WO2017042314A1 - Méthodes et composition pharmaceutique pour le traitement d'épilepsies post-traumatiques - Google Patents
Méthodes et composition pharmaceutique pour le traitement d'épilepsies post-traumatiques Download PDFInfo
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- WO2017042314A1 WO2017042314A1 PCT/EP2016/071269 EP2016071269W WO2017042314A1 WO 2017042314 A1 WO2017042314 A1 WO 2017042314A1 EP 2016071269 W EP2016071269 W EP 2016071269W WO 2017042314 A1 WO2017042314 A1 WO 2017042314A1
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- bumetanide
- thioester
- ester
- furosemide
- dithioester
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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
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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- 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
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the present invention relates to methods and pharmaceutical composition for the treatment of post-traumatic epilepsies.
- PTE post-traumatic epilepsy
- This primary insult initiates a secondary cascade of events including cell death and aberrant network reorganization due to abnormal axonal outgrowth 5 7 .
- the molecular mechanisms involved in this post-insult axonal outgrowth remains to be elucidated.
- the limbic system and in particular the hippocampus is one of the major seizure generation loci following Traumatic Brain Injury (TBI) 8 .
- TBI Traumatic Brain Injury
- TLE temporal lobe epilepsy
- DGCs dentate granule cells
- rMFs recurrent mossy fibers
- GABAA receptor-mediated conductances either hyperpolarize or depolarize a neuron depending on its internal CI " and HC03 concentrations and membrane potential.
- CI " homeostasis can be strongly modified and switch GABAergic signalling from hyperpolarizing to depolarizing 11 13 .
- This major change involved a reduction in expression of the potassium-chloride co -transporter KCC2 14 .
- the present invention relates to methods and pharmaceutical composition for the treatment of post-traumatic epilepsies.
- the present invention is defined by the claims.
- the inventors aim at defining the role of chloride homeostasis in the aberrant axonal outgrowth in dentate gyrus. This work has been performed using pilocarpine animal model since it is a well-established model leading to a reliable and robust aberrant sprouting of rMF in dentate gyrus.
- the data demonstrate for the first time that impaired chloride homeostasis in the early stage following the insult is the precipitating event triggering rMF sprouting. Indeed blockade of Na+-K+-Cl- co -transporter NKCC1 by bumetanide few days after pilocarpine significantly reduce axonal outgrowth in dentate gyrus.
- one aspect of the present invention relates to a method of treating posttraumatic epilepsy (PTE) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an inhibitor of NKCC1 activity or expression.
- PTE posttraumatic epilepsy
- post-traumatic epilepsy or "PTE” has its general meaning in the art and refers to a form of epilepsy that results from brain damage caused by a traumatic brain injury.
- a person with PTE typically suffers repeated post-traumatic seizures.
- traumatic brain injury has its general meaning in the art and includes any trauma, e.g., post-head trauma, impact trauma, and other traumas, to the head such as, for example, traumas caused by accidents and/or sports injuries, concussive injuries, penetrating head wounds, brain tumors, stroke, heart attack, meningitis, viral encephalitis, and other conditions that deprive the brain of oxygen.
- the traumatic brain injury may be a closed head injury which may be transient or prolonged.
- treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
- the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
- therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
- a therapeutic regimen may include an induction regimen and a maintenance regimen.
- the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
- the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
- An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
- maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
- a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
- the method of the present invention is particularly suitable for preventing i) the early and late rMF sprouting and ii) the subsequent development of spontaneous and recurrent seizures.
- the inhibitor of NKCC activity or expression is administered before traumatic brain injury, within 24 hours after traumatic brain injury, 24 hours to 7 days after traumatic brain injury, 7-10 days after traumatic brain injury, 24 hours to 2 weeks after traumatic brain injury, or 24 hours to two months after traumatic brain injury.
- NKCC1 has its general meaning in the art and refers to the Na-K-Cl co -transporter 1 that is a protein that assists in the active transport of sodium, potassium, and chloride into and out of cells. NKCC1 is widely distributed throughout the body but also in the brain and in particular in the developing animal and human brain. It acts to augment intracellular chloride in neurons and thereby to render GAB A more excitatory.
- the inhibitor of NKCC 1 activity or expression also induces the upregulation of KCC2 activity or expression.
- KCC2 has its general meaning in the art and refers to the potassium chloride co -transporter that is a co- transporter of chloride. KCC2 is found in the central nervous system acts to remove intracellular chloride and thereby to augment the inhibitory actions of GABA.
- the inhibitor of NKCC 1 activity is a low molecular weight inhibitor, e. g. a small organic molecule (natural or not).
- small organic molecule refers to a molecule (natural or not) of a size comparable to those organic molecules generally used in pharmaceuticals.
