Use of probenecid in treatment of epileptic diseases, disorders or conditions

Abstract

The present invention relates to probenecid or a pharmaceutically acceptable salt thereof for use in the treatment of neurological disorders in a subject in need thereof wherein administration of probenecid or a pharmaceutically acceptable salt thereof controls clinical or electrographic seizures in said subject. Preferably, the neurological disorder is an epileptic disease, disorder or condition.

Description

[0001] This application is a divisional application of application filed on July 13, 2018, application number 2018800597983, and invention name “Use of probenecid in the treatment of epileptic diseases, disorders or conditions”. Technical Field

[0002] 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 a pharmaceutically acceptable salt thereof in the treatment of epileptic diseases, disorders or conditions. Background Art

[0003] Epilepsy comprises a group of neurological disorders characterized by periodic seizures that impair normal brain function. Despite being one of the most common neurological disorders, affecting approximately 1% of the world's population, there is currently no effective universal treatment, and up to 30% of patients are uncontrolled by current medications.

[0004] Successful pharmacological treatments for epileptic seizures are based on three different general strategies (Sarma et al., Neuropsychiatr Dis Treat. 2016; 12:467-485):

[0005] (1) Use of drugs such as topiramate, lamotrigine, oxcarbazepine, or pregabalin to block ion channels (e.g., voltage-gated Na + , K + and Ca 2+ channels, or NMDA and AMPA glutamate receptors) limit neuronal firing;

[0006] (2) enhancing the activity of inhibitory synapses through GABA receptor activation or GABA reuptake inhibition by using, for example, carbamates, vegabatide, or tegabine; and

[0007] (3) Use neuromodulators such as levetiracetam to control the release of neurotransmitters.

[0008] However, because current antiepileptic drugs (AEDs) act on ubiquitously expressed channels and receptors, involving many physiological processes (Sarma et al., Neuropsychiatr Dis Treat. 2016; 12: 467-485), they have various side effects, which are ultimately severe. Indeed, currently available AEDs have been reported to cause aplastic anemia and liver failure (e.g., nalidixic acid), paresthesias, metabolic acidosis, and glaucoma (topiramate), as well as drowsiness, dizziness (e.g., tegababin and pregabalin), and behavioral and / or psychiatric abnormalities (e.g., levetiracetam or pyranopheniramine).

[0009] Furthermore, although 70% of epilepsy patients are able to adequately control their symptoms (especially seizures) using currently available AEDs, the remaining 30% are unable to escape seizures and exhibit refractory seizures with available AEDs, and are therefore referred to as having "treatment-resistant epilepsy."

[0010] In this case, the mechanisms remain unclear and surgical resection of a specific part of the brain identified as the epileptogenic zone remains the only alternative treatment with positive outcomes for patients.

[0011] Therefore, identifying alternative targets for the development of new antiepileptic therapies has become crucial. Despite advances in surgical procedures and management, routes of AED administration, and electroencephalography technology, treating patients with epilepsy remains challenging due to the complexity of the disease, AED side effects, drug interactions, mortality risk, and medical and / or psychiatric comorbidities. In addition, there are specific patient categories that are more difficult to manage, such as children, pregnant women, the elderly, patients with psychiatric disorders, and patients with HIV / AIDS.

[0012] Probenecid is a highly lipid-soluble benzoic acid derivative with an excellent safety profile. It was developed in the 1950s to reduce the renal tubular excretion of penicillin and has been used to increase the serum concentrations of several antibiotics and antivirals. In the initial studies using probenecid (known as Benemid), it was observed that probenecid had a strong uricosuric effect and quickly became the standard of care for gout. It has been found that by acting as a competitive inhibitor of the organic anion transporter (OAT), inhibiting the reabsorption of organic acids, such as uric acid, through the renal proximal tubule, it can reduce uric acid levels in the serum, thereby preventing OAT-mediated reuptake of uric acid from urine to serum. Although probenecid has minimal adverse effects, its clinical use has declined significantly as other therapies for gout have shown improved efficacy.

[0013] Unexpectedly, the inventors have demonstrated that probenecid can block seizures in human tissue from the epileptic cortex in vitro and in vivo in the Kevant mouse model of temporal lobe epilepsy, paving the way for the search for novel, low-side-effect anti-epileptic therapies.

[0014] Accordingly, the present invention relates to the use of probenecid in treating an epileptic disease, disorder or condition in a subject. SUMMARY OF THE INVENTION

[0015] The present invention relates to probenecid or a pharmaceutically acceptable salt thereof for use in treating a neurological disorder in a subject in need thereof.

[0016] In one embodiment, administration of probenecid or a pharmaceutically acceptable salt thereof inhibits electrographic seizures in a subject.

[0017] In one embodiment, administration of probenecid or a pharmaceutically acceptable salt thereof inhibits compulsive behavior in the subject.

[0018] In one embodiment, administration of probenecid or a pharmaceutically acceptable salt thereof controls clinical seizures or electrographic epileptic seizures in the subject.

[0019] In one embodiment, the neurological disorder is an epileptic disease, disorder or condition.

[0020] In one embodiment, the epileptic disease, disorder or condition is selected from familial epilepsy, genetic epilepsy, structural / metabolic epilepsy, and epilepsy of no known cause.

[0021] In one embodiment, the epileptic disease, disorder or condition is brain tumor-related epilepsy.

[0022] In another embodiment, the epileptic disease, disorder or condition is malformation of cortical development (MCD)-related epilepsy.

[0023] In another embodiment, the epileptic disease, disorder or condition is neurodegeneration-related epilepsy.

[0024] In another embodiment, the epileptic disease, disorder or condition is immune-disordered epilepsy.

[0025] In another embodiment, the epileptic disease, disorder or condition is glioma-associated epilepsy.

[0026] In one embodiment, the subject is a treatment-resistant epileptic disease, disorder, or condition.

[0027] In one embodiment, the subject is a child. In one embodiment, the subject is an adult.

[0028] In one embodiment, probenecid or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 1 mg / kg / day to about 100 mg / kg / day.

[0029] In one embodiment, probenecid or a pharmaceutically acceptable salt thereof is administered orally or by injection.

[0030] The present invention also relates to a pharmaceutical composition comprising probenecid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent for use in preventing or treating an epileptic disease, disorder or condition in a subject in need thereof.

[0031] The present invention also relates to a medicament comprising probenecid or a pharmaceutically acceptable salt thereof for use in preventing or treating an epileptic disease, disorder or condition in a subject in need thereof.

[0032] definition

[0033] In the present invention, the following terms have the following meanings:

[0034] "About" preceding a numerical value means plus or less than 10% of the stated value.

[0035] As used herein, with respect to a composition, pharmaceutical composition or medicament, the term "consisting essentially of probenecid or a pharmaceutically acceptable salt thereof" means that probenecid or a pharmaceutically acceptable salt thereof is the only therapeutic agent, i.e., the only agent that exhibits biological activity in the composition, pharmaceutical composition or medicament.

[0036] As used herein, the terms "epilepsy," "epileptic disease, disorder or condition," and "epileptic syndrome" are used interchangeably and refer to a disease, disorder or condition characterized by the occurrence of epileptic seizures, preferably spontaneous and / or recurrent seizures.

[0037] As used herein, the term "epileptic seizure" or "fit" refers to paroxysmal changes in behavior, sensation, or consciousness caused by the disordered firing of neurons in the central nervous system (CNS), resulting in varying degrees of involuntary muscle contractions, abnormal sensations, abnormal behavior, altered consciousness, and / or loss of consciousness.

[0038] 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. This includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. For human administration, the formulation should meet sterility, apyrogenicity, general safety, and purity standards as required by regulatory agencies such as the FDA or EMA.

[0039] As used herein, the term "pharmaceutically acceptable salt" is intended to include salts of probenecid prepared with relatively nontoxic acids or bases. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., J Pharm Sci. 1977 Jan; 66(1): 1-19).

[0040] Non-limiting examples of probenecid salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). Other examples of probenecid salt include but are not limited to probenecid sodium, probenecid potassium, probenecid magnesium, probenecid bismuth, probenecid tetrahydrate, probenecid cerium trihydrate, probenecid erbium trihydrate, probenecid europium trihydrate, probenecid holmium, probenecid lanthanum trihydrate, probenecid hexahydrate, probenecid samarium trihydrate, probenecid terbium trihydrate, probenecid thallium trihydrate, probenecid thulium trihydrate, probenecid yttrium hexahydrate and probenecid styrene.Preferably, probenecid salt is selected from probenecid sodium, probenecid potassium and probenecid magnesium.These salts can be prepared by methods well known to those skilled in the art.

[0041] As used herein, the term "probenecid" refers to a compound having formula (I):

[0042]

[0043] Probenecid includes the free base probenecid (sometimes also referred to as 4-(dipropylsulfamoyl)benzoic acid, 4-[(dipropylamino)sulfonyl]-benzoic acid or PBN), and its pharmaceutically acceptable salts (4-(dipropylsulfamoyl)benzoate or 4-[(dipropylamino)sulfonyl]-benzoate). Also included are prodrugs, isomers and polymorphs of probenecid. Probenecid can exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Probenecid can exist in polycrystalline or amorphous forms. Generally, all physical forms are equivalent for the purposes of the present invention and are within the scope of the present invention.

[0044] As used herein, the term "prodrug" refers to a probenecid analog that readily undergoes chemical changes under physiological conditions to provide active probenecid. Prodrugs of probenecid can be converted in vivo after administration. Additionally, prodrugs of probenecid can be converted into active probenecid by chemical or biochemical methods in an in vitro environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0045] As used herein, the term "subject" refers to an animal, preferably a warm-blooded animal, more preferably a mammal, even more preferably a person. In one embodiment, the subject can be a mammal. Mammals include but are not limited to all primates (human and non-human), cattle (including cows), horses, pigs, sheep, goats, dogs and cats. In one embodiment, the subject is a person. In one embodiment, the subject is a patient, that is, waiting to receive or receiving medical care or has been / is / will become the object of a medical procedure, or is monitored for the development of an epileptic disease, disease or condition. In one embodiment, the subject is an adult (e.g., a subject older than 18 years of age). In another embodiment, the subject is a child (e.g., a subject younger than 18 years of age). In one embodiment, the subject is a male. In another embodiment, the subject is a female.

[0046] As used herein, a "substantially healthy subject" refers to a subject that has not been previously diagnosed or identified as having or suffering from an epileptic disease, disorder, or condition. In one embodiment, a substantially healthy subject does not exhibit an episode of an epileptic disease, disorder, or condition, i.e., the subject has not acquired, developed, or experienced a first epileptic seizure.

[0047] As used herein, the term "treat" or "alleviate" refers to therapeutic treatment and prophylactic or preventative measures; wherein the purpose is to prevent or slow down (mitigate) the target pathological condition or disorder, such as an epileptic disease, disorder or condition. Those subjects in need of treatment include those who already have a disease, disorder or condition and those who are prone to having a disease, disorder or condition, or those in which the disease, disorder or condition is to be prevented. If, after receiving a therapeutic amount of probenecid according to the present invention, the subject shows an observable and / or measurable reduction in one or more of the following diseases, disorders or conditions: epileptic seizures, particularly clinical epileptic seizures (which may be completely absent); or reduced morbidity and mortality; or improved quality of life issues, the subject is successfully "treated" for a particular disease, disorder or condition, such as an epileptic disease, disorder or condition. The above-mentioned parameters for assessing successful treatment and improvement of a disease, disorder or condition can be easily measured by routine procedures familiar to physicians.

