RS20050775A - A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor - Google Patents

Abstract

The invention refers to a cardiotonic pharmaceutical composition having enhanced therapeutical width. The pharmaceutical composition of the invention comprises (a) an active ingredient having the effect of digitalis and (b) a cGMP phosphodiesterase inhibitor and one or more conventional carrier(s).

Description

A pharmaceutical preparation containing an active agent that has the effect of digitalis i

cGMP phosphodiesterase inhibitor

The present invention relates to a cardiotonic pharmaceutical preparation with an extended therapeutic effect.

State of the art

Active ingredients that have digitalis activity have long been used as cardiotonic drugs for weak heart function and insufficiency of myocardial activity, that is, when heart contractions are insufficiently strong. Active ingredients with digitalis effects inhibit the sarcolemmal Na<+>/K<+->ATPase in cardiac myofibrils, thus increasing the intracellular concentration of free calcium, which is necessary for contraction. In this way, a positive inotropic effect is achieved.

The disadvantage of using active ingredients with a digitalis effect lies in the fact that they easily lead to arrhythmia. This symptom occurs partly due to a decrease in the refractoriness of the myofibrils of the ventricles, and partly due to the appearance of late afterpotentials. Arrhythmias appear as separate ventricular extrasystoles, initially as bigeminy, and later intense ventricular tachycardia occurs. Active ingredients with a digitalis effect are characterized by a relatively narrow therapeutic range, i.e. small difference between the positive inotropic dose (which is the therapeutic dose) and the arrhythmogenic dose. In other words, the therapeutic dose is very close to the dose that causes serious arrhythmias.

Clement et al. conducted a study in which the effect of combined therapy with cicletanine and digoxin on plasma digoxin concentration was examined (Clement et al.: "Lack of Effect of Cicletanine on Plasma Digoxin Levels", Int. J. Clin. Pharm. Res., 8(1), 9 - 11(1988)). The study, which included six patients, showed no significant changes in digoxin plasma concentrations, but found that the combination therapy was well tolerated.

Bukoski et al. investigated the vascular effect of cicletanine (Bukoski, R.D. et al.: "Vascular actions of cicletanine", Archives des Maladies du Coeur et des Vaisseaux, 82 (4), 45 - 50 (1989)). Cycletanin led to relaxation of blood vessels that was not inhibited even when the blood vessels were previously treated with ouabain, moreover, a slight intensification of relaxation was observed at low doses.

Data in the literature do not suggest the existence of any influence of phosphodiesterase inhibitors on the arrhythmogenic effects of digitalis glycosides.

The essence of the invention

The aim of the present invention is to provide a cardiotonic pharmaceutical preparation with an extended therapeutic range, so that the application of the preparation eliminates the risk of developing arrhythmia.

It has been found that the above objective can be achieved by the use of a pharmaceutical preparation consisting of (a) an active ingredient with a digitalis effect and (b) a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor, as well as one or more conventional carriers.

The present invention is based on the knowledge that in the presence of a cGMP phosphodiesterase inhibitor, the cGMP phosphodiesterase enzyme does not decompose the present cyclic guanosine monophosphate. In this way, the effect of nitrogen monoxide (NO), which is continuously created in the human organism, is enhanced, since cGMP activates the enzyme NO synthase, which produces nitrogen monoxide. The higher amount of nitrogen monoxide produced leads to vasodilatation, as well as to the expansion of the therapeutic range of active ingredients with the digitalis effect.

Detailed description of the invention

In the description and patent claims, "active ingredients with a digitalis effect" mean glycosides that can be isolated from plants from the Digitalis subfamily (eg Digitalis purpurea, Digitalis lanata, Digitalis lutea, etc.) or digitaloids, i.e. glycosides that can be isolated from plants of the Strophantus family (eg Strophantus gratus, Strophantus kombe, etc.) or from other plants (eg Scilia maritima, Convallaria majalis, etc.). The term "glycosides" includes pure glycosides, mixtures of glycosides as well as products obtained by chemical transformations of said glycosides. Examples of active ingredients with a digitalis effect are digoxin, digitoxin, lanatoside A, lanatoside B, lanatoside C, lanatoside D, K - strophanthin, G - strophanthin (ouabain), scilaren, convalatoxin, etc.

Of the active ingredients with a digitalis effect, digoxin, digitoxin and ouabain are preferred.

