IT201900006624A1 - Combination of canrenone and enalapril for use in the therapy of diabetic patients. - Google Patents

Description

"Combination of canrenone and enalapril for use in the therapy of diabetic patients"

DESCRIPTION

The present invention relates to the therapeutic use of a combination of canrenone, an aldosterone receptor antagonist, and enalapril, an ACE inhibitor, particularly for the treatment of arterial hypertension, congestive heart failure, myocardial fibrosis or cardiac hypertrophy.

State of the art

The incidence of primary or secondary heart failure to myocardial infarction or consequent to arterial hypertension has been steadily increasing for several years and represents a particularly important health problem. In the diabetic patient this is even more important, as the cardiovascular event is very frequent compared to the non-diabetic population.

Aldosterone promotes Na <2+> reabsorption in the kidney, lower gastrointestinal tract and salivary and sweat glands and also has pro-fibrotic and inflammatory activity.

The role of aldosterone synthesis and metabolism is of crucial importance in the etiopathogenesis of myocardial insufficiency. In particular, the renin-angiotensinaldosterone system plays a decisive role in the development of arterial hypertension. There are two catalytic sites in the angiotensin converting enzyme ("ACE" for short). Angiotensin I exhibits its highest affinity for the C-terminal catalytic site of ACE. ACE can induce tissue fibrosis through the production of angiotensin II and an ACE inhibitor may therefore be useful in attenuating fibrosis. Several ACE inhibitors are known including, for example, benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril and ramipril.

Although drugs are generally well tolerated, side effects are known for ACE inhibitors such as, for example, in the case of enalapril, hypotension, fatigue, insomnia, dizziness or syncope, and dyspnoea.

The aim of the present invention is to provide a combination of antihypertensive active ingredients which is particularly effective for the treatment of arterial hypertension, congestive heart failure, myocardial fibrosis and cardiac hypertrophy in diabetic patients.

Another object of the present invention is to provide a therapy based on a combination of antihypertensive active ingredients comprising enalapril which reduces the typical side effects associated with the administration of enalapril, such as for example hypotension, fatigue, insomnia, dizziness or syncope, and dyspnoea.

Summary of the invention

This task, as well as these and other purposes which will appear better later, are achieved by a combination of canrenone and enalapril for use in the treatment of a selected condition including congestive heart failure, arterial hypertension, myocardial fibrosis and cardiac hypertrophy in diabetic patients.

Further characteristics and advantages of the invention will become clearer from the following detailed description.

Detailed description of the invention

In the context of the present invention, "active ingredient" means a compound that produces a pharmacological effect that leads to a physiological change. Within the scope of the present invention the active ingredients are the aldosterone receptor antagonist canrenone and the ACE inhibitor enalapril which are used in the combination therapy of the invention.

However, the present invention also contemplates the possibility of combining canrenone and enalapril with further active ingredients, in particular with further antihypertensive active ingredients, including diuretics (for example hydrochlorothiazide), beta-blockers (for example bisoprolol), receptor antagonists of angiotensin II (eg irbesartan) and calcium channel blockers (eg amlodipine).

In the context of the present invention, the term "combination" refers to two or more active ingredients for the treatment of a single disease state for use by concomitant administration. The active ingredients can be combined and administered in a single dosage form, can be administered as separate dosage forms at the same time or can be administered as separate dosage forms that are administered alternately or sequentially on the same day or on separate days.

The present invention therefore relates to a combination of canrenone and enalapril for use in the treatment of a selected condition from congestive heart failure, arterial hypertension, myocardial fibrosis and cardiac hypertrophy in diabetic patients.

Although the active ingredients of the combination for the use of the present invention can be administered in pure form, it is preferable that they are formulated as pharmaceutical compositions. In the context of the present invention, canrenone and enalapril can therefore be formulated in a single pharmaceutical composition or each of them can be formulated in a separate pharmaceutical composition.

Of course, each of the pharmaceutical compositions may further comprise any pharmaceutically acceptable excipient normally used in the preparation of pharmaceutical compositions. Such excipients are "acceptable" in the sense that they must be compatible with the other ingredients of the composition and not be harmful to the patient.