[0048] As used herein, the term "therapeutically effective amount" refers to a level or amount of an agent that does not cause significant negative or adverse side effects on the target and achieves the following goals: (1) delaying or preventing the onset of the target disease, disorder, or condition; (2) slowing or stopping the progression, aggravation, or worsening of one or more symptoms of the target disease, disorder, or condition; (3) ameliorating the symptoms of the target disease, disorder, or condition; (4) reducing the severity or incidence of the target disease, disorder, or condition; or (5) curing the target disease, disorder, or condition. A therapeutically effective amount can be administered before the onset of the target disease, disorder, or condition for a prophylactic or preventive effect. Alternatively, or in addition, a therapeutically effective amount can be administered after the onset of the target disease, disorder, or condition to achieve a therapeutic effect. Detailed Description of the Invention

[0049] The present invention relates to probenecid or a pharmaceutically acceptable salt thereof for use in treating a neurological disorder in a subject in need thereof. In one embodiment, the neurological disorder is associated with clinical seizures or electrographic epileptic seizures, and the administration of probenecid or a salt thereof controls the clinical seizures or electrographic epileptic seizures of the subject. In one embodiment, the neurological disorder is associated with electrographic epileptic seizures, and the administration of probenecid or a salt thereof inhibits the electrographic epileptic seizures of the subject. In one embodiment, the neurological disorder is associated with compulsive behavior, and the administration of probenecid or a salt thereof inhibits the compulsive behavior of the subject. In a preferred embodiment, the present invention relates to probenecid or a pharmaceutically acceptable salt thereof for use in treating an epileptic disease, disorder or condition.

[0050] In one embodiment, probenecid or a pharmaceutically acceptable salt thereof is used to prevent a neurological disorder, preferably an epileptic disease, disorder, or condition. In one embodiment, probenecid or a pharmaceutically acceptable salt thereof is used to prevent electrographic epileptic seizures in the subject. In one embodiment, probenecid or a pharmaceutically acceptable salt thereof is used to prevent compulsive behavior in the subject. In one embodiment, probenecid or a pharmaceutically acceptable salt thereof is used to prevent clinical seizures or electrographic epileptic seizures in the subject.

[0051] In one embodiment, probenecid or a pharmaceutically acceptable salt thereof is used to cure a neurological disorder, preferably an epileptic disease, disorder or condition.

[0052] Epilepsy, as understood within the scope of the present invention, is a brain disorder which is classified in the group "paroxysmal and seizure disorders" according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10), with codes G40 and G41.

[0053] In one embodiment, the epilepsy is associated with electrographic seizures.In one embodiment, probenecid or a pharmaceutically acceptable salt thereof can inhibit electrographic seizures in a subject suffering from an epileptic disease, disorder, or condition.

[0054] In one embodiment, epilepsy is associated with compulsive behavior.In one embodiment, probenecid or a pharmaceutically acceptable salt thereof can inhibit compulsive behavior in a subject suffering from an epileptic disease, disorder, or condition.

[0055] In one embodiment, the epilepsy is associated with clinical seizures and / or electrographic seizures.In one embodiment, probenecid or a pharmaceutically acceptable salt thereof can control clinical seizures or electrographic seizures in a subject suffering from an epileptic disease, disorder or condition.

[0056] The ILAE (International League Against Epilepsy) has published a revised classification of epileptic diseases, disorders or conditions in 2010 (Berg et al., Epilepsia. 2010 Apr; 51(4): 676-85, which is incorporated herein by reference). According to the classification, epileptic diseases, disorders or conditions can be classified according to seizure type, etiology, age of onset, cognitive and developmental precursors and consequences, motor and sensory examinations, EEG characteristics, stimuli or triggers and / or seizure occurrence patterns with respect to sleep.

[0057] Seizure types include, but are not limited to, generalized seizures, focal seizures (or partial seizures), seizures with unknown onset, generalized status epilepticus, and focal status epilepticus.

[0058] In one embodiment, the subject is diagnosed as having or being at risk for developing an epileptic disease, disorder, or condition with generalized epileptic seizures. Examples of generalized seizures include, but are not limited to, tonic-clonic seizures (including variations that begin with a clonic or myoclonic phase), clonic seizures (with and without tonic features), typical absence seizures, atypical absence seizures, myoclonic absence seizures, tonic seizures, spasms, myoclonic seizures, massive bilateral myoclonus, eyelid myoclonus (with and without absence), myoclonic atonic seizures, negative myoclonus and atonic seizures.

[0059] In one embodiment, the subject is diagnosed with or is at risk of developing an epileptic disease, disorder, or condition with focal seizures. Examples of focal seizures include, but are not limited to, focal sensory seizures, focal motor seizures, gelastic seizures, hemiclonic seizures, and secondarily generalized seizures.

[0060] In one embodiment, the subject is diagnosed with or is at risk for developing an epileptic disease, disorder, or condition with focal sensory seizures. Examples of focal sensory seizures include, but are not limited to, focal sensory seizures with primary sensory symptoms (e.g., occipital lobe seizures, parietal lobe seizures), focal sensory seizures with experiential sensory symptoms (e.g., temporo-parieto-occipital junction seizures).

[0061] In one embodiment, the subject is diagnosed as suffering from or at risk of developing an epileptic disease, disorder or condition with focal motor seizures. Examples of focal motor seizures include, but are not limited to, focal motor seizures with basic clonic motor signs, focal motor seizures with asymmetric tonic motor seizures (e.g., supplementary motor seizures), focal motor seizures with typical (temporal lobe) automation (e.g., mesial temporal lobe seizures), focal motor seizures with hyperkinetic attacks, focal motor seizures with focal negative myoclonus and focal motor seizures with inhibitory motor seizures.

[0062] In one embodiment, the subject is diagnosed as having or being at risk for developing an epileptic disease, disorder, or condition with generalized status epilepticus. Examples of generalized status epilepticus include, but are not limited to, generalized tonic-clonic status epilepticus, clonic status epilepticus, absence status epilepticus, tonic status epilepticus, and myoclonic status epilepticus.

[0063] In one embodiment, the subject is diagnosed as having or being at risk for developing an epileptic disease, disorder, or condition having focal status epilepticus. Examples of focal status epilepticus include, but are not limited to, Kojenvikov's partial status epilepticus, aura continua, limbic status epilepticus (psychomotor status), and hemiconvulsive status.

[0064] Epileptic diseases, disorders or conditions can also be classified according to their etiology, i.e., their underlying cause. Etiologies of epileptic diseases, disorders or conditions include, but are not limited to, familial epilepsy, genetic epilepsy, structural / metabolic epilepsy, and epilepsy of unknown cause.

[0065] In one embodiment, the subject has a family history of an epileptic disease, disorder, or condition. In another embodiment, the subject does not have any family history of an epileptic disease, disorder, or condition.

[0066] In one embodiment, epileptic disease, disorder or condition is familial focal epilepsy, which can be damaging or non-damaging. Examples of familial focal epilepsy include, but are not limited to, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), familial temporal lobe epilepsy (FTLE), familial mesial temporal lobe epilepsy (FMTLE), familial lateral temporal lobe epilepsy (FLTLE), familial variable focus partial epilepsy (FPEVF), Rolandic epilepsy and benign familial partial epilepsy of childhood. Preferably, epileptic disease, disorder or condition is selected from autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), familial temporal lobe epilepsy (FTLE) and familial focal epilepsy with variable focus (FFEVF).

[0067] In one embodiment, the subject has a genetic environment and / or at least one member of his or her family (i.e., a relative, such as a parent [mother or father], sibling [sister or brother], child [daughter or son], grandparent [grandmother or grandfather], cousin, niece, nephew, aunt, uncle, etc.) that has a genetic environment that predisposes to the development of an epileptic disease, disorder or condition.

[0068] In one embodiment, the subject and / or at least one member of their family is diagnosed as having at least one genetic mutation in at least one allele of at least one gene known or not yet known to be involved in epileptic seizures. Examples of genetic circumstances that predispose to the development of an epileptic disease, disorder, or condition include, but are not limited to, genetic mutations in at least one allele of any one of the following genes: CHRNA4, CHRNA2, CHRNB2, SCN1A, LGI1, KCNT1, ABAT, ABCB1, ADSL, ALDH7A1, ARFGEF2, ARHGEF9, ARX, ASPM, ATP1A2, ATP6AP2, ATR, BRD2, CACNA1A, CACNA1H, CACNB4, CASK, CASR, CCL2, CDK5RAP2, CDK L5, CDON, CENPJ, CEP152, CLCN2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DCX, EFHC1, EFHC2, EMX2, EPM2A, FLNA, FLVCR2, FOLR 1. FOXG1, FOXH1, GABRA1, GABRB3, GABRD, GABRG2, GAMT, GATM, GLI2, GPR56, GRIN1, GRIN2A, HCN1, HCN3, HCN4, KCNA1, KCNAB1, KCNJ10 , KCNJ11, KCNMA1, KCNQ2, KCNQ3, KCNV2, LIS1, MAGI2, MBD5, MCPH1, ME2, MECP2, MEF2C, MFSD8, MTHFR, NDE1, NDUFA1, NHLRC1, NODAL, NRXN1, 5OPHN1, OPRM1, PAFAH1B1, PAFAH1BA, PCDH19, PCNT, PHF6, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRICKLE2, PRRT2, PTCH 1. RELN, SCN10A, SCN11A, SCN1B, SCN2B, SCN3A, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, SCN8A, SCN9A, SHH, SIX3, SLC25A19, SLC25A22, SLC2A1, SLC9A6, SPTAN1, SRPX2, STIL, STXBP1, SYN1, TCF4, TGIF1, TPP1, TSEN2, TSEN34, TSEN54, UBE3A, VANGL1, WDR62, ZEB2, and ZIC2.

[0069] In one embodiment, the epileptic disease, disorder, or condition is structural or metabolic epilepsy. In one embodiment, the structural or metabolic epilepsy is a neurological-related epilepsy. In one embodiment, the structural or metabolic epilepsy is a neurodegeneration-related epilepsy. In one embodiment, the structural or metabolic epilepsy is an injury-related epilepsy.

[0070] In one embodiment, the epileptic disease, disorder or patient's condition is caused by neurological disease and / or damage. The example of the neurological disease or damage causing epileptic disease, disorder or patient's condition includes but is not limited to brain tumor, cortical development malformation (MCD), head or brain trauma, encephalitis (encephalitis), encephalitis (cerebritis), abscess, stroke, tuberous sclerosis, mesial temporal sclerosis, brain dysplasia, hypoxic-ischemic encephalopathy, drinking, using drugs and / or chemicals, quitting drinking and quitting drugs and / or chemicals. In one embodiment, the neurological disease or damage causing epileptic disease, disorder or patient's condition is selected from brain tumor, cortical development malformation (MCD), head or brain trauma, encephalitis (encephalitis), encephalitis (cerebritis), abscess, stroke, tuberous sclerosis, mesial temporal sclerosis, brain dysplasia, hypoxic-ischemic encephalopathy, immune disorder, drinking, using drugs and / or chemicals, quitting drinking and quitting drugs and / or chemicals.

[0071] In one embodiment, the subject is diagnosed with or is at risk of developing brain tumor related epilepsy (BTRE). BTRE includes, but is not limited to, glioma related epilepsy (including glioblastoma, glioblastoma multiforme, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, mixed astrocytoma I and II WHO, oligodendroglioma, anaplastic oligodendroglioma, ependymoma and anaplastic ependymoma), craniopharyngioma related epilepsy, epidermoid cell related epilepsy, lymphoma related epilepsy, meningioma related epilepsy, schwannoma related epilepsy, pituitary adenoma related epilepsy, pinealoma related epilepsy (including pineocytoma and pinealoblastoma) and medulloblastoma related epilepsy.

[0072] In one embodiment, the subject is diagnosed as suffering from or at risk for developing cortical malformation (MCD)-related epilepsy.MCD-related epilepsy includes but is not limited to dysembryoplastic neuroepithelial tumor (DNET)-related epilepsy, cortical malformation-related epilepsy, focal cortical malformation (FCD)-related epilepsy (including 1a, 1b, 2a, 2b, 3a, 3b and 3c types of FCD), microcephaly-related epilepsy, hemimerical epilepsy, megalencephaly-related epilepsy, periventricular heterotopia-related epilepsy, typical lissencephaly-related epilepsy, subcortical heterotopia-related epilepsy and lissencephaly-related epilepsy.

