KR100725263B1 - Antilipemic combinations comprising HMG-CoA reductase inhibitors and carnitines - Google Patents

Abstract

Pharmaceuticals, including L-carnitine or alkanoyl L-carnitine, which preserve the lipid-lowering efficacy of lipid-lowering drugs such as lovastatin, simvastatin, pravastatin and fluvastatin, while substantially eliminating the typical toxic side effects of the drug. The composition is disclosed.

Description

Antilipidemic combinations comprising HMG-CoA reductase inhibitors and carnitines             

The present invention relates to pharmaceutical compositions for the treatment of diseases caused by lipid metabolic diseases, and in particular to pharmaceuticals comprising statins and one of L-carnitine or alkanoyl derivatives thereof, useful for the prevention and treatment of statin-induced toxic side effects. It relates to a composition.

Cardiovascular diseases associated with lipid metabolic diseases are very common in industrialized countries. For example, more than 40% of all mortality rates in Italy (Capocaccia R., Farchi G., Prati S. et al .: La mortalita 'in Italia nell'anno 1989. Rapporto ISTISAN 1992/22). Knowledge of the relationship between cholesterol and coronary heart disease derives from epidemiological studies conducted in recent years. Conclusions on this study indicate that the development of severe coronary atherosclerosis is closely related to serum cholesterol levels (McGill HC Jr. et al .: The International Atherosclerosis Project.Lab.Invest. 18: 463-653, 1968; Keys A .: Seven Countries: Death and Coronary Heart Disease.Harvard University Press, Cambridge, 1980).

Correction of eating habits with proper diet is always the first treatment adopted for hyperlipidemia. However, good results are not always obtained due to the prevalent hypersensitivity of strict diet regimens, the severity of hypercholesterolemia or genotyping resistance.

In such cases, it has been shown that it is necessary to appeal to pharmacological treatment with lipid-lowering drugs in order to obtain the desired results, ie to restore normal blood triglyceride and cholesterol levels. This category includes drugs that effectively reduce cholesterol levels and drugs that effectively reduce triglyceride levels.

The former group of drugs includes statins, probucols and resins, and the latter group includes fibrate, nicotinic acid and omega-3-based fatty acids.

Statins (simvastatin, lovastatin, pravastatin, fluvastatin, etc.) are hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. The agent reduces liver synthesis of cholesterol by inhibiting the enzyme (Lancet 1994; 334: 1383-1389). To compensate for the reduction of intracellular cholesterol, liver cells produce more receptors for the LDL and VLDL families of lipoproteins and in this way remove the lipoproteins from the bloodstream.

In addition, statins allow less intake of cholesterol of dietary origin in the intestine and reduce the production of apoprotein B present in low-density lipoprotein (LDL).

Statins are better resistant than other cholesterol-lowering agents, but offer some disadvantages: the most common side effects caused by these drugs are gastrointestinal disorders, skin rashes and headaches.

Many patients complained of sleep disorders (EJ Schaffer, N Engl J Med, 319: 1222,1988; Lancet, 339: 547, 29 February 1992), while transaminase activity (GOT and GPT) and CK Was observed to be significantly increased compared to baseline in patients taking a 40 mg / kg dose of statins (Schweiz Med Wochenschr June 29, 1991; 121 (26): 977-83).

Moreover, patients treated with simvastatin show side effects associated with muscle disease, rhabdomyolysis, muscle pain and increased serum CK and LDH activity (Dedlypere JP & Vermeulen A. (1991) Ann. Intern. Med. 114: 342; Bizzarro N. et al. (1992) Clin. Chem. 38: 1504).

EP 0383432 discloses a combination of HMG-CoA reductase inhibitor and coenzyme Q10 for the treatment of muscle diseases of skeletal muscle caused by statins.

