ANTILIPEMIC COMBINATIONS THAT INCLUDE INHIBITORS OF HMG-COA REDUCTASE AND CARNITINE
DESCRIPTION OF THE INVENTION The invention described herein is in relation to a pharmaceutical composition for the treatment of diseases caused by disorders of lipid metabolism, and in particular to a pharmaceutical composition comprising a statin and L-carnitine or one of its alkanoyl derivatives, useful for the prevention and treatment of toxic or secondary effects induced by statin. Cardiovascular diseases related to disorders of lipid metabolism are very frequent in industrialized countries. In Italy, for example, they are responsible for more than 40% of the overall mortality (Capocaccia R., Farchi G., Prati S. et al., The mortalite 'in Italia nell'anno 1989. Rapporto ISTISAN 1992/22). Our knowledge of the relationship between cholesterol and heart disease in the heart comes from epidemiological studies carried out in recent years. The conclusions of these studies indicate that the development of severe coronary atherosclerosis is closely related to
REF: 134554 t 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 through proper diet is always the first measure to be adopted in cases of hyperlipidemia. However, good results are not always achieved due to the generalized intolerance of the strict dietary regime, the severity of hypercholesterolemia or genetic resistance. In these cases, to achieve the desired results, that is, to restore normal blood levels of triglycerides and cholesterol, it is necessary to resort to a pharmacological treatment with drugs to decrease lipids. This category includes both drugs that reduce cholesterol levels predominantly and drugs that predominantly reduce triglyceride levels. The previous group of drugs include the statin, probucol and resin, and the last group includes fibrates, nicotinic acid and omega-3 fatty acids. Statins (simvastatin, lovastatin, pravastatin, fluvastatin, and the like) are hydroxymethylglutaryl inhibitors of coenzyme A reductase. By inhibiting this enzyme, they reduce the hepatic synthesis of cholesterol (Lancet 1994; 334: 1383-1389). To compensate for the reduction of intracellular cholesterol, the liver cells produce more receptors for lipoproteins of the LDL and VLDL series, and in this way they are removed from the bloodstream. In addition, statins cause less absorption of dietary cholesterol in the intestine and a reduced output of apoprotein B that is present in low density lipoproteins (LDL). Statics are better tolerated than other agents that lower cholesterol, but they have certain drawbacks: the most common side effects caused by these drugs are gastrointestinal disorders, rashes and migraine. A variety of patients have complained of sleep disorders (EJ Schaffer, N Engl J Med, 319: 1222.1988, Lancet, 339: 547.29 February 1992), whereas significant increases in transaminase activity have been observed
(GOT and GPT) and in the CK compared to the baseline values in patients taking statins at a dose of 40 mg / kg (Sch eiz Med Wochenschr 1991 Jun 29; 121 (26); 977-83). Furthermore, patients treated with simvastatin have secondary effects related to myopathy, rhabdomyolysis, muscle pain and increases in the activity of CK and serum LDH [Dedlypere J.P. & Vermeulen A. (1991) Ann, Intern. Med.114: 342; Bizzarro N, et al, (1992) Clin. Chem. 38: 1504]. EP 0383432 describes the combination of an inhibitor of HMG-CoA reductase and coenzyme Q10 for the treatment of skeletal muscle myopathy caused by statins. It has been reported that statins cause a reduction in the number of deaths due to coronary heart disease, but, on the other hand, also an increase in deaths due to other events such with tumors or traumas as has been noticed in patients undergoing treatment (Davey-Smith G., Song F., Sheldon TA, Cholesterol lowering and mortality: the importance of considering initial level at risk, BMJ 1993; 306: 1367-1373; Ravnshov U .; Cholesterol lowering triáis in coronary heart disease: frequency of citation and outcome: BMJ 1992; 305: 15-19). Young rats treated with different agents to decrease the
Cholesterol (simvastatin, lovastatin, and pravastatin) show signs of myopathy, when high doses of simvastatin are used (Reijneveld J.C. et al., 1976 Pediatr Res. 39: 1028-1035). Furthermore, Bhuiyan et al. (Bhuiyan J. &Seccombe D.W. 1996 Lipids 31: 867-870) have shown that the administration of lovastatin in rabbits causes a significant reduction in the L-carnitine of the skeletal and cardiac muscle and in the liver. The results of experiments in animals and in human subjects suggest that, in order to reduce cholesterol levels, medical treatment with statins should only be used in patients at high risk of coronary heart disease in the short term (JAMA, 1996; 275: 55-60). ). The effects of lowering cholesterol and triglycerides of a variety of alkanoyl carnitines, in particular acetyl L-carnitine, are also well known. The U.S. Patent 4,268,524, describes a therapeutic method to increase the level of high density lipoproteins (HDL) to selectively reduce the LDL + VLDL: HDL ratio in the plasma of patients at risk of cardiovascular disease, in which this proportion is abnormally high. This method includes the daily administration of 5-50 mg / kg of alkanoyl carnitine or one of its pharmacologically acceptable salts. International patent application WO99 / 01126 sent in the name of the applicant describes the use of alkanoyl L-carnitine in combination with statins for the treatment of diseases related to lipid metabolism disorders. WO99 / 01126 does not describe or suggest that L-carnitine or alkanoyl L-carnitine exert a protective action on the toxic or secondary