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EP0794791A1 - New therapeutical utilization of superoxide dismutases - Google Patents

New therapeutical utilization of superoxide dismutases

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Publication number
EP0794791A1
EP0794791A1 EP95941163A EP95941163A EP0794791A1 EP 0794791 A1 EP0794791 A1 EP 0794791A1 EP 95941163 A EP95941163 A EP 95941163A EP 95941163 A EP95941163 A EP 95941163A EP 0794791 A1 EP0794791 A1 EP 0794791A1
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Prior art keywords
sod
specific
brain
use according
aggression
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EP95941163A
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German (de)
French (fr)
Inventor
François BAILLET
Ioannis Lamproglou
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Assistance Publique Hopitaux de Paris APHP
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Assistance Publique Hopitaux de Paris APHP
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/446—Superoxide dismutase (1.15)
    • 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
    • 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 new therapeutic use of superoxide dismutases (SOD).
  • SOD superoxide dismutases
  • SOD was characterized in 1968 by Me CORD and FRIDOVICH; it is an enzyme which promotes the elimination of the superoxide radical (-O 2 -), a priori constitutes a protective mechanism against the deleterious effects of this radical, capable of forming in vivo from oxygen atmospheric, and therefore plays a crucial role in the prevention of toxic effects which could result from exposure to an oxygenated atmosphere.
  • SODs tested those which have a prolonged half-life and a low incidence of immunological accidents are preferred; mention may be made in particular of Cu, Zn-SOD of bovine origin (homodimere which catalyzes the dismutation of the superoxide radical), Mn-SOD, Fe-SOD, liposomal SODs, SODs conjugated with polyethylene glycol, polymers or copolymers of recombinant human SOD, Cu, Zn-SOD and Mn-SOD.
  • the Applicants have found a new use of SOD preparations with prolonged duration of action, for obtaining a medicament intended to treat or prevent disturbances in brain performance, preferably cognitive brain performance, caused by a specific cerebral aggression or by a non-specific aggression.
  • non-specific aggression for example electrical stimulation (plantar shock)
  • specific cerebral aggression for example prolonged overall cranial irradiation
  • said SOD preparation with a prolonged duration of action protects mammals from disturbances of brain performance both preventively and curatively.
  • the preparation of SOD with a prolonged duration of action is in particular selected from liposomal SODs, SOD-polyethylene glycol conjugates and polymers or copolymers of SOD.
  • the superoxide dismutase (SOD) is in particular Cu / Zn-SOD, Mn-SOD, Fe-SOD from mammals (murine, bovine, human) or a recombinant SOD.
  • preparations can be administered either parenterally, preferably subcutaneously, or orally.
  • the preparations based on SOD as defined above can be used, in mammals, and in particular humans, for the curative or preventive treatment of disturbances in cognitive brain performance caused by a specific cerebral aggression (irradiation for example) or by non-specific aggression (electrical stimulation, for example).
  • SOD doses are effective on complications of radiotherapy with a wide range of dosages, ranging from 2.3 mg / kg in pigs to 0.03 mg / kg in humans. In humans, a daily dose of between 0.03 mg / kg and 0.08 mg / kg will preferably be prescribed for the subcutaneous route.
  • the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.
  • EXAMPLE 1 Preventive effect of SOD treatment on non-specific aggression (electrical stimulation).
  • 0.5 mg / kg of liposomal Cu / Zn SOD at a rate of 0.05 ml / 100 g of rat weight is administered subcutaneously to the liposomal Cu / Zn SOD group.
  • the control group received an equivalent volume of 0.9% NaCl.
  • Two-way avoidance The animals must move from one compartment A to another B, in order to avoid the electric shock (1.5 mA for 15 seconds) applied alternately, either to the floor of cage A, or to the floor of cage B.
  • a conditional sound stimulus 300 Hz allows them to avoid this shock, provided that they react within a period of time of 6 seconds (duration of the conditional stimulus and the interval).
  • the learning takes place in three consecutive days at the rate of one session per day. Each session is made up of 15 trials. The interval between tests is 50 seconds. The number of avoidances, escape failures, and the time of exposure to plantar shock are recorded.
  • Cu / Zn liposomal therefore attenuates the harmful effects of a non-specific aggression (electrical stimulation), which disrupts the acquisition of learning. Indeed, prior subcutaneous injections of SOD allow the preservation of the learning capacity.
