The results show that these compounds can also block I _h . Since I _h has been described in different neurons of the visual signal processing system, so the effect of I _h has been shown to explain some of the possible side effects of the current I _f blockers of (visual disturbances). Ciloxydine specifically reduces the heart rate by selectively blocking the I _f channel ("Trolltech Channel") directly in the cardiac sinus node by interacting directly with the major HCN4 channel. This blocking effect is effective and varies with dose and voltage. Due to the high selectivity to I _f current, no effect on vasomotor or myocardial contractility and relaxation of healthy cats was observed at therapeutically relevant doses. The negative shifting effect of cilostatin leads to a decrease in myocardial oxygen demand, a prolonged diastolic interval, and an increase in stroke volume, which in turn increases myocardial oxygen supply.

The preferred Interesting current (I _f) Xi Luolei inhibitor is given, allyloxy given Nepal (alinidine), zatebradine and ivabradine (ivabradine), and is preferably fixed Xi Luolei zatebradine More preferably, it is Siluridine.

Ciloride (3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-(7,8-di) Methoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one) and its hydrochloride are disclosed, for example, in EP-B-0 224 794 and its US counterpart US 5,175,157 As already mentioned, cilostatin is also known to have a beneficial activity in the treatment or prevention of heart failure (see EP-B-1 534 296). Also known as cilostatin, zalidine, and allyleni It has the beneficial activity of treating and inducing the remission of idiopathic hypertrophic cardiomyopathy (HCM), ischemic cardiomyopathy and valvular heart disease (see WO 01/78699).

Allopidine [2-(N-allyl-2,6-dichloro-anilino)-2-imidazolidinyl] is disclosed, for example, in US 3,708,485, and ivabradine 3-[3-[[[ (7S)-3,4-dimethoxybicyclo[4.2.0]octyl-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3, 4,5-Tetrahydro-7,8-dimethoxy-2H-3-benzoazepin-2-one and its hydrochloride are disclosed, for example, in EP-B-534,859.

Zalteidine [1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N -Methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-propane] is disclosed, for example, in EP-B-0 065 229 and its U.S. Patent No. 5,516,773. Zalidine is known to have beneficial activity in the treatment of cardiac insufficiency (see EP-B-0 471 388).

In particular, ivabradine is known to have a beneficial activity for the treatment of cardiomyopathy (see EP-B-534859 or US 5,296,482). Riesem et al. (Riesen, Schober, Smith, Otoni, Xiaobai, Bonagura; AJVR, Vol. 73, No. 2: Effects of ivabradine on heart rate and left ventricular function on healthy cats and cats with hypertrophic cardiomyopathy) HCM's cat cast with Ibrabra set. Here, a significant reduction in heart rate was observed in both healthy and subclinical HCM cats. The negative shift effect with dose changes is shown in healthy cats.

The term "patient" as used herein relates to a feline patient, preferably a cat, and more preferably a domestic cat, specifically a feline having a heart disease, and more preferably a cat suffering from heart failure. According to another embodiment of the invention, the feline patients have heart failure caused by one or more of the following pathogens HCM, DCM, RCM, UCM and/or ARVC.

Therefore, a fungic current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof according to the present invention (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilorie Dinglei or Zalidine, and more preferably cilostatin) is indicated for the treatment and/or prevention of heart disease (preferably heart failure (HF)) in feline patients (preferred cats). Therefore, a fungic current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof according to the present invention (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilostatin Or zalidine, more preferably cilostatin) for the treatment and/or prevention of cat disease (preferably cat) heart disease (preferably in the following sources HCM, DCM, RCM, UCM and / or ARVC) One or more of the causes of heart failure (HF)).

The feline patient (preferably cat) according to the present invention is additionally monitored in consideration of its overall health and mortality. Administration of an I _f channel blocker to a feline patient (specifically, a cat), preferably, not only treats and/or prevents heart failure but also improves quality of life and general health and prolongs life expectancy.

