Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-01
2001-06-12
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S460000, C514S510000, C514S642000
Reexamination Certificate
active
06245800
ABSTRACT:
The invention described herein relates to a pharmaceutical composition for the treatment of diseases caused by lipid metabolism disorders, and in particular a pharmaceutical composition comprising a statin and L-carnitine or one of its alkanoyl derivatives, useful for the prevention and treatment of statin-induced toxic or side effects.
BACKGROUND OF THE INVENTION
Cardiovascular diseases related to lipid metabolism disorders are very frequent in the industrialised countries. In Italy, for instance, they account for more than 40% of the overall mortality (Capocaccia R., Farchi G., Prati S. et al.: La mortalita' in Italia nell'anno 1989. Rapporto ISTISAN 1992/22). Our knowledge of the relationships between cholesterol and coronary heart disease stems from epidemiological studies conducted in recent years. The conclusions of these studies indicate that the development of severe coronary atherosclerosis is closely related to serum cholesterol levels (McGill H. C. 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 an appropriate diet is always the first measure to be adopted in cases of hyperlipidaemia. Good results, however, are not always achieved owing to widespread intolerance of the strict dietary regimen, to the severity of the hypercholesterolaemia or to genetic-type resistance.
In these cases, to achieve the desired results, that is to say to restore normal blood levels of triglycerides and cholesterol, it proves necessary to resort to pharmacological treatment with lipid-lowering drugs. This category includes both drugs that prevalently reduce cholesterol levels and drugs that prevalently reduce triglyceride levels.
The former group of drugs includes statins, probucol and resins, and the latter group fibrates, nicotinic acid and omega-3-series fatty acids.
The statins (simvastatin, lovastatin, pravastatin, fluvastatin and the like) are hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. By inhibiting this enzyme, they reduce the hepatic synthesis of cholesterol (Lancet 1994; 334: 1383-1389). To compensate for the reduction in intracellular cholesterol, the liver cell produces more receptors for lipoproteins of the LDL and VLDL series, which in this way are removed from the bloodstream.
In addition, the statins cause less absorption of cholesterol of dietary origin in the intestine and a reduced output of apoprotein B present in low-density lipoproteins (LDL).
The statins are better tolerated than the other cholesterol-lowering agents, but present certain drawbacks: the most common side effects caused by these drugs are gastrointestinal disorders, skin rashes and headache.
A number of patients have complained of sleep disorders (E J Schaffer, N Engl J Med, 319:1222,1988; Lancet, 339:547, Feb. 29, 1992), while significant increases in transaminase activity (GOT and GPT) and in CK compared to basal values have been observed in patients taking statins in doses of 40 mg/kg (Schweiz Med Wochenschr Jun. 29, 1991; 121 (26): 977-83).
Moreover, patients treated with simvastatin present side effects related to myopathy, rhabdomyolysis, muscle pain and increases in serum CK and LDH activity [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 HMG-CoA reductase inhibitor 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, an increase in deaths due to other events such as tumours or trauma has been noted in treated patients (Davey-Smith G., Song F., Sheldon T. A., Cholesterol lowering and mortality: the importance of considering initial level at risk.
BMJ
1993; 306: 1367-1373; Ravnshov U.; Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome.
BMJ
1992; 305: 15-19). Young rats treated with different cholesterol-lowering agents (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). Moreover, Bhuiyan et al. (Bhuiyan J. & Seccombe D. W. 1996 Lipids 31: 867-870) have demonstrated that the administration of lovastatin to rabbits causes a significant reduction in hepatic, cardiac and skeletal muscle L-carnitine.
The results of experiments in animals and in human subjects have suggested that, to reduce cholesterol levels, pharmacological treatment with statins should be used only in patients at high risk of coronary disease in the short term (JAMA, 1996; 275: 55-60).
Equally well known are the triglyceride- and cholesterol-lowering effects of a number of alkanoyl carnitines, in particular of acetyl L-carnitine. U.S. Pat. No. 4,268,524 describes a therapeutic method for increasing the level of high-density lipoproteins (HDL) so as to selectively reduce the LDL+VLDL:HDL ratio in the plasma of patients at risk of cardiovascular disease, in whom this ratio is abnormally high, This method includes the daily administration of 5-50 mg/kg of alkanoyl carnitine or of one of its pharmacologically acceptable salts.
The international patent application WO99/01126 filed 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 the alkanoyl L-carnitines exert a protective action on statin-induced toxic or side effects.
DESCRIPTION OF THE INVENTION
It has now unexpectedly been found that the co-ordinated use—this term will be defined precisely here below—of L-carnitine or an alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable salts and a statin affords a protective action against statin-induced toxic or side effects.
The well-known lack of toxic and side effects of L-carnitine and of the alkanoyl L-carnitines and the protective action exerted by these compounds on statin-induced toxic or side effects allow the statins to be used at doses higher than those usually administered (10-20 mg/day).
The coordinated use according to the invention is particularly useful and safe for the treatment of both hypercholesterolaemic and/or hyper-triglyceridaemic patients at high risk for cardiovascular disease in the short, medium or long term.
Thanks to the protective effect exerted by L-carnitine or by the alkanoyl L-carnitines, it has been found, in fact, that it is possible to use higher doses of statin than those normally used in human therapy, while the dose of L-carnitine or alkanoyl L-carnitines may be 100-3000 mg/day.
In the context of the invention described herein, what is meant by “co-ordinated use” of the above-mentioned compounds is, indifferently, either (i) co-administration, i.e. the substantially simultaneous administra-tion of L-carnitine or one of the aforesaid alkanoyl L-carnitines or one of their pharmacologically acceptable salts and of a statin, or (ii) the administration of a composition comprising the aforesaid active ingredients in combination and in a mixture, in addition to possible excipients. What is meant by co-administration is also a pack or manufactured article, comprising distinct administration forms of L-carnitine or one of the aforesaid alkanoyl L-carnitines, or one of their pharmacologically acceptable salts and a statin, accompanied by instructions for the co-ordinated simultaneous intake of the active ingredients according to a dosage regimen established by the primary care physician on the basis of the patient's condition.
The invention described herein therefore covers both the co-administration of L-carnitine or one of the aforesaid alkanoyl L-carnitines, or one of their pharmacologically acceptable salts and a
Arduini Arduino
Carminati Paolo
Peschechera Alessandro
Jarvis William R. A.
Kim Vickie
Nixon & Vanderhye
Sigma-Tau
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