Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-10-22
2003-09-30
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06627659
ABSTRACT:
This is a 371 of PCT/EP00/63485 filed Apr. 18, 2000.
The present invention relates to the use of N-acetylcysteine for intravenous administration in dialysed patients to prevent oxidative stress, which is responsible for the onset of numerous diseases.
The number of patients suffering from renal disease is constantly growing all over the world. The number of these patients starting with dialysis is growing too at a rate of 7-9% each year and it has been calculated that there will be more than 350,000 dialysed patients in the USA in 2010.
The hemodialysis procedure is usually carried out three times a week so totalling 156 times a year.
Recent studies have shown that hemodialysis is associated with oxidative stress (see for example the book “Haemodialysis and Oxidant Stress” Editors: Norbert Lameire, Gent; Ciro Tetta, Mirandola; Claudio Ronco, Vicenza—Reprint of “Blood Purification”, vol. 17, No. 2-3, 1999).
Reactive oxygen species are generated as a consequence of cellular metabolism but the dialysis procedure causes a spontaneous and increased production of oxygen radicals. This phenomenon gives raise to several side effects such as lipid peroxidation, protein thiol group oxidation, DNA damage and release of proinflammatory molecules (for example cytokines) due to the oxidative stimulus.
From that, a number of noxious effects exerts such as anaemia, increased susceptibility to infections, accelerated atherosclerosis which has as a consequence the onset of cardiovascular diseases, the main cause of mortality in chronic dialysed patients (responsible for about half of all deaths). In particular, a high prevalence of vascular damages and of congestive heart failure has been observed.
N-acetylcysteine (hereinafter referred to as NAC) is a known drug (The Merck Index, XII ed., page 16, no. 89) used from decades in therapy, mainly as mucolytic.
Moreover, the detoxifying properties of NAC are widely known suggesting its use in the treatment of several pathologies, for example in the liver protection after intoxication from drugs such as paracetamol.
As for the treatment of patients undergoing dialysis, the oral administration of NAC has been recently described in the literature [
Atherosclerosis
120 (1996) 241-244] to be without efficacy.
We have now surprisingly found that the preventive intravenous administration of NAC is able to decrease the effect of the oxidative stress in dialysed patients.
Therefore, object of the present invention is the use of NAC or pharmaceutically acceptable salts thereof for the preparation of a medicament suitable for the intravenous administration to prevent oxidative stress in dialysed patients.
Pharmaceutically acceptable salts of NAC which can be used according to the present invention are inorganic salts, preferably sodium salts.
NAC is preferably used.
The use of NAC or of its salts according to the present invention is a preventive use.
Then, NAC or its salts will be administered in a dosage form pharmaceutically suitable for the intravenous use, generally an aqueous solution, before and during the dialysis session, which generally lasts 3-5 hours.
The dose of NAC or of its salts to be administered for hemodialysis in acute renal disease treatment is generally from 100 to 200 mg/kg, preferably about 160 mg/kg.
The dose of NAC or of its salts to be administered for hemodialysis in the chronic treatment is generally from 500 to 5000 mg, preferably from 1 to 2 g.
REFERENCES:
patent: 0 836 534 (1998-05-01), None
patent: 94/03169 (1994-02-01), None
patent: WO 98/34626 (1998-08-01), None
A. G. Bostom, et al., Atherosclerosis, vol. 120, No. 1-1, pp. 241-244, “Lack of Effect of Oral N-Acetycysteine on the Acute Dialysis-Related Lowering of Total Plasma Homocysteine in Hemodialysis Patients”, 1996.
T. Miyata, et al., The Journal of Clinical Investigation, vol. 98, No. 5, pp. 1088-1094, “The Receptor for Advanced Glycation End Products (RAGE) is a Central Mediator of the Interaction of Age-&bgr;2Microglobulin With Human Mononuclear Phagocytes Via an Oxidant-Sensitive Pathway”, 1996.
L. F. Prescott, Drugs, vol. 25, No. 3, pp. 290-314, “Paracetmol Overdosage Pharmacological Considerations and Clinincal Management”, 1983.
M. Ruprah, et al., The Lancet, vol. 1, No. 8436, pp. 1027-1029, “Acute Carbon Tetrachloride Poisoning in 19 Patients: Implications for Diagnosis and Treatment”, May 4, 1985.
M. G. Salom, et al., Transplantation, vol. 65, No. 10, pp. 1315-1321, “Protective Effect of N-Acetyl-L-cysteine on the Renel Failure Induced by Inferior Vena Cava Occlusion”, May 27, 1998.
M. Damas Fernandez-Figares, et al., Farmacia Hospitalaria, vol. 16, No. 6, pp. 410-412, “Intoxicacion Accidental Por Administracion Rectal De Formaldehido”, 1992.
M.E. Lund, et al., Clinical Toxicology, vol. 22, No. 1, pp. 31-49, “Treatment of Acute Methylmercury Ingestion by Hemodialysis with N-Acetylcysteine (Mucomyst) Infusion and 2,3-Dimercaptoropane Sulfonate”, Jul. 1984.
A. E. Grzybowsky, Journal of Physiology and Pharamacology, vol. 50, No. 3, pp. 463-475, “In Vitro Effect of Glutathione Precursors on Cytotoxicity of Amino Acids to Human Mesothelial Cells”, 1999.
J. Vadoud-Seyedi, et al., British Journal of Determatology, vol. 142, No. 3, pp. 580-581, “Treatment of Haemodialysis-Associated Pseudoporphyria with N-Acetylcysteine: Report of Two Cases”, Mar. 2000.
M. Nakayama, et al., Peritoneal Dialysis International, vol. 19, No. 3, pp. 207-210, “Suppression of Ne-(Carboxymethyl)Lysine Generation by the Antioxidant N-Acetylcysteine”, May 1999.
J. DiMari, et al., American Journal of Physiology, vol. 272, No. 3, Part 2, pp. F292-F298, “N-Acetyl Cysteine Ameliorates Ischemic Renal Failure”, 1997.
Cook Rebecca
Zambon Group S.p.A.
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