HK1085929A - Use of l-carnitine for the treatment of cardiovascular diseases - Google Patents

Description

Use of L-carnitine for the treatment of cardiovascular diseases

The invention described herein relates to the use of L-carnitine as a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the patients treated, in which L-carnitine is administered parenterally within the first few hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by the enteral route.

Acute Myocardial Infarction (AMI) causes changes in morphological function that often lead to progressive left ventricular dilatation (ventricular remodeling phenomenon).

post-AMI ventricular dilation can be considered a comprehensive compensatory mechanism aimed at maintaining appropriate cardiac output with reduced ejection fraction.

The degree of ventricular dilatation is the most important prognostic indicator in AMI patients.

Patients with relatively large ventricular volumes are at greater risk of future cardiac events (Circulation 1987; 76: 44-51).

Therefore, limiting the appearance of ventricular remodeling during the post-infarct time is important for clinical prognosis (Circulation 1994; 89: 68-75). The limitation of this phenomenon can be done by two mechanisms: (a) limiting the extent of infarct size (which is the primary determinant of future expansion) by early myocardial reperfusion (Circulation 1989; 79: 441-444) and/or (b) reducing wall pressure and consequent progressive expansion of the myocardial region not involved in the infarct process by administration of ACE inhibitors.

When the thrombotic occlusion progresses rapidly towards a complete, permanent, vascular closure, the resulting lack of perfusion leads to necrosis of the myocardial cells and thus to infarction at intervals of a few hours. The immediate and long-term prognosis depend on a series of factors, the most important of which are the size of the necrotic area and the early and late complications that arise from it. It is therefore evident that the primary goal of modern therapy for acute infarctions is to reduce the size of the infarcted area. This objective is achieved using reperfusion procedures (pharmacological (thrombolytic agents), mechanical (PTCA) such as angioplasty, or surgery (bypass). Generally, the earlier and more effective the reperfusion is performed, the smaller the necrotic area. Although to a lesser extent, the latter is also affected by other factors, in particular by myocardial oxygen consumption, which is regulated by the heart rate, myocardial contractility and wall tension of the patient. Of fundamental importance would be all those measures (whether pharmacological or otherwise) that reduce cardiac workload while maintaining adequate circulatory capacity.

More than half of all patients who died from infarction do so within the first few hours.

Useful drugs for treating myocardial infarction are known.

Beta-blockers are drugs with antiarrhythmic properties and are significantly more effective if used early in the onset of an infarction.

Nitro derivatives are drugs that are usually administered by intravenous infusion and are used to enhance myocardial perfusion through epicardial vasodilation.

Sodium nitroprusside is a drug that exerts dual effects on the arteriolar and venous regions. The compounds produce coronary and renal vasodilation, thereby increasing myocardial perfusion and diuresis.

L-carnitine is a known compound and the preparation thereof is described in U.S. Pat. No. 4,254,053.

The use of L-carnitine for the treatment of heart diseases is well known.

In Drugs Exp Clin Res 1992; 18(8): 355-65, the authors describe the use of L-carnitine in patients with infarctions, where oral treatment with L-carnitine is started after the patient has been discharged. In this report, the authors do not describe or suggest that L-carnitine is useful in preventing death during acute myocardial infarction.

In Eur Heart J1989 Jun; 10(6): 502-8, the authors describe the use of L-carnitine in infarct victims, in which the antiarrhythmic and metabolic effects of L-carnitine were evaluated. In this study, two deaths were reported in the L-carnitine-treated group and the placebo-treated group, respectively.

In J Am Coll Cardiol 1995 Aug; 26(2): 380-7, the authors describe the prolonged use of L-carnitine in infarct patients, and the effect on left ventricular volume at months 3, 6 and 12 after the start of the treatment. In this study, L-carnitine was administered within 24 hours of infarction and the mortality assessment showed that during hospitalization 11 patients died in the treated group and 14 patients died in the control group. The non-significance of the difference between the number of deaths recorded in the two groups was evident.

At Am Heart J2000 Feb; 139(2Pt 3): s115-9, which is a review of the metabolic role of L-carnitine in the field of cardiology, the authors report that L-carnitine is potent because it has a metabolic role in lipid and glucose metabolism.