  • the rats were anesthetized with 250 mg / kg of chloral hydrate (ip route), at a rate of 0.5 ml / 100 g of their weight.
  • the rat brain was treated by two opposite beams, also weighted of telecobalt. The two beams were treated the same day.
  • a dose of 30 Gy was delivered in 10 fractions over 12 days on isodose 95% of the dose at the isocentre after computer dosimetry.
  • the oral cavity, the muzzle, the eyes and the cervical spinal cord were protected by a personalized lead cover, 5 cm thick, placed close to the skin entry point. The distance between the source of cobalt 60 and the axis is 80 cm. After irradiation, the rats were housed in their original cages (4 to 5 animals each). - Behavioral test:
  • Two-way avoidance The animals must move from compartment A to another B in order to avoid the electric shock (0.8 mA for 15 seconds) applied alternately, either to the floor of cage A, or to the floor of cage B.
  • a stimulus conditional sound 300 Hz allows them to avoid this shock, provided that they react within a period of time of 6 seconds (duration of the conditional stimulus and the interval).
  • the learning takes place in five consecutive days at the rate of one session per day. Each session is made up of 15 trials. The interval between tests is 50 seconds. The test is introduced one month after irradiation. Four recall sessions are offered: 2 1/2, 4 1/2, 8, and 9 months after irradiation. The number of avoidances is recorded.
  • treatment with SOD improves the performance of rats who have become chronically deficient, under the effect of irradiation.
  • irradiation of 30 Gy in 10 sessions and 12 days significantly and chronically alters the cerebral cognitive performance of elderly rats, without causing cerebral morphological anomalies under light microscopy, while subcutaneous injections of SOD 9 months after irradiation significantly improves the performance of rats, bringing them closer to that of non-irradiated control rats.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

New therapeutical utilization of superoxide dismutases (SOD). Said preparation based on SOD with extended activity duration is used to obtain a medicament intended to treat or prevent brain troubles caused by a specific brain agression or by a non specific agression.

Description

NOUVELLE UTILISATION THERAPEUTIQUE  NEW THERAPEUTIC USE
DES SUPEROXYDE DISMUTASES  DISMUTASED SUPEROXIDES
La présente invention est relative à une nouvelle utilisation thérapeutique des superoxyde dismutases (SOD).  The present invention relates to a new therapeutic use of superoxide dismutases (SOD).
La SOD a été caractérisée, en 1968, par Me CORD et FRIDOVICH ; il s'agit d'une enzyme qui favorise l'élimination du radical superoxyde (-O2-), constitue a priori un mécanisme de protection contre les effets délétères de ce radical, susceptible de se former in vivo à partir de l'oxygène atmosphérique, et joue donc un rôle capital dans la prévention des effets toxiques qui pourraient résulter de l'exposition à une atmosphère oxygénée. SOD was characterized in 1968 by Me CORD and FRIDOVICH; it is an enzyme which promotes the elimination of the superoxide radical (-O 2 -), a priori constitutes a protective mechanism against the deleterious effects of this radical, capable of forming in vivo from oxygen atmospheric, and therefore plays a crucial role in the prevention of toxic effects which could result from exposure to an oxygenated atmosphere.
Les radicaux libres dérivés de l'oxygène apparaissant impliqués dans de nombreuses affections, l'utilisation de la SOD en thérapeutique a donc été préconisée dans les arthropathies inflammatoires (R. NORDMANN et al., Cah. Nutr. Diet., 1991, 26, 6, 398-402) ; dans les maladies pulmonaires et plus particulièrement, la dysplasie broncho-pulmonaire ou dans d'autres conditions toxiques, liées à la présence d'oxygène en quantité importante (système nerveux central, ischémie, désordres gastro-intestinaux non vasculaires, désordres oculaires (en local dans la chambre antérieure de l'oeil) ou lutte contre les effets indésirables des traitements anti-cancéreux), la SOD a également été proposée avec plus ou moins de succès (GREENWALD R.A., Free Radical Biol. Med., 1990, 8, 201-209).  Since free radicals derived from oxygen appear to be implicated in many ailments, the use of SOD in therapy has therefore been recommended in inflammatory arthropathies (R. NORDMANN et al., Cah. Nutr. Diet., 1991, 26, 6, 398-402); in pulmonary diseases and more particularly, bronchopulmonary dysplasia or in other toxic conditions, linked to the presence of oxygen in significant quantity (central nervous system, ischemia, non-vascular gastrointestinal disorders, ocular disorders (locally in the anterior chamber of the eye) or combating the undesirable effects of anti-cancer treatments), SOD has also been proposed with more or less success (GREENWALD RA, Free Radical Biol. Med., 1990, 8, 201 -209).
