WO2017130208A1 - Triple drug combination for treatment of status epilepticus and/or partial seizures and/or partial seizures with associated neurological disorders - Google Patents

Triple drug combination for treatment of status epilepticus and/or partial seizures and/or partial seizures with associated neurological disorders Download PDF

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WO2017130208A1
WO2017130208A1 PCT/IN2016/000268 IN2016000268W WO2017130208A1 WO 2017130208 A1 WO2017130208 A1 WO 2017130208A1 IN 2016000268 W IN2016000268 W IN 2016000268W WO 2017130208 A1 WO2017130208 A1 WO 2017130208A1
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seizures
combination
dopamine
pharmaceutical combination
selective
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French (fr)
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Hyder Pottoo FAHEEM
Tabassum NAHIDA
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Faheem Hyder Pottoo
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom

Definitions

  • the present invention belongs to the field of diseases and treatments f r central nervous system disorders (CNS) related to electroencephalographic changes and/or abnormal neurological conductance and/or neurodegeneration such as seizures and/or convulsions and/or epilepsies in particular status epilepticus and/or partial seizures and/ or partial seizures with associated neurological (Depression, Obsessive Compulsive Disorder, Parkinsonism e.t.c) and endocrine disorders (Osteoporosis).
  • CNS central nervous system disorders
  • Epilepsy is a chronic neurological condition characterized by abnonnal, recurrent, unprovoked, intense seizures and related neuronal damage (Blume, W.T., Luders, H.O., Mizrahi, E., Tassinari, C, Van Emde Boas, W., Engel, J. Jr., 2001. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia. 42(9), 1212-8.) Seizures are transient signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain (Fisher, R.
  • Epilepsy affects almost 70 million people of world (Ngugi, A. K., Bottomley, C, Klemschmidt, I., Sander, J.W., Newton, C.R., 2010. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia.
  • epilepsy for low income and middle income countries is estimated as 81.7/100,000/year, while for high income countries 45.0/100,000/year (Ngugi, A.K ., Kariuki, S.M., Bottomley, C, Kleinschmidt, I, Sander, J.W., Newton, C.R., 2011. Incidence of epilepsy A systematic review and meta-analysis. Neurology. 77(10), 1005-1012.).
  • the prevalence of epilepsy for low- and middle-income countries is about twice that of high-income countries (Ngugi, A. K., Bottomley, C, Kleinschmidt, I., Sander, J.W., Newton, C.R., 2010.
  • Partial seizures are those affecting initially only one hemisphere of the brain further classified into simple partial seizures, complex partial seizures and partial seizures with secondary generalization.
  • Generalized seizures begin in diffuse regions of the brain simultaneously in a bilaterally symmetric fashion classified into absence or petit mal seizures, atypical absence seizures, atonic seizures, myoclonic seizures and generalized tonic-clonic or grand mal seizures (Berg, A.T., Berkovic, S.F., Brodie, M.J., Buchhalter, J., Cross J.H., van Emde Boas, W., Engel .Jr., French, J., Glauser, T.A., Mathem, GW., Mosh, S.L., Nordli, D.Jr., Plouin, P., Scheffer, I.E., 2010.Revised terminology and concepts for organization of seizures and epilepsies; report of the ILAE Commission on Classification and Terminology, 2005-2009.
  • Epilepsia 51 , 676-685.
  • Status epilepticus is a medical and neurologic emergency and is defined a seizure that shows no clinical signs of arresting after a duration encompassing the great majority of seizures of that type in most patients or recurrent seizures without interictal resumption of baseline central nervous system function (Blume, W. T., Luders, H.O., Mizrahi, E., Tassinari, C, van Emde Boas, W., Engel, J., Jr. , 2001. Glossary of descriptive terminology for ictal semiology: Report of the ILAE task force on classification and terminology. Epilepsia, 42, 1212-1218).
  • This episode can be triggered through 2 main mechanisms: administration of a chemical convulsant, such as pilocarpine or kainic acid, or electrical stimulation.
  • a chemical convulsant such as pilocarpine or kainic acid
  • electrical stimulation a chemical convulsant
  • Pathological studies have been conducted in several of the status epilepticus models, including the 2 main chemoconvulsant models, the kainate model and the pilocarpine model, as well as electrical models.
  • These studies reported hippocampal pathology resembling typical patterns of mesial temporal sclerosis evident in many patients with temporal lobe epilepsy. (Cavalheiro, E.A., Leite, J.P., Bortolotto, Z.A., Turski, W.A., Ikonomidou, C, Turski, L., 1991.
  • Pilocarpine induced status epilepticus leads to significant loss of 5-HT neurons in the raphe nuclei along with depletion of 5-HT in hippocampus (Lin, W.H., Huang, H.P., Lin, M.X., Chen, S.G., Lv, X.C., Che, C.H., Lin, J.L., 2013. Seizure-induced 5-HT release and chronic impairment of serotonergic function in rats. Neurosci Lett. 534, 1-6).
  • mice with genetically increased 5- HT levels the threshold to kainic acid-induced seizures was increased (Tripathi, P.P., Di Giovannantonio, L.G., Viegi, A., Wurst, W., Simeone, A., Bozzi, Y., 2008. Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice. J. Neurosci. 28, 9271-9276.)
  • fluoxetine in rats was claimed to suppress maximal electroshock- induced seizures (Prendiville, S., Gale, K., 1993. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia.
  • mice Pentetrazole-induced convulsions in mice (Magyar, J., Rusznak, Z., Harasztosi, C, Kortvely, A., Pacher, P., Banyasz, T., Csaba, P., et al. 2003. Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues. Int J Mol Med. 11, 535-542.) audiogenic seizures in genetically epilepsy-prone DBA/2J or GEPRs rats (Dailey, J.W., Yan, Q.S., Mishra, P.K., Burger, R.L., Jobe, P.C., 1992.
