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US20030139472A1 - Use of N-acetylcysteine for the preparation of a medicament suitable for the intravenous administration to prevent oxidative stress in dialysed patients - Google Patents

Use of N-acetylcysteine for the preparation of a medicament suitable for the intravenous administration to prevent oxidative stress in dialysed patients Download PDF

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US20030139472A1
US20030139472A1 US10/354,076 US35407603A US2003139472A1 US 20030139472 A1 US20030139472 A1 US 20030139472A1 US 35407603 A US35407603 A US 35407603A US 2003139472 A1 US2003139472 A1 US 2003139472A1
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acetylcysteine
oxidative stress
patients
nac
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Francesco Santangelo
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Zambon Group SpA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • 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 hemodialysis procedure is usually carried out three times a week so totalling 156 times a year.
  • 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.
  • proinflammatory molecules for example cytokines
  • NAC N-acetylcysteine
  • 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.
  • NAC or of its salts according to the present invention is a preventive use.
  • 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 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.
  • HSA Human serum albumin
  • Isolation of monocytes was performed by an indirect magnetic labelling system which allows the magnetic depletion of non monocytes i.e., T cells, B cells, NK cells, dendritic cells and basophils from a mononuclear cell suspension (obtained by blood sedimentation on a Ficoll gradient) using a cocktail of CD3, CD7, CD19, CD45RA, CD56 and anti-IgE antibodies.
  • Purified monocytes were resuspended at a concentration of 2.5 ⁇ 10 6 /ml in phenol-red free Hank's balanced salt solution (HBSS).
  • Neutrophils from the Ficoll gradient pellet were separated from erythrocytes by sedimentation in dextran. Residual erythrocytes were lysed by treating the cell pellet with lysis buffer containing ammonium chloride. Purified neutrophils were resuspended at a concentration of 5 ⁇ 10 6 /ml in phenol-red free HBSS at pH 7.4 and preincubated with medium alone or various concentrations of NAC.
  • AOPP-HSA The capacity of AOPP-HSA to activate monocyte or neutrophil oxygenation activities was measured by chemiluminescence using dimethylbiacridinium (lucigenin) for NADH oxidase activity or luminol for myeloperoxidase activity as chemoluminogenic substrates.
  • lucigenin dimethylbiacridinium
  • luminol for myeloperoxidase activity as chemoluminogenic substrates.
  • AOPP-HSA As compared to native HSA, AOPP-HSA triggered both monocytes and neutrophil NADPH oxidase and mycloperoxidase activities. NAC induced a dose-dependent inhibition of both NADPH oxidase and mycloperoxidase activities by AOPP-HSA in both monocytes and neutrophils as reported in the following FIGS. 1 and 2.
  • Ascorbyl radical—plasma (100 ⁇ l) is frozen immediately after separation and kept in liquid nitrogen ( ⁇ 176° C.) till measurement.
  • Ascorbyl free radical is a stable free radical derived from the monooxidation of ascorbate and is measured directly using ESR (Electronic Spin Resonance) spectroscopy.
  • ESR Electro Spin Resonance
  • PBMC Inducible NO synthase
  • iNOS Inducible NO synthase
  • PBMC are isolated from the whole blood (2 ml) by Ficoll separation, PBMC proteins are extracted, separated by SDS-PAGE electrophoresis, and transferred on a membrane, where iNOS is immunodetected using an anti-iNOS monoclonal antibody. The complexes antibody-iNOS is revealed using a secondary antibody linked to an enzyme and measuring the activity of this enzyme.
  • the assay consists of a capture antibody anti-TNF ⁇ attached to a microplate and a second antibody again anti-TNF ⁇ attached to an enzyme.
  • the concentration of THF ⁇ is measured with a traditional enzyme assay.

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Abstract

The present invention relates to methods of decreasing the effects of oxidative stress in patients undergoing dialysis by intravenously administering N-acetylcysteine or a pharmaceutically acceptable salt thereof to the patient.

