Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to the combined use of L- carnitine and glucose as a medicament useful for diminishing the number of deaths caused by acute myocardial infarction, for reducing the number of days infarction patients spend in intensive care in hospital, and for reducing the number of episodes of post-infarction heart failure.
• the daily dose of L-carnitine to be administered must be dissolved in two or three 500 ml vials of 5% glucose solution and administered intravenously. It is important that the treatment with the combination according to the invention should begin within only a few hours of the onset of acute myocardial infarction symptoms, at an initial dose of 9 grams a day for 5 days, after which the treatment should be continued at a dose of 4 grams a day with L-carnitine alone, administered orally.
• Post-infarction heart failure is due to inability of the heart to pump blood in sufficient amounts to meet the metabolic needs of the various tissues.
• Acute myocardial infarction causes morphofunctional alterations which often induce progressive left ventricular dilatation (Ventricular remodelling" phenomenon).
• Post-AMI ventricular dilatation may be regarded as a global compensation mechanism aimed at maintaining an adequate cardiac output in the presence of a reduction in ejection fraction.
• the extent of the ventricular dilatation is the most important prognostic indicator in patients with AMI.
• Limitation of the post-infarction ventricular remodelling phenomenon is therefore of major importance from the clinico- prognostic point of view (Circulation 1994; 89:68-75). Limitation of this phenomenon can be achieved by two mechanisms: (a) by limiting the extent of the infarcted area (which is the main determinant of future dilatation) by means of early myocardial reperfusion (Circulation 1989; 79:441-444) and/or (b) by reducing the parietal stress and consequently the progressive dilatation of the area of the myocardium not involved in the infarction process by means of the administration of ACE inhibitors.
• Beta-blockers are drugs endowed with antiarrhythmia properties and are significantly more active if used in the early phases of onset of infarction.
• Nitroderivatives are drugs usually administered by venous infusion, and are useful for improving myocardial perfusion through vasodilatation of the epicardial vessels.
• Sodium nitroprusside is a drug that exerts a dual action on the arteriolar and venous districts. This compound produces coronary and renal vasodilatation, thus enhancing myocardial perfusion and diuresis.
• L-carnitine is a known compound, whose preparation process is described in US 4,254,053.
• US 4,320,145 describes a glucose solution containing L- carnitine which is useful for favouring the muscular absorption of the glucose and thus for preventing excessive insulin secretion.
• L-carnitine for the treatment of heart diseases is also known.
• L- carnitine In Postgrad Med. J. 1996 Jan;72(843):45-50 the use of L- carnitine is described in patients presenting infarction symptoms in the 24-hour period prior to the start of treatment. In this study, L- carnitine was administered at a dose of 2 g/day, and the number of deaths at 28 days after the start of treatment was 6 in the control group and 4 in the treated group. The non-significance of the difference in the number of deaths observed in the two groups tested is evident. In Am. J. Cardiovasc Pathol 1990;3(2):131-42 the use of L- carnitine is described in an experimental cardiac ischaemia model in experimental animals (dogs) where L-carnitine proved active in enhancing cardiac lipid metabolism in these animals.
• L-carnitine in combination with glucose is useful for the treatment of post-infarction heart failure, for reducing the number of days infarction patients spend in intensive care in hospital, and for reducing the number of deaths caused by acute myocardial infarction.
• L-carnitine alone whether using the therapeutic regimens adopted to date and described in the above-cited publications, or in combination with said appropriate and available pharmacological and technical means, though improving the general condition of the patients treated, fails to reduce the mortality compared to patients treated with the normal drugs used.
• L-carnitine is the simultaneous administration of a 5% glucose solution (1000/ 1500 mL/day i.v.) in which 9 grams of L-carnitine are dissolved, or the administration of 5% glucose solution (1000/ 1500 mL/day i.v.) and the parallel administration of 9 grams/ day i.v. of L-carnitine in a single dose or in divided doses (e.g. 3 g x 3 administrations /day i.v).
• compositions that gives rise to no toxic or side effects.
• salts are: chloride, bromide, orotate, aspartate, acid 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, sulphate, acid sulphate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino ethanesulphonate, magnesium 2-amino ethanesulphonate, methanesulphonate, choline tartrate, trichloroacetate, and trifluoroacetate.
• the object of the present invention then is the combined use of L-carnitine or one of its pharmaceutically acceptable salts in combination with glucose, in which the intravenous treatment with L- carnitine and glucose is initiated within only a few hours of onset of the symptoms of acute myocardial infarction, preferably within 6 hours, and more preferably within 4 hours of the onset of acute myocardial infarction symptoms; the treatment is administered for 5 days consecutively at an initial L-carnitine dose of 9 grams a day dissolved in 1000-1500 mL of 5% glucose solution, after which the L- carnitine treatment is continued orally at a dose of 4 grams a day; for the preparation of a medicament useful for diminishing the number of deaths caused by acute myocardial infarction, for reducing the number of days infarction patients spend in intensive care in hospital, and for reducing the number of episodes of post-infarction heart failure.
• Example 1 illustrates the invention.
• a clinical trial was conducted aimed at evaluating the effect of the administration of L-carnitine on short-, medium- and long-term incidence and mortality in patients with acute myocardial infarction.
• the trial design was that of a multicentre randomized, double-blind, placebo-controlled, parallel-group trial.
• the L-carnitine was administered intravenously dissolved in sterile saline solution, while in another group of patients it was administered dissolved in normal 5% glucose solution used in hospital departments.
• the control group received the standard therapy used for the treatment of infarct, without L-carnitine.
• the efficacy parameters evaluated were reduction of mortality, reduction of the number of days spent in intensive care, and reduction of the number of episodes of post-infarction heart failure. Inclusion criteria
• Time interval elapsing between onset of symptoms and study randomisation ⁇ 12 hours; - Age ⁇ 80 years;
• Table I/A here below gives the mortality data in the placebo group compared to patients treated with L-carnitine, regardless of whether the L-carnitine was dissolved in saline or in glucose solution (totality of patients included in the trial).
• Table 1/B here below gives the mortality data in the patient group treated with L-carnitine dissolved in glucose solution compared to the control group treated with placebo.
• the group of patients treated with L-carnitine and glucose solution showed a statistically significant reduction in the number of episodes of post-infarction heart failure compared to the patient group treated with L-carnitine dissolved in saline.
• the L-carnitine doses used according to the present invention and the treatment regimen may be subject to changes, as advised by the primary care physician on the basis of his or her experience and the patient's general condition, also thanks to the lack of toxicity of the compound according to the invention.
• the intravenous administration formulations, according to the present invention include solutions or suspensions in suitable vehicles such as, for example, saline solution, distilled water, glucose solution, or others.
• the oral administration formulations include tablets, capsules, powders, granules, syrups, elixirs, solutions or suspensions. Pomezia 21.06.2005

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