5 TECHNICAL FIELD

The present invention concerns the use of a corticosteroid in association with other active principles for the treatment of vascular stenosis and the prevention of vascular restenosis.

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BACKGROUND ART

Vascular disease and in particular ischemic cardiopathy is the first cause of mortality and morbidity in western society; in fact it is reckoned that one death out of

15 three is due to cardiovascular disease and that ischemic cardiopathy and cardiac insufficiency are the main cause.

One of the main factors that contributes to causing ischemic cardiopathy is the formation of vascular

20 stenoses, that is pathological shrinkage of the lumen of a blood vessel which causes a reduction of the blood flow, due in most cases to atherosclerotic disease which causes thickening of the tunica intima of the blood vessel and the depositing of atheromatous plaques.

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As well as at cardiac level, atherosclerotic disease is frequently found in other vascular districts, sometimes concomitantly, such as for example at the level of the

arteries of the supra-aortic trunk, such as the vessels of the neck and of the upper limbs, or of the lower limbs causing respectively ischemic events of the central nervous system, for example ictus, or ischemia of the legs with functional impotence, for example limping.

It is known the treatment of these occlusive phenomena with percutaneous vascular procedures, to which reference will be made below with the term "angioplasty", as therapy of first choice in particular in the coronary district. This procedure is spreading continuously and the technology at the disposal of operators is more and more sophisticated.

The greatest progress in invasive cardiology and radiology in recent years for the treatment of vascular stenosis has been the introduction of endovascular prostheses, to which reference will be made below with the term "conventional endovascular stents", that is expandable and resistant metal devices which are implanted in a vessel to guarantee its patency.

This therapy is definitive in 70-80% of cases, while in 20-30% of patients there may be stenotic relapse, also called restenosis, which is the main limitation on the use of angioplasty operations. In large calibre vascular districts, such as that of the supra-aortic trunk and the iliac arteries, this restenosis percentage may be less,

but it is higher than 50% in other district such as the femoral, popliteal and tibial districts.

The advent of "drug-eluting stents" (DES), that is of medicated endovascular stents able to release slowly over time medicinal substances that can reduce or even cancel the repetition of stenosis of the treated vessels, has considerably reduced the cases of intra-stent restenosis, thus encouraging the treatment of patients who presented not only a single vascular lesion, but multiple vascular lesions. In particular, drug-eluting stents are known which are able to release drugs such as Rapamycin and Paclitaxel, both available on the market for clinical use.

The advent of drug-eluting stents certainly represents a considerable step forward for avoiding restenosis after angioplasty, but the real efficacy, especially in patients with multiple coronary lesions or in extra- cardiac vascular districts, and the cost-benefit ratio of such a strategy applied on a large scale, are still to be made clear.

In fact, the tests carried out so far which compare the implants of drug-eluting stents and those of conventional endovascular stents have been limited to patients with single lesions.

Moreover the use of drug-eluting stents involves costs that are 3 to 4 times higher for each stent at the expense of the health systems with respect to non- medicated conventional endovascular stents. The extent of the clinical and social-economic problem is clear especially if one considers the exponential increase of the number of operations performed in recent years.

So there is a demand for an anti-restenotic strategy applicable to a wide range of patients with favourable results, which would reduce the problem of restenosis after angioplasty to a minimum percentage of cases, which is inexpensive and therefore allows the extension of the application of that treatment even to health systems with limited economic resources.

DISCLOSURE QF INVENTION

The aim of the present invention is therefore to find a treatment that is able to prevent vascular stenosis and which reduces the incidence of stenotic relapse after angioplasty.

According to the present invention, this aim is achieved by the use of at least one corticosteroid in association with at least one diuretic and at least one antacid for the preparation of a medicament for the treatment of atherosclerotic vascular stenosis and the prevention of restenosis after angioplasty.

Preferably the corticosteroid is selected from the group consisting of prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, betamethasone, dexamethasone, triamcinolone and paramethasone and the salts thereof.

Even more preferably the corticosteroid is prednisone.

Preferably the diuretic is selected from the group consisting of furosemide, bumethanide, ethacrynic acid, torsemide, chlortalidone, hydrochlorothiazide, hydroflumethazide and metazolone.

Even more preferably the diuretic is furosemide.

Preferably the antacid is selected from the group consisting of omeprazole, pantoprazole, esomeprazole, ilaprazole, lansoprazole, rabeprazole, cimetidine, ranitidine, famotidine and nizatidine.

Even more preferably the antacid is omeprazole.