Description

  • 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. [0001]
  • The number of patients suffering from renal disease is constantly growing all over the world. [0002]
  • 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. [0003]
  • The hemodialysis procedure is usually carried out three times a week so totalling 156 times a year. [0004]
  • 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. 23, 1999) [0005]
  • 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. [0006]
  • 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. [0007]
  • 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. [0008]
  • 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. [0009]
  • As for the treatment of patients undergoing dialysis, the oral administration of NAC has been recently described in the literature [[0010] Atherosclerosis 120 (1996) 241-244] to be without efficacy.
  • We have now surprisingly found that the preventive intravenous adminstration of NAC is able to decrease the effect of the oxidative stress in dialysed patients.[0011]
  • 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. [0012]
  • Pharmaceutically acceptable salts of NAC which can be used according to the present invention are inorganic salts, preferably sodium salts. [0013]
  • NAC is preferably used. [0014]
  • The use of NAC or of its salts according to the present invention is a preventive use. [0015]
  • 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 3-5 hours. [0016]
  • 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. [0017]
  • 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. [0018]
  • In vitro Efficacy [0019]
  • The efficacy of NAC in preventing oxidative stress according to the present invention has been demonstrated in vitro by evaluating its effect on the presence of advanced oxidation protein products (AOPP), a marker of oxidative stress in the plasma of uremic patients (Witko-Sarsat V. et al, [0020] The Journal of Immunology, 1998, 161: 2524-2532), according to the following experimental procedure.
  • In vitro Preparation of AOPP [0021]
  • Human serum albumin (HSA) was exposed to HOCI at a molar HSA/HOCI molar ratio of 1/60. The AOPP-HSA preparation was incubated 30 minutes at room temperature and then dialysed overnight against PBS. [0022]
  • Isolation of Monocytes [0023]
  • Isolation of monocytes was performed by an indirect magnetic labelling system which allows the magnetic depletion of non monocytes i.e., T cells, B cells, NK cells, dendritic cells and basophils from a mononuclear cell suspension (obtained by blood sedimentation on a Ficoll gradient) using a cocktail of CD3, CD7, CD19, CD45RA, CD56 and anti-IgE antibodies. Purified monocytes were resuspended at a concentration of 2.5×10[0024] 6/ml in phenol-red free Hank's balanced salt solution (HBSS).
  • Isolation of Polymorphonuclear Neutrophils [0025]
  • Neutrophils from the Ficoll gradient pellet were separated from erythrocytes by sedimentation in dextran. Residual erythrocytes were lysed by treating the cell pellet with lysis buffer containing ammonium chloride. Purified neutrophils were resuspended at a concentration of 5×10[0026] 6/ml in phenol-red free HBSS at pH 7.4 and preincubated with medium alone or various concentrations of NAC.
  • Measurement of Monocyte and Neutrophil Oxygenation Activities [0027]
  • The capacity of AOPP-HSA to activate monocyte or neutrophil oxygenation activities was measured by chemiluminescence using dimethylbiacridinium (lucigenin) for NADH oxidase activity or luminol for myeloperoxidase activity as chemoluminogenic substrates. One hundred microliters of monocyte suspension (2×10[0028] 5/ml) was automatically injected into the luminometer tubes containing 100 μl of HBSS (basal activity), or the tested preparations including: native HSA or AOPP-HSA at 2 mg/ml. Chemiluminescence production was measured in duplicate and luminescence intensity was expressed in counts/min integrated over a 40 minutes period.
  • Results [0029]
  • As compared to native HSA, AOPP-HSA triggered both monocytes and neutrophil NADPH oxidase and mycloperoxidase activities. NAC induced a dose-dependent inhibition of both NADPH oxidase and mycloperoxidase activities by AOPP-HSA in both monocytes and neutrophils as reported in the following FIGS. 1 and 2. [0030]
  • In vivo Efficacy [0031]
  • For the demonstration of the efficacy of NAC in preventing oxidative stress, according to the use object of the present invention the following experimental protocol is followed. [0032]
  • Patients [0033]
  • Patients with prerenal or intrinsic acute renal failure requiring hemodialysis. [0034]
  • Dosage [0035]
  • [0036] NAC 40 mg/Kg as an i.v. loading dose (15 minutes) followed by 0.5 mg/Kg/minute as i.v. slow infusion during the entire hemodialysis session.
  • Treatment Duration [0037]
  • Infusion lasting three to three and half hours during the second hemodialysis session. [0038]
  • Experimental Design [0039]
  • Between-subjects comparison of hemodialysis alone and hemodialysis plus NAC carried out according to an entirely randomised study design. Open treatment with assessor blind procedure. Patients are evaluated during the second day of the hemodialysis treatment. Each patient remains under observation for three consecutive days: day one for general assessment, day two for study treatment, day three for follow-up observations 24 hours after the second hemodialysis session. [0040]
  • Efficacy Assessment [0041]
  • The efficacy of NAC is evaluated by determining the following parameters: [0042]
  • a) Neutrophil phagocytic activity—measured, by flow cytometry, in whole blood after lysis of red blood cells. [0043]
  • b) NO production—spectrophotometrically detected in plasma as the sum of both nitrite and nitrate. [0044]
  • c) Ascorbyl radical—plasma (100 μl) is frozen immediately after separation and kept in liquid nitrogen (−176° C.) till measurement. Ascorbyl free radical is a stable free radical derived from the monooxidation of ascorbate and is measured directly using ESR (Electronic Spin Resonance) spectroscopy. The ESR spectrum of the ascorbyl free radical consists of a doublet identified by a g factor=2.0054 and by the characteristic hyperfine coupling constant α[0045] H=1.88 G.
  • d) Inducible NO synthase (iNOS)—measured in PBMC, by direct measurement of the enzyme in Western Blotting. PBMC are isolated from the whole blood (2 ml) by Ficoll separation, PBMC proteins are extracted, separated by SDS-PAGE electrophoresis, and transferred on a membrane, where iNOS is immunodetected using an anti-iNOS monoclonal antibody. The complexes antibody-iNOS is revealed using a secondary antibody linked to an enzyme and measuring the activity of this enzyme. [0046]
  • e) Cytokine release (TNF[0047] α plasma levels)—measured by enzyme-linked-immunosorbent assay (ELISA). The assay consists of a capture antibody anti-TNFα attached to a microplate and a second antibody again anti-TNFα attached to an enzyme. The concentration of THFα is measured with a traditional enzyme assay.
  • From the evaluation of these parameters the efficacy of NAC in decreasing the oxidative stress in dialysed patients can be showed. [0048]