  • Dopamine (DA) also plays a major role in the control of epileptic seizures arising in the limbic system, through D1/D2 receptor-mediated signalling (Bozzi, Y., Borrelli, E., 2002. Dopamine D2 receptor signalling controls neuronal cell death induced by muscarinic and glutamatergic drugs. Mol. Cell. Neurosci. 19, 263-271 ). The Dl and D2 receptors seem to play opposite roles in regulating the threshold for seizures ( Starr, M. S., 1993. Regulation of seizure threshold by
  • Hyperprolactinaemia and temporal lobe epilepsy in a woman concomitant and persistent prolactin suppression and temporal lobe epilepsy relief.
  • estrogen 170 of estrogen is limited due its proconvulsant nature mediated by facilitation of excitatory (glutaminergic) transmission (Lange, S.C., Mien, R.M., 1978. Re-evaluation of estrogen- induced cortical and thalamic paraoxymal EEG activity in the cat. Electroencephalogr Clin Neurophysiol. 44, 94-103; Foy, M.R., Xu, J., Xie, X., Brinton, R.D., Thompson, R.F., Berger, T. W., 1999. 17 -estradiol enhances nmda receptor-mediated EPSPs and long-term potentiation. J
  • the objective of the present invention is to provide a better and superior therapy for seizures and/or epilepsies and/or convulsions and/or neurodegeneration with or without associated neurological (Depression, Obsessive Compulsive Disorder, Parkinsonism e.t.c) and endocrine 190 disorders (Osteoporosis).
  • Another objective of the invention is to increase tolerability, avoid excessive drug loading, minimize side effects, improve patient compliance and reduce cost of therapy.
  • a further objective of invention is to provide treatment to refractory epilepsies with or without associated neurological degeneration and disorders.
  • Yet another objective of the invention is to maintain function of neuronal circuits and repair damaged neuronal connectivity.
  • An additional objective of the invention is to provide treatment of seizures and/or epilepsy and/or convulsions and/or neurodegeneration with or without associated neurological degeneration and disorders, in pregnant and lactating women.
  • the 210 receptor modulator e.g Raloxifene
  • second compound having activity as selective serotonin reuptake inhibitor e.g Fluoxetine
  • third compound having activity as dopamine (D2) receptor agonist e.g Bromocriptine
  • administered to a mammal in need thereof for the said condition exhibits unexpected synergistic effect.
  • the preferred disorders include status epilepticus (SE) and/or partial seizures and/or partial seizures with associated neurological
  • the preferred formulations include (but not limited to) tablets, capsules, suspensions, emulsions, injectables, ointments, creams.
  • the present invention provides a synergistic pharmaceutical combination, comprising selective estrogen receptor modulators) in combination with selective serotonin
  • 220 reuptake inhibitor(s) and dopamine (D2) receptor agonists, wherein selective estrogen receptor modulators) is selected from raloxifene, clomifene, femarelle, ormeloxifene, tamoxifene, toremifene, lasofoxifene, ospimefene, arzoxifene, avalycoxifene, Idoxifene, afimoxifene, nafoxidine, levormeloxifene or combination thereof, wherein the selective serotonin reuptake inhibitors) is selected from fluoxetine, fluvoxamine, paroxetine, sertraline,
  • dopamine (D2) receptor agonist is selected from Bromocriptine, Ropinirole, Sumanirole, N,N-Propyldihydrexidine, Cabergoline, Talipexole, Piribedil, Pramipexole, Quinpirole , Quinelorane or combination thereof.
  • the selective estrogen receptor modulator is 230 Raloxifene.
  • the selective serotonin reuptake inhibitor is Fluoxetine.
  • the dopamine (D2) receptor agonist is Bromocriptine.
  • the selective estrogen receptor modulator is used in the range of 1 mg to 1000 mg.
  • the selective estrogen receptor modulator is preferably used in the range of 10 mg to 100 mg.
  • the selective serotonin reuptake inhibitor is used 240 in the range of 1 mg to 1000 mg.
  • the selective serotonin reuptake inhibitor is preferably used in the range of 20 mg to 200 mg.
  • the dopamine (D2) receptor agonist is used in the range of 1 mg to 1000 mg.
  • the dopamine (D2) receptor agonist is preferably used in the range of 10 mg to 100 mg.
  • the selective estrogen receptor modulator(s), selective serotonin reuptake inhibitor(s) and dopamine (D2) receptor agonist(s) are present in the form of pharmaceutically acceptable salts, hydrates and prodrugs thereof along with the one or 250 more of nutraceutically or pharmaceutically or dietically acceptable excipients such as diluents, additives, disintegrants, colorants, flavoring agents, sweetening agents.
  • the individual components may be in the form of pharmaceutically acceptable salts, hydrates and prodrugs thereof. While the compositions may optionally comprise one or more of nutraceutically or pharmaceutically or dietically acceptable 255 excipients such as diluents, additives, disintegrants, colorants, flavoring agents, sweetening agents etc.
  • Yet another embodiment of the present invention provides a method for the treatment of seizures and/or convulsions and/or epilepsies and/or electrical conductance related disorders and/or neurodegeneration, comprising administering to a mammal in need of the treatment a 260 therapeutically effective amount of pharmaceutical combination, comprising a selective estrogen receptor modulator, selective serotonin uptake inhibitor and dopamine (D2) receptor agonist wherein the said treatment has a potentiating effect.
  • a 260 therapeutically effective amount of pharmaceutical combination comprising a selective estrogen receptor modulator, selective serotonin uptake inhibitor and dopamine (D2) receptor agonist wherein the said treatment has a potentiating effect.
  • the preferred disorder and/or disease is status epilepticus and/or partial seizures and/or partial seizures with associated neurological disorders 265 (depression, obsessive compulsive disorder, parkinsonism) and endocrine disorders (osteoporosis)
  • the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate 270 administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should be such that both agents are present in the body so as to produce the synergistic effect of the combination.
  • 285 status epilepticus (SE) induction by pilocarpine 285 status epilepticus (SE) induction by pilocarpine.
  • SE 285 status epilepticus
  • the systemic administration of a potent muscarinic agonist pilocarpine in mice promotes sequential behavioral and electrographic changes that can be divided into 3 distinct periods: (a) an acute period that built up progressively into a limbic status epilepticus and that lasts 24 h, (b) a silent period with a progressive normalization of EEG and behavior which varies from 4 to 44 days, and (c) a chronic period
  • SRSs spontaneous recurrent seizures
  • the model was standardized at Pilocarpine (300 mg/kg, i.p) in mice.
