IE83342B1 - Use of a 5-HT4-receptor antagonists in the treatment of atrial fibrillation, including the prevention of stroke - Google Patents

Description

USE OF A 5-HT4-RECEPTOR ANTAGONISTS IN THE TREATMENT OF ATRIAL FIBRILLATION, INCLUDING THE PREVENTION OF STROKE The present invention relates to medicaments for example pharmaceutical compositions, for use in the treatment of atrial fibrillation (for example, human atrial fibrillation) and the prevention of stroke.

Compounds which antagonise the effects of 5—HT 4 receptors in the central nervous system, and gastrointestinal system are known in the art (see for example European Journal of Pharmacology, 146 (1988), 187-88. Naunyn—Scl1miedeberg's Arch. Pharmacol. (1989) 340:403-410) and Br. Journal of Pharmacology 96:247p- 1989).

In addition, 5-HT receptors which may resemble those known to exist in the CNS. have been identified in the human atrium [Br. Journal ' of Pharmacology, 98, 664p, (1989) and Br. Journal of Pharmacology, 100, 879885 (1990)]. These "5-HT4-like" receptors located in the atrium are hereinafter referred to as cardiac 5—HT4 receptors.

However, in spite of these disclosures there is no indication as to the potential clinical usefulness of compounds which block cardiac -HT 4 receptors.

It has now been found that the compound (3-oz-tropanyl)—lH— indazole—3—carboxylic acid ester antagonises cardiac 5—"HT4 receptors and is expected, as a consequence. to be of use in the treatment of atrial fibrillation.

The present invention therefore provides the use of a cardiac —HT4 receptor antagonist in the preparation * of a medicament for use in the treatment of atrial fibrillation, for example, human atrial fibrillation.

Cardiac arrhythmias have been associated with symptomatic cerebral embolism. Cerebral embolism is the most common cause of ischaemic stroke and the heart, the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation (Harrison's Principles of Internal Medicine, 11th Edition). Up to 9% of individuals over the age of 60 have atrial fibrillation (Sima et al. 1990, Stroke 21; 14-22). Atrial fibrillation in combination with rheumatic valvular heart disease is associated with a 17-fold increased risk of stroke, whereas chronic atrial fibrillation without rheumatic valvular heart disease is associated with a 5-fold increased risk of stroke. Only arrhythmias which encourage atrial stasis, - such as atrial fibrillation and atrial disorders cause cerebral and systemic embolism. Thus, specific cardiac 5-HT4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with -HT, would also be expected to reduce occurrence of stroke.

In a further aspect of the invention therefore, said treatment may be for reducing the occurrence of stroke.

As indicated above, the compound (3—ot—tropanyl)-1H-indazole carboxylic acid ester has been found to be a cardiac 57.1-IT4 receptor antagonist and is expected to be of use in the treatment of the conditions hereinbefore defined.

The cardiac 5-HT4 receptor antagonists will usually be formulated in a standard pharmaceutical composition. Said pharmaceutical composition will comprise a cardiac 5—HT4 receptor antagonist in association with a pharmaceutically acceptable carrier. The composition -3.- can be prepared by methods well known in the art of pharmacy, for example, compounds which are active when given orally can be formulated as liquids, for example, syrups, suspensions or emulsions, tablets, capsules and lozenges.

—Liquid formulations will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerine, non—aqueous solvent, for example, polyethylene glycols, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

Tablet compositions can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

Compositions in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be -4.. lyophilised and then reconstituted with a suitable solvent just prior to administration.

Preferably, the composition is in unit dose form such as a tablet or capsule.

Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.

Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

DATA (3—a—Tropanyl)—1H—indazole—3-carboxylic acid ester can be prepared by the procedures described in EP-200444—A.

PIGLET SPONTANEOUS BEATING ATRIA SCREEN Method Arch.

(See A. J. Kaumann, 1990, Naunyn—Schmiedeberg's Pharmacol 342, 619-622).

Piglets of either sex, 2 to 5 days old, were obtained from Usually 2 piglets were from the same litter. The piglets were anaesthetised with halothene; their hearts rapidly removed and washed free of blood with warm solution containing (mM):120 Na+, 5 K+, 2.25 Ca2+, .5 Mg2+, 98.5 c1", 0.5 so42', 34 Hco3', 1 HPo42’, .04 EDTA, deionised and double distilled water in glass, equilibrated with 95% O2 and 5% C02.

After dissection of the right atrium in warm solution, the tissue was set up in an apparatus with a 50 ml. bath (Blinks, 1965 J. Appl. Physiol. 20, 755-757), containing the solution described above supplemented with (mM):15 Na+, 5 fumarate, 5 pyruvate, 5 L-glutamate, 10 glucose.

Experiments were carried out at 37°C. For the study of positive chronotropic effects, the spontaneously beating right atrium was suspended at a resting tension just sufficient for measurable development of tension (to avoid tachycardia induced by stretching the sinoatrial node — Blinks, 1956 Amer. J. Physiol. 186, 299-303). was attached to a Swema SG4-45 strain gauge transducer by The tissue means of a stainless steel wire and force recorded on a Watanabe polygraph.

To avoid possible indirect B-adrenoceptor-mediated effects due to release of noradrenaline all experiments were carried out in the presence of 400 nM (:)—propranolol (about 100 x KB for (1)-propranolol). To reduce tissue capture of 5-HT, all experiments were carried out in the presence of 6 pM cocaine; cocaine potentiates the effects of 5-HT on human atrium [Kaumann et al., Br. J. Pharmacol. 100, 879-885, (1990)). physiological solution and all dilutions of 5-HT contained 0.2 mM ascorbate.

To decrease oxidation of 5-HT the A single cumulative concentration—effect curve was determined by the sequential addition of 5-HT or other was determined. ' Results In the above screen, the potency of a number of known agonists was found to be similar to that published for human atrium [Kaumann et al., Br. J. Pharmacol. 100, -885, (199o)]. hypothesis that the 5-HT receptors of porcine sinoatrial These results are consistent with the node and of human right atrial appendage are the same.

The preliminary screening results shown in Table 1 indicate that (3-a-tropanyl)—1H—indazolecarboxylic acid ester is a competitive antagonist of cardiac 5-HT4 receptors.

TABLE 1 Comparison of blockinq potencies of antaqonists on riqht (3-a—tropanyl)- 1H-indazole—3— carboxylic acid ester Granisetron (EPA) pK = ND = atrial preparations Human (force) Porcine (rate) BK D 25 .1 6 ND - ineffective 2 (20 HM) ineffective 3 (1 HM) -log M equilibrium dissociation constant not determined number of individuals

Claims (7)

Claims

1. Use of a cardiac 5-HT4 receptor antagonist in the preparation of a medicament for use in the treatment of atrial fibrillation.

2. A use according to claim 1 wherein the treatment is for reducing the occurance of stroke.

3. Use as claimed in claim 1 wherein the medicament is for use in the treatment of human atrial fibrillation.

4. Use as claimed in claim 1, 2 or 3 wherein the medicament comprises a pharmaceutical composition comprising the cardiac 5—HT4 receptor antagonist in association with a pharmaceutically acceptable carrier.

5. Use as claimed in claim 4 wherein the cardiac 5-HT4 receptor antagonist is active when given orally and wherein the composition is formulated as a tablet or capsule.

6. Use as claimed in any preceding claim wherein the 5—HT4 receptor antagonist is (3—x-tropanyl)-IH—indazole-3—carboxylic acid ester.

7. Use as claimed in any preceding claim substantially as described herein with reference to the example.