Thus, in accordance with another aspect of the present invention, the inventors have discovered the use of a Trickle Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or Ivabradine, preferably cilostazidine or zalidine, and more preferably cilostatin, may improve the HF and/or the following pathogens HCM, DCM, RCM, UCM and/or ARVC The quality of life of one or more feline patients (specific cats) with heart failure (HF).

Furthermore, the present inventors have discovered Trolltech Current (I _f ) inhibitors or pharmaceutically acceptable salts thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably siro Radiation or zalidine, and more preferably cilostatin) may also improve one or more of the preferred HMC, DCM, RCM, UCM and/or ARVC with HF heart failure (HF) and/or The general health status of feline patients (specific cats) caused by HF.

According to another aspect of the present invention, the present inventors have discovered the use of a Trickle Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or iva Breidin, preferably cilostatin or zalidine, and more preferably cilostatin), may prolong one of the better HF and / or the following sources of HCM, DCM, RCM, UCM and / or ARVC Or the life expectancy of feline patients (specific cats) of HF.

As used herein, the term herein, the dosage amount administered is sufficient to achieve remission with current Interesting heart failure patients when the effect (I _f) inhibitor means that when "effective amount." Advances in the therapy can be monitored by standard cardiology, for example by ultrasound cardiography, cardiac catheterization or cardiac MRI, X-ray, ECG, cardiac biomarkers or cardiac magnetic resonance imaging. The progress of the therapy can also be monitored by clinical symptoms as defined above/here and quality of life related parameters. In addition, the effective amount also allows the patient (preferably a feline patient, and a better cat) to achieve an improvement in quality of life and/or an improvement in general health and/or an increase in life expectancy. The health progress and improvement obtained by the therapy can be monitored by the pet owner and the veterinarian.

dose

The dosage regimen of such compounds of the invention is of course intended to vary according to known factors such as: the specific pharmacological properties of the particular agent and its mode of administration and the route; the species, age, sex, state of health, medical condition of the patient And weight; the nature and extent of the symptoms; the type of combination therapy; the frequency of treatment; the kidney and liver function of the patient and the expected effect.

The physician or veterinarian may determine and prescribe a prescribed effective dose of the desired drug to prevent, counter or arrest the progression of the disease. According to general principles, when used to treat and/or prevent heart failure, each time the active ingredient is administered (preferably a Tricks Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, The dose of zalidine, alleridine or ivabradine, preferably cilostatin or zalidine, and more preferably cilostatin) can be administered at a dose of 0.01 mg/kg to 1.0 per dose. Mg/kg body weight, preferably 0.02 to 0.8 mg/kg body weight per administration, more preferably 0.04 to 0.6 mg/kg body weight, and even more preferably 0.06 mg/kg to 0.4 mg/kg body weight, 0.08 mg/kg to 0.3 mg /kg body weight, optimally ranging from 0.1 mg/kg body weight to 0.3 mg/kg body weight or 0.1 to 0.2 mg/kg body weight. These doses should be administered once or twice daily. The therapy is recommended for use in clinically significant cases, including acute and chronic cases. The administration of such doses also preferably achieves one, two or all of the following: improved quality of life, improved general health, and prolonged life expectancy.

Therefore, according to another aspect of the invention, the invention relates to an interesting current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, Preferably, cilostatin or zalidine, and more preferably cilostatin, for the preparation of a drug/pharmaceutical combination suitable for the treatment and/or prevention of heart failure (preferably feline patients, specific cats) The use of things. According to another aspect, the present invention provides a stimulating current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, Preferably, cilostatin or zalidine, and more preferably cilostatin, for preparing a heart failure disease caused by treating one or more of the following pathogens HCM, DCM, RCM, UCM and/or ARVC The use of a drug/pharmaceutical composition for a patient (preferably a feline patient, a specific cat). The use is also preferably achieved by one, two or all of the following: a cat suffering from heart failure due to heart failure and/or one or more of the following sources HCM, DCM, RCM, UCM and/or ARVC The quality of life of patients with specific conditions (specific cats) improved, general health improved and life expectancy increased.