  • the behavioral progression of pilocarpine induced convulsions were recorded with slight modifications from racine (1972) into 6 stages as i) immobilization and staring ii) head nodding iii) rearing accompanied by forelimb clonus and wet dog shakes iv) falling and wobbling v) jumping, circling, or rolling vi) severe tonic-clonic seizures.
  • mice Swiss albino mice were randomly divided into 12 groups consisting of 10 animals each, a 4-week treatment schedule for oral dosing was followed; raloxifene, fluoxetine and bromocriptine mesylate were selected as representative compounds from selective estrogen receptor modulators, selective serotonin reuptake inhibitors and dopamine (D2) receptor agonists.
  • the treatments arms were classified as:
  • Table 1 Treatment Schedule Pilocarpine induced status epilepticus (SE) in mice.
  • 325 SV Sodium valproate (300 mg/kg) orally once daily for 4 weeks.
  • RF Raloxifene, RF 1 ( 4 mg/kg) and RF 2 (8 mg/kg) orally once daily for 4 weeks.
  • FT Fluoxetine, FT 1 (14 mg/kg) and FT 2 ( 22 mg kg) orally once daily for 4 weeks.
  • BC Bromocriptine, BC 1 (6 mg/kg) and BC 2 (10 mg/kg) orally once daily for 4 weeks.
  • P Pilocarpine (300 mg/kg, i.p) on last day of 4 weeks treatment schedule.
  • 330 TC Toxic control (Pilocarpine, 300 mg/kg, i.p ) administered as a single dose.
  • the present invention relates to a pharmaceutical composition of selective estrogen receptor modulator(s) in combination with selective serotonin reuptake inhibitor(s) and dopamine (D2) receptor agonists.
  • the said combination is used in the prophylaxis and/or management and/or treatment of seizures and/or epilepsies and/or convulsions and/or 355 neurodegeration with or without associated neurological and endocrine disorders.
  • the combination is most preferably given in the form of tablets, capsules, suspensions, emulsions, infusion solution, injection solution, cream, gel, granules, ointment, enema e.t.c
  • the first compound is selected from the group consisting of Raloxifene, Clomifene, Femarelle, Ormeloxifene, Tamoxifene, Toremifene, Lasofoxifene, Ospimefene, Arzoxifene, Bazedoxifene,
  • second compound is selected from the group consisting of Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram, Dapoxetine and/or other agents having such properties or having potential for such activity
  • third compound is selected from the group consisting of Bromocriptine, Ropinirole,
  • Epileptic seizures and epilepsy definitions proposed by the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 46 (4), 470-2.
  • Dopaminergic drugs may counteract behavioral and biochemical changes induced by models of brain injury. Eur. Neuropsychopharmacol. 16, 195-203.

Abstract

Disclosed herein is a pharmaceutical combination or composition, comprising of selective estrogen receptor modulator(s) in combination with selective serotonin reuptake inhibitors) and dopamine (D2) receptor agonists in the treatment and/or management of seizures and/or convulsions and/or epilepsies and/or neurodegeneration with or without associated neurological (Depression, Obsessive Compulsive Disorders, Parkinsonism e.t.c) and endocrine disorders (Osteoporosis), Further the present invention also discloses a preferable synergistic combination of Raloxifene with Fluoxetine and Bromocriptine in the treatment and/or management of above mentioned disorders and/or disease states in paiticular status epilepticus and/or partiai seizures and/or partial seizures with associated neurological and endocrine disorders. Preferred formulations include tablets, capsules, suspensions, emulsions, injectables, ointments, creams and other suitable formulations as may be deemed necessary.

Description

DESCRI PT ION
Triple Dr g Combination for Treatment of Status Epilepticus and/or Partial Seizures and/or Partial Seizures with associated Neurological Disorders.
FIELD OF INVENTION The present invention belongs to the field of diseases and treatments f r central nervous system disorders (CNS) related to electroencephalographic changes and/or abnormal neurological conductance and/or neurodegeneration such as seizures and/or convulsions and/or epilepsies in particular status epilepticus and/or partial seizures and/ or partial seizures with associated neurological (Depression, Obsessive Compulsive Disorder, Parkinsonism e.t.c) and endocrine disorders (Osteoporosis).