Preferably the corticosteroid is administered in a quantity of between 2 mg and 150 mg per day.

Even more preferably, if the corticosteroid is prednisone it is administered in a guantity of between 25 mg and 100

mg per day.

According to a preferred embodiment of the invention, the diuretic is administered in a quantity of between 0.5 mg and 200 mg per day.

Preferably, if the diuretic is furosemide it is administered in a quantity of between 25 mg and 50 mg per day.

According to a preferred embodiment of the invention, the antacid is administered in a quantity of between 20 mg and 800 mg per day.

Preferably, if the antacid is omeprazole, it is administered in a quantity of between 20 mg and 40 mg per day.

Preferably the corticosteroid, the diuretic and the antacid are administered orally.

Preferably the corticosteroid, the diuretic and the antacid are administered in sequence.

Alternatively the corticosteroid, the diuretic and the antacid are administered simultaneously.

Non-limiting examples of pharmaceutical formulations

according to the present invention are given here below.

The corticosteroid in association with the diuretic and the antacid may be in the form of tablets prepared with known methods with pharmaceutically acceptable excipients such as binding agents, filling agents, additives, disintegrants and/or lubricating agents.

Alternatively the corticosteroid in association with the diuretic and the antacid may be prepared in the form of coated tablets or in the form of granulate to be administered orally.

Preferably the corticosteroid, the diuretic and the antacid are administered in a single pharmaceutical formulation and more preferably said single pharmaceutical formulation is a tablet.

Advantageously, the corticosteroid, administered in an immunosuppressive dose, in association with a diuretic and an antacid for the treatment of vascular stenosis and the prevention of vascular restenosis is able to interfere with the tissue inflammatory processes which occur as a consequence of the vascular damage produced by the angioplasty and by the implanting of the conventional metal prosthesis.

This administration of corticosteroid acts both on the

local inflammatory mechanisms and at systemic level, favouring the production of blood cells, such as monolytes and lymphocytes, by the organism.

Further characteristics of the present invention will be made clear from the following description of some examples supplied for purely illustrative purposes, without limitation.

EXAMPLE 1

Prevention of coronary restenosis

The aim of the following example is to describe the treatment of coronary restenosis with angioplasty associated with the use of the composition object of the present invention.

For this experiment 178 patients with multiple coronary lesions were selected. These patients were divided into two groups : - Reference group: 84 patients suffering from coronary atherosclerosis subjected to angioplasty with or without the implant of a conventional endovascular stent on a total of 156 coronary stenoses;

Control group: 94 patients with similar characteristics treated with angioplasty on 165 coronary stenoses.

The patients in the reference group were treated with the

administration in succession and orally of a tablet comprising 100 mg of prednisone, a tablet comprising 40 mg of omeprazole and a tablet comprising 25 mg of furosemide per day for 10 days. The patients were then treated with the administration in succession and orally of a tablet comprising 50 mg of prednisone, a tablet comprising 40 mg of omeprazole and a tablet comprising 25 mg of furosemide per day for 20 days. Lastly the patients were then treated with the administration in succession and orally of a tablet comprising 25 mg of prednisone, a tablet comprising 40 mg of omeprazole and a tablet comprising 25 mg of furosemide per day for 10 days.

Thanks to the use of prednisone in association with furosemide and omeprazole, a significant reduction of restenosis endovascular stents was found, after the implanting of conventional or after treatment with balloon angioplasty alone in comparison with patients who did not receive that therapy.

EXAMPLE 2

Testing of the efficacy of the use of a corticosteroid in association with a diuretic and with an antacid in an experimental model of angioplasty in an animal.

The aim of the following example is to describe the treatment of coronary stenosis with angioplasty associated with the use of the composition object of the

present invention in an animal model.

For this experiment 20 rabbits (Oryctolagus cuniculus New Zealand white rabbits) were selected and divided into two groups:

Reference group: 10 rabbits carriers of a previous atherosclerotic disease induced with a hypercholesterolemic diet treated with bilateral angioplasty on the iliac arteries and implant of conventional endovascular stents;

Control group: 10 rabbits with similar characteristics.

The animals in the reference group were treated with the same therapeutic protocol illustrated in example 1, while the animals in the control group were treated with a placebo.

The angiographic and histological result obtained in the animals in the reference group was then compared with that observed in the animals in the control group.

The histological observations carried out after 40 days showed a significantly higher vascular calibre inside the stents in the animals subjected to treatment in comparison with those receiving the placebo, confirming the anti-restenotic effect of the therapy.