[0073] In one embodiment, the subject is diagnosed as suffering from or at risk of developing a neurodegeneration-related epilepsy. Examples of neurodegeneration-related epilepsy include, but are not limited to, Alzheimer's-related epilepsy, Parkinson's-related epilepsy, and autism-related epilepsy.

[0074] Epileptic diseases, disorders or conditions can be further classified according to the age of the subject at onset, i.e., the age at which the subject acquires, develops or first experiences an epileptic seizure. Epileptic diseases, disorders or conditions can thus be classified as congenital, infantile, juvenile or adult.

[0075] In one embodiment, the epileptic disease, disorder or condition to be treated is infantile or juvenile epilepsy.Infantile and juvenile epilepsy refers to an epileptic disease, disorder or condition as defined above that may occur in childhood (and which may or may not persist in adulthood). Examples of these include, but are not limited to, benign familial neonatal epilepsy (BFNE), benign neonatal seizures (BNS) (including benign familial neonatal seizures), benign familial neonatal convulsions (BFNC), myoclonic epilepsy of infancy (MEI), early myoclonic encephalopathy (EME), epilepsy of infancy with migrating focal seizures, benign childhood epilepsy, benign familial and nonfamilial infantile seizures, febrile seizures, infantile spasms, O'Hara syndrome, juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy (e.g., dense epilepsy), early-onset benign childhood occipital epilepsy (Pantiopouloss type), late-onset childhood occipital epilepsy (Gastaut type), benign epilepsy with temporal spikes (BECTS), myoclonic absence epilepsy, generalized epilepsy of unknown origin, CDKL5 mutations, bilateral polymicrogyria, Dup15q syndrome, SNAP25 mutations, febrile infection-associated epilepsy (FIRES), benign rolandic epilepsy infantile spasms (BENIGN ROLANDIAN TYPE). epilepsy infantile spasm, West syndrome), Landau-Kleffner syndrome, Dravet syndrome, Lennox-Gastaut syndrome, Aicardi syndrome, and idiopathic generalized epilepsy with variable phenotype (juvenile absence epilepsy, juvenile myoclonic epilepsy).

[0076] In one embodiment, epileptic disease to be treated, disease or the patient's condition are adult epilepsy.Adult epilepsy refers to epileptic disease as defined above, disease or the patient's condition that occurs after childhood (and continues or does not continue throughout adulthood).These examples include but are not limited to tonic-clonic, clonic (with or without tonic features), absence (typical or atypical), myoclonic absence, tonic, myoclonic, a large amount of bilateral myoclonus, negative myoclonus, eyelid myoclonus (with or without absence epilepsy), focal epilepsy, familial and sporadic epilepsy, pathological and non-pathological epilepsy, myoclonus-atonic, atonic (atonic), reflex, focal sensory (with basic sensory symptoms, such as occipital and parietal epilepsy, or empirical sensory symptoms, such as temporoparietal occipital connection epilepsy, etc.), focal motor (with basic clonic motor signs , with asymmetric tonic motor signs or seizures, such as supplementary motor seizures, with typical automaticity, also called temporal lobe automaticity, such as mesial temporal lobe epilepsy, with hyperkinetic myoclonus, with focal negative myoclonus, myoclonic atonic seizures, etc.), inhibitory movements, gelastic seizures with hypothalamic hamartoma, hemiclonic, secondary generalized reflex seizures in focal epilepsy syndromes, generalized seizures plus (GEFS+) with febrile seizures, febrile seizures plus (FS+), generalized tonic-clonic status epilepticus, clonic status epilepticus, absence epilepticus status epilepticus, tonic status epilepticus, myoclonic status epilepticus, partial status epilepticus, auracontinua, limbic status epilepticus, hemiconvulsive status epilepticus, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), autosomal dominant epilepsy with auditory features, Panayiopoulos syndrome, Ohtahara syndrome, West syndrome, Dravet syndrome, HH syndrome; Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, neurocutaneous syndrome (syndrome The following are some of the following: progressive myoclonic epilepsy, myoclonic absence epilepsy, myoclonic-astatic seizure epilepsy, continuous spike-wave epilepsy during slow-wave sleep (CSWS other than LKS), idiopathic photosensitive occipital epilepsy, visually sensitive epilepsy, primary reading epilepsy, panic epilepsy, limbic epilepsy, mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS), mesial temporal lobe epilepsy defined by a specific etiology, other types defined by location and etiology, neocortical epilepsy, single or isolated multiple seizures, and rare repetitive seizures (oligo-epilepsy).

[0077] In one embodiment, at least one of the subject and / or their family members has been diagnosed with an epileptic disease, disorder or condition. In one embodiment, the subject is at risk of developing an epileptic disease, disorder or condition.

[0078] In one embodiment of the invention, the onset of an epileptic disease, disorder, or condition is diagnosed in at least one of the subject and / or its family members. In another embodiment, the onset of an epileptic disease, disorder, or condition is not diagnosed in at least one of the subject and / or its family members.

[0079] Methods for diagnosing an epileptic disease, disorder or condition in a subject, such as clinical trials, are well known to those skilled in the art and include, but are not limited to, electroencephalography (EEG), video-EEG of epileptic seizures, neuroimaging methods (e.g., computed tomography (CT) scans, magnetic resonance imaging (MRI), functional MRI, positron emission tomography (PET), and single photon emission computed tomography (SPECT)), sleep studies, blood tests, neuropsychological tests, molecular assays (e.g., genetic tests), and the like.

[0080] In one embodiment, the subject is a mammal, preferably the subject is a human.

[0081] In one embodiment, the subject is a child (under 18 years of age). In one embodiment, the subject is an adult (over 18 years of age).

[0082] In one embodiment, the subject is substantially healthy. In one embodiment, the subject is diagnosed as having an epileptic disease, disorder or condition or is at risk of developing an epileptic disease, disorder or condition. In one embodiment, the subject is diagnosed with epilepsy, i.e., the subject suffers from epileptic seizures. In one embodiment, an epileptic patient is defined as a patient who has had at least one, preferably at least two or more, epileptic seizures separated by less than at least 1, 2, 3, 4, 5 or more years.

[0083] In one embodiment, the onset of an epileptic disease, disorder, or condition is diagnosed in the subject. In another embodiment, the onset of an epileptic disease, disorder, or condition is not diagnosed in the subject.

[0084] In one embodiment where the subject is a child, the subject is diagnosed as suffering from infantile and juvenile epilepsy or is at risk of developing infantile and juvenile epilepsy. In one embodiment where the subject is an adult, the subject is diagnosed as suffering from adult epilepsy or is at risk of developing adult epilepsy. In one embodiment where the subject is an adult, the subject is diagnosed as suffering from infantile and juvenile epilepsy that continues throughout adulthood.

[0085] In one embodiment, the subject has not been previously treated with another treatment for the epileptic disease, disorder, or condition (ie, the method of the invention is a first-line treatment).

[0086] In another embodiment, the subject has been previously treated with at least one, two or more other epileptic diseases, disorders or conditions (i.e., the methods of the invention are second, third or more lines of treatment). In one embodiment, the subject has been previously treated with one or more other treatments for an epileptic disease, disorder or condition but has been unresponsive or inadequately responsive to these treatments, i.e., the treatment has induced no or low therapeutic benefit to the subject. In one embodiment, the subject is diagnosed as having treatment-resistant epilepsy (which may also be referred to as drug-resistant epilepsy).

[0087] In one embodiment, the subject is diagnosed with a brain tumor, including but not limited to gliomas (including glioblastomas, glioblastoma multiforme, astrocytomas, pilocytic astrocytomas, diffuse astrocytomas, anaplastic astrocytomas, mixed I and II WHO astrocytomas, oligodendrogliomas, anaplastic oligodendrogliomas, ependymomas, and anaplastic ependymomas), craniopharyngiomas, epidermoid tumors, lymphomas, meningiomas, schwannomas, pituitary adenomas, pineal tumors (including pineocytoma and pineoblastoma), and medulloblastoma. In one embodiment, the brain tumor is a stage 0 tumor, a stage I tumor (also referred to as an early stage tumor), a stage II tumor, a stage III tumor, or a stage IV tumor (also referred to as an advanced or metastatic tumor).

[0088] In another embodiment, the subject is at risk of developing a brain tumor.Examples of risk factors for developing a brain tumor include, but are not limited to, family history of cancer, genetic susceptibility, and exposure to carcinogens.

[0089] In one embodiment, the subject is diagnosed with or is at risk for developing a malformation of cortical development (MCD). In one embodiment, the subject is diagnosed with or is at risk for developing an MCD-related epilepsy. In one embodiment, the subject is diagnosed with or is at risk for developing a dysembryoplastic neuroepithelial tumor (DNET).

[0090] In one embodiment, the subject is immunosuppressed, i.e., exhibits a compromised immune system. In a specific embodiment, the subject's immune system has an impaired ability to fight a brain tumor.

[0091] In one embodiment, the subject suffers from a neurological immune disorder, with or without known antibodies targeting neural components (eg, NMDA, GABA, GAD...), variably associated with seizures, neurological and psychiatric symptoms.

[0092] The present invention also relates to a composition comprising, consisting of, or consisting essentially of probenecid or a pharmaceutically acceptable salt thereof for treating an epileptic disease, disorder, or condition in a subject in need thereof. In one embodiment, the present invention thus relates to probenecid alone for use in treating an epileptic disease, disorder, or condition in a subject in need thereof.

[0093] In one embodiment, the composition of the present invention does not include excitatory amino acid antagonists or excitatory amino acid receptor antagonists. Examples of excitatory amino acid antagonists or excitatory amino acid receptor antagonists include, but are not limited to, AMPA antagonists, strychnine-insensitive glycine antagonists, or competitive NMDA antagonists. Another example of an excitatory amino acid antagonist or excitatory amino acid receptor antagonist is an anti-glutamatergic drug. In particular, examples of excitatory amino acid antagonists or excitatory amino acid receptor antagonists include, but are not limited to, (2R)-amino-5-phosphonopentanoic acid (AP5), barbiturates, dextromethorphan (DXM), dextrorphan, dezocine, ethanol, ibogaine, ifenprodil, ketamine, memantine, trimethoprim (MXE), nitrous oxide (NO), piperamide, phencyclidine (PCP), quinoxalinedione, quinoxaline acid derivatives, indole derivatives, kynurenine derivatives, pyrrolidone derivatives, D-cycloserine, prodrugs thereof, mixtures thereof, and isatin derivatives. Other examples of excitatory amino acid antagonists or excitatory amino acid receptor antagonists include, but are not limited to, topiramate and felbamate.

[0094] In one embodiment, the composition of the present invention does not include an excitatory amino acid receptor antagonist selected from the group consisting of: (2R)-amino-5-phosphonopentanoic acid (AP5), barbiturates, dextromethorphan (DXM), dextrorphan, dezocine, ethanol, ibogaine, ifenprodil, ketamine, memantine, trimethoprim (MXE), nitrous oxide (NO), perampanel, phencyclidine (PCP), quinoxalinedione, quinoxaline acid derivatives, indole derivatives, kynurenine derivatives, pyrrolidone derivatives, D-cycloserine, prodrugs thereof and mixtures thereof, isatin derivatives, 4-bromo-6-fluorotryptophan, 4-bromo-6-chlorotryptophan, 4-ethyl-6-bromotryptophan, 4,6-dibromotryptophan, 4,6-dichlorotryptophan, 6-chloro-tryptophan, 6-fluorotryptophan, tetrazole derivatives, piperazine derivatives.

[0095] In one embodiment, the compositions of the invention do not comprise an NMDA antagonist.

[0096] Examples of NMDA antagonists are described in, for example, GB2104078, EP420806, EP391850, US4906621, US4898854, EP302826, US4746653, EP275820, US4705781, US4968678, US4902687, US902695, EP418863, US4761405, US4657899, GB2157685, GB2198134, GB2201676, GB2156818, US4918064, EP364996 or EP342558, which are incorporated herein by reference.

