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WO2011144777A1 - Combinaison de n-acétyl-cystéine et d'acide lipoïque pour le traitement d'une maladie à dégénérescence axonale et lésions oxydatives concomitantes - Google Patents

Combinaison de n-acétyl-cystéine et d'acide lipoïque pour le traitement d'une maladie à dégénérescence axonale et lésions oxydatives concomitantes Download PDF

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WO2011144777A1
WO2011144777A1 PCT/ES2011/070195 ES2011070195W WO2011144777A1 WO 2011144777 A1 WO2011144777 A1 WO 2011144777A1 ES 2011070195 W ES2011070195 W ES 2011070195W WO 2011144777 A1 WO2011144777 A1 WO 2011144777A1
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disease
pharmaceutical composition
treatment
nac
combination
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Aurora Pujol Onofre
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Fundacio Privada Institut dInvestigacio Biomedica de Bellvitge IDIBELL
Institucio Catalana de Recerca i Estudis Avancats ICREA
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Fundacio Privada Institut dInvestigacio Biomedica de Bellvitge IDIBELL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a second medical indication of compounds known for their antioxidant activity, N-acetyl-cysteine and aifa-lipoic acid.
  • the invention relates to the use of these compounds for the preparation of medicaments against diseases with axonal damage or axonopathy and concomitant oxidative lesions, and in particular against X-linked adrenoleukodystrophy, a demyelinating disease in the brain with axonal damage in the spinal cord and fatal outcome that There is currently no treatment, except for very specific cases of inflammatory demyelination at the onset of symptoms.
  • the present invention is comprised in the field of drugs suitable for the treatment of said disease.
  • Adrenoleukodystrophy or X-linked adrenoleukodystrophy is a neurometabolic disorder characterized by adrenal gland dysfunction and extensive demyelination of the nervous system in the case of cerebral ALD, or by spinal cord axonopathy in the case of adrenomyeloneuropathy.
  • X-ALD is the most frequent demyelinating, monogenic and inherited disease, with a minimum incidence of 1: 17,000 males.
  • adrenomyeloneuropathy it is a cause of motor disability in adults due to axonal degeneration of the spinal cord and peripheral nerves in the form of a chronic degenerative and disabling disease that slowly ends the patient's life.
  • Mixed forms are possible, in which adult patients begin developing spinal cord axonopathy and end up with a rapidly demyelinating inflammatory reaction in the rapidly lethal brain.
  • the disease mutated gene, ABCD1 codes for an ATP-binding type transporter protein that imports very long chain fatty acids (VLCFA, chain of more than 22 carbon atoms) to the peroxisome for degradation. Its malfunction due to mutations causes the accumulation of VLCFA in tissues and plasma, which is the conspicuous characteristic of the disease.
  • VLCFA very long chain fatty acids
  • bone marrow transplantation has many limitations, e.g. ex. It can only be done in children, when an HLA-compatible donor is available and in a narrow window of opportunity between diagnosis and the onset of the first symptoms. In addition, it has a high mortality rate (25%).
  • Patent ES 2303441 B1 describes the use of valproic acid for the prevention or treatment of the disease.
  • Valproic acid is a histone deacetylase inhibitor, which increases the expression of the ABCD2 gene. It is known that stable overexpression of ABCD2 (or ALDR), a homologue close to ABCD1, in the mouse model of the disease leads to normalization of the biochemical phenotype and ia prevention of neurological phenotype adrenoleukodystrophy throughout life. Thus, since ABCD2 can compensate for the absence of ABCD1 in vivo in the murine model, stimulation of ABCD2 expression in the nervous system of patients should be sufficient to prevent the onset or progression of the disease. However, its effectiveness in improving the clinical symptoms of human patients has not been proven. In a recent pilot clinical study with X-ALD patients treated with valproic acid, side effects such as tremors that further aggravate the symptoms of the disease have been detected.
  • Oxidative stress due to excessive production of Reactive Oxygen Species is described as a common collateral aspect within the group of degenerative diseases, such as Alzheimer's, Parkinson's, amyotropic lateral sclerosis or Huntington's disease (Lin, MT et al. "Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases”. Nature, 2006, Vol. 443. No. 7113, pp 787-795). Also in the pathogenesis of X-ALD there is oxidative stress and in fact there is oxidative damage in spinal cord proteins in mice.
  • ROS Reactive Oxygen Species
  • N-acetylcysteine N-acetylcysteine
  • the Wobbler mouse is a model of degeneration of motor neurons, mainly of the cervical spinal cord and cranial motor nuclei. As a consequence of the disease of the neuron body, secondary axonal atrophy occurs.