DESCRIPTION OF PRIOR ART
Epilepsy is a chronic neurological condition characterized by abnonnal, recurrent, unprovoked, intense seizures and related neuronal damage (Blume, W.T., Luders, H.O., Mizrahi, E., Tassinari, C, Van Emde Boas, W., Engel, J. Jr., 2001. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia. 42(9), 1212-8.) Seizures are transient signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain (Fisher, R. S., van Emde Boas, W., Blume, W., Elger, C, Genton, P., Lee, P., Engel, J. Jr. 2005. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (EBE). Epilepsia. 46 (4), 470-2.) Epilepsy affects almost 70 million people of world (Ngugi, A. K., Bottomley, C, Klemschmidt, I., Sander, J.W., Newton, C.R., 2010. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia. 51 (5), 883-90.) The incidence of epilepsy for low income and middle income countries is estimated as 81.7/100,000/year, while for high income countries 45.0/100,000/year (Ngugi, A.K ., Kariuki, S.M., Bottomley, C, Kleinschmidt, I, Sander, J.W., Newton, C.R., 2011. Incidence of epilepsy A systematic review and meta-analysis. Neurology. 77(10), 1005-1012.). Similarly the prevalence of epilepsy for low- and middle-income countries is about twice that of high-income countries (Ngugi, A. K., Bottomley, C, Kleinschmidt, I., Sander, J.W., Newton, C.R., 2010. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia. 51 (5), 883-90.). The median life time epilepsy prevalence for low income and middle income countries is 15.4 per 1,000 for rural and 10.3 per 1,000 for urban areas while for high income countries 5.8 per 1,000. similarly the median active epilepsy for low- and middle-income countries is 12.7 per 1 ,000 in rural and 5.9 per 1,000 in urban areas and for high income countries 4.9 per 1,000 (Ngugi, A. K., Bottomley, C, Kleinschmidt, I., Sander, J.W., Newton, C.R., 2010. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia. 51 (5), 883-90). The major types of seizures recognized are partial seizures, generalized seizures and status epilepticus (SE). Partial seizures are those affecting initially only one hemisphere of the brain further classified into simple partial seizures, complex partial seizures and partial seizures with secondary generalization. Generalized seizures begin in diffuse regions of the brain simultaneously in a bilaterally symmetric fashion classified into absence or petit mal seizures, atypical absence seizures, atonic seizures, myoclonic seizures and generalized tonic-clonic or grand mal seizures (Berg, A.T., Berkovic, S.F., Brodie, M.J., Buchhalter, J., Cross J.H., van Emde Boas, W., Engel .Jr., French, J., Glauser, T.A., Mathem, GW., Mosh, S.L., Nordli, D.Jr., Plouin, P., Scheffer, I.E., 2010.Revised terminology and concepts for organization of seizures and epilepsies; report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 51 , 676-685). Status epilepticus is a medical and neurologic emergency and is defined a seizure that shows no clinical signs of arresting after a duration encompassing the great majority of seizures of that type in most patients or recurrent seizures without interictal resumption of baseline central nervous system function (Blume, W. T., Luders, H.O., Mizrahi, E., Tassinari, C, van Emde Boas, W., Engel, J., Jr. , 2001. Glossary of descriptive terminology for ictal semiology: Report of the ILAE task force on classification and terminology. Epilepsia, 42, 1212-1218). Status epilepticus is associated with high mortality rates ranging from 3% to 33% (Coeytaux, A., Jallon, P., Galobardes, B., Morabia, A., 2000. Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR). Neurology. 55(5), 693-7). The successful search for new antiepileptic drugs largely lies on choice of appropriate animal models for the initial in vivo testing of potential anticonvulsant compounds. The principal animal models of temporal lobe epilepsy i.e the most common type of partial complex seizure in adulthood involve experimental manipulations in which the epileptic condition results as a downstream consequence of brain damage induced by an acute episode of status epilepticus. This episode can be triggered through 2 main mechanisms: administration of a chemical convulsant, such as pilocarpine or kainic acid, or electrical stimulation. Pathological studies have been conducted in several of the status epilepticus models, including the 2 main chemoconvulsant models, the kainate model and the pilocarpine model, as well as electrical models. These studies reported hippocampal pathology resembling typical patterns of mesial temporal sclerosis evident in many patients with temporal lobe epilepsy. (Cavalheiro, E.A., Leite, J.P., Bortolotto, Z.A., Turski, W.A., Ikonomidou, C, Turski, L., 1991. Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous seizures. Epilepsia. 32, 778-782; Sloviter, R.S., 1987. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science. 235, 73-75; Sloviter, R.S., Dean, E., Sollas, A.L., Goodman, J.H., 1996. Apoptosis and necrosis induced in different hippocampal neuron populations by repetitive perforant path stimulation in the rat. J Comp Neurol. 366, 516— 533; Turski, L., Ikonomidou, C, Turski, W.A., Bortolotto, Z.A., Cavalheiro, E.A.. 1989. Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel model of intractable epilepsy. Synapse. 3, 154-171). Despite the use of traditional antiseizure and/or anti-epileptic drugs such as phenobarbital, primidone, phenytoin, carbamazepine, and valproate as well as newer antiepileptic drugs like felbamate, topiramate, tiagabine, 30% to 40% of patients continue to have seizures ( wan, P., Schachter, S.C., Brodie, M.J., 2011. Drug- resistant epilepsy. N Engl J Med 369:919-926.) and 20-30% of patients with epilepsy have psychiatric disturbances (Vuilleumier, P., Jallon, P., 1998. Epilepsy and psychiatric disorders: epidemiological data. Rev Neurol (Paris). 154(4), 305-17). Thus need of hour is to shift from traditional approach of modulating epileptic seizures via targeting sodium channel, gamma amino butyric acid and calcium channels towards novel targets such as neurotransmitters which would either establish complete amelioration of epileptic seizures and/or serve as base for the same. The neurotransmitters, serotonin and dopamine play a vital role in modulation and regulation of epileptic seizures and/or epilepsy.
Pilocarpine induced status epilepticus leads to significant loss of 5-HT neurons in the raphe nuclei along with depletion of 5-HT in hippocampus (Lin, W.H., Huang, H.P., Lin, M.X., Chen, S.G., Lv, X.C., Che, C.H., Lin, J.L., 2013. Seizure-induced 5-HT release and chronic impairment of serotonergic function in rats. Neurosci Lett. 534, 1-6). In mice with genetically increased 5- HT levels the threshold to kainic acid-induced seizures was increased (Tripathi, P.P., Di Giovannantonio, L.G., Viegi, A., Wurst, W., Simeone, A., Bozzi, Y., 2008. Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice. J. Neurosci. 28, 9271-9276.) Among the SSRIs; fluoxetine in rats was claimed to suppress maximal electroshock- induced seizures (Prendiville, S., Gale, K., 1993. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia. 34, 381-384.) , Pentetrazole-induced convulsions in mice (Magyar, J., Rusznak, Z., Harasztosi, C, Kortvely, A., Pacher, P., Banyasz, T., Csaba, P., et al. 2003. Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues. Int J Mol Med. 11, 535-542.) audiogenic seizures in genetically epilepsy-prone DBA/2J or GEPRs rats (Dailey, J.W., Yan, Q.S., Mishra, P.K., Burger, R.L., Jobe, P.C., 1992. Effects of fluoxetine on convulsions and on brain serotonin as detected by microanalysis in genetically epilepsy- prone rats. J Pharmacol Exp Ther. 2, 533- 540.) and focally evoked limbic motor seizures in rats (Prendiville, S., Gaie, K., 1993. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia.