Preferably, the Tricks Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilostatin Or zalidine, and more preferably cilostatin) for the treatment and/or prevention of heart failure in cats (specific cats), where the dosage range is 0.01 to 2 mg/kg body weight/day, Preferably, the range is from 0.02 to 1.5 mg/kg body weight/day, more preferably from 0.05 to 1 mg/kg body weight/day, still more preferably from 0.07 to 0.7 mg/kg body weight/day, and most preferably from 0.09 to 0.5. Mg/kg body weight/day, specifically 0.1 to 0.3 mg/kg body weight/day or 0.1 mg/kg to 0.2 mg/kg body weight/day.

Preferably, the Tricks Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilostatin Or zalidine, more preferably cilostatin) for the treatment and/or prevention of heart failure in feline patients suffering from one or more of the following sources of HCM, DCM, RCM, UCM and/or ARVC, Wherein the dosage is in the range of 0.01 to 2 mg/kg body weight/day, preferably in the range of 0.02 to 1.5 mg/kg body weight/day, more preferably in the range of 0.05 to 1 mg/kg body weight/day, and even more preferably in the range of 0.07. To 0.7 mg/kg body weight/day, optimal range is 0.09 to 0.5 mg/kg body weight/day, specifically 0.1 to 0.3 mg/kg body weight/day or 0.1 mg/kg to 0.2 mg/kg body weight/day The scope.

Dosing method

The compounds of the present invention can be administered in the form of oral dosage forms, capsules (each of which may include sustained release or sustained release formulations), pills, powders, granules, elixirs, elixirs, suspensions, syrups and emulsions. They may also be administered intravenously (rapid injection or infusion), intraperitoneally, subcutaneously or intramuscularly, all in a dosage form well known to those skilled in the art. a funky current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof according to the present invention (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilostatin or Zalidine, more preferably cilostatin, is intended for oral or parenteral administration.

The Turkic Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilostatin or zalteide) Ding, and better, cilostatin) is administered once, twice or three times a day, preferably once or twice a day, and more preferably once a day.

The Turkic Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilostatin or zalteide) It may be administered separately, but it is generally administered using a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practice.

Combined use

Preferably, the Tricks Current (I _f ) inhibitor (such as cilostatin) is administered in combination with a second active therapeutic agent. Preferably, the second active therapeutic agent is a diuretic. Preferably, the diuretic is a loop diuretic such as furosemide, bumetanide, ethacrynic acid or torsemide; or a thiazide diuretic such as chlorine Chlorotiazide, hydrochlorothiazide, metolazone, or a potassium-sparing diuretic such as spironolactone, eplerenone, triamterene or amiloride Amiloride). Most preferably, the diuretic is furosemide and the residual potassium diuretic is spironolactone. The diuretic (specifically, a ring diuretic such as furosemide) should be administered 1 or 2 times daily at a dose of 0.5 to 5 mg/kg. Once the patient has stabilized, it is best to stop the diuretic (such as furosemide) altogether.

Thus, according to another aspect, the present invention relates to a Trickle Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine) , preferably cilostatin or zalidine, more preferably cilostatin) in combination with a diuretic (preferably a loop diuretic such as furosemide) for the treatment of feline patients with heart failure ( Specific cats). Preferably, the Tc inhibitor (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (specifically, cilostatin, zalidine, allienidine or ivabradine, preferably cilostatin or Zalidine, and more preferably cilostatin) and diuretics (specifically, a loop diuretic such as furosemide) are administered at the dosages described herein.