- the inhibitor of NKCC 1 activity is selected from the group consisting of bumetanide, bumetanide aldehyde, bumetanide methyl ester, bumetanide cyanomethyl ester, bumetanide ethyl ester, bumetanide isoamyl ester, bumetanide octyl ester, bumetanide benzyl ester, bumetanide dibenzylamide, bumetanide diethylamide, bumetanide morpholinoethyl ester, bumetanide 3-(dimethylaminopropyl) ester, bumetanide N,N- diethylglycolamido ester, bumetanide ⁇ , ⁇ -dimethylglycolamido ester, bumetanide pivaxetil ester, bumetanide propaxetil ester, bumetanide methoxy(polyethyleneoxy)n-l -ethyl ester, bumetanide benzyltri
- the inhibitor of NKCC1 activity is selected from the group consisting of furosemide, furosemide aldehyde, furosemide methyl ester, furosemide cyanomethyl ester, furosemide ethyl ester, furosemide iso-amyl ester, furosemide octyl ester, furosemide benzyl ester, fu-rosemide morpholmoethyl ester, furosemide 3- (dimethylaminopropyl) ester, furosemide ⁇ , ⁇ -diethylglycolamido ester, furosemide N,N- dimethylglycolamido ester, furosemide pivaxetil ester, furosemide propaxetil ester, furosemide meth-oxy(polyethyleneoxy)n-l -ethyl ester, furosemide benzyltrimethylam- monium acid salt and furosemide cetyltri
- the inhibitor of NKCC1 activity is selected from the group consisting of molecule described in WO2006110187.
- An "inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene. Therefore, an “inhibitor of NKCC1 expression” denotes a natural or synthetic compound that has a biological effect to inhibit the expression of NKCC1 gene.
- said inhibitor of gene expression is a siR A, an antisense oligonucleotide or a ribozyme.
- an effective amount refers to a quantity sufficient to achieve the desired therapeutic effect.
- the amount of a composition administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
- an effective amount of the inhibitor of NKCC1 activity or expressions for achieving a therapeutic or prophylactic effect range from about 0.1 mg per kilogram body weight per day to about 10 mg per kilogram body weight per day.
- the dosage ranges are from about 0.1 mg per kilogram body weight per day to about 10 mg per kilogram body weight per day.
- dosages can be 1 mg/kg body weight or 10 mg/kg body weight every day, every two days or every three days or within the range of 1-10 mg/kg every week, every two weeks or every three weeks.
- a single dosage of peptide ranges from 0.1-10 micrograms per kg body weight.
- aromatic-cationic peptide concentrations in a carrier range from 0.2 to 2000 micrograms per delivered milliliter.
- the inhibitor of NKCC1 activity or expression is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
- pharmaceutically acceptable excipients such as biodegradable polymers
- pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
- the pharmaceutical compositions contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected.
- saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts
- dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
- Sterile injectable solutions are prepared by incorporating the inhibitor of NKCC1 activity or expression in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
- FIGURES Figure 1 : Altered NKCC1 and KCC2 expression in hippocampus after Status
- the 130-140 kDa and 250 kDa bands correspond to the monomeric and oligomeric proteins, respectively. Corresponding quantification are shown by the bar graph.
- Data are means ⁇ SEM; p value obtained using t test analysis.
- Figure 2 In vivo bumetanide functionnaly reduces ectopic rMFs sprouting, (a)
- the bar graph represents the quantification of the fluorescence intensity of the ectopic rMF sprouting in vehicle- and bumetanide-treated d5pSE rats normalized to control condition.
- LFP Local field potential evoked in the presence of 5 ⁇ gabazine showing an antidromic population spike (arrow) followed by a burst (arrowhead) in vehicle or bumetanide-treated d5pSE rats.
- the corresponding bar graph represents the mean coastline burst index observed in slices from vehicle and bumetanide-treated d5pSE rats.
- Data are means ⁇ SEM; *p ⁇ 0.05, *** p ⁇ 0.001, p value obtained using t test analysis.
- Figure 3 In vivo bumetanide application rescues NKCC1 expression and KCC2 function at d5pSE.
- the 140 kDa bands correspond to the NKCC1 monomeric protein under control condition, after vehicle or bumetanide infusion at d5pSE.
- Corresponding quantification are shown by the bar graph.
- Right western blot of in toto hippocampi labeled with a pan-KCC2 antibody.
- the 130-140 kDa and 250 kDa bands correspond to the monomeric and oligomeric proteins respectively, under control condition, after vehicle or bumetanide infusion at d5pSE.