Statins have been reported to reduce the number of deaths due to coronary heart disease, but on the other hand it has been noted that the number of deaths has increased due to other events such as tumors or trauma in treated patients (Davey-Smith G., Song F ., Sheldon TA, Cholesterol Lowering and Mortality: Importance of Considering Early Risk Levels BMJ 1993; 306: 1367-1373; Ravnshov U .; Cholesterol Lowering Test in Coronary Heart Disease: Frequency of Citation and Results. BMJ 1992; 305: 15-19). Young rats treated with different cholesterol-lowering agents (simvastatin, lovastatin and pravastatin) show signs of muscle disease when using high doses of simvastatin (Reijneveld J.C. et al., 1976 Pediatr. Res. 39: 1028-1035). Furthermore, see Bhuiyan J. & Seccombe D.W. 1996 Lipids 31: 867-870 demonstrated that the administration of lovastatin to rabbits significantly reduced liver, heart and skeletal muscle L-carnitine.

Experimental results in animal and human subjects suggested that pharmacological treatment with statins to reduce cholesterol levels should only be used in patients with high risk of coronary disease for a short time (JAMA, 1996; 275: 55-60).

The triglyceride- and cholesterol-lowering effects of many alkanoyl carnitines, especially acetyl L-carnitine, are equally well known. US Pat. No. 4,268,524 describes a treatment that increases the level of high density lipoprotein (HDL) to selectively reduce the LDL + VLDL: HDL ratio (in which the ratio is abnormally high) in the plasma of patients at risk for cardiovascular disease. A method is disclosed. The method comprises administering 5 to 50 mg / kg of alkanoyl carnitine or one of its pharmacologically acceptable salts per day.

International patent application WO99 / 01126, filed in the name of the applicant, discloses the use of alkanoyl L-carnitine with statins for the treatment of diseases associated with lipid metabolism disorders. WO 99/01126 neither discloses nor discloses that L-carnitine or alkanoyl L-carnitine exerts protective action against statin-induced toxic side effects.
Clin. Ter. 140 (Suppl); 17-22, 1992 teach the use of low dose (10 mg / kg) statins and L-carnitine that fall below the statin limit causing unwanted toxic side effects.
Clin. Ter. 140 (Suppl); 17-22, 1992, do not suggest or teach the use of alkanoyl carnitine associated with high dose statins to avoid unnecessary toxic side effects of statins, nor does it suggest the use of carnitine associated with high dose statins.
Japanese Patent Application Publication No. 62126126 discloses a nutritional composition consisting of an association between L-carnitine, triglycerides and nitrogen sources which can improve the healing effect against various diseases without causing hyperlipidemia and liver disorders. Japanese Patent Application Publication No. 62126126 neither teaches nor teaches the use of alkanoyl carnitine associated with high dose statins to avoid unnecessary toxic side effects of statins, nor does it suggest the use of carnitine associated with high dose statins.

Summary of the Invention

Unexpectedly, according to the present invention, L-carnitine or alkanoyl L-carnitine, wherein linear or branched alkanoyl has 2 to 6 carbon atoms, or one of its pharmacologically acceptable salts and the combined use of statins The term will be defined in detail below), it has been found to provide a protective action against statin-induced toxic side effects.

The protective action exerted by these compounds against the well-known lack of toxic side effects and the statin-induced toxic side effects of L-carnitine and alkanoyl L-carnitine is the dose normally administered to statins (10 to 20 mg / day). Allows use at higher capacities.

The integrated use according to the invention is particularly useful and safe for the short, medium or long term treatment of hypercholesterolemia and / or hypertriglyceridemia patients at high risk of cardiovascular disease.

Indeed, due to the protective effect exerted by L-carnitine or alkanoyl L-carnitine, statin doses higher than those normally used in human therapy (wherein the dose of L-carnitine or alkanoyl L-carnitine is 100 to 3000 mg / Can be used).

In the context of the present invention, the term “integrated use” of the above-mentioned compound means, without discrimination, (i) co-administration, ie either L-carnitine or one of the alkanoyl L-carnitines or pharmacologically thereof. Substantially simultaneous administration of statins with one of the acceptable salts, or (ii) administration of a composition comprising said active ingredients together and in combination in addition to possible excipients. Co-administration also means administration of a separate dosage form of L-carnitine or one of the alkanoyl L-carnitines, or one of its pharmacologically acceptable salts and statins, as determined by the attending physician, based on the condition of the patient. It is a pack or product included with instructions for the integrated simultaneous administration of active ingredients according to the regimen.