According to another aspect, the present invention relates to a two-stage combination therapy for treating a patient suffering from heart failure comprising administering a Trolltech Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof in a first stage ( Especially cilostatin, zalidine, alleridine or ivabradine, preferably cilostatin or zalidine, more preferably cilostatin) and diuretics (especially loop diuretics) a combination of, for example, furosemide, and in the second phase, a Tricks Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (especially cilostatin, zalidine, allienidine or y Valbratidine, preferably cilostatin or zalidine, more preferably cilostatin, but does not use a loop diuretic (such as furosemide). Preferably, the Trickle Current (I _f ) inhibitor (such as cilostatin) and a diuretic (particularly a loop diuretic such as furosemide) are administered at the dosages described herein.

According to another aspect, the present invention relates to a fungic current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (particularly cilostatin, zalidine, allienidine or ivabradine, Preferably, cilostatin or zalidine, more preferably cilostatin, and one or two or more selected from the group consisting of calcium channel blockers, ß-adrenergic receptor antagonists, positive contractions, A pharmaceutically active compound of a group consisting of an ACE inhibitor, an antithrombotic agent, and an antiarrhythmic drug for the combined use of heart failure in treating and/or preventing a patient (preferably a feline patient, a better cat). In another aspect, the invention relates to a Trickle Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof (particularly cilostatin, zalidine, allienidine or ivabradine, Preferably, cilostatin or zalidine, more preferably cilostatin, and one or two or more selected from the group consisting of calcium channel blockers, ß-adrenergic receptor antagonists, positive contractions, A pharmaceutically active compound composed of an ACE inhibitor, an antithrombotic agent, and other antiarrhythmic agents for treating and/or preventing a patient (preferably a feline patient, a better cat) suffering from the following pathogens HCM, DCM, RCM Heart failure caused by one or more of UCM and/or ARVC. The above-mentioned combined use is also applicable to feline patients (especially cats) suffering from heart failure caused by heart failure and/or one or more of the following sources of HCM, DCM, RCM, UCM and/or ARVC ) Achieve one, two or all of the following: improving quality of life, improving general health, and extending life expectancy. Furthermore, the present invention relates to commissural combining therapies, such as diabling diuretics (especially loop diuretics such as furosemide) as needed, to control cat heart failure due to HCM, UCM, RCM, DCM, ARVC.

In various aspects, one subject of the invention relates to a composition comprising cilostatin ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl))) -piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepine-2-one ), cilostatin hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl) )-Methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one hydrochloride), zalidine (1 -(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N-methyl-N- [(2-(3,4-Dimethoxyphenyl)ethyl]amino]-propane) or allienidine (2-(N-allyl-2,6-dichloro-anilino) a pharmaceutical composition of 2-imidazole pyridine, which is suitable for treating an animal (preferably a mammal, more preferably a carnivorous mammal, more preferably a feline, preferably a cat) In the method.

In accordance with the above description, cilostatin or cilostatin hydrochloride is preferred, more preferably cilostatin hydrochloride, wherein particularly preferred use is suitable, for example, by incorporation of separate medical formulations. To treat cat (feline) heart disease (especially Multi-layered granules of heart failure.

It is preferred to use a liquid pharmaceutical composition having a final concentration of the active ingredient of 0.5 to 5 mg/ml, preferably 0.75 to 4 mg/ml, more preferably 0.5 to 3 mg/ml.

The invention thus further provides a Tricks Current (I _f ) inhibitor, or a pharmaceutically acceptable salt thereof, suitable for use in the methods described herein, wherein the Tiratron current (I _f ) inhibitor is selected from the group consisting of zalidine (1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N-methyl-N-[ (2-(3,4-Dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl) Piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one, its mirror image Structure cilostatin ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)--) Base]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one) or allienidine (2-(N-allyl) Base-2,6-dichloro-anilino)-2-imidazolidinyl), preferably cilostatin hydrochloride ((+)-3-[(N-(2-(3,4-dimethyl) Oxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3 - benzoazepin-2-one hydrochloride).

