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Probenecid for Use in Treating Epileptic Diseases, Disorders Or Conditions

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Probenecid for Use in Treating Epileptic Diseases, Disorders Or Conditions (19) TZZ¥ _T (11) EP 3 427 729 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 16.01.2019 Bulletin 2019/03 A61K 31/195 (2006.01) A61P 25/08 (2006.01) (21) Application number: 17305934.6 (22) Date of filing: 13.07.2017 (84) Designated Contracting States: • INSERM (Institut National de la Santé AL AT BE BG CH CY CZ DE DK EE ES FI FR GB et de la Recherche Médicale) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 75654 Paris Cedex 13 (FR) PL PT RO RS SE SI SK SM TR Designated Extension States: (72) Inventors: BA ME • ROUACH, Nathalie Designated Validation States: 75003 PARIS (FR) MA MD • DOSSI, Eléna 92100 Boulogne-Billancourt (FR) (71) Applicants: • Paris Sciences et Lettres - Quartier Latin (74) Representative: Icosa 75006 Paris (FR) 83 avenue Denfert-Rochereau • CENTRE NATIONAL DE LA RECHERCHE 75014 Paris (FR) SCIENTIFIQUE 75016 Paris (FR) (54) PROBENECID FOR USE IN TREATING EPILEPTIC DISEASES, DISORDERS OR CONDITIONS (57) The present invention relates to probenecid or maceutical acceptable salt thereof inhibits compulsive a pharmaceutical acceptable salt thereof for use in the behaviorsor electrographicseizures in said subject. Pref- treatment of a neurological disorder in a subject in need erably, said neurological disorder is an epileptic disease, thereof, wherein administration of probenecid or a phar- disorder or condition. EP 3 427 729 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 427 729 A1 Description FIELD OF INVENTION 5 [0001] The present invention relates to the treatment of epileptic diseases, disorders or conditions in human subjects. In particular, the present invention relates to the use of probenecid or of a pharmaceutically acceptable salt thereof for treating an epileptic disease, disorder or condition. BACKGROUND OF INVENTION 10 [0002] Epilepsy comprises a group of neurological disorders characterized by the periodic occurrence of seizures, which compromise proper brain functioning. Despite being one of the most common neurologic illness, affecting approx- imately 1% of the population worldwide, no effective universal cure is currently available. [0003] Pharmacological therapies that are able to successfully control seizures are mainly based on three different 15 general strategies (Sarma et al., Neuropsychiatr Dis Treat. 2016; 12: 467-485): (1) the limitation of neuronal firing by blocking ion channels, such as voltage-gated Na +, K+ and Ca2+ channels, or NMDA and AMPA receptors, using drugs such as, for example, topiramate, lamotrigine, oxcarbazepine or pregabalin; (2) the enhancement of the activity of inhibitory synapses by GABA receptor activation or GABA reuptake inhibition, 20 using, for example, felbamate, vigabatrin or tiagabine; and (3) the control of neurotransmitter release, using neuromodulators such as, e.g., levetiracetam. [0004] However, current antiepileptic drugs (AEDs) present various and eventually severe side effects, due to their action on ubiquitously expressed channels and receptors, which are involved in many physiological processes (Sarma 25 et al., Neuropsychiatr Dis Treat. 2016; 12: 467-485). Indeed, it has been reported that currently available AEDs can cause aplastic anemia and hepatic failure ( e.g., felbamate), paresthesia, metabolic acidosis and glaucoma (topiramate), as well as somnolence, dizziness (e.g., tiagabine and pregabalin) and behavioral abnormalities (e.g., levetiracetam). [0005] Moreover, although 70% of epileptic patients are able to adequately control their symptoms with the currently available AEDs, the remaining 30% are unable to obtain seizure freedom, display intractable seizures using available 30 AEDs, and are, as such, termed as suffering from "treatment-resistant epilepsy". [0006] In this condition, whose mechanisms are still unclear, the surgical resection of the specific part of the brain identified as the seizure-onset zone remains the only alternative treatment giving a positive outcome to patients. [0007] Therefore, identifying alternative targets to develop novel antiepileptic therapies has become crucial. Advances have been achieved in terms of surgical procedures and management, routes of AED administration and electroen- 35 cephalography technology; however, managing epileptic patients still remains challenging due to the complex nature of the disease, AED side effects, drug interactions and medical and/or psychiatric comorbidities. Furthermore, specific patient categories, such as children, pregnant women, elderly, psychiatric and HIV/AIDS patients, are even more difficult to manage. [0008] Probenecid is a highly lipid