Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-12-28
2001-01-30
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S451000, C514S460000
Reexamination Certificate
active
06180680
ABSTRACT:
The present invention relates to a pharmaceutical composition for the prevention and treatment of cardiovascular diseases caused by abnormal lipid metabolism.
Cardiovascular diseases related to abnormal lipid metabolism are very frequent in 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 mortalit{grave over (a)} in Italia nell'anno 1989. Rapporto ISTISAN 1992/22). Our knowledge of the relationships between cholesterol and coronary heart disease stem from epidemiological studies conducted over the past few years. The conclusions reached in these studies indicate that the development of severe coronary atherosclerosis and coronary heart disease are closely correlated with 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 suitable diet is invariably the first measure adopted in cases of hyperlipidaemia. Satisfactory results are not always achieved, however, owing to widespread intolerance of strict dietary discipline, to the severity of the hypercholesterolaemia, or to genetic-type resistance.
To achieve the desired results in these patients, i.e. normalisation of blood levels of triglycerides and cholesterol, pharmacological treatment has to be resorted to. Hypolipaemic drugs fall into two categories: those which above all reduce cholesterol and those which mainly reduce triglycerides.
The former group of drugs includes the statins, probucol and resins, while the latter group includes the fibrates, nicotinic acid and fatty acids belonging to the omega-3 series.
The statins (lovastatin, sinvastatin, provastatin, fluvastatin, and the like) are inhibitors of hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) 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 cell produces several receptors for LDL and VLDL lipoproteins, which are thus removed from the bloodstream.
The statins also give rise to reduced intestinal absorption of cholesterol of dietary origin and to a reduced output of apoprotein B present in low-density lipoproteins (LDL).
The statins are drugs which are better tolerated than the other anticholesterolaemic agents, but are not without drawbacks, the side effects most commonly induced by these drugs being gastrointestinal disorders, skin rashes and headache.
A number of patients have also reported sleep disorders (E J Schaffer, N Engl J Med, 319; 1222, 1988; Lancet, 339: 547, 29 February 1992), while, in 1-2% of patients taking high doses of statins, an at least 3-fold increase in plasma aminotransferase activity has been noted compared to baseline values, which may even require discontinuation of the treatment.
In addition, it has been reported that though the statins lead to a reduction in the number of deaths due to coronary heart disease, an increase has been observed, in treated patients, of deaths caused by other events such as tumours or trauma (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). The results of experiments in animals and human subjects have suggested that, to reduce cholesterol levels, pharmacological treatment with statins should be given only to patients at high risk for coronary disease in the short term (JAMA, 1996; 275: 55-60).
Equally well known is the antitriglyceridaemic and anticholesterolaemic effect of a number of alkanoyl carnitines, particularly acetyl L-carnitine. U.S. Pat. No. 4,268.524 describes a therapeutic method for increasing high-density lipoprotein (HDL) levels so as to selectively reduce the HDL:(LDL+VLDL) ratio in the plasma of patients at risk for cardiovascular disease, in which this ratio is abnormally high; the method comprises administering 5-50 mg/kg/day of alkanoyl carnitine or one of its pharmacologically acceptable salts.
It has now been found, unexpectedly, that the co-ordinated use—this term being defined precisely here below—of an alkanoyl L-carnitine in which the linear or branched alkanoyl has 2-6 carbon atoms, or of one of its pharmacologically acceptable salts, and a statin enables an enhanced effect on the anticholesterol aemic and antitriglyceridaemic action to be achieved as compared to the separate, independent administration of the two active ingredients. This enables the same therapeutic results to be achieved using lower doses of statins, thus making for a marked reduction in their toxic and side effects.
The well-known lack of toxic and side effects of the alkanoyl L-carnitines and the use of lower doses of statins as compared to the routine doses (10-40 mg/day) makes the co-ordinated use as per the invention particularly useful and safe both for the treatment of hypercholesterolaemic and/or hknpertriglyceridaemic patients at high risk for cardiovascular disease in the short, medium or long term and for the prevention of such diseases.
As a result of the above-mentioned synergistic effect, it has been found, in fact, that the statin dose can be reduced to 5-20 mg/day, whereas the alkanoyl L-carnitine dose can be reduced to 2-30 mg/kg/day.
REFERENCES:
Database Medline US National Library of Medicine (NLM), Savica V et al: “The hypotriglyceridemic action of the combination of L-carnitine+simvastatin vs. L-carnitine and vs. Simvastatin!” XP002081551 see abstract & Clin Ter, Jan. 1992, 140 (1 Pt 2) P17-22, Italy.
Criares Theodore J.
Kim Jennifer
Nixon & Vanderhye
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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