By the term "cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor" is meant a substance that inhibits the metabolism of cyclic guanosine monophosphate. In fact, the mentioned substances inhibit different isoenzyme forms of cGMP phosphodiesterase, whose role is to break down cGMP.

Examples of cGMP phosphodiesterase inhibitors are as follows:

Cycletannin (chemical name: (±)-3-(4-chlorophenyl)-1,3-dihydro-6-methylfuro-[3, 4-c]pyridin-7-ol) or its pharmacologically suitable acid addition salt, which is a known antihypertensive (US-P No. 4,383,998),

vinpocetine (chemical name: (3a,16a)-eburnamenine-14-carboxylic acid ethyl ester), which is a known cerebral vasodilator (US-P No. 4,035,370),

sildenafil (chemical name: 1-[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl-sulfonyl]-4-methylpiperazine) or its pharmacologically acceptable acid addition salt, a known active ingredient in preparations for the treatment of impotence,

Zaprinast (chemical name: 1,4-dihydro-5-(2-propoxyphenyl)-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one) or its pharmacologically suitable acid addition salt, known antiallergic,

ibudilast (chemical name: 2-methyl-l-[2-(l-methylethyl)-pyrazolo[1,5-a]pyridin-3-yl]-l-propanone) or its pharmacologically suitable acid addition salt, a known antiallergic, antiasthmatic and vasodilator (US-P No. 3,850,941),

rolipram (chemical name: 4-[3-cyclopentyloxy-4-(methoxyphenyl)]-2-pyrrolidinone) or its pharmacologically suitable acid addition salt, a known antidepressant (US-P No. 4,193,926),

pimobendan (chemical name: 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone) or its pharmacologically suitable acid addition salt, a known cardiotonic (US-P No. 4,361,563),

Vesnarinone (chemical name: 1-(3,4-dimethoxybenzoyl)-4-(1,2,3,4-tetrahydro-2-oxo-6-quinolinyl)-piperazine) or its pharmacologically suitable acid addition salt, a known cardiotonic (US-P No. 4,415,572),

ODQ (chemical name: 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) or its pharmacologically suitable acid addition salt,

WIN-58237 (chemical name: l-cyclopentyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-one), or its pharmacologically suitable acid addition salt,

ONO-1505 (chemical name: 4-[2-(2-hydroxyethoxy)ethyl-amino]-2-(1H-imidazol-1-yl)-6-methoxyquinazoline methane sulfonate) and

DMPPO (1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-one) or a pharmacologically suitable acid addition salt thereof.

The cGMP phosphodiesterase inhibitors recommended in the present invention are: cicletanin or its pharmacologically suitable acid addition salt, vinpocetine, sildenafil or its pharmacologically suitable acid addition salt and zaprinast or its pharmacologically suitable acid addition salt. Within the scope of the present invention, the use of cicletanin or its pharmacologically suitable addition acid salt, especially the hydrochloride, as an inhibitor of cGMP phosphodiesterase is particularly recommended.

The pharmaceutical composition of the present invention includes an active ingredient with a digitalis effect and a cGMP phosphodiesterase inhibitor, in a weight ratio in the range (1 - 500) -

(500 - 1), and the best in the range (1 - 200) - (200 - 1). If desired and chemically possible, the digitalis effect ingredient and the cGMP phosphodiesterase inhibitor may be in the form of pharmacologically acceptable salts obtained using pharmacologically acceptable bases or acids.

In general, the present invention is a solid or liquid preparation suitable for oral or parenteral administration.

A solid pharmaceutical preparation suitable for oral administration can be in the form of powder, capsules, tablets, film tablets, microcapsules, etc., and can also contain as a carrier: binding substances such as gelatin, sorbitol, poly(vinylpyrrolidine), etc.; fillers such as lactose, glucose, starch, calcium phosphate, etc.; excipients for tableting such as magnesium stearate, talc, poly(ethylene glycol), silicon, etc.; humectants such as sodium lauryl sulfate, etc.

A liquid pharmaceutical preparation suitable for oral administration can be in the form of a solution, suspension or emulsion and can also contain as a carrier: suspending substances such as gelatin, carboxymethylcellulose, etc.; emulsifiers such as sorbitan monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol, etc.; preservatives such as methyl p-hydroxybenzoate etc.