  • Axonal atrophy exists as a side effect that prevents developing a fully developed viable axon in model mice.
  • the primary defect is not found in the body of the neuron but in the axon , which degenerates late once perfectly formed and in good condition for at least 16 months ' of life in the mouse, and more than twenty years on average in patients.
  • Henderson does not directly demonstrate the effect of NAC on oxidative damage; therefore the cause-effect relationship between oxidative damage and axonal atrophy is not discovered.
  • Oxidative stress There are no symptoms as such associated with oxidative stress.
  • Direct consequences of oxidative stress are injuries or damage to macromolecules such as DNA, RNA or proteins. These damages can be repaired or not, depending on the specific cellular homeostatic systems. If the body fails to repair them, the malfunction of oxidized proteins or oxidized nucleic acids causes consequences in the malfunction of metabolic pathways or signaling determined in specific cell types, depending on the mechanisms that these different cell types have, to defend against damage and other primary causes of the disease.
  • the final cellular damages are those that produce the different types of symptoms and pathology, and are autonomous and disconnected from the initial oxidative stress.
  • Specific antioxidants or other agents effective in alleviating molecular lesions due to oxidative stress are unable to improve the pathology of the disease associated with said stress.
  • the general lack of therapeutic effects by antioxidants in clinical trials indicates that the Oxidative stress should not be the biggest contributor to disease pathology. That is, oxidative stress would be associated with the disease without a causal relationship with its symptoms or path
  • Oxidative stress is causative in no human pathology except in Friedreich's Ataxia, a rare disease that presents with functional defects of the frataxin protein. This protein is involved in the functioning of the iron and sulfur transporter in the mitochondria, and therefore directly involved in the homeostasis of oxidative stress.
  • Clinical trials in patients have demonstrated in this particular case the positive effect of an antioxidant, idebenone, on the improvement of the neurogenerative symptoms of the disease (Meier, T. et a !.
  • the application W099926657 affects the antioxidant character of NAC, which inhibits in vitro the production of cytokyries in glial cells.
  • This publication only describes its antioxidant character. Perform the experiments cori tumor cells of glioblastoma or with cells of intestinal macrophages or with primary cultures of rat astrocytes, all in-vitro. These results do not allow to be related to any specific disease. It does not use a cellular model of X-ALD cells. They are not cells obtained from cells of X-ALD patients or from an X-ALD murine model, nor of course in treated patients.
  • the results are based, as explained in Example 2 of the publication, on the artificial generation of cytokines through different stimuli such as LPS, a toxic derived from the bacterial wall that is used to mimic a bacterial infection.
  • the conclusions are based on speculative reasoning about the effect of NAC on the production of cytokines, which is too broad and ambiguous because it could be applied to any disease that occurs with inflammation, that is, with production of cytokines.
  • the effective chemical compounds described for the treatment of diseases with axonal damage are scarce.
  • the nearest publication of the art is the application CA2696310 A1, which describes the treatment of a murine ⁇ experimental autoimmune encephalitis model as a model of multiple sclerosis in humans, a common disease with demyelination and neuronal damage.
  • the treatment is based on the administration of an antioxidant that is a substituted nitrogen heterocycle, Tempol.
  • the antioxidant is described as effective in reducing the severity of clinical symptoms presented by this autoimmune disease model, as well as in reducing the axonal loss associated with inflammation and tissue damage caused by the immune response induced in the murine model.
  • the axonal damage that occurs in the mouse is caused by a harmful inflammatory stimulus, the injection of reactive T cells into an SJL mouse, which is more sensitive to inflammation.
  • the publication works with a model of acquired, non-genetic, inflammatory and demyelinating disease, with an important autoimmune component (Bischof, F. et al. "Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by se.lf-epitopes "Proceedings of the National Academy of Sciences of the United States of America, 2001, Vol. 98. No. 21, pp 12168-12173; Wekerle, H. et al. "Animal modeis". Annals of Neurology, 1994, Vol.
  • the murine models of multiple sclerosis and adrenoleukodystrophy are very different.
  • the X-ALD mouse model suffers the loss of function in the gene that is solely responsible for the disease also in humans, unlike multiple sclerosis and most neurodegenerative diseases of high prevalence, which are diseases multigene whose ⁇ pathogenesis remains mysterious to most of them.