Examples of commonly used excipients include pharmaceutically acceptable carriers or diluents, a flavoring, a sweetener, a preservative, a color, a binder, a suspending agent, a dispersing agent, a disintegrant, a lubricant, a plasticizer, an edible oil or any combination of two or more of the above products.

In one embodiment of the combination for use of the present invention, canrenone and enalapril (pure or as pharmaceutical compositions) are formulated in a single dosage form. This can be advantageous in that the administration of a single dosage form can facilitate patient adherence (compliance) to therapy.

In another embodiment of the combination for use of the present invention, canrenone and enalapril (pure or as pharmaceutical compositions) are formulated in separate dosage forms. This can be advantageous when, for example, it is desirable to vary the quantity of only one of the two active ingredients.

The combination for the use of the present invention is preferably administered orally, by means of suitable solid or liquid dosage forms, such as for example capsules, tablets, powders, granules, solutions, suspensions and emulsions, more preferably oral dosage forms of the type solid as capsules and tablets.

In embodiments of the combination for use of the present invention where canrenone and enalapril are formulated in a single dosage form, such a single dosage form may for example be a capsule or tablet comprising effective amounts of canrenone and enalapril in combination with one or more pharmaceutically acceptable excipients.

In embodiments of the combination for use of the present invention where canrenone and enalapril are formulated in separate dosage forms, the combination can be provided as a kit comprising separate dosage forms for canrenone and enalapril, e.g. capsules or tablets comprising an effective amount of active ingredient in association with one or more pharmaceutically acceptable excipients. Said kit may further comprise instructions for the separate, simultaneous or sequential use of the dosage forms of canrenone and enalapril.

For example, in one embodiment the kit contains a first dosage form comprising canrenone and a second dosage form comprising enalapril.

The dosage of the active ingredients of the combination for the use of the present invention will depend on several factors such as age, weight and sex of the patient, as well as on the severity of the condition to be treated. The dosage can therefore vary within wide limits which can in any case be determined by the expert clinician on the basis of his knowledge and experience.

Generally, in the combination for the use of the present invention the canrenone is preferably present in an amount comprised between 25 and 100 mg and enalapril is preferably present in an amount comprised between 5 and 40 mg.

The present invention will be further described with reference to the following non-limiting example.

Example

The effectiveness of the association of the invention was evaluated with the methods described in Eur. J. Heart Fail. 2009; 11 (1): 68-76; Cardiovasc. Ther.

2017; 35 (1): 47-54; Drug Des. Devel. Ther. 2017; 11: 2293-2300; J Cardiovasc Pharmacol Ther. 2017; 22 (4): 365-367; Ann. Med. 2015; 47 (1): 47-52 and Expert Opinion Pharmacother. 2013; 14 (16): 2161-2169.

A study was conducted to determine the efficacy of the combination of canrenone and enalapril on diabetic and non-diabetic patients divided as follows:

1) Diabetic patients:

■ 92 patients (including 45 males and 47 females) treated with canrenone from 25 to 100 mg / day;

■ 97 patients (including 47 males and 50 females) treated with enalapril from 5 to 40 mg / day;

■ 101 patients (including 52 males and 49 females) treated with canrenone 25 to 100 mg / day in combination with enalapril 5 to 40 mg / day.

2) Non-diabetic patients:

■ 89 patients (including 45 males and 44 females) treated with canrenone from 25 to 100 mg / day;

■ 92 patients (including 46 males and 46 females) treated with enalapril from 5 to 40 mg / day;

■ 99 patients (including 50 males and 49 females) treated with canrenone 25 to 100 mg / day in combination with enalapril 5 to 40 mg / day.

The following Tables 1-4 show the baseline parameters observed in the patients studied in the study. The following abbreviations and acronyms are used in these tables:

PAS = systolic blood pressure;

PAD = diastolic blood pressure;

HR = heart rate;

FPG = fasting blood glucose;

HbAlc = glycated hemoglobin;

Tg = triglycerides;

HOMA index = insulin resistance index; Lp (a) = lipoprotein a;

MMP-2 = metalloprotein-2;

MMP-9 = metalloprotease-9;

MPO = myeloperoxidase.