soluble benzoic acid derivative with an excellent safety profile that was developed 40 in the 1950’s to decrease the renal tubular excretion of penicillin; and has been used to increase the serum concentration of several antibiotics and antivirals. During the initial studies using probenecid (referred to as Benemid), probenecid was observed to have a strong uricosuric effect and quickly became the standard of treatment of gout. It was found to decrease uric acid levels in the serum via inhibition of organic acid reabsorption, such as uric acid, by the renal proximal tube by acting as a competitive inhibitor of the organic anion transporters (OATs) and thus preventing OAT-mediated reuptake 45 of uric acid from the urine to the serum. Even though probenecid has a minimal adverse effect profile, its clinical use has declined significantly as other therapies for gout have shown improved efficacy. [0009] Surprisingly, the Inventors have demonstrated that probenecid was able to block epileptic seizures in epileptic cortical human tissues ex vivo, and in the kainate mouse models of temporal lobe epilepsy in vivo, paving the way for a novel, low-side-effect, antiepileptic therapy. 50 [0010] The present invention thus relates to the use of probenecid for treating an epileptic disease, disorder or condition in a subject. SUMMARY 55 [0011] The present invention relates to probenecid or a pharmaceutical acceptable salt thereof for use in the treatment of a neurological disorder in a subject in need thereof. [0012] In one embodiment, administration of probenecid or a pharmaceutical acceptable salt thereof inhibits compulsive behaviors or electrographic seizures in said subject. 2 EP 3 427 729 A1 [0013] In one embodiment, the neurological disorder is an epileptic disease, disorder or condition. [0014] In one embodiment, the epileptic disease, disorder or condition is selected from the group consisting of familial epilepsy, genetic epilepsy and structural/metabolic epilepsy. [0015] In one embodiment, the epileptic disease, disorder or condition is brain tumor-related epilepsy. 5 [0016] In another embodiment, the epileptic disease, disorder or condition is a malformation of cortical development (MCD)-related epilepsy. [0017] In another embodiment, the epileptic disease, disorder or condition is a neurodegenerative-related epilepsy. [0018] In one embodiment, said subject is suffering from a treatment-resistant epileptic disease, disorder or condition. [0019] In one embodiment, the subject is a child. In one embodiment, said subject is an adult. 10 [0020] In one embodiment, probenecid or the pharmaceutical acceptable salt thereof is to be administered to the subject at a dose ranging from about 1 mg/kg/day to about 100 mg/kg/day. [0021] In one embodiment, probenecid or the pharmaceutical acceptable salt thereof is to be administered orally or by injection. [0022] The present invention also relates to a pharmaceutical composition comprising probenecid or a pharmaceutical 15 acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, for use in the prevention or the treatment of an epileptic disease, disorder or condition in a subject in need thereof. [0023] The present invention further relates to a medicament comprising probenecid or a pharmaceutical acceptable salt thereof, for use in the prevention or the treatment of an epileptic disease, disorder or condition in a subject in need thereof. 20 DEFINITIONS [0024] In the present invention, the following terms have the following meanings: 25 "About" preceding a value means plus or less 10% of said value. [0025] As used herein, the term "consist essentially of probenecid or a pharmaceutically acceptable salt thereof", with reference to a composition, pharmaceutical composition or medicament, is intended to mean that probenecid or the pharmaceutically acceptable salt thereof is the only therapeutic agent, i.e., the only agent exhibiting a biologic activity, 30 within said composition, pharmaceutical composition or medicament. [0026] As used herein, the terms "epilepsy", "epileptic disease, disorder or condition" and "epileptic syndrome" are interchangeable and refer to a disease, disorder or condition characterized by the occurrence of epileptic seizures, preferably of spontaneous and/or recurrent seizures. [0027] As used herein, the terms "epileptic seizure" or "ictal event" refer to an episodic change in the behavior 35 caused by the disordered firing of populations of neurons of the central nervous system (CNS), resulting in varying degrees of any of involuntary muscle contraction, abnormal perceptions, abnormal behaviors, alteration of consciousness and/or loss of consciousness. [0028] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any 40 and all solvents, dispersion media, coatings,
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