La SOD, sous sa forme Cu/Zn bovine liposomiale, s'est révélée particulièrement efficace ur les radiofibroses en clinique (Baillet F. et al., Treatment of radiofibrosis wi th liposomal superoxide dismutase . Preliminary resul ts of 50 cases, Free Rad. Res. Commun., 1, 387-394, Harwood Académie Publishers Gmbb, 1986) et ensuite, expérimentalement, chez le porc (Lefaix JL et al., La fibrose cutanéo-musculaire radio-induite : efficacité thérapeutique majeure de la SOD Cu/Zn liposomiale, Bull. Cancer, 1993, 80, 799-807), résultats d'autant plus intéressants qu'il n'y a pas de produit ayant une action équivalente. SOD, in its Cu / Zn bovine liposomal form, has been shown to be particularly effective in radiofibrosis in clinical settings (Baillet F. et al., Treatment of radiofibrosis wi th liposomal superoxide dismutase. Preliminary resul ts of 50 cases, Free Rad. Commun. Res., 1, 387-394, Harwood Académie Publishers Gmbb, 1986) and then, experimentally, in pigs (Lefaix JL et al., Radiation-induced skin and muscular fibrosis: major therapeutic efficacy of liposomal Cu / Zn SOD, Bull. Cancer, 1993, 80, 799-807), results which are all the more interesting since there is no product having an equivalent action.
Parmi les SOD testées, ce sont celles qui présentent une demi-vie prolongée et une faible incidence des accidents de nature immunologique qui ont la préférence ; on peut citer en particulier la Cu,Zn-SOD d'origine bovine (homodimere qui catalyse la dismutation du radical superoxyde), la Mn-SOD, la Fe-SOD, les SOD liposomales, les SOD conjuguées au polyéthylène glycol, les polymères ou copolymères de SOD, la Cu,Zn-SOD et la Mn-SOD humaines recombinantes.  Among the SODs tested, those which have a prolonged half-life and a low incidence of immunological accidents are preferred; mention may be made in particular of Cu, Zn-SOD of bovine origin (homodimere which catalyzes the dismutation of the superoxide radical), Mn-SOD, Fe-SOD, liposomal SODs, SODs conjugated with polyethylene glycol, polymers or copolymers of recombinant human SOD, Cu, Zn-SOD and Mn-SOD.
Les Demanderesses ont trouvé une nouvelle utilisation des préparations à base de SOD à durée d'action prolongée, pour l'obtention d'un médicament destiné à traiter ou à prévenir les perturbations des performances cérébrales, de préférence les performances cognitives cérébrales, provoquées par une agression cérébrale spécifique ou par une agression non spécifique.  The Applicants have found a new use of SOD preparations with prolonged duration of action, for obtaining a medicament intended to treat or prevent disturbances in brain performance, preferably cognitive brain performance, caused by a specific cerebral aggression or by a non-specific aggression.
On entend, au sens de la présente invention, par agression non spécifique, par exemple une stimulation électrique (choc plantaire), et par agression cérébrale spécifique, par exemple une irradiation crânienne globale prolongée.  For the purposes of the present invention, the term “non-specific aggression”, for example electrical stimulation (plantar shock), and “specific cerebral aggression”, for example prolonged overall cranial irradiation, is understood.
De manière inattendue, ladite préparation de SOD à durée d'action prolongée protège les mammifères des perturbations des performances cérébrales aussi bien à titre préventif, qu'à titre curatif.  Unexpectedly, said SOD preparation with a prolonged duration of action protects mammals from disturbances of brain performance both preventively and curatively.
De manière préférée, la préparation de SOD à durée d'action prolongée est notamment sélectionnée parmi les SOD liposomiales, les conjugués SOD-polyéthylène glycol et les polymères ou copolymères de SOD. De manière avantageuse, la superoxyde dismutase (SOD) est notamment de la Cu/Zn-SOD, de la Mn-SOD, de la Fe-SOD de mammifère (murin, bovin, humain) ou une SOD recombinante. Preferably, the preparation of SOD with a prolonged duration of action is in particular selected from liposomal SODs, SOD-polyethylene glycol conjugates and polymers or copolymers of SOD. Advantageously, the superoxide dismutase (SOD) is in particular Cu / Zn-SOD, Mn-SOD, Fe-SOD from mammals (murine, bovine, human) or a recombinant SOD.