105 34, 381-384.). In addition fluoxetine in combination with phenytoin, carbamazepine and ameltolide has been reported to produce a dose-dependable reduction in their ED50 values against MES-induced tonic-extensor seizures in mice (Leander, J.D., 1992. Fluoxetine, a selective serotonin uptake inhibitor, enhances the anticonvulsant effects of phenytoin, carbamazepine, and ameltolide (LY2011 16). Epilepsia. 33, 573-576.) Also, fluoxetine
110 significantly enhanced the anticonvulsive action of sodium valproate but not that of ethosuximide against PTZ-induced clonic convulsions in mice (Borowicz, K.K., Piskorska, B., Stepniak, B., Czuczwar, S.J., 2012. Effects of fluoxetine on the anticonvulsant action of valproate and ethosuximide in mouse model of myoclonic convulsions. Annals of Agricultural and Environmental Medicine. 19(3), 487-490.) In severe seizure GEPRs (GEPR-s) the
115 combination of fluoxetine with 5-HT1A somatodendritic autoreceptor antagonists (-)-pindolol and LY 206130 (l-[l-H-indol-4-yloxy]-3-[cyclohexylamino]-2-propanol maleate) enhanced the anticonvulsant action. (Browning, R.A., Wood, A.V., Merrill, M.A., Dailey, J.W., Jobe, P.C., 1997. Enhancement of the anticonvulsant effect of fluoxetine following blockade of 5-HT 1A receptors. Eur. J. Pharmacol. 336, 1-6.) It is widely known that enhancement of 5-HT release by
120 standard anti-seizure drugs (e.g., valproic acid, carbamazepine, phenytoin, lamotrigine and zonisamide) partly contributes to their antiseizure effects (Okada, M., Kaneko, S., Hirano, T., Ishida, M., Kondo ,T., Otani, K., Fukushima, Y., 1992. Effects of zonisamide on extracellular levels of monoamine and its metabolite, and on Ca2+-dependent dopamine release. Epilepsy Res. 13, 113—119; Dailey, J.W., Yan, Q.S., Adams-Curtis, L.E., Ryu, J.R., Ko, K.H., Mishra,
125 P.K., Jobe, P.C., 1996. Neurochemical correlates of antiepileptic drugs in the genetically epilepsy-prone rat (GEPR). Life Sci. 58, 259—266; Ahmad, S., Fowler, L.J., Whitton, P.S., 2005. Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5- hydroxytryptamine, dopamine and amino acids. Epilepsy Res. 63, 141— 149.). Contrary depletion in brain levels of 5-HT by agents such as p-chlorophenylalanine enhances the seizure
130 induction (Browning, R.A., Wood, A.V., Merrill, M.A., Dailey, J.W., Jobe, P.C., 1997.
Enhancement of the anticonvulsant effect of fluoxetine following blockade of 5-HT 1A receptors. Eur. J. Pharmacol. 336, 1-6.; Statnick, M.A., Maring-Smith, M.L., Clough, R.W., Wang, C, Dailey, J.W., Jobe, PC, Browning, R.A., 1996. Effect of 5,7-d ydroxytryptamine on audiogenic seizures in genetically epilepsy-prone rats. Life Sci. 59, 1763— 1771.). 135 Dopamine (DA) also plays a major role in the control of epileptic seizures arising in the limbic system, through D1/D2 receptor-mediated signalling (Bozzi, Y., Borrelli, E., 2002. Dopamine D2 receptor signalling controls neuronal cell death induced by muscarinic and glutamatergic drugs. Mol. Cell. Neurosci. 19, 263-271 ). The Dl and D2 receptors seem to play opposite roles in regulating the threshold for seizures ( Starr, M. S., 1993. Regulation of seizure threshold by
140 Dl versus D2 receptors," in D1/D2 Dopamine Receptor Interactions ed. Waddington J., editor.
(New York: Academic Press; ) 235-269. The absence of D2R lowers the threshold for seizures induced by both glutamate and acetylcholine (Bozzi, Y., Borrelli, E., 2002. Dopamine D2 receptor signaling controls neuronal cell death induced by muscarinic and glutamatergic drugs. Mol. Cell. Neurosci. 19, 263-271). Bromocriptine demonstrated anti-epileptic effects , in
145 case of self-induced, drug-resistant epilepsy (Clemens, B., 1988. Dopamine agonist treatment of self-induced pattern-sensitive epilepsy. A case report. Epilepsy Res. 2, 340-343.) and neuroprotective efficacy against KA-induced brain damage (Micale, V., Incognito, T., Ignoto, A., Rampello, L., Sparta, M., Drago, F. , 2006. Dopaminergic drugs may counteract behavioral and biochemical changes induced by models of brain injury. Eur. Neuropsychopharmacol. 16,
150 195-203). While in clinical studies it has shown potential to reduce seizure severity in Temporal lobe epilepsy (TLE) patients affected by pituitary prolactinomas (Gatterau, A., Vezina, J., Rousseau, S., Bielmann, P. , 1990. Hyperprolactinaemia and temporal lobe epilepsy in a woman: concomitant and persistent prolactin suppression and temporal lobe epilepsy relief. J. Endocrinol. Invest. 13, 247-249; Saie, D. J., Sills, E. S., 2005. Hyperprolactinemia presenting
155 with encephalomalacia-associated seizure disorder and infertility: a novel application for bromocriptine therapy in reproductive endocrinology. Neuro Endocrinol. Lett. 26, 533-535.; Deepak, D., Daousi, C, Javadpour, M., MacFarlane, I. A., 2007. Macroprolactinomas and epilepsy.Clin. Endocrinol. 66, 503-507). Interestingly prolonged use of bromocriptine treatment was without any severe side effects (Gatterau, A., Vezina, J., Rousseau, S., Bielmann, P. ,
160 1990. Hyperprolactinaemia and temporal lobe epilepsy in a woman: concomitant and persistent prolactin suppression and temporal lobe epilepsy relief. J. Endocrinol. Invest. 13, 247-249; Saie, D. J., Sills, E. S., 2005. Hyperprolactinemia presenting with encephalomalacia-associated seizure disorder and infertility: a novel application for bromocriptine therapy in reproductive endocrinology. Neuro Endocrinol. Lett. 26, 533-535.; Deepak, D., Daousi, C, Javadpour, M.,
165 MacFarlane, I. A., 2007. Macroprolactinomas and epilepsy.Clin. Endocrinol. 66, 503-507; Chen, S. C, 2006. Epilepsy and migraine: the dopamine hypotheses. Med. Hypotheses. 66, 466-472).
