Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-26
2003-08-26
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S449000, C514S492000, C514S561000
Reexamination Certificate
active
06610699
ABSTRACT:
The invention described herein relates to the use of L-carnitine and alkanoyl L-carnitines in the preparation of medicaments useful in the treatment of tumours, particularly in combination with anticancer agents for the treatment of tumours.
BACKGROUND TO THE INVENTION
It is well-known that the use of anticancer agents in human therapy causes a large number of toxic or side effects which may be life-threatening for the patients. These complications, in fact, may lead to a reduction in the doses of the agents, and occasionally to discontinuation of the therapy itself.
Reduction of the dose or discontinuation of the therapy in many cases causes a deterioration of the individual's general condition because it favours the development of relapses, with consequences which are sometimes fatal for the patient.
Another very important and strongly felt aspect in the hospital setting and among the families of oncological patients is the concept of “improving the quality of life” of the patients under treatment.
It is equally well known that patients undergoing regular polychemotherapy for cancer are subject to a substantial weight loss.
The growing number and importance of the anticancer agents used in human therapy, the main limitation of which continues to be the occurrence of toxic or side effects, mean that this problem is still a matter for considerable concern.
Thus, the discovery of new agents or new, appropriate combinations of different agents capable of substantially reducing the toxic or side effects caused by anticancer agents used in human therapy is much to be desired.
Previous uses of L-carnitine in combination with anticancer agents are already known.
In experimental animal models, it has been demonstrated that rats treated with doxorubicin alone show a greater weight loss than a group of rats treated with the same substance in combination with L-carnitine (Senekowitsch R, Lohninger A, Kriegel H., Staniek H., Krieglsteiner H. P., Kaiser E. Protective effects of carnitine on adriamycin toxicity to heart. In: Kaiser E., Lohninger A., (eds.). Carnitine: its role in lung and heart disorders: 126-137. Karger, Basel-New York, 1987).
U.S. Pat. No. 4,713,370 describes the use of carnitine in combination with cytostatic agents such as daunomycin, N-acetyl-daunomycin and daunomycin oxime to reduce the cardiac toxicity of these compounds. U.S. Pat. No. 4,267,163 describes the use of carnitine in combination with cytostatic agents such as adriamycin, adriamycin-14-octanoate, 4′-epi-adriamycin, adriamycin beta-anomer and 4′-epi-adriamycin gamma-anomer to reduce the cardiac toxicity of these compounds. U.S. Pat. No. 4,751,242 describes the use of acetyl L-carnitine for the therapeutic treatment of peripheral neuropathies.
Other studies have addressed the evaluation of the protective effects of carnitines on anthracycline-induced cardiac toxicity (Neri B., Comparini T., Milani A., Torcia M., Clin. Trial J. 20, 98-103, 1983; De Leonardis V., De Scaizi M., Neri B., et al. Int. J. Clin. Pharm. Res. 70, 307-311, 1987).
The patent and bibliographical references cited above demonstrate that many efforts have been made in an attempt to reduce the toxic or side effects of anticancer agents, without, however, solving this serious problem in a satisfactory manner.
Carboplatin is a structural analogue of cisplatin and its associated nephrotoxicity, though by no means negligible, is less than that of cisplatin.
Vincristine is a well-known anticancer agent which has toxic effects, particularly at the level of the immune system.
Taxol is a natural extract, first isolated from the bark of
Taxus breuifolia
, with anticancer properties and has proved neurotoxic and myelotoxic in human subjects. It is used for the treatment of tumours resistant to platinum therapy, but gives rise to greater cumulative toxicity in the peripheral nervous system. It has also been ascertained that taxol induces neutropenia in the subjects treated (Rowinsky e al.; Semin. Oncol. (Aug. 20, 1993 (4 suppl 3), 1-15; Onetto e al. J. Natl. Cancer Inst. Monogr. (1993); (15):131-9).
Bleomycin is typically used in young patients with testicular cancer, lymphoma, and other types of tumours. The pulmonary toxicity of bleomycin is characterised by destruction of the alveolar epithelial barrier and the consequent intra-alveolar proliferation of fibroblasts and deposition of extracellular matrix components (Karam H et al.; Cell Biol. Toxicol (1998 Feb);14(1):13-22). Type 2 pneumocytes are not capable of regenerating the damaged or lost epithelium.
One of the general problems of pharmacological therapy is the therapeutic index of the agents, that is to say the ratio of the therapeutically effective dose to the toxic dose, or, at any rate, the dose that gives rise to the onset of side effects.
The medical community still perceives the need for therapeutic regimens which allow the patient to face up to the treatment, which, in the case of anticancer chemotherapy is particularly hard to support, while at the same time conserving an acceptable quality of life. These considerations also apply to the therapeutic treatment of animals, for instance, so-called pets.
The natural tendency to reduce the doses, and thus the use of pharmaceutical forms suitable for therapeutically useful administrations without obliging the patient to take the agents too often, contrasts with the minimum effective doses typical of each anticancer agent.
SUMMARY OF THE INVENTION
Surprisingly, it has been found that the co-ordinated use—this term will be precisely defined below—of an anticancer agent and L-carnitine or an alkanoyl L-carnitine, as defined below, exerts an unexpected synergistic effect on the activity of the anticancer agent.
In the context of the invention described herein, it has also been found, in an entirely unexpected way, that the co-ordinated use of a therapeutically effective amount of an anticancer agent, in particular taxol, carboplatin, bleomycin and vincristine, and a detoxifying amount of L-carnitine or of an alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-8 carbon atoms, or one its pharmacologically acceptable salts, affords a potent protective effect against the toxicity and side effects of the anticancer agent, without impairing its efficacy, thus giving rise, amongst other things, to a substantial improvement in the quality of life and a prolonging of life itself in the subjects treated, whether human subjects or animals.
It has also been found that said coordinated use has an inhibitory effect on tumour metastases.
Therefore one object of the invention described herein is the use the compound of formula (I):
where R is hydrogen or an alkanoyl group with 2 to 8 carbon atoms, and X
−
represents the anion of a pharmaceutically acceptable salt, for the preparation of a medicament comprising an anticancer agent, characterised in that said compound produces an synergistic effect on the activity of the anticancer agent.
Also an object of the invention described herein is the co-ordinated use the compound of formula (I) according to which the side effects of the anticancer agent in said medicament are substantially reduced.
A further object of the invention described herein is the use the compound of formula (I) in the preparation of a medicament useful for inhibiting metastases.
Yet another object of the invention described herein are combinations the compound of formula (I) with anticancer agents and the related pharmaceutical compositions.
The well known lack of toxic or side effects of alkanoyl L-carnitines makes the use of these compounds particularly safe even for long periods of treatment, for the prevention or treatment of toxic or side effects, such as weight loss, heart, kidney and central nervous system damage, peripheral nervous system damage, particularly neuropathy or neutropenia caused by taxol, or lung damage induced by bleomycin.
The implementation of the invention described herein also contributes to improving the quality of life of the patients treated; one need only think of the ph
Cavazza Claudio
Pisano Claudio
Vesci Loredana
Goldberg Jerome D.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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