- the corresponding bar graph represents the quantification of the fluorescence intensity of the ectopic MF sprouting in vehicle- and bumetanide-treated 2MpSE rats normalized to control condition.
- b Number of ictal events observed in vehicle- and bumetanide-treated rats per day.
- Data are means ⁇ SEM; *p ⁇ 0.05, p value are obtained using t test analysis.
- - KCC2 and NKCC1 expression is drastically altered at d5pSE (day 5 post SE), at mRNA and protein levels;
- Bumetanide infusion completely inhibited SE induced KCC2 downregulation.
- Bumetanide infusion for 3 days (from day 2 to 5 post SE) in vivo reduces by 50% the frequency of seizure 2 months after the application has been stopped
- NKCC1 and KCC2 expression is altered 5 days post SE (section 1)
- NKCC1 mRNA extracted from in toto hippocampi displays an initial up-regulation at day 1 post-SE (dlpSE) that returns to control levels 14 days after SE (dl4pSE) (Fig. la; Ctrl: 1 ⁇ 0,11; dl : 2,10 ⁇ 0,41; /? ⁇ 0.05; d5: 1,09 ⁇ 0,02; dl4: 0,95 ⁇ 0,2).
- KCC2 mRNA level changes are different showing down-regulation at dlpSE and with a tendency to recover at dl4pSE (Fig. la; ctrl: 1 ⁇ 0,28; dl : 0,46 ⁇ 0,02; /? ⁇ 0.05; d5: 0,73 ⁇ 0,10; dl4: 1,16 ⁇ 0,35).
- NKCC1 and KCC2 were significantly increased to ⁇ 45% and ⁇ 70% of control level at dlpSE and d5pSE respectively with no significant alteration at dl4pSE (Fig. lb; Ctrl: 1 ⁇ 0,08; dl : 1,45 ⁇ 0,13; p ⁇ 0.0 ⁇ ; d5: 1,70 ⁇ 0,24; p ⁇ 0.0 ⁇ ; dl4: 1,62 ⁇ 0,36).
- KCC2 expression was significantly reduced to ⁇ 60% of the control level at d5pSE with a tendency to a partial recovery at dl4pSE (Fig. lb; ctrl: 1 ⁇ 0,095; dl : 1,10 ⁇ 0,17; d5: 0,58 ⁇ 0,08; p ⁇ 0M; dl4: 0,77 ⁇ 0,16).
- KCC2 neuronal distribution of KCC2 is altered after SE.
- DG dentate gyrus
- CA3 Cornu Ammonis 3
- CAl Cornu Ammonis 1
- KCC2 immuno labeling show a strong perisomatic pattern staining in the DG, CA3 and CAl regions, as shown by the narrow pic occurring at the somatic periphery.
- nMDP normalized Mean Deviation Product
- a major hippocampal network reorganization observed in TLE in both human patients and animal model is the ectopic MF sprouting 18-21 .
- This reorganization is responsible for a strong recurrent excitatory circuit within the DG, and partly responsible for the generation of epileptiform activities in human patients and animal models 21 ' 22 ' 27 - 28 .
- the chronic phase of the pathology 23 ' 24 it has been poorly assessed during the early stages after SE 20 ' 21 .
- ectopic MF sprouting is already established at d5pSE. This time point was chosen as it displays the most robust expression differences.
- Bumetanide functionally reduces ectopic MF sprouting.
- NKCC1 up-regulation at d5pSE we asked whether abnormal chloride homeostasis is involved in the establishment of the early morpho-functional change in the dentate gyrus. In order to achieve this we decided to use bumetanide to functionally block NKCC1. Because the ability of bumetanide to cross the blood-brain-barrier has been challenged 17 ' 25 we applied bumetanide (20 ⁇ ) intrahippocampally and continuously for three days from the 2 nd to the 5 th day after SE using osmotic minipumps. Subsequently, we examined the extent of ectopic rMFs sprouting at d5pSE (Fig. 2a).
- Bumetanide blocked NKCC1 upregulation and rescued KCC2 function at d5pSE.
- KCC2 expression in vehicle and bumetanide-treated rats at d5pSE we analysed KCC2 expression in vehicle and bumetanide-treated rats at d5pSE.
- KCC2 global expression (using wester blot) is strongly downregulated at d5pSE in vehicle-treated (vehicle-treated rats: 0,47 ⁇ 0,15 vs 1,40 ⁇ 0,23; /? ⁇ 0.05, normalized to control).
- KCC2 expression was fully restored in bumetanide-treated rats at d5pSE.