Ces préparations peuvent être administrées, soit par voie parentérale, de préférence en sous-cutané, soit par voie orale.  These preparations can be administered either parenterally, preferably subcutaneously, or orally.
Les préparations à base de SOD telles que définies ci-dessus peuvent être utilisées, chez les mammifères, et notamment l'homme, pour le traitement curatif ou préventif des perturbations des performances cognitives cérébrales provoquées par une agression cérébrale spécifique (irradiation par exemple) ou par une agression non spécifique (stimulation électrique, par exemple).  The preparations based on SOD as defined above can be used, in mammals, and in particular humans, for the curative or preventive treatment of disturbances in cognitive brain performance caused by a specific cerebral aggression (irradiation for example) or by non-specific aggression (electrical stimulation, for example).
Les doses de SOD sont efficaces sur les complications des radiotherapies avec un grand éventail de posologies, dont les extrêmes vont de 2,3 mg/kg, chez le porc à 0,03 mg/kg, chez l'homme. Chez l'homme, on prescrira, de préférence, pour la voie sous-cutanée, une dose journalière comprise entre 0,03 mg/kg et 0,08 mg/kg.  SOD doses are effective on complications of radiotherapy with a wide range of dosages, ranging from 2.3 mg / kg in pigs to 0.03 mg / kg in humans. In humans, a daily dose of between 0.03 mg / kg and 0.08 mg / kg will preferably be prescribed for the subcutaneous route.
Outre les dispositions qui précèdent, l'invention comprend encore d'autres dispositions, qui ressortiront de la description qui va suivre, qui se réfère à des exemples de mise en oeuvre du procédé objet de la présente invention.  In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.
Il doit être bien entendu, toutefois, que ces exemples sont donnés uniquement à titre d'illustration de l'objet de l'invention, dont ils ne constituent en aucune manière une limitation.  It should be understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation.
EXEMPLE 1 : Effet préventif d'un traitement à la SOD, sur une agression non spécifique (stimulation électrique). EXAMPLE 1 Preventive effect of SOD treatment on non-specific aggression (electrical stimulation).
- Agression : stimulation électrique.  - Aggression: electrical stimulation.
L'intensité du choc plantaire au-dessus d'un certain seuil (1,1 à 1,2 mA), inhibe fortement l'apparition de la réponse conditionnelle (evitement). Dans l'étude qui suit, des chocs plantaires de 1,5 mA ont été appliqués, alors que les conditions habituelles sont de 0,8 mA. The intensity of plantar shock above a certain threshold (1.1 to 1.2 mA), strongly inhibits the appearance of the conditional response (avoidance). In the following study, plantar shocks of 1.5 mA were applied, while the usual conditions are 0.8 mA.
* Méthodes et matériels :  * Methods and materials:
- Animaux :  - Animals :
12 rats mâles de souche Wistar âgés de 5 mois répartis au hasard sont divisés en 2 groupes de six : 1) groupe témoin et 2) groupe SOD Cu/Zn liposomiale.  12 male rats of Wistar strain aged 5 months distributed at random are divided into 2 groups of six: 1) control group and 2) SOD Cu / Zn liposomal group.
- Traitement :  - Treatment :
2 heures avant chaque séance d'apprentissage, 2 hours before each learning session,
0,5 mg/kg de SOD Cu/Zn liposomiale, à raison de 0,05 ml/100 g de poids de rat est administré par voie sous-cutanée au groupe SOD Cu/Zn liposomiale. Le groupe témoin a reçu un volume équivalent de NaCl à 0,9 %. 0.5 mg / kg of liposomal Cu / Zn SOD, at a rate of 0.05 ml / 100 g of rat weight is administered subcutaneously to the liposomal Cu / Zn SOD group. The control group received an equivalent volume of 0.9% NaCl.