  • the data resulting from the model used by CA 2696310 A1 does not support extrapolation of the procedure to adrenoleukodystrophy or adrenomyeloneuropathy as possible diseases that can be treated.
  • Tempol can act as an antioxidant compound it is not mentioned that it acts as such in the model that uses CA 2696310 A1.
  • the mechanism of action in the case of autoimmune encephalitis is purely speculative and cannot be deduced from the data that provide that other antioxidants protect from diseases related to axonal or myelin loss. Instead,.
  • the applicants do demonstrate that the combination of NAC + alfalipoic acid is effective in correcting oxidative damage.
  • the combination of these two active ingredients improves the oxidative damage in the nervous system to proteins in the spinal cord of the mouse model of adrenoleukodystrophy.
  • the inventors have managed to correlate the correction of oxidative damage with the correction of axonal lesion, and this with the clinical symptomatology developed by the murine model.
  • the problem that arises in the technique is therefore to find a drug to improve in-vivo symptoms of X-ALD.
  • the solution provided by the present invention is the combination of NAC and LA, which are efficient in reducing the production of ROS in human fibroblasts of adrenoleukodystrophy patients and improve the dysfunctions due to the disease.
  • the murine model of X-ALD shows a late neurological phenotype of locomotor deficit disease and axonal degeneration as predominant and proper pathologies.
  • N-acetyl-cysteine (NAC) and alpha-lipoic acid (LA) as pharmaceutically acceptable antioxidants, are capable of preventing the generation of ROS dependent on VLCFA in-vitro.
  • the inventors have also found that the treatment of murine models of X-ALD with these two antioxidants manages to reverse oxidative stress and spinal cord protein-derived lesions as the target organ of the disease on the one hand, but also manages to prevent and correct the locomotor deficit presented by the murine model of the disease and also reverse axonal degeneration, that is, its clinical symptomatology.
  • Axonal damage is expressed by virtue of normalization of the number of accumulations of APP (amyloid precursor protein) and alpha-synaptophysin in degenerate areas.
  • the inventive fact of the present invention has been to determine that oxidative stress is the cause of X-ALD disease. Until now oxidative stress as a cause of axonal damage and degeneration in murine models of human diseases had not been formally tested. An effective antioxidant treatment for axonopathic damage and derived symptomatology had not been described to date.
  • the invention is a combination of NAC and LA, or their pharmaceutically acceptable salts, for the prevention and / or treatment of a disease with axonal damage and concomitant oxidative lesions in a mammal. Also the clinic associated with this axonal damage. It is then a second medical use of the NAC and LA compounds, known separately for their antioxidant activity.
  • the term “combination” refers to an administration of the compounds of the invention simultaneously, sequentially or separately.
  • “combination” refers to simultaneous administration.
  • “combination” refers to the administration sequence !.
  • “combination” refers to administration separately.
  • the delay in administration of the second component should be so that both compounds become present in the patient's body so that they are capable of acting together.
  • Concomitant oxidative lesions are lesions produced in the proteins of the patient's or mouse tissues, due to oxidative stress. Within the scope of the present invention they refer either to pathological lesions with external symptoms of the patient or to molecular or cellular lesions before the patient develops external symptoms of the disease.
  • An embodiment of the invention relates to molecular or cellular lesions before the patient develops external symptoms of the disease, or "prevention" of the disease.
  • Another embodiment of the invention relates to pathological lesions with external symptoms of the patient, or "treatment" of the disease.
  • the inventors have discovered that the combination of NAC and LA antioxidants prevents the production of ROS in human fibroblasts, " and that these antioxidants are capable of reducing oxidative stress injuries in spinal cord in double mutant Dko mice (Abcd1- / Abcd2- / -) 18 months of age This corresponds to behavioral experiments that show that they also prevent locomotor deficit in Dko mice 18 months of age.
  • the Treadmill test counted the number of mice that kept running on a rotating belt as a function of time. Thus, in minute 7, only 60% of the X-ALD model mice can continue, with the test, while all X-ALD mice that have received the antioxidant treatment are kept running, such as the group of controls and the group of controls that have received antioxidant treatment. X-ALD mice with treatment do not differ from controls.
  • X-ALD mice with antioxidant treatment take the same time to cross the bar as controls or controls with treatment, and differ significantly from X-ALD mice that have not received treatment.
  • NAC and LA are beneficial in adrenoleukodystrophy cannot be extrapolated to other antioxidants. The functionality of each one It is not extrapolated.