Table 1 reports the baseline parameters observed in the non-diabetic patient groups treated with canrenone, enalapril, or a combination of canrenone and enalapril, respectively.

Table 1

Data expressed in means ± standard deviations

p - not significant between groups at baseline.

Table 2 reports the baseline parameters observed in the diabetic patient groups treated with canrenone, enalapril, or a combination of canrenone and enalapril, respectively.

Table 2

Data expressed in means ± standard deviations;

p = not significant between groups at baseline.

Table 3 reports the parameters after 12 months treatment in the non-diabetic patient groups treated with canrenone, enalapril or a combination of canrenone and enalapril, respectively.

Table 3

Data expressed in means ± standard deviations

* p <0.05 vs baseline; ; ° p <0.01 vs baseline; ; ^ ρ <0.05 vs canrenone group and enalapril group. ;; Table 4 reports the parameters after 12 months treatment in the diabetic patient groups treated with canrenone, enalapril or a combination of canrenone and enalapril, respectively. ; Table 4 ;; ;; Data expressed in means ± standard deviations; * p <0.05 vs baseline;

° p <0.01 vs baseline;

^ ρ <0.05 vs canrenone group and enalapril group; <§> p <0.05 vs non-diabetic group.

It has been found that the simultaneous administration of canrenone and enalapril allows to decrease the dose of enalapril thus reducing its typical side effects such as for example hypotension, fatigue, insomnia, dizziness or syncope. Additionally, canrenone has a direct effect in preventing or treating such side effects.

Canrenone also reduces systolic and diastolic blood pressure values and its use in combination with enalapril leads to a further reduction in blood pressure without altering the heart rate (which could lead to lipothymias) both in the non-diabetic patient and in the diabetic patient.

In the group of diabetic patients, the combination of canrenone and enalapril is surprisingly significant in reducing blood pressure compared to the group of non-diabetic patients.

Canrenone in combination with enalapril, surprisingly, significantly reduces fasting triglycerides in diabetic patients compared to non-diabetic patients.

Furthermore, canrenone unexpectedly improves insulin resistance in carbohydrate metabolism by enhancing efficacy in combination with enalapril and this is particularly evident in the diabetic patient compared to the non-diabetic patient.

Canrenone in combination with enalapril, particularly in diabetic patients, reduces lipoprotein to [(Lp (a)], a particular molecule that is intermediate between the fibrinolytic system (dissolution of the clot, a component present in the atherosclerotic plaque) and lipid metabolism.

Furthermore, canrenone and enalapril in combination reduce atherosclerotic plaque remodeling enzymes (metalloproteases) showing a synergy that is surprisingly more significant in diabetic patients than in non-diabetic patients.

The effect of canrenone, enalapril and a combination thereof on myeloperoxidase (MPO), an inflammatory molecule, was also evaluated. Administration of canrenone in isolation reduces myeloperoxidase more significantly than administration of enalapril in isolation. The canrenone-enalapril combination shows surprisingly a synergistic effect in the anti-inflammatory action particularly in diabetic patients (Tables 1-4)

In practice it has been found that the combination for use according to the invention fully achieves the intended aim as it provides a therapy for the treatment of congestive heart failure, arterial hypertension, myocardial fibrosis and cardiac hypertrophy which has proved particularly effective in patients diabetics.

Although the combination for use according to the invention is conceived in particular for the therapy in diabetic patients, it can in any case be used for the treatment of congestive heart failure, arterial hypertension, myocardial fibrosis and cardiac hypertrophy in patients in general.

Claims (5)

R IV E N D I C A Z I O N I 1. Combination of canrenone and enalapril for use in the treatment of a selected condition from congestive heart failure, arterial hypertension, myocardial fibrosis and cardiac hypertrophy in diabetic patients. 2 . Combination for use according to claim 1 where canrenone and enalapril are formulated in a single dosage form. Combination for use according to claim 1 where canrenone and enalapril are formulated in separate dosage forms. Combination for use according to any one of the preceding claims where the canrenone is present in an amount comprised between 25 and 100 mg. Combination for use according to any one of the preceding claims wherein enalapril is present in an amount comprised between 5 and 40 mg.