[0097] Examples of NMDA receptor antagonists include, but are not limited to, APV, R-2-amino-5-phosphonopentanoate, methyl-5-phosphono-3-pentenoate and salts thereof, (-)-D-aminophosphonoheptanoic acid and salts thereof, such as (-)-2-amino-7-phosphonoheptanoic acid (1,5-dibromopentane), 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or salts thereof, 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or salts thereof, 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid or salts thereof, 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid or salts thereof, 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or salts thereof, 2-amino- 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester or its salt, 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid or its salt, 2-amino-6-benzoyloxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or its salt, 2-amino-7-hydroxy-4-phosphonomethylhept-3-enoic acid ethyl ester or its salt, 2-amino-7-hydroxy-4-phosphonomethylhept-3-enoic acid or its salt, 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid or its salt, 6-(N-acetyl-N-methyl-amino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester or its salt, (1-acetylpiperidin-4-yl)-2-amino-5-phosphono-pent-3-enoic acid ethyl ester or its salt. Ester or its salt, 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester or its salt, 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid or its salt, 2-amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or its salt, 2-amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid or its salt, 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or its salt, 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid or its salt, 2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester or its salt, 2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid or its salt, 2-amino-6-(N- 2-amino-6-(N-methylamino)-4-phosphonomethyl-hex-3-enoic acid or its salt, 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or its salt, 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or its salt, 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or its salt, 2-amino-4-(piperidin-4-yl)-5-phosphonopent-3-enoic acid or its salt, 2-amino-4-(piperidin-4-yl)-5-phosphonopent-3-enoic acid or its salt, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid or its salt, their salts, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid or its salt,2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester or its salt, 2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester or its salt, 2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester or its salt, cis-4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid ethyl ester or its salt, trans-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid or its salt, trans-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid or its salt, cis-4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid or its salt, phosphonopropyl)-2-piperidinecarboxylic acid or a salt thereof, cis-4-phosphonomethyl-2-piperidinecarboxylic acid or a salt thereof, cis-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid or a salt thereof, cis-4-phosphonomethyl-2-piperidinecarboxylic acid ethyl ester or a salt thereof, 4-[1-(3-phosphonopropyl)-1-enyl)piperidine-2-carboxylic acid or a salt thereof, cis-5-methyl-4-phosphonomethyl-2-piperidinecarboxylic acid or a salt thereof, -)-cis-4-phosphonomethyl-2-piperidinecarboxylic acid or a salt thereof, cis-4-phosphonomethyl-2-piperidinecarboxylic acid methyl ester or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester, E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate methyl ester or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof, E-2-amino-4-methyl-5-phosphono-3-pentenoate methyl ester or a salt thereof, E-2-amino-4-methyl-5-phosphono-3n-propylpentanoic acid or a salt thereof, N-butyl E-2-amino-4-methyl-5-phosphono-3-pentenoate or a salt thereof salts thereof, isobutyl E-2-amino-4-methyl-5-phosphono-3-pentenoate or its salts, n-hexyl E-2-amino-4-methyl-5-phosphono-3-pentenoate or its salts, (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoate or its salts, (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoate or its salts, ethyl (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoate or its salts, ethyl (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoate or its salts, ethyl (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoate or its salts, 4-(α-phosphonoacetylamino)-piperidine-2-carboxylic acid or its salts, 4-(2-phosphonoethylamino)piperidine-2-carboxylic acid or its salts,4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid and its salts, 4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid and its salts, trans-3-[1-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid and its salts, trans-3-[1-(4-phosphonobut-2-enyl)]-pyrrolidine-2-carboxylic acid and its salts, cis-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid and its salts, trans-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid and its salts, cis-4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid and its salts, trans-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid and its salts, )]-piperidine-2-carboxylic acid and its salts, cis-3-[1-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid and its salts, 4-(phosphono-substituted lower alkyl or lower alkenyl)piperazine-2-carboxylic acid and its salts, esters and amides, 4-[(1(2)H-tetrazol-5-yl)methyl]-2-piperidinecarboxylic acid or its diastereoisomer or stereospecific isomer or salt, cis-(-)-4[(1(2)H-tetrazol-5-yl)methyl]-2-piperidinecarboxylic acid or its salts, 4-[2-(1(2)H-tetrazol-5-yl)ethyl]-2-piperidinecarboxylic acid or its diastereoisomer or stereospecific isomer or salt, 4-[3-(1(2)H-tetrazol-5-yl)propyl]-2-piperidinecarboxylic acid or its diastereoisomer diastereomers or stereoisomers or salts thereof, 4-[(1(2)H-tetrazol-5-yl)methylene]-2-piperidinecarboxylic acid or its diastereomers or stereoisomers or salts, 4-[3-(1(2)H-tetrazol-5-yl)propyl]-2-piperazinecarboxylic acid and its salts, 4-[2-(1(2)H-tetrazol-5-yl)ethyl]-2-piperazinecarboxylic acid and its salts, N-benzyloxycarbonyl-D-aspartic acid, N-benzyloxycarbonyl-3-methyl-D,L-aspartic acid, N-benzoylcarbonyl-D-2-aminoadipic acid, R-5-oxo-4-acetic acid-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, S-5-oxo-4-acetic acid-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R,S-5-oxo-4-acetic acid-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R-5-oxo-4-(α-methylacetic acid)-3-oxazolidinecarboxylic acid, 3-phenyl(methyl) ester, R-5-oxo-4-butyryl-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R-5-oxo-4-(acetyl chloride)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, S-5-oxo-4-(acetyl chloride)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R,S-5-oxo-4-(α-methyl-acetyl chloride)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R-5-oxo-4-(butyryl chloride)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R-4-[3-(diethoxyphosphinyl)-2-oxopropyl]-5-oxo-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester,S-4-[3-(diethoxyphosphinyl)-2-oxopropyl]-5-oxo-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, 4-[3-(diethoxyphosphinyl)-1-methyl-2-oxopropyl]-5-oxo-3-diethylphosphonate)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, 4-[3-(diethoxyphosphinyl)-1,3-dimethyl-2-oxopropyl]-5-oxo-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R-4-[3-(diethoxyphosphinyl-3-methyl-2-oxopropyl]-5-oxo-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R-4-[5-(diethoxyphosphinyl)-4-oxopentyl]-5-oxo 3-(phenylmethyl)-2-oxo-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester, R-4-oxo-5-phosphononorvaline, S-4-oxo-5-phosphononorvaline, 3,4-dimethyl-4-oxo-5-phosphononorvaline, 3-methyl-4-oxo-5-phosphononorvaline, R-5-methyl-4-oxo-5-phosphononorvaline, R-2-amino-6-oxo-7-phosphonoheptanoic acid, 4-(2-oxo-3-phosphonopropyl)-2-piperazinecarboxylic acid, 2-methyl-4-oxo-5-phosphononorvaline, 5-(hydroxymethoxyphosphinyl)-4-oxonorvaline, 4-(hydroxyimino)-5-phosphononorvaline, 4-(methoxyimino)-5-phosphononorvaline acid, 4-[(phenylmethoxy)imino]-5-phosphononorvaline, 4-[(2'-phenylethoxy)imino]-5-phosphononorvaline, 4-(benzylhydrazine)-5-phosphononorvaline, R-4-oxo-5-phosphononorvaline methyl ester, R-4-oxo-5-phosphononorvaline ethyl ester, 3-{2-phosphonoethylcyclohexyl}-2-aminopropionic acid, 4-[2-phosphonomethylcyclohexyl]-2-aminobutyric acid, 4-[2-phosphonomethylphenyl]-2-aminobutyric acid, ethyl 3-[2-(2-diethylphosphonoethyl)-phenyl]-2-acetylamino-2-carboethoxypropanoate, 3-[2-(2-phosphonoethyl)-phenyl]-2-aminopropionic acid, 3-[2-phosphonomethylphenyl]-2-aminopropionic acid, 3-[2-(3-phosphonopropyl)-phenyl]-2-aminopropionic acid, 5-[2-phosphonomethylphenyl]-2-amino-pentanoic acid, 3-((+ / -)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, α-amino-α-(3-alkylphenyl)alkyl-acetic acid, its esters or amides or salts thereof, (+ / -)-α-amino-3-(4'-chloro-5-phosphonomethyl-[1,1'-biphenyl]-3-yl)propionic acid or its salts, (+ / -)-α-amino-3-(3-phosphonomethyl)phenylpropionic acid or its salts, (+ / -)-α-amino-3-(5-phosphonomethyl-[1,1'-biphenyl]-3-yl)propionic acid or its salts,(+ / -)-α-amino-3-(5-octyloxy-3-phosphonomethyl)phenylpropionic acid or its salt, (+ / -)-α-amino-3-(5-diethoxyphosphinyl)methyl-[1.1']-3-yl]propionic acid ethyl ester or its salt, (+(-)-α-amino-3-(5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid ethyl ester or its salt, (+ / -)-α-amino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)propionic acid amide or its salt, (+ / -)-α-amino-3-(4'-chloro-5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid amide or its salt, (+ / -)-α-palmitoylamino-3-(5 -phosphonomethyl-[1.1'-biphenyl]-3-yl) propionic acid or its salt, (+ / -)-α-amino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)propionic acid methyl ester or its salt, (+ / -)-α-amino-3-(4'-chloro-5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid methyl ester or its salt, (+ / -)-α-amino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)propionic acid or its salt, (+ / -)-α-tert-butoxycarbonylamino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)propionic acid or its salt, (+ / -)- α-tert-Butoxycarbonylamino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)cinnamyl propionate, (+ / -)-α-amino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)cinnamyl propionate or its salt, (+ / -)-α-amino-3-(4'-chloro-5-phosphonomethyl-[1.1'-biphenyl]-3-yl)cinnamyl propionate or its salt, (+ / -)-α-amino-3-(5-cyclo-2,2-dimethylpropylenephosphinyl)methyl-[1.1'-biphenyl]-3-yl)ethyl propionate or its salt, (+ / -)-α-amino-3-(4'-tert-butyl-5-phosphonomethyl-[1.1'-biphenyl]-3 -yl)propionic acid or its salt, (+ / -)-α-amino-3-(4-'phenyl-5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid or its salt, (+ / -)-α-amino-3-(4-chloro-5-(phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid benzoylmethyl ester or its salt, (+ / -)-α-amino-3-(5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid methyl ester or its salt, (+ / -)-α-acetylamino-3-(5-phosphononiothyl-[1.1'-biphenyl]-3-yl)propionic acid or its salt, (+ / -)-α-amino-3-(3-amino-5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid or its salt,Ethyl (+)-α-amino-3-(5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)propionate or its salt, Ethyl (+)-α-amino-3-(5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionate or its salt, (+)-α-amino-3-(5-phosphonomethyl-[1.1'-biphenyl]-3-yl)propionic acid or its salt, Ethyl (-)-α-amino-3-(5-(diethoxyphosphinyl)methyl-[1.1'-biphenyl]-3-yl)propionate or its salt, Ethyl (-)-α-amino-3-(5-phosphonomethyl]-[1.1'-biphenyl]-3-yl)propionate or its salt, Ethyl (-)-α-amino-3-(5-phosphonomethyl]-[1.1'-biphenyl]-3-yl)propionate or its salt, [R-(E)]-4-(3-phosphono-2-propenyl)-2-piperazinecarboxylic acid or a salt thereof, (+)-S-(3-phosphonopropyl)-D-cysteine or a salt thereof, S-(3-phosphonopropyl)-D,L-cysteine or a salt thereof, S-(2-phosphonoethyl)-D,L-homocysteine or a salt thereof, N-benzyloxycarbonyl-S-(3-phosphonopropyl)-D,L-cysteine or a salt thereof, S-[3-[(dodecyloxy)hydroxyphosphono]propyl]-D,L-cysteine or a salt thereof, (-)-N-(carboxymethyl)-N-phenyl-D-glutamine or a salt thereof, (+)-N-(carboxymethyl)-N-phenyl-L-glutamine or a salt thereof, (-) -N-(Carboxymethyl)-N-(4-chlorophenyl)-D-glutamine or a salt thereof, (-)-3-((3-phosphonopropyl)sulfinyl]-D-alanine or a salt thereof, (+)-3-((3-phosphonopropyl)sulfonyl-D-alanine or a salt thereof, 4-(phosphonomethyl)phenylglycine, 4-(ethylphosphonomethyl)phenylglycine, 2,5-dimethyl-4-(phosphonomethyl)phenylglycine hydrochloride, 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline hydrochloride, 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-phosphono-1,2,3,4,5,8-hexahydroisoquinoline, 3-carboxy-5-phosphono-1,2,3,4, 5,6,7,8-octahydroisoquinoline, 3-carboxy-5-phosphono-6-methyl-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-phosphono-7-methyl-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-phosphono-8-methyl-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-phosphono-6-chloro-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-phosphono-7-chloro-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-phosphono-8-chloro-1,2,3,4-tetrahydroisoquinoline, (D)-3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline, (L)-3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline,5-Phosphono-3-(ethoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline, 5-(ethylphosphono)-3-carboxy-1,2,3,4-tetrahydroisoquinoline, 3-cis-carboxy-5-cis-phosphono-cis-2-azadecalin, 3-cis-carboxy-5-trans-phosphono-cis-2-azadecalin, 3-trans-carboxy-5-trans-phosphono-cis-2-azadecalin, 3-cis-carboxy-5-cis-phosphono-trans-2-azadecalin, 3-cis-carboxy-5-trans-phosphono-trans-2-azadecalin, Azadecalin, 3-trans-carboxy-5-cis-phosphono-trans-2-azanaphthyridine, 3-carboxy-5-(phosphonomethyl)-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-(2-phosphonoethyl)-1,2,3,4-tetrahydroisoquinoline, 3-carboxy-5-(2-phosphonovinyl)-1,2,3,4-tetrahydroisoquinoline, D,L-3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline, D-3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline, (+)-3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline, 5-phosphono-3-(ethoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline, 3-carboxy- 5-Phosphono-6-methyl-1,2,3,4-tetrahydroisoquinoline, 3-Carboxy-5-(phosphonomethyl)-1,2,3,4-tetrahydroisoquinoline, 3-Carboxy-5-phosphono-1,2,3,4,5,8-hexahydroisoquinoline, 3-Carboxy-5-phosphono-1,2,3,4,5,6,7,8-octahydroisoquinoline, 3-Carboxy-5-phosphono-2-azadecalin, 2R,4S,5R-2-amino-4,5-methylene-adipic acid, 2R,4R,5R-2-amino-4,5-methylene-adipic acid, 2R,4S,5S-2-amino-4,5-methylene-adipic acid, 2R,4R,5S-2-amino-4,5-methylene-adipic acid, 2S,4S ,5R-2-amino-4,5-methylene-adipic acid, 2S,4R,5R-2-amino-4,5-methylene-adipic acid, 2S,4S,5S-2-amino-4,5-methylene-adipic acid, 2S,4R,5S-2-amino-4,5-methylene-adipic acid, 2R,4S,5R-2-amino-4,5-methylene-adipic acid diethyl ester, 2R,4R,5R-2-amino-4,5-methylene-adipic acid diethyl ester, 2R,4S,5S-2-amino-4,5-methylene-adipic acid diethyl ester, 2R,4R,5S-2-amino-4,5-methylene-adipic acid diethyl ester, 2S,4S,5R-2-amino-4,5-methylene-adipic acid diethyl ester,2S,4R,5R-2-Amino-4,5-methylene-adipate diethyl ester, 2S,4S,5S-2-Amino-4,5-methylene-adipate diethyl ester, 2S,4R,5S-2-Amino-4,5-methylene-adipate diethyl ester, 2R,4S,5R-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2R,4R,5R-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2R,4S,5S-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2R,4R,5S-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2S, 4S,5R-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2S,4R,5R-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2S,4S,5S-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2S,4R,5S-2-Amino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2R,4S,5R-2-Acetamido-4,5-methylene-adipate, 2R,4R,5R-2-Acetamido-4,5-methylene-adipate, 2R,4S,5S-2-Acetamido-4,5-methylene-adipate, -Acetamido-4,5-methylene-adipic acid, 2S,4S,5R-2-Acetamido-4,5-methylene-adipic acid, 2S,4R,5R-2-Acetamido-4,5-methylene-adipic acid, 2S,4S,5S-2-Acetamido-4,5-methylene-adipic acid, 2S,4R,5S-2-Acetamido-4,5-methylene-adipic acid, 2R,4S,5R-2-Acetamido-4,5-methylene-adipic acid diethyl ester, 2R,4R,5R-2-Acetamido-4,5-methylene-adipic acid diethyl ester, 2R,4S,5S-2-Acetamido-4,5-methylene-adipic acid diethyl ester, 2R,4R,5S-2-Acetamido-4,5-methylene-adipic acid diethyl ester, 2R,4R,5S-2-Acetamido-4,5-methylene-adipic acid diethyl ester, -4,5-methylene-adipic acid diethyl ester, 2S,4S,5R-2-acetamido-4,5-methylene-adipic acid diethyl ester, 2S,4R,5R-2-acetamido-4,5-methylene-adipic acid diethyl ester, 2S,4S,5S-2-acetamido-4,5-methylene-adipic acid diethyl ester, 2S,4R,5S-2-acetamido-4,5-methylene-adipic acid diethyl ester, 2R,4S,5R-2-benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester, 2R,4R,5R-2-benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester, 2R,4S,5S-2-benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester,2R,4R,5S-2-Benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester 2S,4S,5R-2-Benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester, 2S,4R,5R-2-Benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester, 2S,4S,5S-2-Benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester, 2S,4R,5S-2-Benzyloxycarbonylamino-4,5-methylene-adipic acid diethyl ester, 2R,4S,5R-2-Benzyloxycarbonylamino-4,5-methylene-adipic acid-1-methyl-6-ethyl ester, 2R,4R,5R-2-Benzyloxycarbonylamino-4,5-methylene-adipic acid-1-methyl-6-ethyl ester, 2R,4S,5S-2-Benzyloxycarbonylamino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2R,4R,5S-2-Benzyloxycarbonylamino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2S,4S,5R-2-Benzyloxycarbonylamino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2S,4R,5R-2-Benzyloxycarbonylamino-4,5-methylene-adipate-1-methyl-6-ethyl ester, 2S,4S,5S-2-Benzyloxycarbonylamino-4,5-methylene-adipate-1-methyl-6-ethyl ester and 2S,4R,5S-2-Benzyloxycarbonylamino-4,5-methylene-adipate-1-methyl-6-ethyl ester. ,