  • the NAC works by increasing the intracellular pool of glutathione, which is decreased in X-ALD fibroblasts. Fibroblasts are sensitive to glutathione depletion caused by L-buthionine-S, R-sulfoximine (BSO) and die (Fourcade, S. et ai. "Early oxidative damage underlying neurodegeneration in. X-adrenoleukodystrophy.” Human Molecular Genetics, 2008, Vol. 17. No. 12, pp 1762-1773).
  • alpha-lipoic acid can neutralize different types of free radicals, in addition to regenerating reduced glutathione from oxidized glutathione (Arivazhagan, P. et al. "Effect of DL-alpha-lipoic acid on neural antioxidants in aged rats ". Pharmacological Research, 2000, Vol. 42. No. 3, pp 219 ⁇ 222).
  • alpha-lipoic acid acts as a cofactor for the enzyme dehydrolipoyl dehydrogenase, which when oxidized and released from the cofactor exhibits activity, degenerates and is one of the main producers of free radicals in the mitochondria.
  • this enzyme is oxidized in spinal cord extracts of X-ALD, which proposes LA as an ideal antioxidant for the treatment of X-ALD.
  • NAC and LA are beneficial in adrenoleukodystrophy due to its mechanism of action indicates that the treatment can be extrapolated to those diseases with similar pathology.
  • said disease with axonal damage and concomitant oxidative lesions is selected from the group of peripheral neuropathies and spastic paraplegias (SPG); preferably a leukodystrophy and more preferably metachromatic leukodystrophies, Pelizaeus Merzbacher disease, megaloencephalic leukodystrophies or Gaucher's disease.
  • SPG spastic paraplegias
  • said leukodystrophy is X-linked adrenoleukodystrophy.
  • said X-linked adrenoleukodystrophy is adremieloneuropathy.
  • a further embodiment of the invention is a pharmaceutical composition comprising the combination of NAC and LA, together with pharmaceutically acceptable excipients, for the prevention and / or treatment of a disease associated with axonal damage and concomitant oxidative lesions in a mammal.
  • This composition is presented in any pharmaceutically viable form for administration to the mammal in need thereof.
  • a preferred embodiment is that said pharmaceutical composition is a dosage unit, preferably a tablet.
  • the NAC is present in an acceptable amount in its oral administration, and in.
  • Another embodiment plus LA is present in an acceptable amount in oral administration.
  • a very preferable embodiment is that the pharmaceutical composition of the invention be administered orally.
  • Other embodiments of the invention are parenteral, topical, mucosal, intravenous, muscular or intramuscular administration.
  • the present invention extends its protection to any mammal that presents a pathology with axonal damage and concomitant oxidative lesions, due to its similar casuistry in all of them. So in one embodiment said mammal is a rodent, and in another more preferable embodiment said mammal is a human.
  • the combination of the invention may constitute a simple mixture with another therapeutic agent indicated for pathologies with axonal damage and concomitant oxidative lesions.
  • a further embodiment is a pharmaceutical composition comprising the combination of the invention, together with pharmaceutically acceptable excipients and at least one other therapeutic agent.
  • a very preferred embodiment of the invention is a kit that includes separate containers containing at least two pharmaceutical formulations comprising NAC and LA together or separately, together with pharmaceutically acceptable excipients, and instructions for the use of one of those components in conjunction with The other component.
  • it is a kit comprising NAC and LA suitable for simultaneous, separate 'or sequential use for treatment of a disease associated with axonal loss and concomitant oxidative damage in a mammal, preferably a human disease.
  • the most preferable embodiment of the invention is a pharmaceutical composition in the form of tablets comprising the . combination of NAC and LA, together with pharmaceutically acceptable excipients, for the prevention and / or treatment of X-ALD in a human.
  • Another embodiment of the invention is a method of treating a disease with axonal damage and concomitant oxidative lesions in a mammal, preferably human, comprising administering to said mammal affected by the disease a therapeutically effective amount of the combination of NAC and LA, or its pharmaceutically acceptable salts.
  • another more preferable embodiment is a method of treatment of a disease with axon damage! and concomitant oxidative lesions, which comprises administering a therapeutically effective amount of a pharmaceutical composition comprising the combination of NAC and LA to a subject, preferably human, in need thereof.
  • human X-ALD patients are characterized by high levels of markers of oxidative lesion in peripheral lymphocytes.
  • these oxidative lesion markers can be used as biomarkers to monitor the antioxidant effects of specific treatments.