In Lancet 1982 Jun 19; 1(8286): in 1419-20, the authors reported analysis of cardiac tissue specimens from patients who died from infarctions, in parallel with cardiac tissue specimens from patients who died from diseases other than infarctions, which showed that in the region of the heart not affected by the infarct (heart disease patients), the level of free carnitine was the same as in the control group, whereas the level of free carnitine in the region of the infarcted heart tissue was lower than in the control group.

In Postgrad Med J1996 Jan; 72(843): 45-50, the authors describe the use of L-carnitine in patients presenting with symptoms of infarction during the 24-hour period before the start of the treatment. In this study, L-carnitine was administered at a dose of 2 g/day, the number of deaths in the control group at 28 days after the start of treatment was 6, and the number of deaths in the treatment group was 4. The non-significance of the difference in the number of deaths recorded in the two groups tested was evident.

In Am J Cardiovasc Pathol 1990; 3(2): 131-42, the authors describe the use of L-carnitine in experimental models of cardiac ischemia in experimental animals (dogs), in which it was demonstrated that L-carnitine is effective in improving the cardiac lipid metabolism in these animals.

In this study, the authors do not describe or suggest that L-carnitine is useful in preventing death during acute myocardial infarction.

There are also many other publications relating to the use of L-carnitine in the field of cardiology; however, neither these nor the above publications describe or suggest the use of L-carnitine as a medicament for reducing the number of deaths caused by acute myocardial infarction, in which L-carnitine is administered intravenously within the first few hours of onset of the symptoms of acute myocardial infarction.

The document found which describes the only known technique for the application of L-carnitine in the first few hours of acute myocardial infarction is drug Exptl. Clin. Res. X (4) 219-. In this publication, the authors describe the use of L-carnitine at a dose of 40mg/kg/day (2.8 g/day), the number of deaths being 1 in the control group, while none of the treated groups were dead. Furthermore, in this study, the treatment group was divided into two subgroups, one of which was treated with L-carnitine within 4 hours of the onset of the infarct symptoms, and the other of which was treated more than 4 hours after the onset of the infarct symptoms. In their discussion of the results, the authors indicated that they found no significant difference between patients treated within 4 hours of the onset of infarct symptoms and those treated more than 4 hours after the onset of such symptoms.

In another publication published by Pergamon Press in 1986 under the name "Clinical aspects0f human carnitine deficience", the authors described a blinded Clinical trial in which 351 patients with acute myocardial infarction were recruited, whose infarct symptoms had already started within 8 hours of the start of treatment with L-carnitine. In this clinical trial, patients received 3 grams (9 grams/day) of L-carnitine every 8 hours by the intravenous route, and L-carnitine treatment lasted 48 hours (control group received saline solution). Mortality analysis revealed no significant difference between the control and L-carnitine treated groups 7 days after the start of treatment.

This further confirms that the known techniques not only do not demonstrate or suggest the use of L-carnitine early after onset of an infarction to reduce the number of deaths, but also (if at all) bias one technically towards such use, i.e. L-carnitine has the same effect whether used within the first few hours of an infarction or later.

In the medical field, it is very important to use drugs at the time most suitable for treating a given disease such as acute myocardial infarction. The above beta-blockers prove significantly more effective if used early in the onset of infarction.

A certain number of patients with acute myocardial infarction continue to die during the first week of hospitalization and thereafter, even when treated with all appropriate and available pharmacological and technical approaches. Furthermore, the use of L-carnitine alone, or in combination with said suitable and available pharmacological and technical means, in the treatment regimens adopted so far and described in the above publications, although improving the general condition of the patients treated, does not reduce the number of deaths compared to the patients treated with the usual drugs.

There is therefore a strongly felt need for new and known drugs that are effective and that can be used to reduce the number of deaths due to acute myocardial infarction, alone or in combination with common known drugs that alone cannot save from death the part of patients that still die within or after the first week after the onset of infarction.

It has now been found, surprisingly and unexpectedly, that L-carnitine or one of its pharmaceutically acceptable salts, which is administered intravenously within the first few hours of onset of AMI symptoms at an initial dose of 9 grams a day for 5 days, is capable of reducing the number of deaths caused by acute myocardial infarction and of improving the short-and long-term prognosis in the patients treated with it, after which the treatment is continued at a dose of 4 grams a day by mouth.

The pharmaceutically acceptable salt of L-carnitine means any salt thereof with an acid which does not cause toxicity or side effects.

These acids are well known to pharmacologists and to experts in pharmacy. Examples of such salts (although not exclusively) are: chloride, bromide, orotate, aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate and trifluoroacetate.