effects induced by statins. It has been unexpectedly discovered that the coordinated use (this term is defined precisely below) of L-carnitine or of the alkanoyl L-carnitine, wherein the linear or branched alkanoyl has 2-6 carbon atoms, or one of its pharmacologically acceptable salts and a statin give a protective action against the toxic or secondary effects induced by the statin. The known lack of toxic or secondary effects of L-carnitine and alkanoyl L-carnitine and the protective action exerted by these compounds in the toxic or secondary effects induced by the statin, allow statins to be used at higher doses of those that are usually administered (10-20 mg / day). The coordinated use according to the invention is particularly useful and safe for the treatment of both hypercholesterolemic and / or hypertriglyceridemic patients with high risk of cardiovascular disease in the short, medium or long term. Thanks to the protective effect exerted by L-carnitine or alkanoyl L-carnitine, in fact it has been discovered that it is possible to use higher doses of statins than those normally used in human therapy, while the dose of L-carnitine or alkanoyl L-carnitine can be 100-3000 mg / day. Clin. Ter. 140 (Suppl): 17-22, 1992, shows the use of L-carnitine and a low dose of statin (10 mg / day) that falls below the threshold at which statins cause unwanted side effects. Clin. Ter. 140 (Suppl): 17-22, 1992, does not suggest or show the use of alkanoyl carnitine in association with high doses of statin, nor does it suggest the use of carnitine in association with high doses of statin, to avoid its toxic effects or unwanted side
The publication number for Japanese Patent Application No. 62126126 describes a nutritional composition composed of the association between L-carnitine, triglycerides and a nitrogen source capable of enhancing the therapeutic effect in various diseases without causing hyperlipidemia and hepatic disorder. JP Pub. No. 62126126 does not suggest or show the use of alkanoyl carnitine in association with high doses of statin, nor does it suggest the use of carnitine in association with high doses of statin to avoid its unwanted secondary toxic effects. In the context of the invention described herein, what is implied by the term "coordinated use" of the aforementioned compounds is, indifferently, either (i) co-administration, i.e. the substantially simultaneous administration of L-carnitine or one of its aforementioned alkanoyl L-carnitine or one of its pharmacologically acceptable salts and a statin, or (ii) the administration of a composition comprising the above-mentioned active ingredients in combination and in a mixture, in addition to its possible excipients. What is meant by the term co-administration is also a package or a manufactured article, comprising the different forms of administration of L-carnitine or one of its aforementioned alkanoyl L-carnitine or one of its pharmacologically acceptable salts and statin, accompanied by 5 instructions for the simultaneous and coordinated taking of the active ingredients according to a dosing regimen established by the main physician attending based on the condition of the patient. Therefore, the invention described herein,
10 covers both co-administration of L-carnitine or one of the aforementioned alkanoyl L-carnitines or one of its pharmacologically acceptable salts and a statin, and pharmaceutical compositions that can be administered orally or parenterally, comprising a mixture of two
15 active ingredients. The subject of the invention described herein also includes the use of a therapeutically effective amount of a statin of an amount of the toxicant of L-carnitine or an alkanoyl L-carnitine wherein the alkanoyl
Linear or branched has 2-6 carbon atoms, or one of its pharmacologically acceptable salts for the preparation of a medicinal agent useful for the treatment of diseases caused by disorders in the metabolism
- * £ áá & s & amp &x? x * uMt? i.t lipid, characterized in that the medicinal agent presents a reduction of toxic or secondary effects induced by the statin. Another subject of the invention described herein is the use of an amount of the toxicant of L-carnitine or an alkanoyl L-carnitine, wherein the linear or branched alkanoyl has 2-6 carbon atoms, or one of its pharmacologically acceptable salts , for the preparation of a medicinal agent useful for the treatment of toxic or secondary effects induced by statin. The invention described herein also comprises the use of L-carnitine or an alkanoyl L-carnitine wherein the linear or branched alkanoyl has 2-6 carbon atoms, or one of its pharmacologically acceptable salts, for the preparation of an agent useful for the treatment of toxic or secondary effects induced by the statin. The statin is preferably selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, while the alkanoyl L-carnitine is preferably selected from the group consisting of acetyl L-carnitine, propionyl L-carnitine,
- '-. & -jfc. * • butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or one of its pharmacologically acceptable salts. 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 its pharmacologically acceptable salts. What is meant by the pharmacologically acceptable salt term of an alkanoyl L-carnitine is any salt thereof with an acid that does not give rise to toxic or secondary effects. These acids are well known by pharmacologists and experts in pharmaceutical technology. Examples of the pharmaceutically acceptable salts of alkanoyl L-carnitine, although not exclusively these, are chloride, bromide, orotate, aspartate acid, citrate acid, acid phosphate, fumarate and fumarate acid, maleate and acid maleate, mucate, acid oxalate , acid sulfate, glucose phosphate, tartrate and acid tartrate. By favoring the use of higher doses of statins, the combination according to the invention allows a better treatment of the diseases related to the disorders of the