[0098] In one embodiment, the composition according to the present invention does not include kynurenine or kynurenine derivatives.The example of kynurenine derivatives is described in, for example, EP386839 or EP303387, which are incorporated herein by reference.The example of kynurenine derivatives includes, but is not limited to, 4,6-dichloro-kynurenine, 4-fluoro-6-bromo-kynurenine, 4-chloro-6-bromo-kynurenine, 4,6-dibromo-kynurenine, 6-ethyl-4-bromo-kynurenine, 4-chloro-kynurenine, 4-fluoro-kynurenine, 6-bromo-4-chloro-kynurenine and 6-bromo-4-bromo-kynurenine.

[0099] In one embodiment, the composition of the present invention does not include quinoxalinedione.The example of quinoxalinedione is described in, for example, EP377112, EP374534, EP348872, EP315959, EP260467, US4889855 or US4812458, which are incorporated herein by reference.The example of quinoxalinedione includes but is not limited to 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H)-dione, 7-chloro-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H)-dione, 1-hydroxy-7-aminosulfonyl-6-trifluoromethylquinoxaline-2,3 (1H, 4H)-dione, and 7-acetyl-6-cyano-1-hydroxyquinoxaline-2,3 (1H, 4)-dione, 4-hydroxy-benzo [f] quinoxaline-2,3 ( 1H,4H)-dione, 6-cyano-4-hydroxy-benzo[f]quinoxaline-2,3(1H,4H)-dione, 4-hydroxypyrido[3,2-f]quinoxaline-2,3(1H,4H)-dione, 7,8,9,10-tetrahydro-4-hydroxybenzo[f]quinoxaline-2,3(1H,4H)-dione, 7,8-dihydroxy-1-methyl-4-nitro-1H-1,2,3-triazolo[4,5-f]quinoxaline, 7,8-dihydroxy-3-methyl- 4-Nitro-3H-1,2,3-triazolo[4,5-f]quinoxaline, 8-carboxy-2,3-dihydroxythieno[3,2-f]quinoxaline, 7,8-dihydroxy-4-nitro-1,2,5-thiadiazolo(3,4-f)quinoxaline, 1-cyclohexyl-6-nitroquinoxaline-2,3(1H,4H)-dione, 1-benzyl-6-nitroquinoxaline-2,3(1H,4H)-dione, 4-methylbenzo[f]quinoxaline-2,3(1H,4H)-dione 1-Hydroxy-7-nitro-2,3-dihydroxyquinoxaline, ...

[0100] In one embodiment, the compositions of the present invention do not comprise a quinoxalinedione AMPA antagonist, such as ACEA-1011 (5-chloro-7-(trifluoromethyl)quinoxaline-2,3-diol), AMP397 (({[(7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-5-quinoxalinyl)methyl]amino}methyl)phosphonic acid; Becampanel), CNQX (7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile), DNQX (6,7-dinitroquinoxaline-2,3-dione), MPQX ({[7-(4-morpholinyl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydro-1(2H)-quinoxalinyl]methyl}phosphonic acid; Fanapanel), ACEA- 1021 (6,7-dichloro-1,4-dihydro-5-nitro-2,3-quinoxalinedione, LiCostinel), NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide), PNQX (1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3,4-f]quinoxaline-2,3-dione), YM90K (6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride), YM872 ((2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxaline-yl)-acetic acid monohydrate; Zonampanel) and their derivatives.

[0101] In one embodiment, the composition of the present invention does not comprise a quinoxalic acid derivative.

[0102] In one embodiment, the composition of the present invention does not include indole derivatives. The example of indole derivatives is described in, for example, US4960786 or EP396124, which are incorporated herein by reference. The example of indole derivatives includes, but is not limited to, 3-(2-carboxyl-6-methoxyindole-3-yl) propionic acid, 3-(2-carboxyl-6-chloroindole-3-yl) propionic acid, 3-(2-carboxyl-4,6-dichloroindole-3-yl) propionic acid, 3-(2-carboxyl-6-trifluoromethoxyindole-3-yl) propionic acid, 3-(2-carboxyl-4-trifluoromethylindole-3-yl) propionic acid, 3-(2-carboxyl-6-trifluoromethylindole-3-yl) propionic acid, -(2-carboxy-4-fluoroindol-3-yl)propionic acid, 3-(2-carboxy-4-nitroindol-3-yl)propionic acid, 3-(2-carboxy-6-nitroindol-3-yl)propionic acid, ethyl 3-(2-carboxyethyl-4,6-dichloroindol-3-yl)propanoate, benzyl 3-(2-carboxybenzyl-4,6-dichloroindol-3-yl)propanoate, 3-(2-carboxamido-4,6-dichloroindol-3-yl)propionamide, 2-(2-carboxy-6- chloroindol-3-yl)acetic acid, 4-(2-carboxy-6-chloroindol-3-yl)butanoic acid, 5-(2-carboxy-6-chloroindol-3-yl)pentanoic acid, 3-(2-carboxy-4,6-dichloro-1-methylindol-3-yl), 3-(2-carboxy-6-methoxyindol-3-yl)propionic acid, 3-(2-carboxy-6-chloroindol-3-yl)propionic acid, 2-carboxy-3-indoleacetic acid, 2-carboxy-1-methyl-3-indoleacetic acid, 2-carboxy ethyl 2-carboxy-6-chloro-3-indoleacetic acid, 2-carboxy-6-chloro-3-indoleacetic acid ester, 2-carboxy-6-chloro-3-indoleacetic acid amide, 2-carboxy-6-chloro-3-indoleacetic acid 3-ethylamide, ethyl 6-chloro-3-(2-chloroethyl)-2-indolecarboxylate, 2-carboxy-6-chloro-3-indoleacetic acid and 2-carboxy-6-chloro-3-indoleacetic acid.