The present invention therefore provides a co-administration of statins with one of L-carnitine or one of the alkanoyl L-carnitines or pharmacologically acceptable salts thereof, and a mixture of the two active ingredients which can be administered orally or non-orally. Includes all pharmaceutical compositions that comprise.

The subject matter of the present invention is also directed to therapeutically effective amounts of statins and detoxifying amounts of L-carnitine or alkanoyl L-carnitine, wherein linear or branched alkanoyls are used for the preparation of a medicament useful for the treatment of diseases caused by lipid metabolism disorders. Having 2 to 6 carbon atoms) or one of the pharmacologically acceptable salts thereof, characterized in that the medicament reduces statin-induced toxic side effects.

A further subject matter of the present invention is a detoxifying amount of L-carnitine or alkanoyl L-carnitine, wherein the linear or branched alkanoyl has 2 to 6 carbon atoms for the manufacture of a medicament useful for the treatment of statin-induced toxic side effects. ) Or one of its pharmacologically acceptable salts.                 

The invention also relates to L-carnitine or alkanoyl L-carnitine, wherein linear or branched alkanoyl has 2 to 6 carbon atoms or pharmacologically thereof for the manufacture of a medicament useful for the treatment of statin-induced toxic side effects. The use of one of the acceptable salts.

The statin is preferably selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, and the alkanoyl L-carnitine is preferably acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L -Carnitine and isovaleryl L-carnitine, and pharmacologically acceptable salts thereof.

More preferably, the statin is simvastatin and the alkanoyl L-carnitine is propionyl L-carnitine or one of its pharmacologically acceptable salts.

Even more preferably, the statin is simvastatin and the carnitine is L-carnitine or one of the pharmacologically acceptable salts thereof.

What is meant by pharmacologically acceptable salts of alkanoyl L-carnitine is any salt of the compound with an acid that does not cause toxic side effects. Such acids are well known to pharmacologists and pharmaceutical technical experts.

Examples of pharmaceutically acceptable salts of alkanoyl L-carnitine include, but are not limited to, chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid maleate, Mate, acid oxalate, acid sulfate, glucose phosphate, tartrate and acid tartrate.

By imparting the use of higher doses of statins, the combination according to the invention allows for better treatment of diseases associated with lipid metabolism disorders and thus achieves greater therapeutic success.

The combination according to the invention also contributes to the healing and prolongation of life of the treated patient, thanks to the increased success rate of treatment, in particular due to the possibility of maintaining the intended treatment protocol for longer periods of time without interruption of treatment due to the toxic side effects of statins.

The protective action of L-carnitine or alkanoyl L-carnitine against toxic side effects of statins was confirmed by the results of the experimental studies reported below.

Although only L-carnitine is referred to in these examples, it is to be understood that such protection is also provided by the above-mentioned alkanoyl L-carnitines and their pharmacologically acceptable salts.

Example 1

23-day-old male Wistar rats weighing 45-50 g were used. Five animals per cage were housed in polycarbonate cages with a constant temperature of 22 ± 2 ° C. and a relative humidity of 55 ± 15% and a 12-hour contrast cycle, fed 4RF21 pellet feed (Mucedola) and tap water. I gave it to you.

The control group consisted of 14 animals, whereas the groups treated with various doses of simvastatin and simvastatin + L-carnitine consisted of 10 animals each according to the following experimental design:

-Control (not processed);

Simvastatin 70 mg / kg;

Simvastatin 140 mg / kg;

Simvastatin 210 mg / kg;

Simvastatin 70 mg / kg + L-carnitine 400 mg / kg;

Simvastatin 140 mg / kg + L-carnitine 400 mg / kg;

Simvastatin 210 mg / kg + L-carnitine 400 mg / kg.

L-carnitine was administered orally twice a day (2 × 200 mg / kg) via gastric feeding tube, in a statin treated group in 0.5% carboxymethylcellulose (CMC), or in water when administered alone. Provided.

Simvastatin was orally administered by suspending in 0.5% carboxy-methylcellulose (CMC) (10 mL / kg).

Treatment duration was 9 days.

Twenty four hours after the last treatment, animals were anesthetized and blood samples were taken from the sublingual vein.