.,! - < i i xií lipid metabolism, and therefore achieves greater therapeutic success. The combination according to the invention also contributes to the cure and prolongation of the lives of patients undergoing treatment, among other things, thanks to the increase in the rates of therapeutic success due to the possibility of maintaining the programmed protocols of treatment during periods longer, without having to discontinue the treatment due to the toxic or secondary effects of statins. The protective action of L-carnitine or an alkanoyl L-carnitine on the toxic or secondary effects of statins has been confirmed by the results of the experimental studies, which are recorded below. Although reference is made in these examples only to L-carnitine, however, it should be understood that this protection is also produced by the alkanoyl L-carnitines mentioned above and by their pharmacologically acceptable salts. Example 1 Male Wister rats 23 days old and weighing 45-50 g are used. The animals are housed in cages of
.IA polycarbonate, 5 animals per cage, are kept at a constant temperature of 22 ± 2 ° C and a relative humidity of 55 ± 15%, with a light-dark cycle of 12 hours, feeding on feed pellets 4RF21 (Mucedola ), with natural water to drink ad libi tum. The control group consists of 14 animals, while the groups subjected to treatment with simvastatin at various doses and with simvastatin plus L-carnitine consist of 10 animals each, according to the following design PXDPGi mpnt '? 1: - Witness (without treatment); - 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 is given by oral administration by means of a gastric tube, twice a day (2 x 200 mg / kg) suspended in 0.5% carboxymethylcellulose (CMC) to the statin-treated groups, or in water when administered only
yi? ZZ ^ ¿£? Simvastatin is administered orally and suspended in 0.5% carboxymethylcellulose (CMC) (10 mL / kg). The duration of the treatment is 9 days. 24 hours after the last treatment, the animals are anesthetized and blood samples are taken from the sublingual vein. The blood is centrifuged at 400 rpm for 30 minutes and the serum obtained is used to evaluate the plasma levels of CK, GOT, GPT and cholesterol. The cholesterol and CK, GOT, and GPT analyzes are carried out using a Cobas Mira S automated analyzer (Roche) and a Roche brand diagnostic reagent set. Since the enzymatic activity of the plasma shows a highly skewed distribution, it was decided to analyze the data using the nonparametric Mann-Whitney U test; the data of the analysis are shown as values of the proportional mean, together with the associated ranges. The results obtained are recorded in Table 1.
Table 1
^ Mz? - * zi,.
Mann-Whitney U test - importance: *** = p < 0.002; ** = p < 0.02; * = p < 0.05;
- the importance of the groups undergoing statin treatment (only) is calculated against the control group; - the importance of the groups undergoing statin treatment in combination with L-carnitine is calculated against the group undergoing treatment with the statin alone. The results presented in Table 1 indicate that the administration of simvastatin at the highest dose (210 mg / kg) makes a substantial and significant increase in the GOT (p <0.002), GPT (p <0.002), and CK (p <0.05) plasma compared to controls. At a lower dose (140 mg / kg), the treatment with simvastatin causes an increase in all the enzymatic activities analyzed, being GOT (p <0.002) and GPT (p <0.02). Treatment with simvastatin at its lowest dose (70 mg / kg) does not significantly increase the enzymatic activity analyzed. The level of cholesterol is significantly decreased only in the highest dose of simvastatin that is used.
The administration of L-carnitine to the groups undergoing treatment with simvastatin shows a decrease in the activity of plasma CK compared to the group subjected to treatment with simvastatin alone. Statistically, the administration of L-carnitine is significantly effective to counteract the elevation of plasma CK in doses of simvastatin of 140 and 210 mg / kg (Table 1). Treatment with simvastatin at its lowest dose (70 mg / kg) in combination with L-carnitine reduces the activity of plasma CK compared to simvastatin only at the same dose, although not to a statistically significant degree. The results of these studies provide substantial evidence of the protective action of L-carnitine and alkanoyl L-carnitine on the secondary toxic effects of statins, which forms the basis for the invention described herein. In a second experiment carried out in the same way as the first, the only difference being that L-carnitine is administered in the drinking water of the animals, comparable results are obtained.
Therefore, another embodiment of the invention described herein, comprises the coordinated use of L-carnitine or one of its alkanoyl derivatives or one of its pharmacologically acceptable salts and of a statin according to the above definitions, in the treatment of animals, such as, for example, livestock and particularly pets. In this particular embodiment, L-carnitine or one of its derivatives, may be in solid form, such as, for example, fumarate, tartrate or mucate to dissolve in the
10 drinking water, or it may be in liquid form for measured dose to be diluted. It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for
15 the manufacture of the objects or products to which it refers.