[0103] In one embodiment, the composition of the invention does not comprise a pyrrolidone derivative. Examples of pyrrolidone derivatives are described in, for example, US 4925867, US 4863953 or GB 2231048, which are incorporated herein by reference. Examples of pyrrolidone derivatives include, but are not limited to, cis-3-amino-1-hydroxy-4-methylpyrrolidin-2-one or a salt thereof, (3R,4R)-3-amino-1-hydroxy-4-methylpyrrolidin-2-one or a salt thereof, cis-3-amino-1-hydroxy-4-ethylpyrrolidin-2-one or a salt thereof, (3R)-3-amino-1-hydroxypyrrolidin-2-one, (3R)-3-amino-1-hydroxypyrrolidin-2-one, (3R)-amino-1-hydroxypyrrolidin-2-one, 2,6-diaza-6-hydroxy-7-oxobicyclo-[3.2.1]-octane and a salt thereof, 2,6-diaza-6-hydroxy-8-endomethyl-7-oxobicyclo-[3.2.1]-octane and a salt thereof, and the like.

[0104] In one embodiment, the compositions of the present invention do not include D-cycloserine, its prodrug or its mixture. Examples of D-cycloserine, its prodrug or its mixture are described in, for example, EP387867, EP378134 or US4904681, which are incorporated herein by reference. Examples of D-cycloserine include, but are not limited to, 4-amino-3-isoxazolidinone, D-4-amino-3-isoxazolidinone or its salt.

[0105] In one embodiment, the composition of the present invention does not comprise an isatin derivative.

[0106] In one embodiment, the composition of the present invention does not include a bicyclic derivative. Examples of bicyclic derivatives are described in, for example, US4902695, which is incorporated herein by reference. Examples of bicyclic derivatives include, but are not limited to, decahydro-6-5-[1(2)H-tetrazol-5-ylmethyl]-3-isoquinolinecarboxylic acid or a salt thereof, 3-carboxydecahydro-6-isoquinolineacetic acid or a salt thereof, decahydro-6-(phosphomethyl)-3-isoquinolinecarboxylic acid or a salt thereof, decahydro-6-(phosphomethyl)-1-isoquinolinecarboxylic acid hydrochloride hemihydrate, decahydro-6-tetrazol-5-ylmethyl)-1-isoquinolinecarboxylic acid, decahydro-6-(phosphomethyl)-3-isoquinolinecarboxylic acid ethyl ester, decahydro-6-(phosphomethyl)-3-isoquinolinecarboxylic acid butyl ester, decahydro-6-5.

[0107] In one embodiment, the composition of the present invention does not comprise eslicarbazepine, eslicarbazepine acetate, or derivatives thereof.

[0108] In one embodiment, the composition of the present invention does not comprise a compound of formula (II) or a salt thereof:

[0109]

[0110] Where X is a linear C 1-4 Alkylene or S; m is an integer from 1 to 4; Z is hydrogen, C 1-4 Alkyl, phenyl, substituted phenyl or alkylphenyl substituents, wherein the phenyl ring may be optionally substituted; R is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, CF3, OCF3, OH, NO2 or CN; R1 and R2 are each independently -OH, -OR3, -NR4R5, -OCH2OR3 or -O-(CH2) n -NR6R7, wherein n is an integer from 1 to 4; R3 is C 1-4 Alkyl, phenyl, substituted phenyl or alkylphenyl substituents, wherein the phenyl ring may be optionally substituted; R4 and R5 are each independently hydrogen or C 1-4 Alkyl; R6 and R7 are each independently hydrogen or C 1-4 alkyl, or R6 and R7 together with the adjacent nitrogen atom form a piperidino, morpholino or pyrrolidinyl group, provided that if X is C 1-4 alkylene, then m is 0.

[0111] In one embodiment, the composition of the present invention does not comprise a compound of formula (III) or a salt thereof:

[0112]

[0113] wherein R, Z and R2 are as defined above in formula (II); B is hydrogen, C 1-4 Alkyl, optionally substituted alkylphenyl or -CH2-COR2; Y is SO2 or CO; A is phenyl, substituted phenyl or C(O)D, wherein D is as defined for R2 in formula (II).

[0114] In one embodiment, the composition of the present invention does not comprise a compound of formula (IV) or a salt thereof:

[0115]

[0116] Where E is hydrogen, C 1-4 Alkyl or -CF3; A is a methylene or trimethylene bridging group; E1 is hydrogen, C 1-4 Alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl or substituted phenyl.

[0117] In one embodiment, the composition of the present invention does not comprise a compound of formula (V) or a salt thereof:

[0118]

[0119] wherein E and E1 are as defined above in formula (IV); E2 is hydrogen, C1-4 Alkyl, phenyl, alkylphenyl or cyclohexylmethyl; E5 is hydrogen, straight chain C 1-4 Alkyl or alkylphenyl.

[0120] In one embodiment, the composition of the present invention does not comprise a compound of formula (VI) or a salt thereof:

[0121]

[0122] wherein R1 is aryl, furyl, benzofuranyl, thienyl, benzothienyl, quinolyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl or quinazolinyl, each optionally substituted with one to four substituents independently selected from R7; R2 and R3 are the same or different and are independently hydrogen or lower alkyl; R4 represents one to four optional substituents, each of which is the same or different and is independently selected from halogen, hydroxy, lower alkyl or lower alkoxy; R5 and R6 are the same or different and are independently -(CH2) a C(=O)R9, -(CH2) a C(=O)OR9, -(CH2) a C(=O)NR9R 10 、-(CH2) a C(=O)NR9(CH2) b C(=O)R 10 、-(CH2) a NR9C(=O)R 10 、-(CH2) a NR 11 C(=O)NR9R 10 、-(CH2) a OR9, -(CH2) a SO c R9 or -(CH2) a SO2NR9R 10 ; or R5 and R6 together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle; R7 is independently, at each occurrence, halogen, hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, heterocycloalkyl, substituted heterocycloalkyl, -C(=O)OR8, -OC(=O)R8; -C(=O)NR8R9, -C(=O)NR8OR9, -SO c R8, -SO c NR8R9, -NR8SOc R9, -NR8R9, -NR8C(=O)R9, -NR8C(=O)(CH2) b OR9, -NR8C(=O)(CH2) b R9, -O(H2) b NR8R9, or a heterocyclic ring fused with a phenyl group; R8, R9, R 10 and R 11 are the same or different and are independently selected at each occurrence from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl or substituted heterocycloalkyl; or R8 and R9 together with the atom or atoms to which they are attached form a heterocycle or a substituted heterocycle; a and b are the same or different and are independently selected at each occurrence from 0, 1, 2, 3 or 4; and c is 0, 1 or 2 at each occurrence.

[0123] In one embodiment, the composition of the invention does not comprise a compound of formula (VIIa) or a salt thereof:

[0124]

[0125] wherein X and Y are each independently selected from Cl, Br, F, CH3 and CH2CH3.

[0126] In one embodiment, the composition of the present invention does not comprise a compound of formula (VIIIa) or a salt thereof:

[0127]

[0128] wherein X and Y are each independently selected from Cl, Br, F, CH3 and CH2CH3.

[0129] In one embodiment, the composition of the invention does not comprise a compound of formula (VIIb) or a salt thereof:

[0130]

[0131] Wherein Hal is a halogen atom.

[0132] In one embodiment, the composition of the present invention does not comprise a compound of formula (VIIIb) or a salt thereof:

[0133]

[0134] Wherein Hal is a halogen atom.

[0135] In one embodiment, the composition of the present invention does not comprise a compound of formula (IX) or a salt thereof:

[0136]

[0137] wherein D is C(O)OR1, C(O)NR1R2, wherein R1 and R2 are each independently hydrogen or C1-C6 alkyl; Z (which may be located at position 3, 5, 6, 7 or 8 and may represent up to 3 non-hydrogen substituents) is a substituent selected from hydrogen, -OH, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 alkoxy, -OCF3 and CF3; and X is one of the following substituents:

[0138] -(CY2) n CY3, -(CT2) n CT3,

[0139] wherein Y is Cl; T is F; n is an integer from 0 to 3; when B is hydrogen, A is a substituent selected from hydrogen, -OH, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 alkoxy, -OCF3, -CF3, and may be represented by up to 3 non-hydrogen substituents; when B is not hydrogen, there may be up to 2 A substituents on the benzene ring; when X is a thiophene ring, A may represent up to 2 identical or different non-hydrogen substituents; B is a substituent selected from hydrogen, C(O)OR1, C(O)NR1R2, NH2, NR1R2, NHC(O)R3, NHC(O)OR3, NHC(O)NHR3, NH-SO2-CF3, NH-SO2-C6H5; wherein R1 and R2 are as defined above, R3 is C 1- C6 alkyl; provided that: 1) when D is C(O)OCH3 and X is phenyl (wherein A is p-methyl and B is hydrogen), then Z is not hydrogen or 5,7-dichloro substituent; 2) when D is C(O)OC2H5 and X is phenyl (wherein A is p-methyl and B is hydrogen), then Z is not 6-methoxy, 7-methoxy or 5,8-dimethoxy; 3) when B is not hydrogen, the total number of A plus B cannot exceed 3 substituents.

[0140] In one embodiment, the compositions of the present invention do not include a dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor). Examples of DPP-IV inhibitors include, but are not limited to, sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin, andagliptin, tilligliptin, alogliptin, trelagliptin, alogliptin, ipagliptin, dutoliptin, berberine, lupeol, and derivatives thereof.

[0141] Another object of the present invention is a pharmaceutical composition for treating an epileptic disease, disorder or condition in a subject in need thereof, comprising, or consisting essentially of, or consisting of, probenecid or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0142] Suitable excipients include, but are not limited to, water, saline, Ringer's solution, dextrose solution and ethanol solution, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (PEG), phosphates, acetates, gelatin, collagen, Vegetable oils, etc. One may additionally include suitable preservatives, stabilizers, antioxidants, antimicrobial agents, and buffers, such as BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.

[0143] Other examples of pharmaceutically acceptable excipients that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone), cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates or salts, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0144] In addition, some excipients may include, but are not limited to, surfactants (e.g., hydroxypropylcellulose); suitable carriers, such as solvents and dispersion media, which contain, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof; vegetable oils, such as peanut oil and sesame oil; isotonic agents, such as sugars or sodium chloride; coating agents, such as lecithin; agents that delay absorption, such as aluminum monostearate and gelatin; preservatives, such as benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal, etc.; buffers, such as boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, acetic acid, sodium, sodium dihydrogen phosphate, etc.; tonicity agents such as dextran 40, dextran 70, dextrose, glycerol, potassium chloride, propylene glycol, sodium chloride; antioxidants and stabilizers such as sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea, etc.; non-ionic wetting agents or clarifiers such as polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol; viscosity modifiers such as dextran 40, dextran 70, gelatin, glycerol, hydroxyethyl cellulose, hydroxymethylpropyl cellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, etc.

[0145] Another object of the present invention is a medicament for treating an epileptic disease, disorder or condition in a subject in need thereof, comprising, consisting of, or consisting essentially of probenecid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0146] In one embodiment, the composition, pharmaceutical composition or medicament of the invention is administered systemically or locally.

[0147] In one embodiment, the composition, pharmaceutical composition or medicament of the present invention is administered orally, buccally, by injection, transdermally, parenterally, intraperitoneally, endoscopically, topically, transdermally, transmucosally, nasally, by inhalation spray, rectally, vaginally, intratracheally and via an implanted reservoir.