Pharmaceutical preparations suitable for parenteral use consist of sterile solutions of active ingredients, generally speaking.

The pharmaceutical preparation of the subject invention is prepared by mixing the active ingredient with one or more carriers and further processing this mixture into a preparation, in a way that

is known per se.

The above dosage formulas, other dosage formulas, as well as the preparation of the above preparations and other useful carriers can be found in the literature, see, e.g. Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, USA

(1990). In general, a pharmaceutical preparation contains a unit dose.

A preferred pharmaceutical composition of the present invention contains an active ingredient with a digitalis effect, for example, digoxin, and cicletanin, vinpocetine, sildenafil, zaprinast, ibudilast, rolipram, pimobendan, vesnarinone, ODQ, WIN-58237, ONO-1505 or DMPPO, or, if desirable and chemically possible, pharmacologically suitable or salts obtained using pharmacologically suitable bases or acids, with the addition of one or more carriers.

It is particularly recommended to use a pharmaceutical preparation of the patent invention containing an active ingredient with a digitalis effect, for example, digoxin and cicletanin, vinpocetine, sildenafil, zaprinast or, if desirable and chemically possible, pharmacologically suitable salts obtained by using pharmacologically suitable bases or acids, with the addition of one or more usual carriers.

The best choice of pharmaceutical composition of the preparation of the present invention is a composition containing digoxin and cicletanin or cicletanin hydrochloride with the addition of one or more conventional carriers.

The beneficial therapeutic effect of the pharmaceutical composition of the subject invention was examined by the following tests.

1. Determination of 50% of maximum inotropic effect and "torsade des pointes"

ventricular tachycardia in rabbits.

Animals were pretreated with 5mg/kg of atropine given intravenously. Then ouabain was administered in the form of intermittent infusion, i.e. an initial dose of 20 ug/kg of ouabain was given intravenously by infusion over 4 minutes. This was followed by a 20-minute rest period, after which a dose of 10 µg/kg ouabain was administered every ten minutes until a bout of torsade des pointes (TdP) ventricular tachycardias occurred. These experiments were carried out after the administration of an intravenous bolus injection of 10 mg/kg or 30 mg/kg cicletanine, or a placebo injection as a control. Each group consisted of 6 animals. The total doses of ouabain that induced half maximal inotropic effect (dP/dtso) as well as those that induced TdP are given in Table 1.

From Table 1, it is obvious that in cardiotonic therapy, 49 mg/kg of ouabain must be used to achieve 50% of the maximum positive inotropic effect. When cycletannin was also administered, a dose of ouabain that was only about 60% of the control value (ie, 26 to 30 ug/kg ouabain) was sufficient to cause the effect described above.

It can be seen from Table 1 that, in the presence of cicletanine, the unwanted side effect of cardiotonic therapy with uabain, ventricular tachycardia, appeared only with the use of much higher doses of uabain than in the absence of cicletanine.

2. Effects of cicletanine on the range of safe administration of ouabain in guinea pigs

Test groups consisting of 10 guinea pigs were given an intravenous bolus injection of cicletanin, in doses of 10 and 30 mg/kg. Animals were anesthetized by intraperitoneal injection of 30 mg/kg pentobarbital sodium. Animals were also pretreated with atropine (1.0 mg/kg i.p.). After that, ouabain was given as an intramittent infusion. An initial dose of 60 u-g/kg ouabain was given by infusion over 5 minutes, followed by a 30-minute rest period. A dose of 30 µg/kg of ouabain was then administered every ten minutes until the heart stopped. Under these conditions, various forms of heart rhythm disturbances occurred, in the following order: single ventricular ectopic beats, bigeminy (BG), accelerated indioventricular rhythm (AIVR), ventricular tachycardia (VT), ventricular fibrillation (VF) and finally, cardiac arrest. The cumulative doses of ouabain required to induce BG, AIVR, VT, and VF in the absence and presence of cicletanine are given in Table 2 .

It can be seen from Table 2 that even in guinea pigs, in the presence of cicletanin, the unwanted side effects of cardiotonic therapy with uabain appeared only with the use of much higher doses of uabain than in the absence of cicletanin.

The results of the presented tests show that cGMP phosphodiesterase inhibitors expand the therapeutic range of digitalis glycosides, which can be seen by reducing the dose necessary for successful cardiotonic therapy, as well as by increasing the dose that causes arrhythmogenic side effects.