In addition, pharmaceutically acceptable salts of L-carnitine are FDA-approved salts listed in int.J pharm.33(1986), 201-217, which is incorporated herein by reference.

One of the objects of the present invention is therefore the use of L-carnitine or one of its pharmaceutically acceptable salts for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the patients treated, in which L-carnitine is administered intravenously within the first few hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.

Another object of the present invention is the use of L-carnitine or one of its pharmaceutically acceptable salts for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the patients treated, in which L-carnitine is administered intravenously within 6 hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.

Another object of the present invention is the use of L-carnitine or one of its pharmaceutically acceptable salts for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the patients treated, in which L-carnitine is administered intravenously within 4 hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.

Another object of the present invention is the use of L-carnitine or one of its pharmaceutically acceptable salts in combination with one or more known drugs and/or known mechanical and/or surgical techniques which alone are not capable of reducing the number of deaths in infarct victims, for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the patients treated with it, in which L-carnitine is administered intravenously within the first few hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.

Another object of the present invention is the use of L-carnitine or one of its pharmaceutically acceptable salts in combination with one or more known drugs and/or known mechanical and/or surgical techniques, which alone are not able to reduce the number of deaths in infarct victims, for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the treated victims, in which L-carnitine is administered intravenously within 6 hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.

Another object of the present invention is the use of L-carnitine or one of its pharmaceutically acceptable salts in combination with one or more known drugs and/or known mechanical and/or surgical techniques, which alone are not able to reduce the number of deaths in infarct victims, for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the treated victims, in which L-carnitine is administered intravenously within 4 hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.

Examples of such known drugs used in intensive care that alone cannot reduce the number of deaths in infarcted patients are (though not exclusively) the following: beta-blockers, calcium antagonists, aspirin, angiotensin converting enzyme inhibitors or ACE inhibitors, wherein the ACE inhibitor is selected from alacepril, benazepril, benazeprilat, captopril, cilazapril, delapril, enalapril, enalaprilat (enaprilat), fosinopril, imidapril, indopril, lisinopril, moexipril, perindopril, pentopril, pivalopril, quinapril, ramipril, spirapril, temocapril, trandolapril or zoinopril.

Preferred calcium antagonists are diltiazem, nifedipine, verapamil, nicardipine and nimodipine.

Preferred mechanical and/or surgical techniques are angioplasty and bypass surgery.

The following examples illustrate the invention.

Example 1

Clinical trials were conducted to evaluate the effect of L-carnitine administration on the short-and long-term mortality and incidence of heart failure in patients with acute myocardial infarction. The trial design was a multicenter, parallel group, double-blind, placebo-controlled randomized trial.

A total of 2,296 male and female patients aged 80 years and younger were recruited. Study compound L-carnitine was administered intravenously at a dose of 9 g/day for the first 5 days and orally at 4 g/day for days 6-180.

Concomitant therapy was administered following the procedures employed in local clinical practice.

The end point of efficacy of the test is a reduction in mortality and heart failure.

Inclusion criteria

Typical chest pain lasts > 30 minutes, failing to resolve with oral or intravenous administration of nitrate;

ECG with ST segment offset ≧ 0.2mV in D and aVL and/or in two or more adjacent precordial associations;

-the time interval from symptom onset to trial randomization was < 12 hours;

-age < 80 years;

-written informed consent.

Exclusion criteria

-pregnancy or lactation;

-hemodynamically meaningful heart valve disorders;

-hypertrophic or dilated cardiomyopathy;

-congenital heart disease;

-clinically severe liver or kidney disease;

-alcohol abuse;

other diseases associated with a short life expectancy;

conditions that may lead to poor treatment compliance and/or regular visits;

inclusion in other tests.

The results obtained are given in table 1.

TABLE 1

	Number of deaths
									3 days	5 days	7 days	1 month	2 months old	6 months old	12 months old
Placebo	34	43	45	58	65	74	75
								L-carnitine	23	27	31	45	53	64	67
RR	0.68	0.63	0.69	0.78	0.81	0.86	0.89
								P	0.1357	0.0498	0.097	0.1766	0.238	0.3546	0.4555

RR ═ relative danger

These results indicate that the compounds of the invention, with the particular treatment regimen employed in this clinical trial, can produce a statistically significant reduction in the number of deaths (P < 0.05) after 5 days of treatment and also at other observation times.