Furthermore, the invention thus further provides a Tricks Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof, which is suitable for use in the methods described herein, wherein the Tiratron Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof comprises The final concentration of the singular current ( _IF ) inhibitor or a pharmaceutically acceptable salt thereof in the total liquid form of the pharmaceutical composition is from 0.5 to 5 mg/ml, preferably from 0.75 to 4 mg/ml, more preferably from 0.5 to 3 mg/ml.

The invention thus also provides a use of a Troll Current (I _f ) inhibitor, or a pharmaceutically acceptable salt thereof, as described herein for the preparation of a medicament, wherein the Tirafluous (I _f ) inhibitor is selected from the group consisting of Zatire (1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N-methyl -N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy-phenyl) )-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one , the mirror image isomer of cilostatin ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)- Base)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one) or allienidine (2-( N-allyl-2,6-dichloro-anilino)-2-imidazolidinyl), preferably cilostatin hydrochloride ((+)-3-[(N-(2-(3, 4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro -2H-3-benzoazepin-2-one hydrochloride).

Further, the present invention thus provides a use of a Tricks Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament, wherein the Tira positive current (I _f ) inhibitor or a pharmaceutically acceptable thereof Interesting to the salt comprising current (I _f) inhibitor, or a pharmaceutically acceptable salt thereof in a generally liquid form of the pharmaceutical composition of the final concentration of 0.5 to 5 mg / ml, preferably 0.75 to 4 mg / ml, more preferably 0.5 to 3 mg/ml.

The invention thus also provides a method for achieving the following effects on feline patients (preferably cats) as described herein: - treating or preventing heart failure and / or - improving quality of life and / or - improving general health and / or - prolonging life expectancy wherein the Troll current (I _f ) inhibitor is selected from zalidine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-) Benzoazin-2-one-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1, 3,4,5-tetrahydro-2H-3-benzoazepin-2-one, its mirror image isomer, cilostazide ((+)-3-[(N-(2-(3,4-) Dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H -3-benzoazepin-2-one) or allienidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazolidinyl), preferably in West Lore Hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl] -(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one hydrochloride).

Furthermore, the present invention thus provides a method for achieving the following effects on feline patients (preferably cats) as described herein: - treating or preventing heart failure and / or - improving quality of life and / or - improving general health and / Or - extending the life expectancy, wherein the singular current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition comprising the singular current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof in an overall liquid form The final concentration is from 0.5 to 5 mg/ml, preferably from 0.75 to 4 mg/ml, more preferably from 0.5 to 3 mg/ml.

Instance

The following examples are intended to further illustrate the invention; however, such examples are not to be construed as limiting the scope of the invention disclosed herein.

Example 1

Formulation method for compounds for the treatment of heart disease

This example is intended to formulate the compound (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl) in liquid form. )-Methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.

In order to produce a multi-layered particle for incorporation into a liquid dosage form, a three-step process is employed, which is summarized in Table 1.

Step 1: Drug coating layer

As in Example 1, microcrystalline cellulose particles having an average particle diameter of 100 μm were used as a starting material, and water was used as a solvent to coat a layer of the active ingredient and the binder. The material layer consisted of 66.6% (w/w) pharmaceutically active ingredient, 31.7% (w/w) HPMC (Pharmacoat® 606; see Example 1) and 1.7% (w/w) magnesium stearate dispersed in pure water. In the middle, a spray liquid containing about 19% solids was obtained.

The ingredients of the IR pellets produced are shown in Table 2.

Step 2: Seal the coating layer

The IR pellets prepared in step 1 are further processed in the same apparatus and the seal coating component is sprayed onto the IR pellets. The material used to seal the coating component is PVP K 30 (trade name Kollidon ® 30 from BASF, supplied by BASF, Ludwigshafen, Germany) / talc, dispersed in a mixture of acetone and ethanol 94:6 by weight, 75.4:22.5 Composition in (m/m). After coating the PVP K 30/talc mixture and drying the organic solvent, 0.5% (w/w) highly dispersible (colloidal) cerium oxide (Aerosil® 200, available from Evonik) was added (in the intermediate step). Seal the coating material.