  • Several human individuals with adrenomyeloneuropathy will be enrolled in the assay, from which their levels of protein oxidation in said peripheral lymphocytes will be determined before treatment with and after the combination of the invention. The doses may be adjusted individually, until satisfactory levels of oxidative damage correction in lymphocytes are achieved. These experiments can last about 12 months.
  • Figure 1 Level of oxidative markers present in the spinal cord.
  • CML carboxymethylillisin
  • CEL carboxymethylisin
  • MDAL malonalderidoidis
  • the treadmill treadmill tests (A) and the bar-cross bar (B-C) were carried out in 18-month-old mice.
  • the mice walked on the treadmill at a constant speed of 20 cm / s with a slope of 30 °.
  • the amount of mice able to stay on the tape was measured every minute, and is represented as a percentage of mice (A).
  • the number of errors on the bar (B) and the time taken to travel it from the beginning to the end (C) were quantified.
  • Example 1 Evolution of oxidative lesions in spinal cord proteins.
  • the generation and genotyping of the double Abcd1 / abcd2 knockout mice used as an adrenoleukodystrophy model is previously described (Lu, JF et al. "A mouse model for X-linked adrenoleukodystrophy". Proceedings of t ⁇ e National Academy of Sciences of the United States of America, 1997, Vol. 94. No. 17, pp 9366-9371; Pujol A, et al: Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a ⁇ herapeutic target for X-adrenoleukodystrophy.
  • ALD ABCD1
  • ADR ABCD2
  • mice used for the experiments had a pure genetic background in strain C57BL / 6J.
  • Alpha lipolco acid (LA) is supplemented at 0.5% w / w by mixing it with Dyets AIN-76A pellet meal (Bethlehem, PA) (Hagen, TM et al. "Feeding acetyl-L-carnitine and lipoic acid to hear rats significantly improves metabolic function while decreasing oxidative stress. "Proceedings of the National Academy of Sciences of the United States of America, 2002, Vol. 99. No. 4, pp 1870-1875).
  • Group II Abcdl- / Abcd2 -) Double knockout mice Abcdl- / Abcd2, (
  • Glutamic and aminoadipic semialdehydes are the main carbonyl produc ⁇ s of metal-catalyzed oxidation of proteins. Proc Nati Acad Sci US A. 2001 Vol 2; 98 (1) p 69-77.)
  • GC / MS analyzes were carried out on a 6890 Hewlett-Packard 6890 gas chromatograph, equipped with a 30 m HP5MS capillary column (30m x 0.25mm x 0, 25 ⁇ ) coupled to a Hewlett-mass detector
  • Packard model 5973A (Agilent, Barcelona, Spain). The injection temperature was 275 ° C; The temperature program was: 5 min at 110 ° C, then 2 ° C / min up to 150 ° C, 5 ° C / min up to 240 ° C, 25 ° C / min up to 300 ° C and finally 300 ° C for 5 min. Quantification was performed by external standardization, with standard curves made from mixtures of deuterated and non-deuterated standards. Analytes were detected by selective GC / MS monitoring.
  • the ions used were: lysine and d8-iisin, m / z 180 and 187, respectively; CML and d4-CML, m / z 392 and 396, respectively; CEL and d4-CEL, m / z 379 and 383, respectively; and MDAL and d8-MDAL, m / z 474 and 482, respectively.
  • the quantities of products were expressed as micromole ratios of CML, CEL or MDAL / moles of lysine.
  • the results of the experiment are shown in Fig. 1, indicating that glycooxidation (CEL, CML) and lipooxidation (MDAL) injury markers are normalized by the effect of the antioxidants used.
  • Example 3 Normalization of the clinical symptomatology of Abcdl - / abcd2- mice.
  • the treadmill apparatus consists of a variable speed belt in terms of speed and slope.
  • An electrified grid is placed on the back of the belt, which is used to manage discharges when mice stop running on the belt.
  • the treadmill used (Panlab, Barcelona, Spain) consisted of a tape 50 cm long and 20 cm wide, varying in terms of speed (5 to 150 cm / s) and slope (0 or 25 °), enclosed in a plexiglass camera. The number of downloads received and the time in seconds that the downloads are made are measured as fitness parameters. The mice were evaluated during five trials in a single one-day session. In the first trial, the speed of the tape was 20 cm / s and the inclination of 5 o .
  • the speed of the tape was 10 cm / s and the slope was increased to 10 ° and 20 ° respectively.
  • the inclination was maintained at 20 °, and the speed was increased to 20 and 30 cm / s, respectively.
  • the mice ran 1 minute.