The dosage of L-carnitine used in the present invention and in the treatment regimen may vary at his or her discretion depending on the experience of the primary care physician and the general condition of the patient, again because the compounds of the present invention are not toxic.

Formulations of the invention for intravenous administration include solutions or suspensions in a suitable carrier such as saline solution, distilled water, dextrose solution, or others.

The formulations for oral administration of the present invention include tablets, capsules, powders, granules, syrups, elixirs, solutions or suspensions.

The compounds of the invention may be administered in single or multiple doses.

When a compound of the invention (in single or multiple doses) is administered in combination with one or more of the above-mentioned known drugs used in intensive care therapy alone, which does not reduce the number of deaths in infarcted patients, the combination can be administered as a single pharmaceutical composition, i.e. the active ingredients are combined in a pharmaceutically acceptable carrier, or the active ingredients can be administered separately, simultaneously or sequentially via the same or different routes of administration.

When the compound of the present invention is administered in combination with other drugs, the administration may be carried out in combination of any suitable dosage forms, for example, oral L-carnitine/oral drug used in combination therewith; or L-carnitine can be injected/used in combination with it as an oral medicine; or L-carnitine orally/in the form of an injectable drug used in combination with it.

The invention also relates to a kit for combining the active ingredients separately in a single package.

The kit is particularly useful when the components have to be administered by different routes and/or at different times.

Claims (17)

1. Use of L-carnitine or one of its pharmaceutically acceptable salts for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the patients treated with it, in which L-carnitine is administered intravenously within the first few hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.
2. Use of L-carnitine or one of its pharmaceutically acceptable salts in combination with one or more known drugs and/or known mechanical and/or surgical techniques, which alone are not capable of reducing the number of deaths in infarct victims, for the preparation of a medicament for reducing the number of deaths caused by acute myocardial infarction and for improving the short-and long-term prognosis in the treated victims, in which L-carnitine is administered intravenously within the first few hours of onset of the symptoms of acute myocardial infarction at an initial dose of 9 grams a day for 5 days, after which the treatment is continued at a dose of 4 grams a day by mouth.
3. 3. The use according to claim 1 or 2, wherein L-carnitine is administered intravenously within 6 hours of onset of symptoms of acute myocardial infarction.
4. 4. The use according to claim 1 or 2, wherein L-carnitine is administered intravenously within 4 hours of onset of symptoms of acute myocardial infarction.
5. 5. The use of claims 1-4, wherein the pharmaceutically acceptable salt of L-carnitine is selected from the group consisting of chloride, bromide, orotate, aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate and trifluoroacetate.
6. 6. Use according to claim 2, wherein the drug which alone does not reduce the number of deaths in infarcted patients is selected from the group consisting of beta-blockers, calcium antagonists, aspirin, angiotensin converting enzyme inhibitors or ACE inhibitors.
7. 7. The use of claim 6, wherein the ACE inhibitor is selected from the group consisting of: alacepril, benazepril, benazeprilat, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, indopril, lisinopril, moexipril, perindopril, pentopril, pivalapril, quinapril, ramipril, spirapril, temocapril, trandolapril or zoinopril.
8. 8. The use according to claim 6, wherein the calcium antagonist is selected from the group consisting of: diltiazem, nifedipine, verapamil, nicardipine or nimodipine.
9. 9. The use of claim 2, wherein the mechanical technique is angioplasty and the surgical technique is bypass surgery.
10. 10. The use according to claim 1 or 2, wherein the L-carnitine for oral administration is in the form of tablets, capsules, powders, granules, syrups, elixirs, suspensions or solutions.
11. 11. The use according to claim 1 or 2, wherein the L-carnitine for intravenous administration is in the form of a suspension or solution in a suitable carrier.
12. 12. Use according to claim 11, wherein the carrier is selected from distilled water, saline solution or glucose solution.
13. 13. The use according to claim 2, wherein the combination can be administered as a single pharmaceutical composition combining the active ingredients in a suitable pharmaceutically acceptable carrier.
14. 14. Use according to claim 2, wherein the active ingredients are administered separately in parallel or sequentially.
15. 15. Use according to claim 2, wherein the active ingredients present in the combination can be administered in any suitable dosage form or combination thereof.
16. 16. The use according to claim 2, wherein the combination is in the form of a kit of parts for combining the active ingredients separately in a single package.
17. 17. The use according to claim 16, wherein the kit components are administered by different routes and/or at different times.