The overall composition of the SC (sealed coating) pellets (cilostatin seal coated pellets) prepared in this step is shown in Table 3.

Table 3: Containing (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]- Composition of SC pellets of (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one hydrochloride

Step 3: Final coating layer (masking coating layer)

The SC pellets prepared in step 2 are further processed in the same apparatus, and the final coating component is sprayed onto the SC pellets. The material used for the final masking taste and/or odor coating component is from EC/HPMC/magnesium stearate 55.2:23.8:19.8 by weight (the EC/HPMC ratio in the film coating component is about 70:30). )composition. For this purpose, EC, HPMC and magnesium stearate were dispersed in a 1:1 mixture (v/v) of methanol and dichloromethane and then sprayed onto the SC pellets.

The coating component was applied to a thickness of 75% of the initial amount of SC pellets.

As in step 2, 0.5% colloidal cerium oxide (Aerosil® 200) was added to the final product prior to screening.

The EC selected was Ethocel® 45 cps STD Premium, available from Dow Chemical Company of Schwalbach, Germany. The HPMC selected for this layer was Methocel ® E5 Premium LV, available from Dow Chemical. Aerosil ® 200 from Evonik.

The overall composition of the final multilayer particles is shown in Table 4.

Table 4: Containing (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]- Composition of the final multi-layered particles of (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one hydrochloride

Table 5 specifically discloses that (+)-3-[(N-(2-(3,4-dimethoxy)) is prepared according to steps 1 to 3 of this example and assuming that the physical properties of the respective materials have physicochemical properties. -phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzene The overall composition of the taste-masked multilayer particles of azepine-2-one hydrochloride.

Dissolution experiment

The multilayer particles prepared in this example were subjected to the solubility test at the different pH values of 6.8 and 1 according to the same method as the particles of Example 1. The measured values are the total percentage of released material measured after each time point and corrected by the theoretical drug content.

The results are shown in Table 6.

Based on these data, the coated EC/HPMC pellets delay dissolution, thus effectively masking the bitter drug (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl) )-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2- The taste and/or odor of the ketone hydrochloride. This can be verified by a fully formulated liquid composition prepared as described below, based on an acceptability test conducted using a laboratory cat.

Generally, the sustained release properties of the EC/HPMC membrane are independent of pH. However, in this case, the product is surprisingly shown at pH 6.8 to favor the present invention. Slow release (ie effective masking of taste in the mouth) and faster release in acidic stomach. This can be illustrated by the lipophilic form of the more lipophilic cilostatin HCl salt at neutral pH. This, along with the coating coating applied, may result in slower release.

Liquid pharmaceutical composition

In order to prepare a liquid pharmaceutical composition, the final multi-layered granules containing the active ingredient cilostatin prepared by the method described above are incorporated into an oily liquid. The liquid system consists of medium chain triglyceride (Miglyol® 821, available from Sasol, Hamburg, Germany), hydrophilic colloidal cerium oxide (Aerosil ® 200, Evonik), hydrophobic colloidal cerium oxide (Aerosil ® R972) , Evonik) and meat flavorings, consisting of a mixture of the weight ratios shown in Table 7.

The multilayered particles prepared according to step 3 were suspended in the above liquid composition to an amount of about 3.8% (w/v) such that the concentration of the pharmaceutically active ingredient was 2 mg/ml (calculated based on the hydrochloride).

It has been found that the composition of an oily solvent (especially a mixture of hydrophilic and hydrophobic colloidal cerium oxide) ensures that the suspension has suitable viscosity properties, generally The top can remain unchanged during storage. During storage, the suspension showed a high viscosity to prevent precipitation of the suspended cilostatin pellets. If oscillated, the viscosity of the suspension will decrease instantaneously, so it can be easily applied via a syringe-shaped oral applicator.