The blood was centrifuged at 400 rpm for 30 minutes and the serum obtained as above was used to assess plasma levels of CK, GOT, GPT and cholesterol.

The CK, GOT, GPT and Cholesterol assays were performed using a Cobas Mira S (Roche) automated analyzer and Roche diagnostic kit.

Since plasma enzyme activity showed a very uneven distribution, it was decided to analyze this data using a non-parametric Mann-Whitney U test; The test data are shown as median along with the relevant ranges.

The obtained results are shown in Table 1.

The results in Table 1 indicate that administration of the highest dose (210 mg / kg) of simvastatin significantly increased plasma GOT (p <0.002), GPT (p <0.002) and CK (p <0.05) compared to the control group. . At lower doses (140 mg / kg), simvastatin treatment resulted in elevations of GOT (p <0.002) and GPT (p <0.02) in all enzyme activities tested.

The lowest dose (70 mg / kg) simvastatin treatment did not significantly increase the enzyme activity tested.

Cholesterol levels were significantly lower only at the highest simvastatin doses used.

Administration of L-carnitine to the simvastatin-treated group was shown to lower plasma CK activity compared to the simvastatin-only group. Statistically, L-carnitine administration was markedly effective at offsetting plasma CK elevations at simvastatin doses of 140 and 210 mg / kg (Table 1).

The lowest dose (70 mg / kg) of simvastatin treatment in combination with L-carnitine reduced plasma CK activity compared to treatment with simvastatin alone at the same dose, but not to a statistically significant extent.

These findings provide considerable evidence of the protective action of L-carnitine and alkanoyl L-carnitine against the toxic side effects of statins that form the basis of the present invention.

In the second experiment conducted in the same manner as the first, the only difference was the administration of L-carnitine to the drinking water of the animals, and comparable results were obtained.                 

Thus, a further realization of the present invention is a statin with one of the L-carnitine or alkanoyl derivatives thereof, or one of its pharmacologically acceptable salts, in accordance with the above definition in the treatment of animals, for example livestock and especially pets. Includes integrated use of In this particular implementation, one of the L-carnitines or derivatives thereof may be in solid form, such as fumarate, tartrate or mucate, which is dissolved in the liquid form of the beverage or metered dose to be diluted.

Claims (22)

A therapeutically effective amount of statins of at least 20 mg / day; And A detoxifying amount of L-carnitine, a linear or branched alkanoyl L-carnitine of 2 to 6 carbon atoms, and a pharmacologically acceptable salt thereof, comprising: The statin is any one selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, A pharmaceutical composition for reducing statin-induced toxicity while preserving the therapeutic efficacy of statins. delete The pharmaceutical composition of claim 1, wherein the statin is simvastatin. The method of claim 1, wherein the alkanoyl L-carnitine is any one selected from the group consisting of acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine. Pharmaceutical composition, characterized in that. 5. The pharmaceutical composition of claim 4, wherein said alkanoyl L-carnitine is propionyl L-carnitine. The pharmaceutical composition of claim 1, wherein L-carnitine is present. The method of claim 1, wherein the pharmacologically acceptable salt of L-carnitine or alkanoyl L-carnitine is selected from chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, Mali Pharmaceutical composition, characterized in that any one selected from the group consisting of acid and acid maleate, mucate, acid oxalate, acid sulfate, glucose phosphate, tartrate and acid tartrate. delete delete delete delete delete delete delete delete delete delete At least 20 mg / day of a therapeutically effective amount of statins included in the pharmaceutical composition of claim 1; And Any one selected from the above-described detoxification amounts of L-carnitine, linear or branched alkanoyl L-carnitine of 2 to 6 carbon atoms, and pharmacologically acceptable salts thereof A product comprising the pharmaceutical composition of claim 1, wherein is separately packaged for sequential or simultaneous administration at predetermined doses. delete delete The dose of any one of the L-carnitine, linear or branched alkanoyl L-carnitine having 2 to 6 carbon atoms, and a pharmacologically acceptable salt thereof is 100 to 3000 mg / day. Pharmaceutical composition. The pharmaceutical composition of claim 1, wherein the statin-induced toxic side effects are any one or more selected from gastrointestinal disorders, skin rashes, headaches, sleep disorders, and muscle diseases.