Claims (5)

1) Use of N-acetylcysteine or pharmaceutically acceptable salts thereof for the preparation of a medicament suitable to the intravenous administration to prevent oxidative stress in dialysed patients.
2) Use according to claim 1 wherein N-acetylcysteine is used.
3) Use according to claim 1 wherein the sodium salt of N-acetylcysteine is used.
4) Use according to claim 1 in acute renal disease treatment wherein the dose of N-acetylcysteine or its salts is from 100 to 200 mg/kg.
5) Use according to claim 1 in the chronic treatment wherein the dose of N-acetylcysteine or its salts is from 500 to 5000 mg.
US10/354,076 1999-04-21 2003-01-30 Use of N-acetylcysteine for the preparation of a medicament suitable for the intravenous administration to prevent oxidative stress in dialysed patients Abandoned US20030139472A1 (en)

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ITMI99A000831 1999-04-21
IT1999MI000831A IT1312086B1 (en) 1999-04-21 1999-04-21 USE OF NAC FOR THE PREPARATION OF A DRUG SUITABLE FOR INTRAVENOUS ADMINISTRATION FOR STRESS PREVENTION
US09/926,363 US6627659B1 (en) 1999-04-21 2000-04-18 Methods of decreasing the effects of oxidative stress using N-acetylcysteine
US10/354,076 US20030139472A1 (en) 1999-04-21 2003-01-30 Use of N-acetylcysteine for the preparation of a medicament suitable for the intravenous administration to prevent oxidative stress in dialysed patients

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EP1889635A1 (en) * 2006-06-08 2008-02-20 Unipharm AD Haemodialysis concentrates

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US6566401B2 (en) * 2001-03-30 2003-05-20 The Board Of Trustees Of The Leland Stanford Junior University N-acetylcysteine compositions and methods for the treatment and prevention of drug toxicity
ITMI20032528A1 (en) * 2003-12-19 2005-06-20 Francesco Santangelo USE OF CYSTINE OR CISTEIN FOR PREVENTION AND THE
US20070232422A1 (en) * 2006-03-30 2007-10-04 Jung-Shih Chang Baseball bat with a break resistant structure
ATE489950T1 (en) * 2006-06-22 2010-12-15 Gambro Lundia Ab SOLUTION CONTAINING N-ACETYLCYSTEIN AND GLUCONIC ACID,AND METHOD FOR REDUCING, TREATING AND/OR PREVENTING OXIDATIVE STRESS AND CELL ACTIVATION
CN102526237B (en) * 2012-01-21 2014-06-25 南方医科大学南方医院 Medicinal composition for removing advanced oxidation protein final product and application thereof
US10705093B2 (en) 2014-07-25 2020-07-07 Bloodworks Determination of small-molecule thiols and disulfides: protein bound cys and total cysteine as biomarkers of oxidative stress
IT201900002919A1 (en) * 2019-02-28 2020-08-28 Solongevity Nutraceuticals S R L ANTIOXIDANT COMPOSITION

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ES2114817B1 (en) * 1996-05-16 1999-02-16 Zambon S A PHARMACOLOGICAL ASSOCIATION BETWEEN N-ACETILCISTEINA AND LEVULOSA FOR THE PREVENTION OF CELL DEATH AND ASSOCIATED DISEASES.
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