- Test comportemental :  - Behavioral test:
Evitement actif bilatéral ( Two-way avoidance) . Les animaux doivent passer d'un compartiment A à un autre B, afin d'éviter le choc électrique (1,5 mA pendant 15 secondes) appliqué alternativement, soit au plancher de la cage A, soit au plancher de la cage B. Un stimulus conditionnel sonore (300 Hz) leur permet d'éviter ce choc, à condition qu'ils réagissent dans un laps de temps d'une durée de 6 secondes (durée du stimulus conditionnel et de l'intervalle). L'apprentissage se déroule en trois jours consécutifs à raison d'une séance par jour. Chaque séance est composée de 15 essais. L'intervalle entre les essais est de 50 secondes. Le nombre d'évitements, d'échecs d'échappement, et le temps d'exposition au choc plantaire sont enregistrés.  Two-way avoidance. The animals must move from one compartment A to another B, in order to avoid the electric shock (1.5 mA for 15 seconds) applied alternately, either to the floor of cage A, or to the floor of cage B. A conditional sound stimulus (300 Hz) allows them to avoid this shock, provided that they react within a period of time of 6 seconds (duration of the conditional stimulus and the interval). The learning takes place in three consecutive days at the rate of one session per day. Each session is made up of 15 trials. The interval between tests is 50 seconds. The number of avoidances, escape failures, and the time of exposure to plantar shock are recorded.
- Statistiques :  - Statistics :
A partir des données individuelles brutes, les valeurs moyennes, les erreurs standard affectées aux moyennes (sem), les effectifs, et les valeurs de t de Student, ont été calculés. Les comparaisons sont effec tuées entre les deux groupes sur l'ensemble des résultats obtenus. From the raw individual data, the mean values, the standard errors assigned to the means (wk), the numbers, and the values of Student's t, were calculated. Comparisons are effective killed between the two groups on the set of results obtained.
* Résultats :  * Results:
- Pourcentage d' evitement :  - Percentage of avoidance:
La comparaison entre groupe témoin et groupe Comparison between control group and group
SOD Cu/Zn liposomiale (Tableau I) montre une différence significative dès le premier jour d'apprentissage en faveur du groupe traité (12,22 % vs 0 %, p=0,02). Cette différence persiste dans un moindre degré le deuxième jour (14,44 % vs 1,11 %, p=0,15) et le troisième (23,33 % vs 4,45 %, p=0,09). Cu / Zn liposomal SOD (Table I) shows a significant difference from the first day of learning in favor of the treated group (12.22% vs 0%, p = 0.02). This difference persisted to a lesser degree on the second day (14.44% vs 1.11%, p = 0.15) and the third day (23.33% vs 4.45%, p = 0.09).
- Pourcentage d'échec d'échappement :  - Percentage of exhaust failure:
On constate (Tableau II) que le traitement par la SOD Cu/Zn liposomiale diminue significativement les échecs d'échappement au premier jour (13,33 % vs 58,88 %, p=0,02) et cette diminution se maintient à un certain niveau au deuxième jour d'apprentissage (0 % vs 14,45 %, p=0,11).  It can be seen (Table II) that treatment with liposomal Cu / Zn SOD significantly reduces exhaust failures on the first day (13.33% vs 58.88%, p = 0.02) and this decrease is maintained at a certain level on the second day of learning (0% vs 14.45%, p = 0.11).
- Durée d'exposition au choc plantaire par séance :  - Duration of plantar shock exposure per session:
L'administration de SOD Cu/Zn liposomiale (Tableau III, figure 1) permet aux rats de mieux maîtriser l'agression due au stimulus inconditionnel (choc de 1,5 mA), puisqu'ils diminuent leurs temps d'exposition au choc de façon significative le premier jour (88,93 sec vs 165,62 sec, p=0,04), le troisième jour (13,61 sec vs 45,64, p=0,03) et dans une certaine mesure le deuxième jour d'apprentissage (37,52 sec vs 82,50 sec, p=0,15). Cela laisse supposer que pendant le déroulement des 15 essais qui composent la séance, la SOD Cu/Zn liposomiale agit efficacement non seulement au moment du choc mais aussi pendant la période de repos (50 sec), séparant deux essais consécutifs. * Conclusion : Administration of liposomal Cu / Zn SOD (Table III, FIG. 1) allows the rats to better control the aggression due to the unconditional stimulus (shock of 1.5 mA), since they reduce their exposure times to significantly the first day (88.93 sec vs 165.62 sec, p = 0.04), the third day (13.61 sec vs 45.64, p = 0.03) and to some extent the second day learning time (37.52 sec vs 82.50 sec, p = 0.15). This suggests that during the course of the 15 trials that make up the session, the liposomal Cu / Zn SOD acts effectively not only at the time of shock but also during the rest period (50 sec), separating two consecutive trials. * Conclusion:
Sur les trois paramètres étudiés au cours de l'acquisition d'un evitement actif bilatéral, l'effet protecteur de la SOD Cu/Zn liposomiale est manifeste.  Of the three parameters studied during the acquisition of active bilateral avoidance, the protective effect of the liposomal Cu / Zn SOD is manifest.