Example 2

Treatment of cats with HF caused by HCM

HCM cats were treated with either cilostatin (initial dose: 0.2 mg/kg po. twice daily) or placebo (dose: 0.0 mg/kg po. twice daily) for double-dose, control, Randomized, therapeutic range studies. The dose of cilostatin can be adjusted during the study (dose range 0.1 to 0.5 mg/kg, orally, 2 times daily). Furosemide was administered to both groups. All cats were hospitalized during the first week of the study (days 1 to 6 of the study) and then (from days 7 to 85 of the study) let them go home.

The study included cats diagnosed with HCM. The diagnosis of HCM was determined by using an echocardiogram to show the overall, local or segment thickness of the iliac and/or left ventricular wall in the diastolic ventricle greater than 6 mm. Other inclusion criteria are as follows:

Systolic pressure less than 170 mmHg

Serum thyroxine (T4) is normal

Weigh more than 2 kg.

Informed consent was signed by the owner to allow the animal to participate in the study. Cats with heart disease use a 4-level scoring system that scores 1, 2 or 3 points according to ISACHC:

1 point: Heart disease (auscultation, ultrasound cardiogram and radiography) can be detected without clinical signs.

2 points: The clinical signs of heart failure are significant and negatively affect the quality of life. Typical signs include difficulty breathing/breathing, lung congestion, weakness/sleepiness, anorexia, and exercise without endurance.

3 points: Immediately show clinical signs of advanced heart failure. Such clinical signs may include respiratory distress, severe ascites/pulmonary congestion, severe exercise without endurance, or insufficient perfusion under rest.

4 points: Severe cases: sudden death of the individual, suffering from cardiogenic shock or acute hind limb paralysis / paralysis. Forced hospitalization.

Exclude cats with one or more of the following criteria:

Cats have received one or more of the following pretreatments: calcium channel blockers such as diltiazem, angiotensin converting enzyme inhibitors, beta-blockers, acetylsalicylic acid, and drone glycosides. (Cats that have received only pretreatment with furosemide may be included in either group as long as they meet all of the above inclusion criteria)

The serum T4 concentration is increased.

Serum blood urea nitrogen (BUN) concentrations increased by more than 90 mg / dL or serum creatinine concentration increased by more than 3 mg / dL.

The systolic arterial blood pressure is greater than or equal to 170 mmHg.

Dilated cardiomyopathy (DCM)

Cardiac disease with a score of 4 (according to the ISACHC score) within 30 days prior to enrollment or an unrecorded heart failure episode (2 or 3 points).

Determine aortic stenosis.

Female cat who is pregnant or lactating

The kitten in the scorpion.

Weighs less than 2 kg.

Sinus rhythm is slow (the heart rate is less than 120 bpm at the time of consultation).

The quality of life of cats was assessed daily using the following grading system: 1 (better), 2 (same), 3 (worse).

The rate of heartbeat of cats receiving cilostatin slowed throughout the study, while the rate of heartbeat of cats receiving placebo increased (see Table 8).

The reduction in sputum thickness in the ventricles of cats receiving cilostatin was considerable compared to cats receiving placebo (see Table 9).

In addition, right heart enlargement was assessed by X-ray using the following scoring system:

1 point: standard size

2 points: slightly enlarged

3 points: moderate expansion

4 points: severely expanded

At the end of the study, X-rays were used to observe a slight enlargement of the right side of the heart in cats receiving placebo. In contrast, the right side of the heart of the cat receiving cilostatin throughout the study period was normal (see Table 10).