- bumetanide is able to severely attenuate the seizure frequency in vivo by inhibiting morpho functional changes at early stages. Indeed, in the present study we show for the first time that the ectopic rMF sprouting, described as a characteristic of the chronic phase of the pathology 23 ' 24 , is already established during the latent phase, as early as 5 days after the SE. This change is dependent on NKCCl mediated intracellular chloride accumulation. In the present study, we propose to use bumetanide 2 days after the SE (for 3 days) to functionally block the early ectopic rMF sprouting; via partially blocked NKCCl upregulation and induced functional rescue of KCC2. Altogether this will in turn reduce the frequency of chronic seizures in adult experimental epilepsy in vivo.
- bumetanide as a potent prophylactic therapeutically drug in PTE to prevent i) the early and late rMF sprouting and ii) the subsequent development of spontaneous and recurrent seizures.
- the mechanism of these effects is mediated by a post SE bumetanide induced upregulation of KCC2 and inhibition of NKCCl upregulation. These two effects lead to the unexpected inhibition of rMF sprouting.
- Similar to SE other types of brain injury also display axonal growth and ectopic synaptogenesis e.g. TBI, ischemic stroke, Alzheimer and Parkinson. These are associated with development of injury-induced epilepsy.
- KCC2 and NKCC1 expression are also observed in these types of brain disturbances it plausible that a prophylactic therapeutic strategy using bumetanide could be also effective in ischemic stroke.
- other embodiments displaying axonal ectopic sprouting as mayor characteristic could also benefit from the presented treatment.
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Abstract
La présente invention concerne des méthodes et une composition pharmaceutique pour le traitement d'épilepsies post-traumatiques. La présente invention concerne en particulier une méthode de traitement d'épilepsies post-traumatiques (PTE) chez un patient en ayant besoin, ledit procédé consistant à administrer audit patient une quantité thérapeutiquement efficace d'un inhibiteur de l'activité ou de l'expression de NKCC1.
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CN112367970A (zh) * | 2018-04-12 | 2021-02-12 | J·大卫格莱斯顿研究所-根据J·大卫格莱斯顿遗嘱的遗嘱信托 | 用于治疗apoe4/4相关病症的方法 |
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WO2007047698A2 (fr) * | 2005-10-17 | 2007-04-26 | Neurotherapeutics Pharma, Inc. | Procedes et compositions pour traiter des troubles neuropsychiatriques et des troubles lies a la dependance |
WO2011011692A2 (fr) * | 2009-07-24 | 2011-01-27 | Stc.Unm | Méthodes de traitement et de prévention/réduction du risque d'épilepsie mésiale du lobe temporal |
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WO2007047698A2 (fr) * | 2005-10-17 | 2007-04-26 | Neurotherapeutics Pharma, Inc. | Procedes et compositions pour traiter des troubles neuropsychiatriques et des troubles lies a la dependance |
WO2011011692A2 (fr) * | 2009-07-24 | 2011-01-27 | Stc.Unm | Méthodes de traitement et de prévention/réduction du risque d'épilepsie mésiale du lobe temporal |
Non-Patent Citations (4)
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KATHRIN TÖLLNER ET AL: "A novel prodrug-based strategy to increase effects of bumetanide in epilepsy", ANNALS OF NEUROLOGY., vol. 75, no. 4, 1 April 2014 (2014-04-01), BOSTON, US, pages 550 - 562, XP055252583, ISSN: 0364-5134, DOI: 10.1002/ana.24124 * |
VOLODYMYR DZHALA ET AL: "Acute and Chronic Efficacy of Bumetanide in an in vitro Model of Posttraumatic Epileptogenesis", CNS NEUROSCIENCE & THERAPEUTICS, vol. 21, no. 2, 12 December 2014 (2014-12-12), GB, pages 173 - 180, XP055252582, ISSN: 1755-5930, DOI: 10.1111/cns.12369 * |
WANG S ET AL: "In vivoeffects of bumetanide at brain concentrations incompatible with NKCC1 inhibition on newborn DGC structure and spontaneous EEG seizures following hypoxia-induced neonatal seizures", NEUROSCIENCE, vol. 286, 12 February 2015 (2015-02-12), pages 203 - 215, XP029188342, ISSN: 0306-4522, DOI: 10.1016/J.NEUROSCIENCE.2014.11.031 * |
WOLFGANG LÖSCHER ET AL: "New avenues for anti-epileptic drug discovery and development", NATURE REVIEWS. DRUG DISCOVERY, vol. 12, no. 10, 20 September 2013 (2013-09-20), GB, pages 757 - 776, XP055253606, ISSN: 1474-1776, DOI: 10.1038/nrd4126 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112367970A (zh) * | 2018-04-12 | 2021-02-12 | J·大卫格莱斯顿研究所-根据J·大卫格莱斯顿遗嘱的遗嘱信托 | 用于治疗apoe4/4相关病症的方法 |
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