De manière inattendue, l'administration de SOD Unexpectedly, the administration of SOD
Cu/Zn liposomiale atténue donc les effets néfastes d'une agression non spécifique (stimulation électrique), qui perturbe l'acquisition d'un apprentissage. En effet, des injections sous-cutanées préalables de SOD permettent la conservation de la capacité d'apprentissage. Cu / Zn liposomal therefore attenuates the harmful effects of a non-specific aggression (electrical stimulation), which disrupts the acquisition of learning. Indeed, prior subcutaneous injections of SOD allow the preservation of the learning capacity.
EXEMPLE 2 Dysfonctionnement cognitif induit par l'irradiation crânienne : effet curatif de la superoxyde dismutase Cu/Zn liposomiale chez le rat irradié à l'âge de 4 mois. EXAMPLE 2 Cognitive dysfunction induced by cranial irradiation: curative effect of liposomal Cu / Zn superoxide dismutase in rats irradiated at 4 months of age.
* Méthodes et matériels :  * Methods and materials:
- Animaux :  - Animals :
15 rats mâles de souche Wistar irradiés à l'âge de 4 mois sont divisés en 2 groupes : 1) groupe témoin, n=7 et 2) groupe traité 9 mois après irradiation par la SOD Cu/Zn liposomiale, n=8.  15 male rats of Wistar strain irradiated at the age of 4 months are divided into 2 groups: 1) control group, n = 7 and 2) group treated 9 months after irradiation with Cu / Zn liposomal SOD, n = 8.
- Traitement :  - Treatment :
Une fois par jour et pendant cinq jours consécutifs, 0,5 mg/kg de SOD Cu/Zn liposomiale, à raison de 0,05 ml/100 g de poids de rat, est administré par voie sous-cutanée sur les animaux du groupe 2 tandis que le groupe 1 a reçu un volume équivalent de NaCl à 0,9 %. Trois jours plus tard et deux heures avant le test comportemental, une sixième injection de SOD Cu/Zn liposomiale ou de NaCl à 0,9 % a été pratiquée.  Once daily and for five consecutive days, 0.5 mg / kg of liposomal Cu / Zn SOD, at a rate of 0.05 ml / 100 g of rat weight, is administered subcutaneously to the animals in the group 2 while group 1 received an equivalent volume of 0.9% NaCl. Three days later and two hours before the behavioral test, a sixth injection of liposomal Cu / Zn SOD or 0.9% NaCl was made.
- Irradiation (9 mois avant traitement) :  - Irradiation (9 months before treatment):
Les rats ont été anesthésiés par 250 mg/kg d'hydrate de chloral (voie i.p.), à raison de 0,5 ml/100 g de leur poids. L'encéphale du rat a été traité par deux faisceaux opposés également pondérés de télécobalt. Les deux faisceaux ont été traités le même jour. Une dose de 30 Gy a été délivrée en 10 fractions sur 12 jours sur l'isodose 95 % de la dose à l'isocentre après dosimétrie par ordinateur. La cavité buccale, le museau, les yeux et la moelle épinière cervicale ont été protégés par un cache personnalisé de plomb de 5 cm d'épaisseur, placé à proximité de la portée d'entrée cutanée. La distance entre la source de cobalt 60 et l'axe est de 80 cm. Après irradiation, les rats ont été logés dans leurs cages d'origine (4 à 5 animaux chacune). - Test comportemental : The rats were anesthetized with 250 mg / kg of chloral hydrate (ip route), at a rate of 0.5 ml / 100 g of their weight. The rat brain was treated by two opposite beams, also weighted of telecobalt. The two beams were treated the same day. A dose of 30 Gy was delivered in 10 fractions over 12 days on isodose 95% of the dose at the isocentre after computer dosimetry. The oral cavity, the muzzle, the eyes and the cervical spinal cord were protected by a personalized lead cover, 5 cm thick, placed close to the skin entry point. The distance between the source of cobalt 60 and the axis is 80 cm. After irradiation, the rats were housed in their original cages (4 to 5 animals each). - Behavioral test:
Evitement actif bilatéral ( Two-way avoidance) . Les animaux doivent passer d'un compartiment A à un autre B afin d'éviter le choc électrique (0,8 mA pendant 15 secondes) appliqué alternativement, soit au plancher de la cage A, soit au plancher de la cage B. Un stimulus conditionnel sonore (300 Hz) leur permet d'éviter ce choc, à condition qu'ils réagissent dans un laps de temps d'une durée de 6 secondes (durée du stimulus conditionnel et de l'intervalle). L'apprentissage se déroule en cinq jours consécutifs à raison d'une séance par jour. Chaque séance est composée de 15 essais. L'intervalle entre les essais est de 50 secondes. Le test est introduit un mois après irradiation. Quatre séances de rappel sont proposées : 2 1/2, 4 1/2, 8, et 9 mois après irradiation. Le nombre d'évitements est enregistré.  Two-way avoidance. The animals must move from compartment A to another B in order to avoid the electric shock (0.8 mA for 15 seconds) applied alternately, either to the floor of cage A, or to the floor of cage B. A stimulus conditional sound (300 Hz) allows them to avoid this shock, provided that they react within a period of time of 6 seconds (duration of the conditional stimulus and the interval). The learning takes place in five consecutive days at the rate of one session per day. Each session is made up of 15 trials. The interval between tests is 50 seconds. The test is introduced one month after irradiation. Four recall sessions are offered: 2 1/2, 4 1/2, 8, and 9 months after irradiation. The number of avoidances is recorded.
- Statistiques :  - Statistics :
A partir des données individuelles brutes, les valeurs moyennes, les écarts-types, les erreurs standard affectées aux moyennes (sem), les effectifs et les valeurs de t de Student pour séries appariées, sont calculés.  From the raw individual data, the mean values, the standard deviations, the standard errors assigned to the means (wk), the student numbers and the t values for Student for paired series are calculated.
* Résultats :  * Results:
- Pourcentage d'evitement :  - Percentage of avoidance:
La comparaison intra-groupes (Tableau IV) montre une différence significative quant à l'évolution du pourcentage d' evitement au sein du groupe irradié traité (30,83 % vs 49,170 %, p=0,05, degré de liberté The intra-group comparison (Table IV) shows a significant difference in terms of the change in the percentage of avoidance within the irradiated group treated (30.83% vs 49.170%, p = 0.05, degree of freedom
(dd1)=7) entre le troisième rappel du test (J257) et celui (quatrième) appliqué après 6 injections de la SOD Cu/Zn liposomiale (J283). Evolution non observée chez le groupe irradié témoin (36,19 % vs 34,29 %, p=0,83), pour la même période. (dd1) = 7) between the third recall of the test (J257) and that (fourth) applied after 6 injections of the liposomal Cu / Zn SOD (J283). Evolution not observed in the irradiated control group (36.19% vs 34.29%, p = 0.83), for the same period.
* Conclusion : * Conclusion:
Sur le paramètre étudié au cours du quatrième rappel (J283) d'un evitement actif bilatéral, l'effet curatif post-irradiation de la SOD Cu/Zn liposomiale s'avère significativement important. L'amélioration de l'expression d'une réponse déficitaire induite par l'irradiation serait à rapprocher de l'effet protecteur constaté précédemment (exemple 1).  On the parameter studied during the fourth reminder (J283) of a bilateral active avoidance, the post-irradiation curative effect of the liposomal Cu / Zn SOD appears to be significantly significant. The improvement in the expression of a deficit response induced by irradiation should be compared to the protective effect noted previously (Example 1).
De manière inattendue, le traitement par la SOD améliore les performances des rats devenus chroniquement déficitaires, sous l'effet de l'irradiation.  Unexpectedly, treatment with SOD improves the performance of rats who have become chronically deficient, under the effect of irradiation.
En effet, une irradiation de 30 Gy en 10 séances et 12 jours altère de façon importante et chronique les performances cognitives cérébrales des rats âgés, sans entraîner d'anomalies morphologiques cérébrales en microscopie optique, alors que des injections souscutanées de SOD 9 mois après l'irradiation améliorent les performances des rats de façon importante, les rapprochant de celles des rats témoins non irradiés.  Indeed, irradiation of 30 Gy in 10 sessions and 12 days significantly and chronically alters the cerebral cognitive performance of elderly rats, without causing cerebral morphological anomalies under light microscopy, while subcutaneous injections of SOD 9 months after irradiation significantly improves the performance of rats, bringing them closer to that of non-irradiated control rats.