The present invention involves the use of a cGMP phosphodiesterase inhibitor in the preparation of a pharmaceutical preparation in order to expand the therapeutic range of the active ingredient with the digitalis effect. When such a pharmaceutical preparation is applied to patients who are already under therapy with an active ingredient with a digitalis effect, the desired goal is also achieved, i.e. the therapeutic range of the active ingredient with the digitalis effect is extended.

In addition, the subject invention also includes a method for expanding the therapeutic range of the active ingredient with digitalis effect in the treatment of patients who need cardiotonic therapy, a therapy in which, along with the active ingredient with digitalis effect, a cGMP phosphodiesterase inhibitor is given to the patient.

Daily dose of active ingredient with digitalis effect, e.g. digoxin, is usually 0.05 to 0>75mg/kg in adults, while the daily dose of a cGMP phosphodiesterase inhibitor such as cicletanine hydrochloride is usually 1 to 100mg/kg of body weight, preferably 1 to 20mg/kg.

The subject invention is also illustrated by the following examples.

Examples

Example 1: Preparation of capsules from solid gelatin

Each capsule contains 0.07 mg of digoxin, 200 mg of cicletanin hydrochloride and 250 mg of microcrystalline cellulose. The ingredients are mixed and filled into hard gelatin capsules.

Example 2: Preparation of tablets

Each tablet contains 0.1 mg of digoxin, 400 mg/kg of cicletanine hydrochloride, 9.9 mg of silicon, 50 mg of carboxymethyl cellulose, 30 mg of microcrystalline cellulose and 10 mg of magnesium stearate. The ingredients are mixed and compressed into tablets of 0.5 g each.

Claims (8)

1. Cardiotonic pharmaceutical preparation with an extended therapeutic effect, indicated by the fact that it contains (a) an active ingredient with a digitalis effect and (b) a cGMP phosphodiesterase inhibitor, with the addition of one or more usual carriers. 2. Pharmaceutical preparation according to claim 1, characterized in that the active ingredient with digitalis effect is digoxin or ouabain. 3. Pharmaceutical preparation according to claim 1, characterized in that the cGMP phosphodiesterase inhibitor is cicletanin, vinpocetine, sildenafil, zaprinast, or, if chemically possible, a pharmacologically suitable acid addition salt of these compounds. 4. Pharmaceutical preparation according to claim 1, characterized in that it contains (a) digoxin and (b) cycletanin or its pharmacologically suitable acid addition salt. 5. The use of cGMP phosphodiesterase inhibitors for the preparation of a pharmaceutical preparation, characterized by the fact that the therapeutic range of the active ingredient with the digitalis effect is extended. 6. Use according to claim 5, characterized in that the applied cGMP phosphodiesterase inhibitor is cicletanin, vinpocetine, sildenafil, zaprinast or, if chemically possible, a pharmacologically suitable acid addition salt of these compounds. 7. Use according to claim 6, characterized in that the applied cGMP phosphodiesterase inhibitor is cycletannin or its pharmacologically suitable acid addition salt. 8. Method for extending the therapeutic range of the active ingredient with digitalis effect. characterized by the fact that in a patient who needs cardiotonic therapy with an active ingredient with a digitalis effect, an inhibitor of cGMP phosphodiesterase is administered along with an active ingredient with a digitalis effect. 1. The use of cGMP phosphodiesterase inhibitors for the preparation of a pharmaceutical preparation, indicated by the fact that it eliminates the occurrence of arrhythmogenic side effects of cardiotonic therapy with digitalis glycoside or digitaloid. 2. Use according to claim 1, characterized in that the cGMP phosphodiesterase inhibitor is cicletanine, vinpocetine, sildenafil or zaprinast or, if chemically possible, their pharmacologically suitable acid addition salt. 3. Use according to claim 2, characterized in that the cGMP phosphodiesterase inhibitor is cycletannin or its pharmacologically suitable acid addition salt. 4. The procedure for reducing the dose of digitalis glycoside or digitaloid necessary for cardiotonic therapy, indicated by the fact that in a patient who needs cardiotonic therapy with digitalis glycoside or digitaloid, in addition to digitalis glycoside or digitaloid, a cGMP phosphodiesterase inhibitor is also administered.