These neurotransmitter systems work not only in isolation but are directly affected by the organizational effects exhibited by ovarian hormones especially estrogen in the development stage of brain and activational effects of estrogen, which come in adulthood stage. However use
170 of estrogen is limited due its proconvulsant nature mediated by facilitation of excitatory (glutaminergic) transmission (Lange, S.C., Mien, R.M., 1978. Re-evaluation of estrogen- induced cortical and thalamic paraoxymal EEG activity in the cat. Electroencephalogr Clin Neurophysiol. 44, 94-103; Foy, M.R., Xu, J., Xie, X., Brinton, R.D., Thompson, R.F., Berger, T. W., 1999. 17 -estradiol enhances nmda receptor-mediated EPSPs and long-term potentiation. J
175 Neurophysiol. 81, 925-929). These limitations have been overcome by selective estrogen receptor modulators (SERMs) which act as estrogen agonist and antagonist in a tissue specific manner. Raloxifene, a SERM approved for osteoporosis, has been demonstrated to protect the hippocampus from the excitotoxic effects of kainic acid (Ciriza, I., Carrero, P., Azcoitia, I., Lundeen, S. G., Garcia-Segura, L. M., 2004. Selective estrogen receptor modulators protect
180 hippocampal neurons from kainic acid excitotoxicity: differences with the effect of estradiol. J Neurobiol. 61, 209-221). It has also been shown to reduce morbidity, number of seizures and to delay the latency to seizures after pilocarpine-induced status epilepticus (SE) in rats (Scharfman, H. E.( Malthankar-Phatak, G. H., Friedman, D., Pearce,P. P., McCloskey, D. P., Harden, C. L & MacLusky, N. J. (2009) A Rat Model of Epilepsy in Women: a Tool to Study Physiological
185 Interactions Between Endocrine Systems and Seizures. Endocrinology. 150(9), 4437-42.).
OBJECTIVES OF THE INVENTION:
The objective of the present invention is to provide a better and superior therapy for seizures and/or epilepsies and/or convulsions and/or neurodegeneration with or without associated neurological (Depression, Obsessive Compulsive Disorder, Parkinsonism e.t.c) and endocrine 190 disorders (Osteoporosis).
Another objective of the invention is to increase tolerability, avoid excessive drug loading, minimize side effects, improve patient compliance and reduce cost of therapy.
A further objective of invention is to provide treatment to refractory epilepsies with or without associated neurological degeneration and disorders.
195 Yet another objective of the invention is to maintain function of neuronal circuits and repair damaged neuronal connectivity.
An additional objective of the invention is to provide treatment of seizures and/or epilepsy and/or convulsions and/or neurodegeneration with or without associated neurological degeneration and disorders, in pregnant and lactating women. 200 SUMMARY OF INVENTION:
Patients with uncontrolled seizures experience significant morbidity and mortality and face social stigma and discrimination as well .The applicant has perceived that instead of several efforts made in the art, there is still a need to develop a effective synergistic therapeutic combination for treating and/or controlling and/or decreasing incidence of all types of seizures
205 and/or epilepsies and/or convulsions and/or neurodegeneration with or without associated neurological and endocrine disorders, as the existing drugs afford only symptomatic relief, The 30-40% patients remain refractory and 20-30% of patients with epilepsy have associated psychiatric disturbances. During research work it was surprisingly found that combination of effective amounts of three compounds; first compound having activity as selective estrogen
210 receptor modulator (e.g Raloxifene), second compound having activity as selective serotonin reuptake inhibitor (e.g Fluoxetine) and third compound having activity as dopamine (D2) receptor agonist (e.g Bromocriptine) administered to a mammal in need thereof for the said condition exhibits unexpected synergistic effect. The preferred disorders include status epilepticus (SE) and/or partial seizures and/or partial seizures with associated neurological
215 disorders. The preferred formulations include (but not limited to) tablets, capsules, suspensions, emulsions, injectables, ointments, creams.
DETAILED DESCRIPTION OF INVENTION:
Accordingly, the present invention provides a synergistic pharmaceutical combination, comprising selective estrogen receptor modulators) in combination with selective serotonin
220 reuptake inhibitor(s) and dopamine (D2) receptor agonists, wherein selective estrogen receptor modulators) is selected from raloxifene, clomifene, femarelle, ormeloxifene, tamoxifene, toremifene, lasofoxifene, ospimefene, arzoxifene, bazedoxifene, droloxifene, Idoxifene, afimoxifene, nafoxidine, levormeloxifene or combination thereof, wherein the selective serotonin reuptake inhibitors) is selected from fluoxetine, fluvoxamine, paroxetine, sertraline,
225 citalopram, escitalopram, dapoxetine or combination thereof. Wherein dopamine (D2) receptor agonist is selected from Bromocriptine, Ropinirole, Sumanirole, N,N-Propyldihydrexidine, Cabergoline, Talipexole, Piribedil, Pramipexole, Quinpirole , Quinelorane or combination thereof.
In another embodiment of the present invention, the selective estrogen receptor modulator is 230 Raloxifene. In another embodiment of the present invention, the selective serotonin reuptake inhibitor is Fluoxetine.
In another embodiment of the present invention, the dopamine (D2) receptor agonist is Bromocriptine.
235 In yet another embodiment of the present invention, the selective estrogen receptor modulator is used in the range of 1 mg to 1000 mg.
In another embodiment of the present invention, the selective estrogen receptor modulator is preferably used in the range of 10 mg to 100 mg.
In another embodiment of the present invention, the selective serotonin reuptake inhibitor is used 240 in the range of 1 mg to 1000 mg.
In another embodiment of the present invention, the selective serotonin reuptake inhibitor is preferably used in the range of 20 mg to 200 mg.