Ainsi que cela ressort de ce qui précède, l'invention ne se limite nullement à ceux de ses modes de mise en oeuvre, de réalisation et d'application qui viennent d'être décrits de façon plus explicite ; elle en embrasse au contraire toutes les variantes qui peuvent venir à l'esprit du technicien en la matière, sans s'écarter du cadre, ni de la portée, de la présente invention.  As is apparent from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application which have just been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of the technician in the matter, without departing from the framework, or the scope, of the present invention.

Claims

REVENDICATIONS
1°) Utilisation d'une préparation à base de SOD à durée d'action prolongée, pour l'obtention d'un médicament destiné à traiter ou à prévenir les perturbations des performances cérébrales, provoquées par une agression cérébrale spécifique ou par une agression non spécifique.  1 °) Use of a preparation based on SOD with prolonged duration of action, for obtaining a medicament intended to treat or prevent disturbances of the cerebral performances, caused by a specific cerebral aggression or by a non aggression specific.
2°) Utilisation selon la revendication 1, caractérisée en ce que ladite préparation est destinée à être administrée par voie parenterale, de préférence en sous-cutané.  2 °) Use according to claim 1, characterized in that said preparation is intended to be administered parenterally, preferably subcutaneously.
3°) Utilisation selon la revendication 2, caractérisée en ce que ladite préparation est destinée à être administrée à une dose journalière comprise entre 0,03 mg/kg et 0,08 mg/kg.  3 °) Use according to claim 2, characterized in that said preparation is intended to be administered at a daily dose of between 0.03 mg / kg and 0.08 mg / kg.
4°) Utilisation selon la revendication 1, caractérisée en ce que ladite préparation est destinée à être administrée par voie orale.  4 °) Use according to claim 1, characterized in that said preparation is intended to be administered orally.
5°) Utilisation selon l'une quelconque des revendications 1 à 4, dans la prévention des perturbations des performances cognitives cérébrales, provoquées par une agression non spécifique.  5 °) Use according to any one of claims 1 to 4, in the prevention of disturbances in cognitive brain performance, caused by non-specific aggression.
6°) Utilisation selon l'une quelconque des revendications 1 à 4, dans le traitement des perturbations des performances cognitives cérébrales, provoquées par une agression non spécifique.  6 °) Use according to any one of claims 1 to 4, in the treatment of disturbances of brain cognitive performance, caused by non-specific aggression.
7°) Utilisation selon l'une quelconque des revendications 1 à 4, dans la prévention des perturbations des performances cognitives cérébrales, provoquées par une agression cérébrale spécifique.  7 °) Use according to any one of claims 1 to 4, in the prevention of disturbances of brain cognitive performance, caused by a specific brain attack.
8°) Utilisation selon l'une quelconque des revendications 1 à 4, dans le traitement des perturbations des performances cognitives cérébrales, provoquées par une agression cérébrale spécifique.  8 °) Use according to any one of claims 1 to 4, in the treatment of disturbances of brain cognitive performance, caused by a specific brain attack.
EP95941163A 1994-11-30 1995-11-29 New therapeutical utilization of superoxide dismutases Withdrawn EP0794791A1 (en)

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FR9414354A FR2727316B1 (en) 1994-11-30 1994-11-30 NEW THERAPEUTIC USE OF DISMUTASE SUPEROXIDES
PCT/FR1995/001579 WO1996016670A1 (en) 1994-11-30 1995-11-29 New therapeutical utilization of superoxide dismutases

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EP1314579A2 (en) 1999-09-17 2003-05-28 Mavic S.A. Bicycle rim and wheel with such a rim

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NO316757B1 (en) 1998-01-28 2004-04-26 Baker Hughes Inc Device and method for remote activation of a downhole tool by vibration
CN112891521A (en) * 2019-12-04 2021-06-04 凯睿恒济生物医药(杭州)有限公司 Application of manganese type high-stability superoxide dismutase in preventing or treating cerebral apoplexy

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JPH0653670B2 (en) * 1985-10-28 1994-07-20 日研フ−ド株式会社 Side effect reducing agent for chemotherapeutic agents
JPH06199690A (en) * 1992-03-06 1994-07-19 Yunie:Kk Agent for promoting cerebral metabolism and improving cerebral function

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ES2107400T1 (en) 1997-12-01
FR2727316A1 (en) 1996-05-31
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WO1996016670A1 (en) 1996-06-06
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