Example 3

The half-life of cilostatin in healthy male individuals after oral administration (po) once a day is 10.1 to 13.9 h. The administration was continued for 7 days (see Table 11 and Table 12). Ciloleidine hydrochloride is in the form of a capsule administered at a dose of 5, 10 and 20 mg per body. Assuming a body weight of 70 kg, this dose is equivalent to a dose of 0.07, 0.14, and 0.28 mg/kg of cilostatin hydrochloride. Conversely, the half-life of cilostatin in healthy cats after oral administration for 4 days is 2.53 to 3.52 h. Ciloleidine hydrochloride was administered as a suspension at doses of 0.1 mg/kg and 0.3 mg/kg. Interestingly, heart rate was observed to decrease with dose in both humans and cats within 9 hours after the above doses of cilostatin. There are some differences in the pharmacokinetics of cilostatin between cats. This may be associated with differences in absorption, metabolism, distribution or excretion.

In summary, although similar pharmacodynamic characteristics were observed in humans and cats, this phenomenon was not consistent with the different pharmacokinetic profiles observed between cats and humans.

Based on the above examples, it is concluded that cats suffering from heart failure treated with cilostatin showed that although their half-life in cats was significantly shorter than in humans, their life was significantly improved at very low doses. Quality and general health.

Example 4

In the conscious cat, the pharmacodynamic characteristics of cilostatin hydrochloride were analyzed by administering the drug once or twice daily at two doses. The study consisted of two groups of three European Short Hair cats, each weighing between 4.15 kg and 4.75 kg on the first treatment day.

Each cat was cross-designed and received cilostatin hydrochloride once daily (sid) and twice daily (bid) with 0.1 or 0.3 mg/kg. The interval between treatments was 24 hours (sid) or 12 hours (bid). A 7-day exclusion period was set between the two administration periods.

First, a remote detector is implanted in the cat to measure the heart rate. The remote detection measurement is recorded for 15 seconds at a sampling rate of 500 Hz every 5 minutes, at D-2, D-1, D0 to D9, and D16 to D25 (but not including D4 and D20 for blood samples).

Under the experimental conditions used, cilostatin hydrochloride was orally administered at a dose of 0.1 and 0.3 mg/kg per day, and the heart rate was induced with dose changes.

Figure 1 depicts the quality of life of cats receiving cilostatin (black squares) or placebo (open circles).

Claims (13)

A pharmaceutical composition comprising a funny current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof for use in a feline patient: treating or preventing heart failure and/or improving quality of life and/or improving general Health status and / or extended life expectancy. The pharmaceutical composition of claim 1, wherein the feline patients have heart failure caused by HCM, DCM, RCM, UCM and/or ARVC. The pharmaceutical composition according to claim 1, wherein the singular current (I _f ) inhibitor is selected from the group consisting of cilobradine, zatebradine, alinidine, and ivabradine. (ivabradine) group. The pharmaceutical composition according to any one of claims 1 to 3, wherein the singular current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof is used orally or parenterally. The pharmaceutical composition according to any one of claims 1 to 3, wherein the singular current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof is in a pharmaceutical form at a dose of 0.01 to 2 mg/kg body weight per day. use. The pharmaceutical composition of claim 5, wherein the drug is a solid or liquid formulation. The pharmaceutical composition of claim 6, wherein the drug is a solid formulation, the 0.001 to 0.2 mg of the inhibitor or a pharmaceutically acceptable salt thereof per mg of the solid formulation. The pharmaceutical composition of claim 6, wherein the drug is a liquid formulation, Each mg of the liquid formulation contains from 0.1 to 20 mg of the inhibitor or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 3, wherein the Tricks Current ( _IF ) inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of 0.01 to 2 mg/kg body weight. The pharmaceutical composition according to any one of claims 1 to 3, wherein the Tricks Current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof is administered together with a diuretic (combination therapy). The pharmaceutical composition according to claim 7, wherein the diuretic is administered once or twice daily at a dose of 0.5 to 10 mg/kg of body weight. Use of a funky current (I _f ) inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in a feline patient: treating or preventing heart failure and/or improving quality of life and/or improving general health And / or extend life expectancy. The use of claim 12 for feline patients suffering from HF caused by HCM, DCM, RCM, UCM and/or ARVC improves quality of life and/or general health and/or prolongs life expectancy.