  • the time of the experiment was respectively 3 and 7 minutes. The mice were placed on the highest part of the moving belt in the opposite direction of the movement to start, so they had to run forward to avoid shocks on the hind legs. When the animals fell from the belt, the electric shocks were applied for a maximum duration of 1 second.
  • the horizontal bar test is performed using a wooden bar 100 cm long and 2 cm in diameter. This bar is just wide enough for the mice to stay with their hind legs hovering at the edge of the circular bar, which implies that any false lateral passage will result in a slip.
  • the bar is placed 50cm high on the surface of the table to prevent mice from jumping spontaneously, but not to hurt themselves if they fall.
  • the double Abcd1 / abcd2 mutants that took a standard diet are supplemental, often showed difficulties in maintaining balance at the bar and had a greater number of falls and slips, as well as also demonstrated a longer latency at reach the platform that is at the other end of the bar.
  • Some mice in this group showed an abnormal posture, as they hugged the bar literally with the legs in front and behind, showing signs of ataxia. The beneficial effects of antioxidants were very noticeable.
  • the Abcd1 / abcd2 knockout mice that took an antioxidant diet normalized the time spent crossing the bar and the number of slips, showing no differences with the controls of the wild type and wild type groups with antioxidants.

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Abstract

La présente invention concerne une combinaison de N-acétyl-cystéine (NAC) et d'acide alpha-lipoïque (LA), ou leurs sels acceptables sur le plan pharmaceutique, pour la prévention et/ou le traitement d'une maladie à dégénérescence axonale et lésions oxydatives concomitantes chez un mammifère, en particulier de l'adrénoleucodystrophie liée à l'X (X-ALD). Le modèle murin de X-ALD montre un phénotype neurologique tardif de la maladie de déficit locomoteur et dégénérescence axonale comme pathologies prédominantes et propres de la maladie. Les inventeurs ont démontré que le traitement de modèles murins de X-ALD avec ces deux principes actifs permet d'inverser le stress oxydatif et les lésions dérivées de protéines de la moelle épinière comme organe cible de la maladie d'une part, et d'autre part que le traitement permet de prévenir et d'inverser la dégénérescence axonale et de corriger le déficit locomoteur que présente le modèle murin de la maladie, à savoir, sa symptomatologie clinique.
PCT/ES2011/070195 2010-05-17 2011-03-24 Combinaison de n-acétyl-cystéine et d'acide lipoïque pour le traitement d'une maladie à dégénérescence axonale et lésions oxydatives concomitantes Ceased WO2011144777A1 (fr)

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ES201030728 2010-05-17
ES201030728A ES2377381B1 (es) 2010-05-17 2010-05-17 Uso de una combinación de n-acetil-cisteína y ácido lipoico para la preparación de un medicamento útil para el tratamiento de una enfermedad con daño axonal y lesiones oxidativas concomitantes.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2997977A1 (fr) * 2014-09-19 2016-03-23 Fundación de la Comunidad Valenciana Centro de Investigación Principe Felipe Inhibiteurs de MTOR spécifiques dans le traitement d'une adrénoleucodystrophie à liaison X
JP2018529081A (ja) * 2015-07-14 2018-10-04 フンダシオ インスティトゥト ディンベスティガシオ ビオメディカ デ ベイビジャ（イ デ イ ベ エ エレ エレ）Ｆｕｎｄａｃｉｏ Ｉｎｓｔｉｔｕｔ Ｄ’Ｉｎｖｅｓｔｉｇａｃｉｏ Ｂｉｏｍｅｄｉｃａ Ｄｅ Ｂｅｌｌｖｉｔｇｅ （Ｉｄｉｂｅｌｌ） 副腎白質ジストロフィーの診断ならびに治療のための方法および組成物

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026657A1 (fr) 1997-11-25 1999-06-03 Musc Foundation For Research Development Inhibiteurs de la monoxyde d'azote-synthase
WO2001002004A1 (fr) * 1999-07-02 2001-01-11 Lee Hibahl Solution de dialyse peritoneale contenant un antioxydant pour traiter les insuffisances renales
WO2005067972A1 (fr) * 2003-12-31 2005-07-28 Integrative Health Consulting, Inc. Compositions nutritives et methodes permettant d'ameliorer l'efficacite du systeme immunitaire
CA2696310A1 (fr) 2007-08-14 2009-02-19 Government Of The United States Of America, Represented By The Secretary , Department Of Health And Human Services, The Procede de traitement de maladie impliquant la perte de myeline et/ou perte axonale
US20090143433A1 (en) * 2004-12-01 2009-06-04 Curt Hendrix Cocktail for modulation of alzheimer's disease
ES2303441B1 (es) 2006-05-05 2009-06-22 Fundacio Privada Institut D`Investigacio Biomedica De Bellvitge (Idibell) Uso del acido valproico o de una sal farmaceuticamente aceptable del mismo para la prevencion y/o el tratamiento de la adenoleucodistrofia ligada a x.