In another embodiment of the present invention, the dopamine (D2) receptor agonist is used in the range of 1 mg to 1000 mg.
245 In another embodiment of the present invention, the dopamine (D2) receptor agonist is preferably used in the range of 10 mg to 100 mg.
In another embodiment of the present invention, the selective estrogen receptor modulator(s), selective serotonin reuptake inhibitor(s) and dopamine (D2) receptor agonist(s) are present in the form of pharmaceutically acceptable salts, hydrates and prodrugs thereof along with the one or 250 more of nutraceutically or pharmaceutically or dietically acceptable excipients such as diluents, additives, disintegrants, colorants, flavoring agents, sweetening agents.
In another embodiment of the present invention, the individual components may be in the form of pharmaceutically acceptable salts, hydrates and prodrugs thereof. While the compositions may optionally comprise one or more of nutraceutically or pharmaceutically or dietically acceptable 255 excipients such as diluents, additives, disintegrants, colorants, flavoring agents, sweetening agents etc.
Yet another embodiment of the present invention provides a method for the treatment of seizures and/or convulsions and/or epilepsies and/or electrical conductance related disorders and/or neurodegeneration, comprising administering to a mammal in need of the treatment a 260 therapeutically effective amount of pharmaceutical combination, comprising a selective estrogen receptor modulator, selective serotonin uptake inhibitor and dopamine (D2) receptor agonist wherein the said treatment has a potentiating effect.
In another embodiment of the present invention, the preferred disorder and/or disease is status epilepticus and/or partial seizures and/or partial seizures with associated neurological disorders 265 (depression, obsessive compulsive disorder, parkinsonism) and endocrine disorders (osteoporosis)
Herein, the term "combination" is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to simultaneous administration. In another aspect of the invention "combination" refers to separate 270 administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should be such that both agents are present in the body so as to produce the synergistic effect of the combination.
The following description is put forth so as to provide those of ordinary skill in the art with a 275 complete disclosure and description of the effectiveness of the compositions and methods of the invention and are not intended to limit the scope of what the inventors regard as their invention.
Experimental Design:
The successful search for new antiepileptic drugs largely lies on choice of appropriate animal models for the initial in vivo testing of potential anticonvulsant compounds. At present,
280 preclinical animal studies are indispensable in exploring the efficacy and safety of an investigational AED before its introduction in human volunteers, one such preclinical evaluation employs pilocarpine induced status epilepticus (SE) model. The pilocarpine model was developed by Turski's group (1983). These initial studies provided a qualitative but extensive description of the behavioral, electroencephalographic and histopathological consequences of
285 status epilepticus (SE) induction by pilocarpine. The systemic administration of a potent muscarinic agonist pilocarpine in mice promotes sequential behavioral and electrographic changes that can be divided into 3 distinct periods: (a) an acute period that built up progressively into a limbic status epilepticus and that lasts 24 h, (b) a silent period with a progressive normalization of EEG and behavior which varies from 4 to 44 days, and (c) a chronic period
290 with spontaneous recurrent seizures (SRSs). It has been shown that duration of SE during the initial insult is critical to the duration of latent period and subsequent development of SRSs and brain damage. Lemos and Cavalheiro (1995) conducted first study of its kind where adult male wistar rats were injected with a single dose of pilocarpine (300-320 mg/kg, i.p.) followed by a combined diazepam (10 mg/kg) and pentobarbital (30 mg kg) treatment and a progressive increase in the mean latency to the first spontaneous seizure and a decrease in seizure frequency in animals with shorter SE (1 and 2 h) was observed along with less severe neuropathological alterations in the said animals. Finally study ended up showing that animals experiencing only 30 min of SE did not develop SRSs (Lemos and Cavalheiro, 1995). Contrary Klitgaard et al (2002) observed SRSs in rats that had experienced 30 min SE, and has terminated SE by injecting diazepam intravenously at 10 mg/kg. Nevertheless the probability, latency and severity of SRSs and of neuropathological changes decreases with decreased SE duration (Liu et al., 1994; Lemos and Cavalheiro, 1995). Hence if a drug abolishes the onset of SE or restricts its duration to few minutes the subsequent development of chronic epilepsy can be prevented.
The model was standardized at Pilocarpine (300 mg/kg, i.p) in mice. The behavioral progression of pilocarpine induced convulsions were recorded with slight modifications from racine (1972) into 6 stages as i) immobilization and staring ii) head nodding iii) rearing accompanied by forelimb clonus and wet dog shakes iv) falling and wobbling v) jumping, circling, or rolling vi) severe tonic-clonic seizures.
Swiss albino mice were randomly divided into 12 groups consisting of 10 animals each, a 4-week treatment schedule for oral dosing was followed; raloxifene, fluoxetine and bromocriptine mesylate were selected as representative compounds from selective estrogen receptor modulators, selective serotonin reuptake inhibitors and dopamine (D2) receptor agonists. The treatments arms were classified as:
Table 1: Treatment Schedule Pilocarpine induced status epilepticus (SE) in mice.
Figure imgf000012_0001
Abbreviations:
325 SV : Sodium valproate (300 mg/kg) orally once daily for 4 weeks.
RF: Raloxifene, RF 1 ( 4 mg/kg) and RF 2 (8 mg/kg) orally once daily for 4 weeks.
FT: Fluoxetine, FT 1 (14 mg/kg) and FT 2 ( 22 mg kg) orally once daily for 4 weeks.
BC: Bromocriptine, BC 1 (6 mg/kg) and BC 2 (10 mg/kg) orally once daily for 4 weeks.
P: Pilocarpine (300 mg/kg, i.p) on last day of 4 weeks treatment schedule.
