Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-01-03
2003-11-25
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06653349
ABSTRACT:
This application is the U.S. national phase of international application PCT/IT00/00313 filed Jul. 25, 2000, which designated the U.S.
The present invention relates to a composition suitable for the prevention and treatment of kidney dysfunctions and diseases.
Correspondingly, the composition may take the form and exert the activity of a food supplement or of an actual medicinal drug, depending upon the support or preventive action or the strictly therapeutic action which the composition is intended to exert according to the particular individuals for whom it is to be used.
More specifically, the composition according to the present invention is suitable for the prevention and treatment of all forms of nephropathy, whether caused by external agents such as nephrotoxic drugs like lithium, antibiotics and anticancer drugs with a nephrotoxic potential, environmental contaminants such as mycotoxins of the ochratoxin type, or due to kidney function deficits of metabolic origin.
The composition according to the present invention comprises as its characterising ingredients acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof which will be identified hereinbelow.
The use of “carnitines” in the field of nephrology (where the term “carnitines” refers collectively to both L-carnitine and to the lower alkanoyl L-carnitines such as acetyl, propionyl, butyryl L-carnitine, etc.) is already known.
U.S. Pat. Nos. 4,272,549 and 4,287,167 (Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.) describe the use of L-carnitine and of the above-mentioned respective alkanoyl L-carnitines to prepare polysaline solutions which are fed into the dialysis compartment of artificial kidneys. The purpose of the presence of said carnitines in the dialysis fluid is to counteract the loss of L-carnitine in the blood and tissues which habitually occurs in patients undergoing regular haemodialysis treatment, with the consequent onset of disorders of the skeletal muscle and myocardium.
It is equally well known that a lack of L-carnitine may be the cause of tubular necrosis following kidney transplantation.
Finally, EP 0722 724 discloses the use of L-carnitine or lower alkonyl L-carnitine for preparing a medicament apt to inhibit nephro- and vasculotoxicity induced by the administration of immunosuppressants such as cyclosporin-A, tacrolimus, rapamicine and deoxyspargualine; and Drugs Exptl. Clin Res. XXI (6), 221-228 (1995) specifically reports on the protective effect of propionyl L-carnitine on cyclosporine-induced nephrotoxicity.
In contrast, neither known nor suggested by the vast amount of knowledge available on the role of the carnitines and their possible therapeutic applications, particularly as developed over the past few decades, is the fact that the composition according to the present invention, consisting of a combination of acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof presents a potent kidney-protecting action, particularly as regards the prevention and treatment of kidney function impairments caused by toxic agents or metabolism disorders.
In the combination composition according to the invention the w/w ratio of acetyl L-carnitine to propionyl L-carnitine ranges from 1:1 to 1:10.
The composition may also contain an additional carnitine selected from the group consisting of L-carnitine, butyryl L-carnitine, valeryl L-canitine and isovaleryl L-carnitine or their pharmacologically acceptable salts. The w/w ratio of acetyl L-carnitine and propionyl L-carnitine to this additional carnitine ranges from 1:0.5 to 1:2.
Additional optional components comprise vitamins, coenzymes, minerals and antioxidants.
It is advisable to administer 2-5 mg of acetyl L-carnitine and 2-5 mg of propionyl L-carnitine per kg body weight per day, though higher doses can also be administered in view of the very low toxicity of the components.
The marked kidney-protecting activity exerted by the combination of acetyl L-carnitine and propionyl L-carnitine is shown by the results of a number of experimental tests which are reported here below.
These tests were selected in such a way as to be predictive of the efficacy of the combination in human subjects and in the clinical field. They also demonstrate the surprisingly potent synergistic action exerted when acetyl L-carnitine and propionyl L-carnitine are used in combination.
Toxicology Tests
Both acetyl L-carnitine and propionyl L-carnitine are known to be characterised by very low toxicity, Toxicology tests showed that even high doses of acetyl L-carnitine (750 mg/kg) in combination with propionyl L-carnitine (750 mg/kg) administered intraperitoneally to rats did not cause the deaths of any of the animals thus treated. The same result was obtained with the oral administration of 1.25 g of acetyl L-carnitine together with 1.25 g of propionyl L-carnitine.
The oral administration of 500 mg/kg of acetyl L-carnitine together with 500 mg/kg of propionyl L-canitine for thirty consecutive days was also well tolerated.
No abnormalities of body growth or blood crasis were detected, in fact, as compared to control animals, neither were any abnormalities detected in the animals thus treated after performing blood-chemistry tests.
Anatomico-pathological and histological examinations carried out on the main organs and tissues also failed to reveal any significant abnormalities, thus confirming the very low toxicity and good tolerability of the two compounds used in combination.
Protective Activity Against Experimentally Induced Renal Insufficiency
To assess the kidney-protecting activity exerted by the combination of acetyl L-carnitine and propionyl L-carnitine, renal insufficiency resembling the so-called “crush syndrome” in man (Stein J. H., Lifschitz M. D., Bernes L. D., Am. J. Physiol:, 234, F171, 1978) was experimentally induced in rats by intramuscular injection of glycerol, as described by Young (Young J. H. K., Meth. Find. Exptl. Clin. Pharmacol., 13, 23, 1991). For this purpose, different groups of anaesthetised male Sprague-Dawley rats with a mean weight of 300 g, deprived of drinking water for the previous 24 hours, received intramuscular injections of 10 mg/kg of an aqueous solution of 50% glycerol. Whereas the first of these groups was kept as a control group, the other groups were treated orally immediately after glycerol injection for the three days preceding the test with 100 mg/kg or 500 mg/kg of acetyl L-carnitine, or with 100 mg/kg or 500 mg/kg of propionyl L-carnitine or with the same doses of the two drugs in combination. Intraperitoneal administration was done for the same period of time with 50 mg/kg or 250 mg/kg of acetyl L-carnitine or with 50 mg/kg or 250 mg/kg of propionyl L-carnitine or with the same doses of the two drugs in combination. Twenty-four hours after injection, blood samples were taken from the animals thus treated as well as from the control animals. On the plasma obtained by centrifuging, creatinine was determined according to the Taussky method (Taussky H. H., Clin. Chem. Acta, 1, 20, 1956), plasma proteins according to the Lowry method (Lowry O. H., Rosembrough N. J., Fan A. L., Randall R. Y., J. Biol. Chem., 193, 265, 1951) and urea by means of reaction with diacetyl monoxime.
The glycerol-induced acute renal insufficiency was demonstrated by a substantial increase in plasma concentrations of both urea and creatinine.
Administration of acetyl L-carnitine or propionyl L-carnitine alone produced only slight changes in the elevated plasma urea and creatinine concentrations, whereas a surprisingly marked reduction was noted when acetyl L-carnitine and propionyl L-carnitine were administered in combination.
The synergistic effect of acetyl L-carnitine and propionyl L-carnitine in terms of the protection afforded against glycerol-induced renal insufficiency was marked both when acetyl L-carnitine and propionyl L-carnitine were administered orally and when they were administered intraperitoneally (see Table 1).
TABLE 1
Protective activity again
Nixon & Vanderhye P.C.
Sigma-Tau HealthScience S.p.A.
Srivastava Kakash C.
Tate Christopher R.
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