EP2087902A1 (fr) * 2008-02-05 2009-08-12 Bios Line S.p.a. Formules orales conçues pour protéger les voies respiratoires, avec une référence spéciale aux symptômes inflammatoires et néoplastiques

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026657A1 (fr) 1997-11-25 1999-06-03 Musc Foundation For Research Development Inhibiteurs de la monoxyde d'azote-synthase
WO2001002004A1 (fr) * 1999-07-02 2001-01-11 Lee Hibahl Solution de dialyse peritoneale contenant un antioxydant pour traiter les insuffisances renales
WO2005067972A1 (fr) * 2003-12-31 2005-07-28 Integrative Health Consulting, Inc. Compositions nutritives et methodes permettant d'ameliorer l'efficacite du systeme immunitaire
US20090143433A1 (en) * 2004-12-01 2009-06-04 Curt Hendrix Cocktail for modulation of alzheimer's disease
ES2303441B1 (es) 2006-05-05 2009-06-22 Fundacio Privada Institut D`Investigacio Biomedica De Bellvitge (Idibell) Uso del acido valproico o de una sal farmaceuticamente aceptable del mismo para la prevencion y/o el tratamiento de la adenoleucodistrofia ligada a x.
CA2696310A1 (fr) 2007-08-14 2009-02-19 Government Of The United States Of America, Represented By The Secretary , Department Of Health And Human Services, The Procede de traitement de maladie impliquant la perte de myeline et/ou perte axonale
EP2087902A1 (fr) * 2008-02-05 2009-08-12 Bios Line S.p.a. Formules orales conçues pour protéger les voies respiratoires, avec une référence spéciale aux symptômes inflammatoires et néoplastiques

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
ARIVAZHAGAN, P. ET AL.: "Effect of DL-alpha-lipoic acid on neural antioxidants in aged rats", PHARMACOLOGICAL RESEARCH, vol. 42, no. 3, 2000, pages 219 - 222
BISCHOF, F. ET AL.: "Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by self-epitopes", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 98, no. 21, 2001, pages 12168 - 12173
CARTIER, N. ET AL.: "Hematopoietic stem cell gene therapy with a lenfiviral vector in X-linked adrenoleukodystrophy", SCIENCE, vol. 326, no. 5954, 2009, pages 818 - 823
CUI, X.: "Chronic systemic D-galactose exposure induces memory loss; neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid", JOURNAL OF NEUROSCIENCE RESEARCH, vol. 84, no. 3, 2006, pages 647 - 654
FOURCADE STEPHANE ET AL: "Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy", HUMAN MOLECULAR GENETICS, vol. 17, no. 12, June 2008 (2008-06-01), pages 1762 - 1773, XP002652786 *
FOURCADE, S. ET AL.: "Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy", HUMAN MOLECULAR GENETICS, vol. 17, no. 12, 2008, pages 1762 - 1773, XP002652786, DOI: doi:10.1093/hmg/ddn085
FOURCADE, S. ET AL.: "Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy", HUMAN MOLECULAR GENETICS, vol. 17, no. T2, 2008, pages 1762 - 1773, XP002652786, DOI: doi:10.1093/hmg/ddn085
HAGEN, T. M. ET AL.: "Feeding acetyl-L-camitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 99, no. 4, 2002, pages 1870 - 1875
HENDERSON, J. T. ET AL.: "Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine", JOURNAL OF NEUROSCIENCE, vol. 16, no. 23, 1996, pages 7574 - 7582
LIN, M. T. ET AL.: "Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases", NATURE, vol. 443, no. 7113, 2006, pages 787 - 795, XP009134768, DOI: doi:10.1038/nature05292