330 TC: Toxic control (Pilocarpine, 300 mg/kg, i.p ) administered as a single dose.
By the end of 4 week treatment schedule each group except the normal control which received vehicle were subjected to pilocarpine induced status epilepticus and were evaluated for anticonvulsant effect. The criterion for the anticonvulsant effect was decrease in seizure severity of
335 drug treated groups compared with toxic group. The normal control was compared with toxic control while all treatment arms were compared with toxic control. The monotherapy with Fluoxetine was ineffective while monotherapy with Raloxifene and Bromocriptine exhibited anti-seizure effects. Raloxifene + Fluoxetine + Bromocriptine (4 mg/kg + 14 mg/kg + 6 mg/kg) combination however exhibited best anti-convulsant effect by scoring minimum on seizure
340 severity scale compared to toxic control. Also, Raloxifene + Fluoxetine + Bromocriptine (4 mg/kg + 14 mg/kg + 6 mg/kg) combination exhibited synergistic effect compared to monotherapy with Raloxifene (4 mg/kg) and Bromocriptine (6 mg/kg) as otherwise monotherapy with Fluoxetine (14 mg/kg) was ineffective to suppress pilocarpine induced seizures. Hence it is evident that triple drug combination therapy with Raloxifene + Fluoxetine + Bromocriptine
345 ameliorated status epilepticus in most of animals while in other restricted the duration of status epilepticus leading to protection of said animals from subsequent SRSs or Chronic Epilepsy or Temporal lobe epilepsy. The said combination exhibited much better results than observed with standard anti-epileptic drug i.e Sodium Valproate (Table 2; Figure 1 )
350 STATEMENT OF THE INVENTION.
Accordingly, the present invention relates to a pharmaceutical composition of selective estrogen receptor modulator(s) in combination with selective serotonin reuptake inhibitor(s) and dopamine (D2) receptor agonists. Wherein the said combination is used in the prophylaxis and/or management and/or treatment of seizures and/or epilepsies and/or convulsions and/or 355 neurodegeration with or without associated neurological and endocrine disorders. The combination is most preferably given in the form of tablets, capsules, suspensions, emulsions, infusion solution, injection solution, cream, gel, granules, ointment, enema e.t.c
The first compound is selected from the group consisting of Raloxifene, Clomifene, Femarelle, Ormeloxifene, Tamoxifene, Toremifene, Lasofoxifene, Ospimefene, Arzoxifene, Bazedoxifene,
360 Droloxifene, Idoxifene, Afimoxifene, Nafoxidine, Levormeloxifene and/or other agents having such properties or having potential for such activity, second compound is selected from the group consisting of Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram, Dapoxetine and/or other agents having such properties or having potential for such activity and third compound is selected from the group consisting of Bromocriptine, Ropinirole,
365 Sumanirole, N,N-Propyldihydrexidine, Cabergoline, Talipexole, Piribedil, Pramipexole, Quinpirole , Quinelorane and/or other agents having such properties or having potential for such activity.
370
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515

Claims

520 Claims: We Claim
1. A synergistic pharmaceutical combination, comprising selective estrogen receptor modulator(s) in combination with selective serotonin reuptake inhibitor(s) and dopamine (D2) receptor agonists, wherein selective estrogen receptor modulator(s) is selected from raloxifene,
525 clomifene, femarelle, ormeloxifene, tamoxifene, toremifene, lasofoxifene, ospimefene, arzoxifene, bazedoxifene, droloxifene, Idoxifene, afimoxifene, nafoxidine, levormeloxifene or combination thereof, wherein the selective serotonin reuptake inhibitor(s) is selected from fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, dapoxetine or combination thereof, wherein dopamine (D2) receptor agonist is selected from Bromocriptine,
530 Ropinirole, Sumanirole, Ν,Ν-Propyldihydrexidine, Cabergoline, Talipexole, Piribedil, Pramipexole, Quinpirole , Quinelorane or combination thereof.
2. The synergistic pharmaceutical combination as claimed in claim 1 , wherein the selective estrogen receptor modulator is Raloxifene.
3. The synergistic pharmaceutical combination as claimed in claim 1, wherein the selective 535 serotonin reuptake inhibitor is Fluoxetine.
4. The synergistic pharmaceutical combination as claimed in claim 1, wherein the dopamine (D2) receptor agonist is Bromocriptine.
5. The synergistic pharmaceutical combination as claimed in claim 1, wherein the selective estrogen receptor modulator is used in the range of 1 mg to 1000 mg, more preferably in the
540 range of 10 mg to 100 mg.
6. The synergistic pharmaceutical combination as claimed in claim 1, wherein the selective serotonin reuptake inhibitor is used in the range of 1 mg to 1000 mg, more preferably in the range of 20 mg to 200 mg.
7. The synergistic pharmaceutical combination as claimed in claim 1 , wherein the dopamine 545 (D2) receptor agonist is used in the range of 1 mg to 1000 mg, more preferably in the range of 10
- 100 mg.
8. The synergistic pharmaceutical combination as claimed in claim 1, wherein the selective estrogen receptor modulator, selective serotonin reuptake inhibitor and dopamine (D2) receptor agonist are synergistic pharmaceutical combination as claimed in any preceding claims, wherein 550 the individual components may be in the form of pharmaceutically acceptable salts, hydrates and prodrugs thereof. While the compositions may optionally comprise one or more of nutraceutically or pharmaceutically or dietically acceptable excipients such as diluents, additives, disintegrants, colorants, flavoring agents, sweetening agents etc.
9. A method for the treatment of seizures and/or convulsions and/or epilepsies and/or electrical 555 conductance related disorders and/or neurodegeneration, comprising administering to a mammal in need of the treatment a therapeutically effective amount of pharmaceutical combination/ composition, comprising a selective estrogen receptor modulator, selective serotonin uptake inhibitor and dopamine (D2) receptor agonist wherein the said treatment has a potentiating effect.
560 10. The method of treatment as claimed in claim 9, where the preferred disorder and/or disease is status epilepticus and/or partial seizures and/or partial seizures with associated neurological disorders (depression, obsessive compulsive disorder, parkinsonism) and endocrine disorders (osteoporosis).
PCT/IN2016/000268 2016-01-29 2016-11-15 Triple drug combination for treatment of status epilepticus and/or partial seizures and/or partial seizures with associated neurological disorders WO2017130208A1 (en)

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* Cited by examiner, † Cited by third party
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WO2004037229A1 (en) * 2002-10-24 2004-05-06 Columbia Laboratories (Bermuda) Limited Extended, controlled release pharmaceutical compositions comprising charged polymers

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