[0148] In one embodiment, the composition, pharmaceutical composition or medicament of the present invention is injected, preferably systemically. Examples of formulations suitable for systemic injection include, but are not limited to, liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to injection.

[0149] The example of systemic injection includes but is not limited to intravenous, intratumoral, intracranial, intralymphatic, intraperitoneal, intramuscular, subcutaneous, intradermal, intraarticular, intrasynovial, intrasternal, intrathecal, intravesical, intrahepatic, intralesional, infusion technique and perfusion. In another embodiment, when injected, the composition of the present invention, pharmaceutical composition or medicine are sterile. The method for obtaining sterile pharmaceutical composition includes but is not limited to GMP synthesis (GMP stands for "good manufacturing practice").

[0150] In another embodiment, the compositions, pharmaceutical compositions or medicines of the present invention are for oral administration. Examples of formulations suitable for oral administration include, but are not limited to, solid forms, liquid forms and gels. Examples of solid forms suitable for oral administration include, but are not limited to, pills, tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, compressed tablets, cachets, wafers, dragees, sugar-coated tablets or dispersible / disintegrating tablets, powders, solid forms suitable for being dissolved in liquids or suspended in liquids before oral administration and effervescent tablets. Examples of liquid forms suitable for oral administration include, but are not limited to, solutions, suspensions, drinkable solutions, elixirs, sealed vials, potions, drenches, syrups and liquids.

[0151] In another embodiment, the compositions, pharmaceutical compositions or medicaments of the present invention are administered topically. Examples of formulations suitable for topical administration include, but are not limited to, sticks, lipsticks, waxes, creams, lotions, ointments, balms, gels, glosses, sunscreen formulations, makeup, facial masks, leave-on lotions or cleansers, depilatories and / or the like.

[0152] Topical administration is characterized by delivering, administering or applying the composition, pharmaceutical composition or medicament of the present invention directly to the site of interest to obtain a local effect (usually on one or more exposed or external surfaces thereof, such as the outermost layer of the epidermis, which is exposed and visually observable), such as using the hands, fingers or a variety of applicators (roll-ups, roll-ons or other stick containers, tubular containers, cotton balls, puffs, cotton swabs, pumps, brushes, pads, cloths and / or the like). For example, it can be applied by placing, rubbing, sweeping, pouring, smearing and / or massaging it into or onto the skin, or by any other convenient or suitable method. Preferably, topical administration is effected without the components of the composition being significantly absorbed by the subject's bloodstream (to avoid systemic effects).

[0153] The compositions, pharmaceutical compositions, or medicaments of the present invention can be mixed with, for example, 1% or 2% (w / w) of benzyl alcohol, emulsifying wax, glycerol, isopropyl palmitate, lactic acid, purified water, and sorbitol solutions as preservatives to form a white, smooth, uniform, opaque cream or lotion. In addition, the compositions can contain polyethylene glycol 400 (PEG 400). They can be mixed with, for example, 2% (w / w) of benzyl alcohol, white petrolatum, emulsifying wax, and Tenox II (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol) as preservatives to form an ointment. Woven pads or rolls of dressing material, such as gauze, can be impregnated with the solution of the composition, and lotions, creams, ointments, or other forms can also be used for topical application.

[0154] In one embodiment of the invention, the composition of the present invention, pharmaceutical composition or medicine can be used in combination with a delivery system that promotes the delivery of a drug to the central nervous system. For example, various blood-brain barrier (BBB) permeability enhancers can be used to instantaneously and reversibly increase the permeability of the blood-brain barrier to therapeutic agents. Such BBB permeability enhancers include but are not limited to leukotrienes, bradykinin agonists, histamine, tight junction disruptors (such as zonulin, zot), hypertonic solutions (such as mannitol), cytoskeleton contractiles and short-chain alkyl glycerols (such as 1-O-pentyl glycerol). Oral, sublingual, parenteral, implant, nasal and inhalation routes can provide active agent delivery to the central nervous system. In some embodiments, the compound of the present invention can be applied to the central nervous system with minimal impact on the peripheral nervous system.

[0155] The blood-brain barrier (BBB) is a physical barrier and system of cellular transport mechanisms between the blood vessels in the central nervous system (CNS) and most areas of the CNS itself. The BBB maintains steady state by limiting the entry of potential harmful chemicals from the blood and allowing the entry of essential nutrients. However, the BBB can provide a difficult barrier, making it difficult for drugs to be delivered to the CNS to treat disorders (such as epileptic diseases, disorders or conditions) or to maintain or enhance normal and required brain functions (such as cognition, learning and memory).

[0156] In one embodiment, the inhibitor, composition, pharmaceutical composition or medicament is administered in a sustained release form. In another embodiment, the composition, pharmaceutical composition or medicament comprises a delivery system that controls the release of the modulator.

[0157] In one embodiment, probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention is administered at a dose determined by a skilled person, and the dose is individually adjusted to suit each subject. It should be understood that the total daily usage of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition and medicament of the present invention will be determined by the attending physician within the scope of sound medical judgment. The dose is adjusted to provide a sufficient level of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention, or to maintain the desired effect of reducing signs or symptoms of the targeted epileptic disease, disorder or condition, or reducing the severity of the epileptic disease, disorder or condition. The specific therapeutically effective amount for any particular patient will depend on a variety of factors, including, but not limited to, the disease, disorder, or condition being treated; the severity of the epileptic disease, disorder, or condition (e.g., the frequency and duration of seizures); the prognosis of the disease; the location of the onset of seizures; the specific composition employed; the timing and frequency of administration, route of administration, and duration of treatment; drugs used in combination or concomitantly with probenecid, or a pharmaceutically acceptable salt, composition, pharmaceutical composition, or medicament of the present invention; reaction sensitivities; tolerance / response to treatment; the general health of the subject; the age, weight, sex, and diet of the subject; and similar factors well known in the medical arts.

[0158] In one embodiment, a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition, or medicament of the present invention is administered at least once a day, twice a day, or at least three times a day.

[0159] In another embodiment, the therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention is administered once every two days, three days, four days, five days or six days.

[0160] In another embodiment, the therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention is administered twice a week, once a week, once every two weeks, or once a month.

[0161] In one embodiment of the present invention, the daily dose range of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention to be administered to a subject is about 25 mg / day to about 10 g / day, about 50 mg / day to about 9 g / day, about 75 mg / day to about 8 g / day, about 100 mg / day to about 7 g / day, about 200 mg / day to about 6 g / day, about 300 mg / day to about 5 g / day, about 400 mg / day to about 4 g / day, about 500 mg / day to about 6 g / day. About 3 g / day, about 550 mg / day to about 2 g / day, about 600 mg / day to about 1.9 g / day, about 650 mg / day to about 1.8 g / day, about 700 mg / day to about 1.7 g / day, about 750 mg / day to about 1.6 g / day, about 800 mg / day to about 1.5 g / day, about 850 mg / day to about 1.5 g / day, about 900 mg / day to about 1.4 g / day, about 950 mg / day to about 1.3 g / day, about 1 g / day to about 1.3 g / day.

[0162] In one embodiment of the invention, the daily dose range of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the invention to be administered to a subject is about 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1 g / day, 1.1 g / day, 1.2 g / day, 1.3 g / day, 1.4 g / day, 1.5 g / day, 1.6 g / day, 1.7 g / day, 1.8 g / day, 1.9 g / day, 2 g / day, 2.5 g / day, 3 g / day, 4 g / day or 5 g / day.

[0163] In one embodiment of the present invention, the daily dose range of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention to be administered to a subject is from about 1 mg / kg / day to about 100 mg / kg / day, from about 2 mg / kg / day to about 90 mg / kg / day, from about 3 mg / kg / day to about 80 mg / kg / day, from about 4 mg / kg / day to about 70 mg / kg / day, from about 5 mg / kg / day to about 60 mg / kg / day, from about 6 mg / kg / day to about 50 mg / kg / day, from about 7 mg / kg / day to about 80 mg / kg / day, from about 8 mg / kg / day to about 90 mg / kg / day, g / day to about 35 mg / kg / day, about 9 mg / kg / day to about 30 mg / kg / day, about 10 mg / kg / day to about 25 mg / kg / day, about 11 mg / kg / day to about 24 mg / kg / day, about 12 mg / kg / day to about 23 mg / kg / day, about 13 mg / kg / day to about 22 mg / kg / day, about 14 mg / kg / day to about 21 mg / kg / day, about 15 mg / kg / day to about 20 mg / kg / day, about 16 mg / kg / day to about 19 mg / kg / day, about 16 mg / kg / day to about 18 mg / kg / day.

[0164] In one embodiment of the present invention, the daily dose range of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention to be administered to a subject is about 1 mg / kg / day, about 2 mg / kg / day, about 3 mg / kg / day, about 4 mg / kg / day, about 5 mg / kg / day, about 6 mg / kg / day, about 7 mg / kg / day, about 8 mg / kg / day, about 9 mg / kg / day, about 10 mg / kg / day, about 11 mg / kg / day, about 12 mg / kg / day, about 13 mg / kg / day, about 14 mg / kg / day, about 15 mg / kg / day, about 16 mg / kg / day, about 17 mg / kg / day, about 18 mg / kg / day, about 19 mg / kg / day, about 20 mg / kg / day, about 21 mg / kg / day, about 22 mg / kg / day, about 23 mg / kg / day, about 24 mg / kg / day, about 25 mg / kg / day, about 26 mg / kg / day, about 27 mg / kg / day, about 28 mg / kg / day, about 29 mg / kg / day, about 30 mg / kg / day.

[0165] In one embodiment of the invention, probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the invention is administered at a dose of about 1 mg to about 10 g, about 10 mg to about 10 g, about 10 mg to about 7.5 g, about 25 mg to about 7.5 g, about 50 mg to about 7.5 g, about 75 mg to about 7.5 g, about 100 mg to about 5 g, about 200 mg to about 4 g, about 300 mg to about 3 g, about 500 mg to about 3 g, about 750 mg to about 3 g, about 750 mg to about 2 g, about 800 mg to about 2 g, about 900 mg to about 2 g, about 900 mg to about 1.5 g, about 1 g to about 1.4 g or about 1 g to about 1.3 g.

[0166] In another embodiment, probenecid or a pharmaceutically acceptable salt, composition, pharmaceutical composition or medicament of the present invention is administered at a dose of about 1 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g.

[0167] In another embodiment, the methods of the present invention are used for chronic treatment. In another embodiment, the methods of the present invention are used for acute treatment.

[0168] In one embodiment, probenecid or its pharmaceutically acceptable salt, composition, pharmaceutical composition or medicine of the present invention is administered in the form of a bolus injection, continuous infusion or a combination of bolus injection and continuous infusion. The term "bolus injection" is understood to mean an injection in which a dose is delivered over a relatively short period of time. The term "continuous infusion" is understood to mean an injection delivered, for example, by intravenous drip, wherein the dose is delivered in a metered manner over the desired time period for the treatment of probenecid. In one embodiment, probenecid or its pharmaceutically acceptable salt, composition, pharmaceutical composition or medicine of the present invention is administered via continuous infusion over a time period ranging from about 30 minutes / day to about 24 hours / day. In another embodiment, probenecid or its pharmaceutically acceptable salt, composition, pharmaceutical composition or medicine of the present invention is administered over a time period from about 8 hours / day to about 24 hours / day. In some cases, probenecid or its pharmaceutically acceptable salt, composition, pharmaceutical composition or medicine of the present invention is administered by continuous drip over at least one day and up to seven days. In other cases, probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention may be administered for even longer periods of time, such as multiple weeks, months or even years, as needed to treat the symptoms of the subject. Thus, embodiments of the present invention relate to long-term administration of probenecid or a pharmaceutically acceptable salt thereof, composition, pharmaceutical composition or medicament of the present invention to treat epileptic diseases, disorders or conditions and related symptoms of brain dysfunction.