LOPEZ ERAUSKIN J ET AL: "ANTIOXIDANTS AS A THERAPEUTIC HOPE FOR X-LINKED ADRENOLEUKODYSTROPHY", GLIA, vol. 57, no. 13, Suppl. S, October 2009 (2009-10-01), & 9TH EUROPEAN MEETING ON GLIAL CELLS IN HEALTH AND DISEASE; PARIS, FRANCE; SEPTEMBER 08 -12, 2009, pages S100 - S101, XP002652785, ISSN: 0894-1491 *
LU, J. F. ET AL.: "A mouse model for X-linked adrenoleukodystrophy", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 94, no. 17, 1997, pages 9366 - 9371
MEIER, T. ET AL.: "Idebenone: an emerging therapy for Friedreich ataxia", JOURNAL OF NEUROLOGY, vol. 256, no. 1, 2009, pages 25 - 30, XP019714422
MEYERHOFF D J ET AL: "Axonal injury and membrane alterations in Alzheimer's disease suggested by in vivo proton magnetic resonance spectroscopic imaging", ANNALS OF NEUROLOGY, vol. 36, no. 1, 1994, pages 40 - 47, XP002652787, ISSN: 0364-5134 *
PERRY GEORGE ET AL: "Lipoic acid and N-acetyl cysteine protect against mitochondrial related oxidative stress in fibroblasts from Alzheimer disease patients", FASEB JOURNAL, FED. OF AMERICAN SOC. FOR EXPERIMENTAL BIOLOGY, US, vol. 21, no. 5, 1 April 2007 (2007-04-01), pages A73, XP009150411, ISSN: 0892-6638 *
PUJOL A ET AL.: "Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy", HUM MOL GENET, vol. 1, no. 13, 2004, pages 2997 - 3006
REQUENA ET AL.: "Glutamic and aminoadipic semialdehydes are the main carbonyl products of metal-catalyzed oxidation of proteins.", PROC NATL ACAD SCI U S A., vol. 2, no. 1, 2001, pages 69 - 77
SCHULZ, J. B. ET AL.: "Clinical experience with high-dose idebenone in Friedreich ataxia", JOURNAL OF NEUROLOGY, vol. 256, no. 1, 2009, pages 42 - 45, XP019714425
SEMMLER A ET AL: "Therapy of X-linked adrenoleukodystrophy", EXPERT REVIEW OF NEUROTHERAPEUTICS, FUTURE DRUGS, LONDON, GB, vol. 8, no. 9, 1 January 2008 (2008-01-01), pages 1367 - 1379, XP009150422, ISSN: 1473-7175, DOI: DOI:10.1586/14737175.8.9.1367 *
SHAPIRO, E. ET AL.: "Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy", LANCET, vol. 356, no. 9231, 2000, pages 713 - 718, XP004821227, DOI: doi:10.1016/S0140-6736(00)02629-5
TOLAR J ET AL: "N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy", BONE MARROW TRANSPLANTATION, vol. 39, no. 4, February 2007 (2007-02-01), pages 211 - 215, XP002652784, ISSN: 0268-3369 *
WEKERTE, H. ET AL.: "Animal models", ANNALS OF NEUROLOGY, vol. 36, 1994, pages 47 - 53

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EP2997977A1 (fr) * 2014-09-19 2016-03-23 Fundación de la Comunidad Valenciana Centro de Investigación Principe Felipe Inhibiteurs de MTOR spécifiques dans le traitement d'une adrénoleucodystrophie à liaison X
WO2016042166A1 (fr) * 2014-09-19 2016-03-24 Fundación De La Comunidad Valenciana Centro De Investigación Príncipe Felipe Inhibiteurs de mtor spécifiques dans le traitement de l'adrénoleucodystrophie liée à l'x
CN107206087A (zh) * 2014-09-19 2017-09-26 瓦伦西亚普林西比菲利普中心团体投资基金会 X连锁肾上腺脑白质营养不良的治疗中的特异性mtor抑制剂
US10071063B2 (en) 2014-09-19 2018-09-11 Fundacion De La Comunidad Valenciana Entro De Investigacion Principe Felipe Specific mTOR inhibitors in the treatment of X-linked adrenoleukodystrophy
JP2018529081A (ja) * 2015-07-14 2018-10-04 フンダシオ インスティトゥト ディンベスティガシオ ビオメディカ デ ベイビジャ（イ デ イ ベ エ エレ エレ）Ｆｕｎｄａｃｉｏ Ｉｎｓｔｉｔｕｔ Ｄ’Ｉｎｖｅｓｔｉｇａｃｉｏ Ｂｉｏｍｅｄｉｃａ Ｄｅ Ｂｅｌｌｖｉｔｇｅ （Ｉｄｉｂｅｌｌ） 副腎白質ジストロフィーの診断ならびに治療のための方法および組成物

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