[0169] In some cases, a combination of bolus and continuous infusion may be needed to treat a subject. For example, a loading dose, i.e., a dose of probenecid or its pharmaceutically acceptable salt, can be delivered using bolus to quickly achieve the desired therapeutic level of probenecid or its pharmaceutically acceptable salt in a subject, and continuous infusion can be used to maintain or even titrate the desired therapeutic level within the desired treatment duration. After the initial bolus, the subject may need to subsequently, for example, perform maintenance administration or titration of probenecid or its pharmaceutically acceptable salt by continuous infusion within a period of time thereafter. In an alternative, the maintenance administration of probenecid or its pharmaceutically acceptable salt can be completed with subsequent bolus. The continuous infusion of probenecid or its pharmaceutically acceptable salt is also used to treat a subject suffering from an epileptic disease, illness, or condition.

[0170] The present invention also relates to a method for treating a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0171] The present invention also relates to a method for inhibiting electrographic seizures in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0172] The present invention also relates to a method for inhibiting compulsive behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0173] The present invention also relates to a method for controlling clinical or electrographic seizures in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0174] The present invention also relates to a method for treating an epileptic disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0175] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof for treating a neurological disorder in a subject in need thereof.

[0176] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof for inhibiting electrographic epileptic seizures in a subject in need thereof.

[0177] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof for inhibiting compulsive behavior in a subject in need thereof.

[0178] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof for controlling clinical or electrographic epileptic seizures in a subject in need thereof.

[0179] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof for treating an epileptic disease, disorder or condition in a subject in need thereof.

[0180] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurological disorder in a subject in need thereof.

[0181] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting electrographic epileptic seizures in a subject in need thereof.

[0182] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof in preparing a medicament for inhibiting compulsive behavior in a subject in need thereof.

[0183] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for controlling clinical or electrographic epileptic seizures in a subject in need thereof.

[0184] The present invention also relates to the use of a therapeutically effective amount of probenecid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an epileptic disease, disorder or condition in a subject in need thereof.

[0185] The present invention also relates to a method for reducing the frequency and / or duration of ictal discharges, preferably resulting in a reduction in the frequency by at least 25%, preferably at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more, and / or resulting in a reduction in the duration by at least 25%, preferably at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.

[0186] The present invention relates to a method for reducing the frequency and / or duration of induced spontaneous epileptic seizures, preferably resulting in a reduction in the frequency by at least 25%, preferably at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more, and / or a reduction in the duration by at least 25%, preferably at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.

[0187] BRIEF DESCRIPTION OF THE DRAWINGS

[0188] Figure 1A (Top) Schematic diagram of the experimental protocol: Human cortical slices mounted on MEAs were incubated under pro-epileptic conditions to induce ictal discharges (ID); after ID induction, PBN was applied. (Bottom) Examples of ID activity recorded from human epileptic cortical slices before (left) and after (right) treatment with PBN (1 mM, 30 minutes). When Panx1 channels were blocked by PBN, ID (dashed black line) disappeared, but PID (solid black dots) did not.

[0189] Figure 1B Figure 2 is a graph depicting the quantification of the effect of PBN on ID frequency and duration (p=0.0313, n=6 sections from 2 glioma and 2 MCD patients, Wilcoxon matched pairs test). Glioma and MCD section values are represented by black and gray solid circles, respectively.

[0190] Figure 1C (Left) Schematic diagram of the experimental protocol: EEG recordings were performed in KA mice 48 hours before and 24 hours after a single intraperitoneal injection of PBN (200 mg / kg). (Right) Examples of EEG recordings performed 4 hours before (black) and 4-8 hours after (gray) PBN treatment. The seizure observed in the CT and indicated by the asterisk is enlarged in the rectangle.

[0191] Figure 1Dis a graph depicting the quantification of the effect of PBN on seizure frequency and duration at Ct, 4-8h, and 20-24h after treatment (p=0.0370 and 0.0247, for frequency and duration, respectively; n=5, Friedman test with Dunn Post hoc test). Asterisks indicate statistical significance (*, p<0.05). Example

[0192] Materials and methods

[0193] Preparation of human cortical slices

[0194] Excised cortical blocks were prepared according to Dossi et al. (J Vis Exp. 2014 Oct 26;(92):e51870). Briefly, postoperative tissue was transported in a cold solution containing (in mM) 250 D-sucrose, 25 NaHCO3, 3 KCl, 1 CaCl2, 10 MgCl2, and 10 D-glucose and oxygenated with a carbogen (95% O2 and 5% CO2). Meninges, blood clots, and blood vessels were gently removed, and transverse cortical sections (400 μm thick) were cut using a vibratome (HM650V, Micro Microtech, France). Before recording, they were maintained at 37°C in an interface chamber equilibrated with 95% O2 and 5% CO2 and continuously perfused at 2 ml / min with artificial cerebrospinal fluid (ACSF) containing (in mM) 124NaCl, 3KCl, 26NaHCO3, 1.6CaCl2, 1.3MgCl2 and 10D-glucose for at least 1 hour.

[0195] Multi-electrode array (MEA) recordings

[0196] Cortical slices were transferred to planar MEA dishes (200–30 ITO electrodes organized in a 12 × 12 matrix with an internal reference, 30 μm diameter and 200 μm inter-electrode distance; Multichannel Systems, Germany) and held in place with platinum anchors and continuously perfused with ACSF at a rate of 5–6 ml / min.

[0197] Images of cortical slices on the MEA were acquired using a video microscope stage (MEA-VMT1; Multichannel Systems, Germany) using MEA_Monitor software (Multichannel Systems, Germany) to identify the position of the electrodes relative to the pial surface of the slice. Data were sampled at 10 kHz and slice activity was recorded at 37°C using a MEA2100-120 system (Bandwidth 1-3000 Hz, gain 5x; Multichannel Systems, Germany) using MC_Rack 4.5.1 software (Multichannel Systems, Germany). The slices were recorded in ACSF containing (in mM) 124 NaCl, 3 KCl, 26 NaHCO3, 1.6 CaCl2, 1.3 MgCl2, and 10 D-glucose and in ACSF containing (in mM) 6 KCl, 0 MgCl2, and 0 MgCl2. 2+ Slice activity was recorded in high potassium, magnesium-free, epileptogenic ACSF (6K 0Mg-ACSF).

[0198] Temporal lobe epilepsy mouse model

[0199] Six-week-old C57BL / 6j male mice were injected unilaterally with kainate (KA; 0.05 μl, 20 mM in saline) in the CA1 region of the right hippocampus (-2 mM anterior-posterior, +1.5 mM lateral, -1.4 mM dorsoventral) at a rate of 0.5 μl / min using a stereotaxic apparatus and a cannula (0.29 mm diameter) connected to a precision pump. The mice were then placed for 3 weeks to stabilize the chronic epileptic phenotype.

[0200] Telemetry EEG and video recording

[0201] EEG experiments were performed using a wireless ETA-F10 transmitter (DataSciences International, USA) for chronic EEG recording and video monitoring 3 weeks after KA injection. After anesthesia (ketamine, 95 mg / kg; xylazine, 10 mg / kg; ip), a 1 cm midline sagittal incision was made starting above the midline of the skull and extending along the neck to create a pocket for subcutaneous placement of the transmitter along the dorsal side of the animal. Recording flexible electrodes (stereotaxic coordinates: -2 mm, +1.5 mm anterior-posterior and -1.5 mm lateral) were implanted subdurally through a small hole drilled in the skull and held in place with dental cement. Two weeks after KA injection, mice were implanted with a wireless ETA-F10 transmitter and allowed to recover for 7 days before recording.

[0202] EEG signals were collected by a DSI radiofrequency receiver placed under each cage. EEG data were obtained using a DSI Dataquest ART system (version 4.33) at a sampling rate of 200 Hz. In order to evaluate the therapeutic potential of probenecid, KA mice were recorded in their cages with ETA-F10 DSI EEG electrodes for 48 hours, injected with probenecid (200 mg / kg in corn oil, Sigma-Aldrich; ip), and recorded 24 hours after treatment. NeuroScore software (DataSciences International, USA) was used to analyze seizures; seizures were detected on the EEG as spike trains with a minimum amplitude of 1.5X baseline, a minimum duration of 5s, and a frequency of ≥1 Hz (Bergstrom et al., Sci Rep. 2013; 3:1483.doi:10.1038 / srep01483). Artifacts were automatically detected using a high detection threshold and manually removed.

[0203] result

[0204] Probenecid completely blocks ictal discharges in human epileptic cortical tissue

[0205] To investigate whether the drug probenecid could be used as a treatment for epileptic seizures, electrophysiological activity of human epileptic cortical slices was recorded in epileptogenic conditions before and after probenecid administration (1 mM, 30 min).

[0206] Treatment with probenecid completely suppressed ictal discharges (IDs) in five of six human cortical slices, whereas it halved the duration of IDs in the remaining slice (Table 1, Figure 1A and B).

[0207]

[0208] Table 1; n = 6

[0209] Importantly, this control occurs in human tissues from a variety of pathological conditions, such as gliomas, focal cortical dysplasia, and dysembryoplastic neuroepithelial tumors (DNETs), suggesting that probenecid modulation of seizure activity may be a general mechanism underlying human epileptic seizures associated with a variety of diseases.

[0210] Finally, when ID-like events disappear, only small-amplitude interictal discharges (IIDs) or high-amplitude discharges previously described as preictal discharges (PIDs) persist ( Figure 1A and B).

[0211] Probenecid completely blocks spontaneous seizures in the kainic acid mouse model of temporal lobe epilepsy do

[0212] To further evaluate the therapeutic potential of probenecid, we tested the in vivo effects of probenecid administered i.p. in a kainate (KA) mouse model of chronic temporal lobe epilepsy. To this end, electroencephalogram (EEG) ( Figure 1C ).

[0213] A single probenecid injection completely blocked spontaneous seizures 4 to 8 hours after treatment (in all mice tested). Seizures then reappeared in 2 of 5 mice 20-24 hours after treatment, but of significantly shorter duration (Table 2, Figure 1C and D).

[0214]

[0215] Table 2; n=5

[0216] Together, these data suggest that probenecid, a well-established FDA- and EMA-approved uricosuric agent traditionally used to treat gout (Hediger et al., Physiology (Bethesda). 2005 Apr; 20: 125-33), may also be used as a therapy for human epilepsy and epileptic syndromes.

Claims

1. Use of probenecid or a pharmaceutically acceptable salt thereof as the sole active ingredient in the manufacture of a medicament for treating focal epilepsy in a human subject in need thereof.

2. The method according to claim 1, wherein the epilepsy is selected from familial epilepsy, genetic epilepsy, structural / metabolic epilepsy and epilepsy of unknown cause.

3. The use according to claim 1, wherein the epilepsy is brain tumor-related epilepsy. The use according to claim 1 , wherein the epilepsy is malformation of cortical development (MCD)-related epilepsy. The use according to claim 1 , wherein the epilepsy is neurodegeneration-related epilepsy. The use according to claim 1 , wherein the epilepsy is immune abnormality epilepsy.

7. Use according to any one of claims 1 to 6, wherein the epilepsy is treatment-resistant epilepsy.

8. The use according to any one of claims 1 to 6, wherein the subject is a child.

9. The use according to any one of claims 1 to 6, wherein the subject is an adult.

10. The use according to any one of claims 1 to 6, wherein probenecid or a pharmaceutically acceptable salt thereof is administered to the subject at a dose ranging from 1 mg / kg / day to 100 mg / kg / day.

11. The use according to any one of claims 1 to 6, wherein probenecid or a pharmaceutically acceptable salt thereof is for oral administration or injection.

12. Use of probenecid or a pharmaceutically acceptable salt thereof as the sole active ingredient in the manufacture of a medicament for treating a neurological disorder in a human subject in need thereof.

13. Use of probenecid or a pharmaceutically acceptable salt thereof as the sole active ingredient in the manufacture of a medicament for controlling clinical or electrographic epileptic seizures in a subject in need thereof.

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